In Vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems

This study was supported by a Wellcome Trust-NIH PhD Studentship to SB, WDF and NV. Grant number 098252/Z/12/Z. SB, CHC and WDF are supported by the Intramural Research Program, NCI, NIH. NHG and WL are supported by the Intramural Research Program, NIA, NIH.Peer reviewedPublisher PD

Shared mechanism of teratogenicity of anti-angiogenic drugs identified in the chicken embryo model

Acknowledgements The authors would like to thank Maria Kisakyamaria and Scott McMenemy for preliminary experimental data. This work was supported by a Wellcome Trust-NIH PhD Studentship awarded to SB, WDF and NV (Grant number 098252/Z/12/Z). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government.Peer reviewedPublisher PD

Validation of Analytic Methods for Biomarkers Used in Drug Development

The role of biomarkers in drug discovery and development has gained precedence over the years. As biomarkers become integrated into drug development and clinical trials, quality assurance and in particular assay validation becomes essential with the need to establish standardized guidelines for analytical methods used in biomarker measurements. New biomarkers can revolutionize both the development and use of therapeutics, but is contingent upon the establishment of a concrete validation process that addresses technology integration and method validation as well as regulatory pathways for efficient biomarker development. This perspective focuses on the general principles of the biomarker validation process with an emphasis on assay validation and the collaborative efforts undertaken by various sectors to promote the standardization of this procedure for efficient biomarker development

Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues

The authors thank Scott McMenemy for carrying out preliminary, early studies looking at effects of Gu compounds upon chicken embryology, as well as Charles D. Crowe, Jeffrey E. Roth, and Adam C. Rolt for critical comments on the article. fli1:EGFP zebrafish were obtained from the Zebrafish International Research Center (27). mpo:GFP zebrafish [also termed Tg(MPO:GFP)114] zebrafish were obtained from Dr. Stephen Renshaw, University of Sheffield (Sheffield, South Yorkshire, UK; ref. 29).Peer reviewedPostprin

Antiangiogenic Activity and in Silico Cereblon Binding Analysis of Novel Thalidomide Analogs

Funding: This research was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (ZIA SC006538); in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E; the Intramural Research Program of the National Institute on Aging, National Institutes of Health; and a Wellcome Trust-NIH PhD Studentship to SB, WDF, and NV (Grant number 098252/Z/12/Z). Acknowledgments: The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.Peer reviewedPublisher PD

Families with BAP1-tumor predisposition syndrome in The Netherlands: Path to identification and a proposal for genetic screening guidelines

Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene cause the BAP1-tumor predisposition syndrome (BAP1-TPDS, OMIM 614327). BAP1-TPDS is associated with an increased risk of developing uveal melanoma (UM), cutaneous melanoma (CM), malignant mesothelioma (MMe), renal cell carcinoma (RCC), meningioma, cholangiocarcinoma, multiple non-melanoma skin cancers, and BAP1-inactivated nevi. Because of this increased risk, it is important to identify patients with BAP1-TPDS. The associated tumors are treated by different medical disciplines, emphasizing the need for generally applicable guidelines for initiating genetic analysis. In this study, we describe the path to identification of BAP1-TPDS in 21 probands found in the Netherlands and the family history at the time of presentation. We report two cases of de novo BAP1 germline mutations (2/21, 9.5%). Findings of this study combined with previously published literature, led to a proposal of guidelines for genetic referral. We recommend genetic analysis in patients with ≥2 BAP1-TPDS-associated tumors in their medical history and/or family history. We also propose to test germline BAP1 in patients diagnosed with UM <40 years, CM <18 years, MMe <50 years, or RCC <46 years. Furthermore, other candidate susceptibility genes for tumor types associated with BAP1-TPDS are discussed, which can be included in gene panels when testing patients

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: from recent successes and failures

<p>Abstract</p> <p>Men with metastatic castration-resistant prostate cancer (mCRPC) carry poor prognosis despite the use of docetaxel-based regimens which has modest survival benefit shown by randomized clinical trials. Significant progress in the discovery of novel therapeutic agents has been made in the past few years. While sipuleucel-T, cabazitaxel, and abiraterone gained regulatory approval in 2010 and 2011, several highly promising candidates/regimens have failed in large scale clinical trials. Challenges remain to optimize the design and interpretation of clinical trial results and develop more effective strategies for mCRPC. In this review, we examined the positive and negative clinical trials in mCRPC in the past and discussed the various aspects of clinical trial design including selection of targets and appropriate outcome measures, biomarker development and implementation, and strategies for combination therapy.</p