Sympathetic ß2-adrenergic receptor blockade overcomes docetaxel resistance in prostate cancer.

PURPOSE: Due to the limited effective therapies, resistance to docetaxel is ordinarily fatal and remains a critical clinical challenge.ß2-adrenergic receptor(ß2-AR)can promote the metastasis and invasion of prostate cancer, but the role in chemotherapy-resistant prostate cancer remains unclear. METHODS: By downloading the GEO database in NCBI, the expression of ß2-AR in different prostate tissues was analyzed. We constructed docetaxel-resistant prostate cancer cell lines by the method of dose-escalation. LC3B-labeled stable cells and shAtg5 knockdown stable cells were constructed by lentivirus infection. The molecular mechanism of ß2-AR affecting docetaxel sensitivity through apoptosis and autophage were investigated by flow cytometry, mitochondrial membrane potential and western blot. Then we detected the interaction between autophagy and apoptotic by performing immunoprecipitation assay. RESULTS: We show that restraining the activity of ß2-AR sensitized the cell response and reduced the resistance to docetaxel. The mechanism involves the regulation of ß2-AR in the cellular response to docetaxel through apoptosis and autophagy via caspase signaling and Atg5/AMPK/mTOR pathway as well as the effect of ß2-AR on the crosstalk between apoptosis and autophagy via p38 MAPK and JNK/c-Jun/FOXO3a signaling pathways. CONCLUSION: Our data demonstrate that ß2-AR inhibitor-induced autophagy and apoptosis contribute to the effectiveness responses to docetaxel in castration-resistant prostate cancer, and in combination with pharmacological agents of ß2-AR and autophagy inhibitors may provide a potential therapeutic strategy to enhance the limited capacity of docetaxel to control castration-resistant prostate cancer.

TAK1 blockade as a therapy for retinal neovascularization.

Retinal neovascularization, or pathological angiogenesis in the retina, is a leading cause of blindness in developed countries. Transforming growth factor-ß-activated kinase 1 (TAK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) activated by TGF-ß1 and other proinflammatory cytokines. TAK1 is also a key mediator of proinflammatory signals and plays an important role in maintaining vascular integrity upon proinflammatory cytokine stimulation such as TNFα. However, its role in pathological angiogenesis, particularly in retinal neovascularization, remains unclear. Here, we investigate the regulatory role of TAK1 in human endothelial cells responding to inflammatory stimuli and in a rat model of oxygen-induced retinopathy (OIR) featured retinal neovascularization. Using TAK1 knockout human endothelial cells that subjected to inflammatory stimuli, transcriptome analysis revealed that TAK1 is required for activation of NFκB signaling and mediates its downstream gene expression related to endothelial activation and angiogenesis. Moreover, pharmacological inhibition of TAK1 by 5Z-7-oxozeaenol attenuated angiogenic activities of endothelial cells. Transcriptome analysis also revealed enrichment of TAK1-mediated NFκB signaling pathway in the retina of OIR rats and retinal neovascular membrane from patients with proliferative diabetic retinopathy. Intravitreal injection of 5Z-7-oxozeaenol significantly reduced hypoxia-induced inflammation and microglial activation, thus attenuating aberrant retinal angiogenesis in OIR rats. Our data suggest that inhibition of TAK1 may have therapeutic potential for the treatment of retinal neovascular pathologies.

Detection of the freshness of rice by chemiluminescence.

Reactive oxygen species (ROS) are usually produced in rice under aerobic environmental conditions, resulting in peroxidative changes in polyunsaturated fatty acids, and affecting the deterioration of rice during storage. In addition, as an important enzyme that participates in removing ROS, peroxidase is also present in rice, and takes part in protecting rice from attack by ROS. Moreover, loss of peroxidase activity may give rise to rice deterioration during storage. Therefore, measuring peroxidase activity makes it possible to ascertain the freshness of rice. In addition, peroxidase can also catalyze the luminol-hydrogen peroxide system. Based on this, in this work we established a new chemiluminescence (CL) method that was used to detect the freshness of stored rice. Under optimal experimental conditions, we showed that the freshness of rice can be measured using this CL method. This study is the first to detect the freshness of rice using a CL method, opening up a novel direction for the application of CL.

Clinical validation of a 90-gene expression test for tumor tissue of origin diagnosis: a large-scale multicenter study of 1417 patients.

BACKGROUND: Once malignancy tumors were diagnosed, the determination of tissue origin and tumor type is critical for clinical management. Although the significant advance in imaging techniques and histopathological approaches, the diagnosis remains challenging in patients with metastatic and poorly differentiated or undifferentiated tumors. Gene expression profiling has been demonstrated the ability to classify multiple tumor types. The present study aims to assess the performance of a 90-gene expression test for tumor classification (i.e. the determination of tumor tissue of origin) in real clinical settings. METHODS: Formalin-fixed paraffin-embedded samples and associated clinicopathologic information were collected from three cancer centers between January 2016 and January 2021. A total of 1417 specimens that met quality control criteria (RNA quality, tumor cell content ≥ 60% and so on) were analyzed by the 90-gene expression test to identify the tumor tissue of origin. The performance was evaluated by comparing the test results with histopathological diagnosis. RESULTS: The 1417 samples represent 21 main tumor types classified by common tissue origins and anatomic sites. Overall, the 90-gene expression test reached an accuracy of 94.4% (1338/1417, 95% CI: 0.93 to 0.96). Among different tumor types, sensitivities were ranged from 74.2% (head&neck tumor) to 100% (adrenal carcinoma, mesothelioma, and prostate cancer). Sensitivities for the most prevalent cancers of lung, breast, colorectum, and gastroesophagus are 95.0%, 98.4%, 93.9%, and 90.6%, respectively. Moreover, specificities for all 21 tumor types are greater than 99%. CONCLUSIONS: These findings showed robust performance of the 90-gene expression test for identifying the tumor tissue of origin and support the use of molecular testing as an adjunct to tumor classification, especially to those poorly differentiated or undifferentiated tumors in clinical practice.

A drug-tunable Flt23k gene therapy for controlled intervention in retinal neovascularization.

Gene therapies that chronically suppress vascular endothelial growth factor (VEGF) represent a new approach for managing retinal vascular leakage and neovascularization. However, constitutive suppression of VEGF in the eye may have deleterious side effects. Here, we developed a novel strategy to introduce Flt23k, a decoy receptor that binds intracellular VEGF, fused to the destabilizing domain (DD) of Escherichia coli dihydrofolate reductase (DHFR) into the retina. The expressed DHFR(DD)-Flt23k fusion protein is degraded unless "switched on" by administering a stabilizer; in this case, the antibiotic trimethoprim (TMP). Cells transfected with the DHFR(DD)-Flt23k construct expressed the fusion protein at levels correlated with the TMP dose. Stabilization of the DHFR(DD)-Flt23k fusion protein by TMP was able to inhibit intracellular VEGF in hypoxic cells. Intravitreal injection of self-complementary adeno-associated viral vector (scAAV)-DHFR(DD)-Flt23k and subsequent administration of TMP resulted in tunable suppression of ischemia-induced retinal neovascularization in a rat model of oxygen-induced retinopathy (OIR). Hence, our study suggests a promising novel approach for the treatment of retinal neovascularization. Schematic diagram of the tunable system utilizing the DHFR(DD)-Flt23k approach to reduce VEGF secretion. a The schematic shows normal VEGF secretion. b Without the ligand TMP, the DHFR(DD)-Flt23k protein is destabilized and degraded by the proteasome. c In the presence of the ligand TMP, DHFR(DD)-Flt23k is stabilized and sequestered in the ER, thereby conditionally inhibiting VEGF. Green lines indicate the intracellular and extracellular distributions of VEGF. Blue lines indicate proteasomal degradation of the DHFR(DD)-Flt23k protein. Orange lines indicate the uptake of cell-permeable TMP. TMP, trimethoprim; VEGF, vascular endothelial growth factor; ER, endoplasmic reticulum.

Gene expression profiling for the diagnosis of multiple primary malignant tumors.

BACKGROUND: The incidence of multiple primary malignant tumors (MPMTs) is rising due to the development of screening technologies, significant treatment advances and increased aging of the population. For patients with a prior cancer history, identifying the tumor origin of the second malignant lesion has important prognostic and therapeutic implications and still represents a difficult problem in clinical practice. METHODS: In this study, we evaluated the performance of a 90-gene expression assay and explored its potential diagnostic utility for MPMTs across a broad spectrum of tumor types. Thirty-five MPMT patients from Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University and Fudan University Shanghai Cancer Center were enrolled; 73 MPMT specimens met all quality control criteria and were analyzed by the 90-gene expression assay. RESULTS: For each clinical specimen, the tumor type predicted by the 90-gene expression assay was compared with its pathological diagnosis, with an overall accuracy of 93.2% (68 of 73, 95% confidence interval 0.84-0.97). For histopathological subgroup analysis, the 90-gene expression assay achieved an overall accuracy of 95.0% (38 of 40; 95% CI 0.82-0.99) for well-moderately differentiated tumors and 92.0% (23 of 25; 95% CI 0.82-0.99) for poorly or undifferentiated tumors, with no statistically significant difference (p-value > 0.5). For squamous cell carcinoma specimens, the overall accuracy of gene expression assay also reached 87.5% (7 of 8; 95% CI 0.47-0.99) for identifying the tumor origins. CONCLUSIONS: The 90-gene expression assay provides flexibility and accuracy in identifying the tumor origin of MPMTs. Future incorporation of the 90-gene expression assay in pathological diagnosis will assist oncologists in applying precise treatments, leading to improved care and outcomes for MPMT patients.

Non-specific pain and 30-day readmission in acute coronary syndromes: findings from the TRACE-CORE prospective cohort.

BACKGROUND: Patients with acute coronary syndromes often experience non-specific (generic) pain after hospital discharge. However, evidence about the association between post-discharge non-specific pain and rehospitalization remains limited. METHODS: We analyzed data from the Transitions, Risks, and Actions in Coronary Events Center for Outcomes Research and Education (TRACE-CORE) prospective cohort. TRACE-CORE followed patients with acute coronary syndromes for 24 months post-discharge from the index hospitalization, collected patient-reported generic pain (using SF-36) and chest pain (using the Seattle Angina Questionnaire) and rehospitalization events. We assessed the association between generic pain and 30-day rehospitalization using multivariable logistic regression (N = 787). We also examined the associations among patient-reported pain, pain documentation identified by natural language processing (NLP) from electronic health record (EHR) notes, and the outcome. RESULTS: Patients were 62 years old (SD = 11.4), with 5.1% Black or Hispanic individuals and 29.9% women. Within 30 days post-discharge, 87 (11.1%) patients were re-hospitalized. Patient-reported mild-to-moderate pain, without EHR documentation, was associated with 30-day rehospitalization (odds ratio [OR]: 2.03, 95% confidence interval [CI]: 1.14-3.62, reference: no pain) after adjusting for baseline characteristics; while patient-reported mild-to-moderate pain with EHR documentation (presumably addressed) was not (OR: 1.23, 95% CI: 0.52-2.90). Severe pain was also associated with 30-day rehospitalization (OR: 3.16, 95% CI: 1.32-7.54), even after further adjusting for chest pain (OR: 2.59, 95% CI: 1.06-6.35). CONCLUSIONS: Patient-reported post-discharge generic pain was positively associated with 30-day rehospitalization. Future studies should further disentangle the impact of cardiac and non-cardiac pain on rehospitalization and develop strategies to support the timely management of post-discharge pain by healthcare providers.

Evaluating the use of a recommender system for selecting optimal messages for smoking cessation: patterns and effects of user-system engagement.

BACKGROUND: Motivational messaging is a frequently used digital intervention to promote positive health behavior changes, including smoking cessation. Typically, motivational messaging systems have not actively sought feedback on each message, preventing a closer examination of the user-system engagement. This study assessed the granular user-system engagement around a recommender system (a new system that actively sought user feedback on each message to improve message selection) for promoting smoking cessation and the impact of engagement on cessation outcome. METHODS: We prospectively followed a cohort of current smokers enrolled to use the recommender system for 6 months. The system sent participants motivational messages to support smoking cessation every 3 days and used machine learning to incorporate user feedback (i.e., user's rating on the perceived influence of each message, collected on a 5-point Likert scale with 1 indicating strong disagreement and 5 indicating strong agreement on perceiving the influence on quitting smoking) to improve the selection of the following message. We assessed user-system engagement by various metrics, including user response rate (i.e., the percent of times a user rated the messages) and the perceived influence of messages. We compared retention rates across different levels of user-system engagement and assessed the association between engagement and the 7-day point prevalence abstinence (missing outcome = smoking) by using multiple logistic regression. RESULTS: We analyzed data from 731 participants (13% Black; 73% women). The user response rate was 0.24 (SD = 0.34) and user-perceived influence was 3.76 (SD = 0.84). The retention rate positively increased with the user response rate (trend test P < 0.001). Compared with non-response, six-month cessation increased with the levels of response rates: low response rate (odds ratio [OR] = 1.86, 95% confidence interval [CI]: 1.07-3.23), moderate response rate (OR = 2.30, 95% CI: 1.36-3.88), high response rate (OR = 2.69, 95% CI: 1.58-4.58). The association between perceived message influence and the outcome showed a similar pattern. CONCLUSIONS: High user-system engagement was positively associated with both high retention rate and smoking cessation, suggesting that investigation of methods to increase engagement may be crucial to increase the impact of the recommender system for smoking cessation. TRIAL REGISTRATION: Registration Identifier: NCT03224520 . Registration date: July 21, 2017.

Facilitators and barriers to post-discharge pain assessment and triage: a qualitative study of nurses' and patients' perspectives.

BACKGROUND: After hospital discharge, patients can experience symptoms prompting them to seek acute medical attention. Early evaluation of patients' post-discharge symptoms by healthcare providers may improve appropriate healthcare utilization and patient safety. Post-discharge follow-up phone calls, which are used for routine transitional care in U.S. hospitals, serve as an important channel for provider-patient communication about symptoms. This study aimed to assess the facilitators and barriers to evaluating and triaging pain symptoms in cardiovascular patients through follow-up phone calls after their discharge from a large healthcare system in Central Massachusetts. We also discuss strategies that may help address the identified barriers. METHODS: Guided by the Practical, Robust, Implementation and Sustainability Model (PRISM), we completed semi-structured interviews with 7 nurses and 16 patients in 2020. Selected nurses conducted (or supervised) post-discharge follow-up calls on behalf of 5 clinical teams (2 primary care; 3 cardiology). We used thematic analysis to identify themes from interviews and mapped them to the domains of the PRISM model. RESULTS: Participants described common facilitators and barriers related to the four domains of PRISM: Intervention (I), Recipients (R), Implementation and Sustainability Infrastructure (ISI), and External Environment (EE). Facilitators include: (1) patients being willing to receive provider follow-up (R); (2) nurses experienced in symptom assessment (R); (3) good care coordination within individual clinical teams (R); (4) electronic health record system and call templates to support follow-up calls (ISI); and (5) national and institutional policies to support post-discharge follow-up (EE). Barriers include: (1) limitations of conducting symptom assessment by provider-initiated follow-up calls (I); (2) difficulty connecting patients and providers in a timely manner (R); (3) suboptimal coordination for transitional care among primary care and cardiology providers (R); and (4) lack of emphasis on post-discharge follow-up call reimbursement among cardiology clinics (EE). Specific barriers for pain assessment include: (1) concerns with pain medication misuse (R); and (2) no standardized pain assessment and triage protocol (ISI). CONCLUSIONS: Strategies to empower patients, facilitate timely patient-provider communication, and support care coordination regarding pain evaluation and treatment may reduce the barriers and improve processes and outcomes of pain assessment and triage.

ß2 -adrenergic receptor signaling drives prostate cancer progression by targeting the Sonic hedgehog-Gli1 signaling activation.

BACKGROUND: Considerable evidence suggests that the sympathetic nervous system, mainly via adrenergic signaling, contributes to prostate cancer (PCa) progression. However, the underlying molecular mechanisms remain unknown. METHODS: The expression level of ß2 -adrenergic receptor (ß2 -AR) in tissue microarray was evaluated by immunohistochemistry. The effects of isoproterenol (ISO) or Sonic Hedgehog (Shh) signaling inhibitor on tumor growth were analyzed in proliferation and colony formation assays. The apoptosis of cells was analyzed by flow cytometry. Small hairpin RNA-based knockdown of ß2 -AR or Gli1 was validated by Western blot analysis and real-time PCR. Effects of ß2 -AR on prostate carcinogenesis in vivo were observed in a mouse xenograft model. The expression levels of the indicated proteins in xenograft tissues were evaluated by immunohistochemistry. Expression levels of Shh signaling components and downstream proteins were assessed by immunoblotting. RESULTS: We determined that ß2 -AR was expressed at significantly higher levels in carcinoma than in normal prostate tissues. ß2 -AR signaling also played an essential role in sustaining PCa cell proliferation in vivo and in vitro. We also found that inhibition of Shh signaling or knockdown of Gli1 expression significantly restrained ISO-induced cell proliferation in vitro. ISO alleviated the apoptosis induced by suppressing or knocking down of Gli1. The ß2 -AR agonist ISO upregulated the transcription and protein expression of target genes of Shh signaling, including c-Myc, Cyclin D1, and VEGFA. Conversely, knocking down ß2 -AR markedly suppressed the expression of Shh components in vivo and in vitro. In Gli1 knockdown cells, ISO failed to increase the expression of target genes of Shh signaling. CONCLUSIONS: In this study, we uncovered an important role of ß2 -AR signaling in regulating the Shh pathway activity in PCa tumorigenesis and provide further insight into the mechanism of the involvement of the Hh signaling pathway. Furthermore, given the efficacy of ß2 -adrenergic modulation on PCa, our study might also add evidence for potential therapeutic options of ß-blockers for PCa.

The Association Between Patient-reported Clinical Factors and 30-day Acute Care Utilization in Chronic Heart Failure.

BACKGROUND: Heart failure patients have high rates of repeat acute care use. Current efforts for risk prediction often ignore postdischarge data. OBJECTIVE: To identify postdischarge patient-reported clinical factors associated with repeat acute care use. RESEARCH DESIGN: In a prospective cohort study that followed patients with chronic heart failure for 30 days postdischarge, for 7 days after discharge (or fewer days if patients used acute care within 7 days postdischarge), patients reported health status, heart failure symptoms, medication management, knowledge of follow-up plans, and other issues using a daily interactive automatic phone call. SUBJECTS: A total of 156 patients who had responded to phone surveys. MEASURES: The outcome variable was dichotomous 30-day acute care use (rehospitalization or emergency department visit). We examined the association between each patient-reported issue and the outcome, using multivariable logistic regression to adjust for confounders. RESULTS: Patients were 63 years old (SD=12.4), with 51% African-American and 53% women. Within 30 days postdischarge, 30 (19%) patients used acute care. After adjustment, poor health status [odds ratio (OR)=3.53; 95% confidence interval (CI), 1.06-11.76], pain (OR=2.44; 95% CI, 1.02-5.84), and poor appetite (OR=3.05; 95% CI, 1.13-8.23) were positively associated with 30-day acute care utilization. Among 58 reports of pain in follow-up nursing notes, 39 (67%) were noncardiac, 2 (3%) were cardiac, and 17 (29%) were indeterminate. CONCLUSIONS: Patient-reported poor health status, pain, and poor appetite were positively associated with 30-day acute care utilization. These novel postdischarge markers require further study before incorporation into risk prediction to drive quality improvement efforts.

Circular RNA Circ_ANKMY2 Regulates Temporal Lobe Epilepsy Progression via the miR-106b-5p/FOXP1 Axis.

Temporal lobe epilepsy (TLE) is common intractable epilepsy that affects the patient's lives. The circular RNA circ_ANKMY2 (circ_ANKMY2) has been reported to be abnormally expressed in TLE. Nevertheless, the role and mechanism of circ_ANKMY2 in TLE are unclear. A human neuroblastoma cell line (SK-N-AS) was used for a series of studies. Expression levels of circ_ANKMY2, miR-106b-5p, and Forkhead Box Protein 1 (FOXP1) mRNA in TLE tissues were assessed through quantitative real-time polymerase chain reaction (qRT-PCR). Cell colony formation, proliferation, and apoptosis were determined by cell colony formation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), or flow cytometry assays. The levels of FOXP1 protein, Ki67, B cell lymphoma (Bcl-2), Bcl-2 Associated X (Bax), and Cleaved caspase-3 were evaluated by western blot analysis. The relationship between circ_ANKMY2 or FOXP1 and miR-106b-5p was verified with dual-luciferase reporter assay. We observed that circ_ANKMY2 and FOXP1 expression were reduced while miR-106b-5p expression was increased in TLE tissues. Overexpression of circ_ANKMY2 decreased spontaneous recurrent seizures (SRSs) in rat TLE model and blocked cell colony formation, proliferation, and induced cell apoptosis in SK-N-AS cells. Importantly, circ_ANKMY2 was verified as a sponge for miR-106b-5p. In addition, miR-106b-5p mimics abolished circ_ANKMY2 elevation-mediated effects on colony formation, proliferation, and apoptosis of SK-N-AS cells. Also, FOXP1 served as a target for miR-106b-5p. And FOXP1 silencing overturned the effects of miR-106b-5p inhibitors on the colony formation, proliferation, and apoptosis of SK-N-AS cells. In sum, circ_ANKMY2 modulated TLE advancement via regulation of FOXP1 expression through sponging miR-106b-5p, and circ_ANKMY2 might be an underlying target for the improvement of TLE.

Detecting Hypoglycemia Incidents Reported in Patients' Secure Messages: Using Cost-Sensitive Learning and Oversampling to Reduce Data Imbalance.

BACKGROUND: Improper dosing of medications such as insulin can cause hypoglycemic episodes, which may lead to severe morbidity or even death. Although secure messaging was designed for exchanging nonurgent messages, patients sometimes report hypoglycemia events through secure messaging. Detecting these patient-reported adverse events may help alert clinical teams and enable early corrective actions to improve patient safety. OBJECTIVE: We aimed to develop a natural language processing system, called HypoDetect (Hypoglycemia Detector), to automatically identify hypoglycemia incidents reported in patients' secure messages. METHODS: An expert in public health annotated 3000 secure message threads between patients with diabetes and US Department of Veterans Affairs clinical teams as containing patient-reported hypoglycemia incidents or not. A physician independently annotated 100 threads randomly selected from this dataset to determine interannotator agreement. We used this dataset to develop and evaluate HypoDetect. HypoDetect incorporates 3 machine learning algorithms widely used for text classification: linear support vector machines, random forest, and logistic regression. We explored different learning features, including new knowledge-driven features. Because only 114 (3.80%) messages were annotated as positive, we investigated cost-sensitive learning and oversampling methods to mitigate the challenge of imbalanced data. RESULTS: The interannotator agreement was Cohen kappa=.976. Using cross-validation, logistic regression with cost-sensitive learning achieved the best performance (area under the receiver operating characteristic curve=0.954, sensitivity=0.693, specificity 0.974, F1 score=0.590). Cost-sensitive learning and the ensembled synthetic minority oversampling technique improved the sensitivity of the baseline systems substantially (by 0.123 to 0.728 absolute gains). Our results show that a variety of features contributed to the best performance of HypoDetect. CONCLUSIONS: Despite the challenge of data imbalance, HypoDetect achieved promising results for the task of detecting hypoglycemia incidents from secure messages. The system has a great potential to facilitate early detection and treatment of hypoglycemia.

A Natural Language Processing System That Links Medical Terms in Electronic Health Record Notes to Lay Definitions: System Development Using Physician Reviews.

BACKGROUND: Many health care systems now allow patients to access their electronic health record (EHR) notes online through patient portals. Medical jargon in EHR notes can confuse patients, which may interfere with potential benefits of patient access to EHR notes. OBJECTIVE: The aim of this study was to develop and evaluate the usability and content quality of NoteAid, a Web-based natural language processing system that links medical terms in EHR notes to lay definitions, that is, definitions easily understood by lay people. METHODS: NoteAid incorporates two core components: CoDeMed, a lexical resource of lay definitions for medical terms, and MedLink, a computational unit that links medical terms to lay definitions. We developed innovative computational methods, including an adapted distant supervision algorithm to prioritize medical terms important for EHR comprehension to facilitate the effort of building CoDeMed. Ten physician domain experts evaluated the user interface and content quality of NoteAid. The evaluation protocol included a cognitive walkthrough session and a postsession questionnaire. Physician feedback sessions were audio-recorded. We used standard content analysis methods to analyze qualitative data from these sessions. RESULTS: Physician feedback was mixed. Positive feedback on NoteAid included (1) Easy to use, (2) Good visual display, (3) Satisfactory system speed, and (4) Adequate lay definitions. Opportunities for improvement arising from evaluation sessions and feedback included (1) improving the display of definitions for partially matched terms, (2) including more medical terms in CoDeMed, (3) improving the handling of terms whose definitions vary depending on different contexts, and (4) standardizing the scope of definitions for medicines. On the basis of these results, we have improved NoteAid's user interface and a number of definitions, and added 4502 more definitions in CoDeMed. CONCLUSIONS: Physician evaluation yielded useful feedback for content validation and refinement of this innovative tool that has the potential to improve patient EHR comprehension and experience using patient portals. Future ongoing work will develop algorithms to handle ambiguous medical terms and test and evaluate NoteAid with patients.

Inhibition of Experimental Choroidal Neovascularization by a Novel Peptide Derived from Calreticulin Anti-Angiogenic Domain.

Choroidal neovascularization (CNV) is a key pathological feature of several leading causes of vision loss including neovascular age-related macular degeneration. Here, we show that a calreticulin anti-angiogenic domain (CAD)-like peptide 27, CAD27, inhibited in vitro angiogenic activities, including tube formation, migration of endothelial cells, and vascular sprouting from rat aortic ring explants. In a rat model of laser-induced CNV, we demonstrate that intravitreal injection of CAD27 significantly attenuated the formation of CNV lesions as measured via fundus fluorescein angiography and choroid flat-mounts (19.5% and 22.4% reductions at 10 µg and 20 µg of CAD27 injected, respectively). Similarly, the reduction of CNV lesions was observed in rats that had received topical applications of CAD27 (choroid flat-mounts: 17.9% and 32.5% reductions at 10 µg/mL and 20 µg/mL of CAD27 instilled, respectively). Retinal function was unaffected, as measured using electroretinography in both groups receiving interareal injection or topical applications of CAD27 for at least fourteen days. These findings show that CAD27 can be used as a potential therapeutic alternative for targeting CNV in diseases such as neovascular age-related macular degeneration.

Unsupervised ensemble ranking of terms in electronic health record notes based on their importance to patients.

BACKGROUND: Allowing patients to access their own electronic health record (EHR) notes through online patient portals has the potential to improve patient-centered care. However, EHR notes contain abundant medical jargon that can be difficult for patients to comprehend. One way to help patients is to reduce information overload and help them focus on medical terms that matter most to them. Targeted education can then be developed to improve patient EHR comprehension and the quality of care. OBJECTIVE: The aim of this work was to develop FIT (Finding Important Terms for patients), an unsupervised natural language processing (NLP) system that ranks medical terms in EHR notes based on their importance to patients. METHODS: We built FIT on a new unsupervised ensemble ranking model derived from the biased random walk algorithm to combine heterogeneous information resources for ranking candidate terms from each EHR note. Specifically, FIT integrates four single views (rankers) for term importance: patient use of medical concepts, document-level term salience, word co-occurrence based term relatedness, and topic coherence. It also incorporates partial information of term importance as conveyed by terms' unfamiliarity levels and semantic types. We evaluated FIT on 90 expert-annotated EHR notes and used the four single-view rankers as baselines. In addition, we implemented three benchmark unsupervised ensemble ranking methods as strong baselines. RESULTS: FIT achieved 0.885 AUC-ROC for ranking candidate terms from EHR notes to identify important terms. When including term identification, the performance of FIT for identifying important terms from EHR notes was 0.813 AUC-ROC. Both performance scores significantly exceeded the corresponding scores from the four single rankers (P<0.001). FIT also outperformed the three ensemble rankers for most metrics. Its performance is relatively insensitive to its parameter. CONCLUSIONS: FIT can automatically identify EHR terms important to patients. It may help develop future interventions to improve quality of care. By using unsupervised learning as well as a robust and flexible framework for information fusion, FIT can be readily applied to other domains and applications.

Discovery of 5-methyl-2-(4-((4-(methylsulfonyl)benzyl)oxy)phenyl)-4-(piperazin-1-yl)pyrimidine derivatives as novel GRP119 agonists for the treatment of diabetes and obesity.

A series of fused-pyrimidine derivatives were prepared and evaluated for their agonistic activities against human GPR119. Compound 9i showed high potent agonistic activity against HEK293T cells over-expressing human GPR119 and improved glucose tolerance in dose-dependent manner, as well as promoted insulin secretion. In a DIO mice model, 9i also ameliorated the obese-related symptoms by decreasing the body weights without markedly changing food intake, normalized some serum biomarkers, such as ALT, AST, ALP, GLU, CHOL, HDL, and LDL, and exerted therapeutic activity on fat deposition in liver tissue. We consider 9i to have utility as a GPR119 agonists for the treatment of type 2 diabetes mellitus and obese-related symptoms.

Pan-cancer transcriptome analysis reveals a gene expression signature for the identification of tumor tissue origin.

Carcinoma of unknown primary, wherein metastatic disease is present without an identifiable primary site, accounts for ~3-5% of all cancer diagnoses. Despite the development of multiple diagnostic workups, the success rate of primary site identification remains low. Determining the origin of tumor tissue is, thus, an important clinical application of molecular diagnostics. Previous studies have paved the way for gene expression-based tumor type classification. In this study, we have established a comprehensive database integrating microarray- and sequencing-based gene expression profiles of 16 674 tumor samples covering 22 common human tumor types. From this pan-cancer transcriptome database, we identified a 154-gene expression signature that discriminated the origin of tumor tissue with an overall leave-one-out cross-validation accuracy of 96.5%. The 154-gene expression signature was first validated on an independent test set consisting of 9626 primary tumors, of which 97.1% of cases were correctly classified. Furthermore, we tested the signature on a spectrum of diagnostically challenging tumors. An overall accuracy of 92% was achieved on the 1248 tumor specimens that were poorly differentiated, undifferentiated or from metastatic tumors. Thus, we have identified a 154-gene expression signature that can accurately classify a broad spectrum of tumor types. This gene panel may hold a promise to be a useful additional tool for the determination of the tumor origin.

Design, synthesis and biological evaluation of a series of pyrano chalcone derivatives containing indole moiety as novel anti-tubulin agents.

A new series of pyrano chalcone derivatives containing indole moiety (3-42, 49a-49r) were synthesized and evaluated for their antiproliferative activities. Among all the compounds, compound 49b with a propionyloxy group at the 4-position of the left phenyl ring and N-methyl-5-indoly on the right ring displayed the most potent cytotoxic activity against all tested cancer cell lines including multidrug resistant phenotype, which inhibits cancer cell growth with IC50 values ranging from 0.22 to 1.80µM. Furthermore, 49b significantly induced cell cycle arrest in G2/M phase and inhibited the polymerization of tubulin. Molecular docking analysis demonstrated the interaction of 49b at the colchicine binding site of tubulin. In experiments in vivo, 49b exerted potent anticancer activity in HepG2 human liver carcinoma in BALB/c nude mice. These results indicated these compounds are promising inhibitors of tubulin polymerization for the potential treatment of cancer.

Synthesis and biological evaluation of 3-methyl-5-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione derivatives for the treatment of diet-induced obesity.

Triglycerides are the main part of fats and half of the lipids in hepatocytes, and play an important role in metabolism as energy sources and transporters of dietary fat. In this study, 33 derivatives based on 3-methyl-5-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione were synthesized and evaluated for their lipid-lowering activity. Among them, compound 1i was found to exhibit potent triglyceride-lowering potency in 3T3-L1 adipocytes which was comparable to that of the adenosine monophosphate-activated protein kinase (AMPK) agonist Acadesine (AIACR). Furthermore, oral administration of 1i at a dose of 50 mg kg(-1) d(-1) for 5 weeks could reduce the mean body weight and liver weight by 12.02% and 32.00%, respectively, and regulated serum levels of triglycerides in diet-induced obese mice. The results indicate that compound 1i is a potential small-molecule for the treatment of diet-induced obesity and related diseases.