Predicting potential antitumor targets of Aconitum alkaloids by molecular docking and protein–ligand interaction fingerprint

Aconitine compounds are found in Aconitum Ouwu head, Chuan Wu, Aconitum, and other Ranunculaceae aconitum plants, which are not only active ingredient but also toxic component. In present study, 20 antitumor target proteins of different types were selected from Protein Data Bank (http://www.rcsb.org), for the purpose of finding potential antitumor targets of aconitum alkaloids, top ranked proteins were screened by molecular docking method, using the docking module in Sybyl-X 1.1 and Molecular Operating Environment (MOE) 2008, and screening result was verified by protein–ligand interaction fingerprint (PLIF) in MOE. Mesaconitine showed a C-shaped conformation when docking into heat-shock protein 90 (HSP90), which was similar with ANSA ring of geldanamycin. And the PLIF indicated that they shared many common amino acid residues interacted with HSP90; equally, Yunaconitine was found having similar conformation with the inhibitor of poly ADP-ribose polymerase-1 (PARP-1).     

Institutional Denial or Minimization: Substance Abuse Training in Social Work Education

ABSTRACT

Substance abuse in the United States has reached catastrophic proportions. 23.6 million people needed treatment for an illicit drug or alcohol use problem (1 U.S. Department of Health and Human Services. 2004. Substance Abuse: A National Challenge Prevention, Treatment, and Research at HHS Available at: http://www.hhs.gov/news/factsheet/subabuse.html Accessed January 10, 2007 [Google Scholar]). According to the National Association of Social Workers, 60% of all mental health services are carried out by social workers (3 SAMSHA. October 2006. October, Washington, DC: United States Department of Labor; Bureau of Labor Statistics (BLS). Available at: http://data.bls.gov/oep/servlet/oep.noeted.servlet.ActionServlet Accessed December 10, 2008 [Google Scholar]). Therefore, social workers are in a critical and unique position to address substance abuse. This study examined the education and training new social workers receive at 216 graduate programs accredited or in-candidacy for accreditation by the Council of Social Work Education. An overwhelming number did not have substance abuse courses as a requirement for all students, and a significant number did not have one course dedicated to substance abuse. These astounding deficiencies can only be described as an institutional denial or minimization.     

Assessment of Equivalence Using a Concordance Correlation Coefficient in a Repeated Measurements Design

ABSTRACT

Some assay validation studies are conducted to assess agreement between repeated, paired continuous data measured on the same subject with different measurement systems. The goal of these studies is to show that there is an acceptable level of agreement between the measurement systems. Equivalence testing is a reasonable approach in assay validation. In this article, we use an equivalence-testing criterion based on a decomposition of a concordance correlation coefficient proposed by Lin (1989 Lin , L. K. ( 1989 ). A concordance correlation coefficient to evaluate reproducibility . Biometrics 45 : 255 – 268 . [PUBMED] [INFOTRIEVE] [CSA] [Crossref], [PubMed], [Web of Science ®] , [Google Scholar] 1992 Lin , L. K. ( 1992 ). Assay validation using the concordance correlation coefficient . Biometrics 48 : 599 – 604 . [CSA] [Crossref], [Web of Science ®] , [Google Scholar]). Using a variance components approach, we develop bounds for conducting statistical tests using the proposed equivalence criterion. We conduct a simulation study to assess the performance of the bounds. The criteria are the ability to maintain the stated test size and the simulated power of the tests using these bounds. Bounds that perform well for small sample size are preferred. We present a computational example to demonstrate the methods described in the article.     

Mixture of Normal Distributions in Multivariate Null Intercept Measurement Error Model

In this paper we propose the use of a multivariate null intercept measurement error model, where the true unobserved value of the covariate follows a mixture of two normal distributions. The proposed model is applied to a dental clinical trial presented in Hadgu and Koch (1999 Hadgu , A. , Koch , G. ( 1999 ). Application of generalized estimating equations to a dental randomized clinical trial . Journal of Biopharmaceutical Statistics 9 ( 1 ): 161 – 178 . [INFOTRIEVE] [CSA] [CROSSREF] [Taylor &; Francis Online] , [Google Scholar]). A Bayesian approach is considered and a Gibbs Sampler is used to perform the computations.     

Duffy-Santner Confidence Intervals for the Two-Stage Three-Outcome Design

Although the three-outcome phase II clinical trial design (Sargent et al., 2001 Sargent , D. J. , Chan , V. , Goldberg , R. M. ( 2001 ). A three-outcome design for phase II clinical trials . Control Clin Trials 22 : 117 – 125 . [INFOTRIEVE] [CSA] [CROSSREF] [Crossref], [PubMed] , [Google Scholar]) has seen increasing use, confidence interval methodology for the binary endpoint had not been explicitly defined. Typical phase II clinical trial designs with binomial endpoints use a sequential binomial confidence interval (SBCI) algorithm (Duffy and Santner, 1987 Duffy , D. E. , Santner , T. J. (1987). Confidence intervals for a binomial parameter based on multistage tests. Biometrics 43:81–93. [CSA] [CROSSREF] [Crossref], [Web of Science ®] , [Google Scholar]). We reviewed the SBCI literature and software in order to describe the construction of confidence intervals for the three-outcome setting. Simulations confirmed that proper application of the SBCI algorithm provides appropriate coverage for the three-outcome design.     

United Nations Office on Drugs and Crime International Network of Drug Dependence Treatment and Rehabilitation Resource Centres: Treatnet

ABSTRACT

Key to the dissemination of evidence-based addiction treatments is the exchange of experiences and mutual support among treatment practitioners, as well as the availability of accurate addiction training materials and effective trainers. To address the shortage of such resources, the United Nations Office on Drugs and Crime (UNODC) created Treatnet, a network of 20 drug dependence treatment resource centers around the world. Treatnet's primary goal is to promote the use of effective addiction treatment practices. Phase I of this project included (1 United Nations. 1998. Declaration on the Guiding Principles of Drug Demand Reduction, Vienna: United Nations. Available at: http://www.un.org/ga/20special/demand.htm. Accessed August 20, 2009 [Google Scholar]) selecting and establishing a network of geographically distributed centers; (2 Harwood, H J, Kowalski, J and Ameen, A. 2004. The need for substance abuse training among mental health professionals. Adm Policy Ment Health Ment Health Serv Res., 32: 189–205. [Crossref], [PubMed] , [Google Scholar]) conducting a capacity-building program consisting of a training needs assessment, development of training packages, and the training of 2 trainers per center in 1 content area each; and (3 United Nations Office on Drugs and Crime and World Health Organization. 2008, March. Principles of Drug Dependence Treatment, Vienna: Author. Available at: http://www.who.int/substance_abuse/publications/principles_drug_dependence_treatment.pdf. Accessed August 20, 2009 [Google Scholar]) creating good-practice documents. Data on the training activities conducted by the trainers during their first 6 months in the field are presented. Plans for Phase II of the Treatnet project are also discussed.     

Acetyl-CoA carboxylase (ACC) as a therapeutic target for metabolic syndrome and recent developments in ACC1/2 inhibitors

ABSTRACT

Introduction: Acetyl-CoA Carboxylase (ACC) is an essential rate-limiting enzyme in fatty acid metabolism. For many years, ACC inhibitors have gained great attention for developing therapeutics for various human diseases including microbial infections, metabolic syndrome, obesity, diabetes, and cancer.

Areas covered: We present a comprehensive review and update of ACC inhibitors. We look at the current advance of ACC inhibitors in clinical studies and the implications in drug discovery. We searched ScienceDirect (https://www.sciencedirect.com/), ACS (https://pubs.acs.org/), Wiley (https://onlinelibrary.wiley.com/), NCBI (https://www.ncbi.nlm.nih.gov/) and World Health Organization (https://www.who.int/). The keywords used were Acetyl-CoA Carboxylase, lipid, inhibitors and metabolic syndrome. All documents were published before June 2019.

Expert opinion: The key regulatory role of ACC in fatty acid synthesis and oxidation pathways makes it an attractive target for various metabolic diseases. In particular, the combination of ACC inhibitors with other drugs is a new strategy for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Expanding the clinical indications for ACC inhibitors will be one of the hot directions in the future. It is also worth looking forward to exploring safe and efficient inhibitors that act on the BC domain of ACC.     

Decision-Theoretic Views on Simultaneous Testing of Superiority and Noninferiority

ABSTRACT

In a simultaneous testing of noninferiority and superiority in clinical trials, there is no multiplicity penalty. Ng (2003 Ng , T. H. (2003). Issues of simultaneous tests for noninferiority and superiority. J. Biopharm. Stat. 13:629–639. [PUBMED] [INFOTRIEVE] [CSA] [CROSSREF] [Taylor &; Francis Online] , [Google Scholar]), however, argues that even though there is no inflation of the Type I error rate, this type of simultaneous testing is problematic because it may lead to loss of power in the subsequent confirmatory trial. And he recommends to conduct only one test chosen on the basis of the sponsor's preliminary assessment. We view the question of whether one should simultaneously test for noninferiority and superiority from a decision-theoretic view point. We develop the loss function approach implicit in Ng's research and compare his recommendation to simultaneous testing procedures indexed by a variety of design parameters. We find that the simultaneous testing procedure generally provides smaller loss than Ng's method, except when the prior distribution allocates a large probability to equivalence of the two treatments.     

A Ratio Test in Active Control Non-Inferiority Trials with a Time-to-Event Endpoint

ABSTRACT

There are essentially two kinds of non-inferiority hypotheses in an active control trial: fixed margin and ratio hypotheses. In a fixed margin hypothesis, the margin is a prespecified constant and the hypothesis is defined in terms of a single parameter that represents the effect of the active treatment relative to the control. The statistical inference for a fixed margin hypothesis is straightforward. The outstanding issue for a fixed margin non-inferiority hypothesis is how to select the margin, a task that may not be as simple as it appears. The selection of a fixed non-inferiority margin has been discussed in a few articles (Chi et al., 2003 Chi , G. Y. H. , Chen , G. , Rothmann , M. , Li , N. ( 2003 ). Active control trials . Encylopedia of Biopharmaceutical Statistics 9 – 15 . [CSA]  [Google Scholar]; Hung et al., 2003 Hung , H. M. J. , Wang , S. J. , Tsong , Y. , Lawrence , J. , O'Neill , R. T. (2003). Some fundamental issues for non-inferiority testing in active controlled trials. Stat. Medicine 22:213–225. [CSA] [Crossref], [PubMed], [Web of Science ®] , [Google Scholar]; Ng, 1993 Ng , T. H. ( 1993 ). A specification of treatment difference in the design of clinical trials with active controls . Drug Information Journal 27 : 705 – 719 . [CSA]  [Google Scholar]). In a ratio hypothesis, the control effect is also considered as an unknown parameter, and the non-inferiority hypothesis is then formulated as a ratio in terms of these two parameters, the treatment effect and the control effect. This type of non-inferiority hypothesis has also been called the fraction retention hypothesis because the ratio hypothesis can be interpreted as a retention of certain fraction of the control effect. Rothmann et al. (2003 Rothmann , M. , Li , N. , Chen , G. , Chi , G. Y. H. , Temple , R. , Tsou , H. H. ( 2003 ). Design and analysis of non-inferiority mortality trials in oncology . Statistics in Medicine 22 : 239 – 264 . [PUBMED] [INFOTRIEVE] [CSA] [CROSSREF] [Crossref], [PubMed], [Web of Science ®] , [Google Scholar]) formulated a ratio non-inferiority hypothesis in terms of log hazards in the time-to-event setting. To circumvent the complexity of having to deal with a ratio test statistic, the ratio hypothesis was linearized to an equivalent hypothesis under the assumption that the control effect is positive. An associated test statistic for this linearized hypothesis was developed. However, there are three important issues that are not addressed by this method. First, the retention fraction being defined in terms of log hazard is difficult to interpret. Second, in order to linearize the ratio hypothesis, Rothmann's method has to assume that the true control effect is positive. Third, the test statistic is not powerful and thus requires a huge sample size, which renders the method impractical. In this paper, a ratio hypothesis is defined directly in terms of the hazard. A natural ratio test statistic can be defined and is shown to have the desired asymptotic normality. The demand on sample size is much reduced. In most commonly encountered situations, the sample size required is less than half of those needed by either the fixed margin approach or Rothmann's method.     

LPS and neuroinflammation: a matter of timing

Lipopolysaccharide (LPS) administration has been repeatedly shown to elicit central inflammation, regardless of the route of administration. In a recent study, Tiwari et al. (Inflammopharmacology  10.1007/s10787-016-0274-3, 2016) dispute the potential of peripheral administration of LPS to induce neuroinflammation. Here, I summarise literature indicating that the neuroinflammatory effects of LPS are time dependent, and suggest that their findings can be explained by the time at which they chose to measure neuroinflammation.     

Antimicrobial Products: Statistical Challenges and Opportunities

According to a 2013 United States Centers for Disease Control and Prevention (CDC) (2013), Antibiotic Resistance Threats in the United States. Available at http://www.cdc.gov/drugresistance/pdf/ar-threats-2013–508.pdf.  [Google Scholar] report of the Centers for Disease Control and Prevention, more than 2 million people in the United States develop illness from antibiotic-resistant infections yearly and at least 23,000 die as a direct result of antibiotic-resistant infections. Despite an alarming number of antibiotic-resistant infections, antibacterial drug development has been slow. The consequences of the lack of new effective antibiotics may be dire to our global public health.

There are scientific, economic, and regulatory challenges that underpin the sparse antibiotic pipeline. In this article, we outline critical design and analysis elements that impact clinical trials of new antibiotics and include some of the complex scientific challenges unique to antibacterial products. The challenges also present opportunities for statisticians to provide innovative strategies to the design and analysis of these trials.     

Fallback Tests in Dose-Response Clinical Trials

This article introduces a general testing procedure for performing dose-control comparisons in dose-response trials with one or more endpoints. The procedure (termed multi-stage fallback procedure) is an extension of the fallback test proposed by Wiens (2003 Wiens , B. ( 2003 ). A fixed-sequence Bonferroni procedure for testing multiple end-points . Pharm. Stat. 2 : 211 – 215 . [CSA] [CROSSREF] [Crossref], [Web of Science ®] , [Google Scholar]). The multi-stage fallback procedure features a simple stepwise form and improves the power of dose-control tests at higher doses by taking into account the ordering of the doses. It also serves as an efficient tool for handling multiplicity caused by multiple endpoints. It is shown in this article that the multi-stage fallback procedure can be formulated as a closed testing procedure and thus controls the Type I error rate with respect to multiple dose-control comparisons as well as multiple endpoints. The proposed testing method is illustrated using examples from dose-response clinical trials with single and multiple endpoints.     

A Local Influence Sensitivity Analysis for Incomplete Longitudinal Depression Data

In the analyses of incomplete longitudinal clinical trial data, there has been a shift, away from simple ad hoc methods that are valid only if the data are missing completely at random (MCAR), to more principled (likelihood-based or Bayesian) ignorable analyses, which are valid under the less restrictive missing at random (MAR) assumption. The availability of the necessary standard statistical software allows for such analyses in practice. Although the possibility of data missing not at random (MNAR) cannot be ruled out, it is argued that analyses valid under MNAR are not well suited for the primary analysis in clinical trials. Therefore, rather than either forgetting about or blindly shifting to an MNAR framework, the optimal place for MNAR analyses is within a sensitivity analysis context. Such analyses can be used, for example, to assess how sensitive results from an ignorable analysis are to possible departures from MAR and how much results are affected by influential observations. In this article, we apply the local influence sensitivity tool (Verbeke et al., 2001 Verbeke , G. , Molenberghs , G. , Thijs , H. , Lesaffre , E. , Kenward , M.G. ( 2001 ). Sensitivity analysis for non-random dropout: a local influence approach . Biometrics 57 : 43 – 50 [CROSSREF] [CSA]  [Google Scholar]) to a longitudinal depression trial, thereby applying it to continuous outcomes from clinical trials.     

Understanding differences in alcohol consumption and depressed mood between U.S.- and foreign-born Asian and Caucasian college students

The number and proportion of foreign-born individuals in the U.S. population has increased in recent decades. From 1970 to 2007, the foreign-born population more than tripled to approximately 37 million (U.S. Census Bureau, 1997 U.S. Census Bureau. (1997). Statistical abstract of the United States 1997. Retrieved from http://www.census.gov/prod/3/97 pubs/97statab/pop.pdf [Google Scholar], 2008 U.S. Census Bureau. (2008). The 2009 statistical abstract: The national data book. Retrieved from http://www.census.gov/compendia /statab/2009/2009edition.html [Google Scholar]). Foreign-born students are a key subpopulation of college students. About 23% of U.S. undergraduate college students in 2007–2008 were either born outside of the United States (10%) or were children of at least one first-generation immigrant parent (13%; National Center for Education Statistics, U.S. Department of Education [NCES], 2012 National Center for Education Statistics, U. S. Department of Education (NCES). (2012). New Americans in postsecondary education: A profile of immigrant and second-generation American undergraduates (NCES 2012–213). Retrieved from http://nces.ed.gov/pubs2012/2012213.pdf [Google Scholar]). Asian students constitute the majority (30%) of foreign-born undergraduates. Although foreign-born Asian students compose nearly one-quarter of the college population, limited research has examined how rates of alcohol use and depression differ between foreign-born and U.S.-born Asian college students (Gonzalez, Reynolds, & Skewes, 2011 Gonzalez, V. M., Reynolds, B., & Skewes, M. C. (2011). Role of impulsivity in the relationship between depression and alcohol problems among emerging adult college drinkers. Experimental and Clinical Psychopharmacology, 19, 303–313. doi:10.1037/a0022720[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]; Ralston & Palfai, 2012 Ralston, T. E., & Palfai, T. P. (2012). Depressive symptoms and the implicit evaluation of alcohol: The moderating role of coping motives. Drug and Alcohol Dependence, 122(2), 149–151. doi:10.1016/j.drugalcdep.2011.09.011[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]). The limited research is worrisome given their increasing rates of college enrollment (U.S. Census Bureau, 2011 U.S. Census Bureau. (2011). Statistical abstract of the United States: 2012 (131st ed.). Retrieved from http://www.census.gov/compendia/statab/2012/tables/12s0279.pdf [Google Scholar]), alcohol consumption (Aud, Fox, & KewalRamani, 2010 Aud, S., Fox, M., & KewalRamani, A. (2010). Status and trends in the education of racial and ethnic groups (NCES 2010–015). U.S. Department of Education, National Center for Education Statistics. Washington, DC: U.S. Government Printing Office. [Google Scholar]), alcohol abuse and dependence (Grant et al., 2004 Grant, B. F., Dawson, D. A., Stinson, F. S., Chou, S. P., Dufour, M. C., & Pickering, R. P. (2004). The 12-month prevalence and trends in DSM-IV alcohol abuse and dependence: United States, 1991–1992 and 2001–2002. Drug and Alcohol Dependence, 74, 223–234. doi:10.1016/j.drugalcdep.2004.02.004[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]), and underutilization of mental health services (U.S. Department of Health and Human Services, 2001 U.S. Department of Health, & Human Services. (2001). Mental health: Culture, race, and ethnicity. A supplement to mental health: A report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Office of the Surgeon General. [Google Scholar]). Collectively, these factors point to the need for further research tailored to Asian college drinkers.     

Bongkrekic Acid—a Review of a Lesser-Known Mitochondrial Toxin

Introduction

Bongkrekic acid (BA) has a unique mechanism of toxicity among the mitochondrial toxins: it inhibits adenine nucleotide translocase (ANT) rather than the electron transport chain. Bongkrekic acid is produced by the bacterium Burkholderia gladioli pathovar cocovenenans (B. cocovenenans) which has been implicated in outbreaks of food-borne illness involving coconut- and corn-based products in Indonesia and China. Our objective was to summarize what is known about the epidemiology, exposure sources, toxicokinetics, pathophysiology, clinical presentation, and diagnosis and treatment of human BA poisoning.

Methods

We searched MEDLINE (1946 to present), EMBASE (1947 to present), SCOPUS, The Indonesia Publication Index (http://id.portalgaruda.org/), ToxNet, book chapters, Google searches, Pro-MED alerts, and references from previously published journal articles. We identified a total of 109 references which were reviewed. Of those, 29 (26 %) had relevant information and were included. Bongkrekic acid is a heat-stable, highly unsaturated tricarboxylic fatty acid with a molecular weight of 486 kDa. Outbreaks have been reported from Indonesia, China, and more recently in Mozambique. Very little is known about the toxicokinetics of BA. Bongkrekic acid produces its toxic effects by inhibiting mitochondrial (ANT). ANT can also alter cellular apoptosis. Signs and symptoms in humans are similar to the clinical findings from other mitochondrial poisons, but they vary in severity and time course. Management of patients is symptomatic and supportive.

Conclusions

Bongkrekic acid is a mitochondrial ANT toxin and is reported primarily in outbreaks of food-borne poisoning involving coconut and corn. It should be considered in outbreaks of food-borne illness when signs and symptoms manifest involving the liver, brain, and kidneys and when coconut- or corn-based foods are implicated.

     

Hypothesis Testing and Bayesian Estimation using a Sigmoid E max Model Applied to Sparse Dose-Response Designs

Application of a sigmoid E _max model is described for the assessment of dose-response with designs containing a small number of doses (typically, three to six). The expanded model is a common E _max model with a power (Hill) parameter applied to dose and the ED ₅₀ parameter. The model will be evaluated following a strategy proposed by Bretz et al. (2005 Bretz , F. , Pinheiro , J. , Branson , M. ( 2005 ). Combining multiple comparisons and modeling techniques in dose-response studies . Biometrics 61 : 738 – 748 . [INFOTRIEVE] [CSA] [CROSSREF] [Crossref], [PubMed], [Web of Science ®] , [Google Scholar]). The sigmoid E _max model is used to create several contrasts that have high power to detect an increasing trend from placebo. Alpha level for the hypothesis of no dose-response is controlled using multiple comparison methods applied to the p-values obtained from the contrasts. Subsequent to establishing drug activity, Bayesian methods are used to estimate the dose-response curve from the sparse dosing design. Bayesian estimation applied to the sigmoid model represents uncertainty in model selection that is missed when a single simpler model is selected from a collection of non-nested models. The goal is to base model selection on substantive knowledge and broad experience with dose-response relationships rather than criteria selected to ensure convergence of estimators. Bayesian estimation also addresses deficiencies in confidence intervals and tests derived from asymptotic-based maximum likelihood estimation when some parameters are poorly determined, which is typical for data from common dose-response designs.     

A Note on Variance Estimation in Random Effects Meta-Regression

ABSTRACT

For random effects meta-regression inference, variance estimation for the parameter estimates is discussed. Because estimated weights are used for meta-regression analysis in practice, the assumed or estimated covariance matrix used in meta-regression is not strictly correct, due to possible errors in estimating the weights. Therefore, this note investigates the use of a robust variance estimation approach for obtaining variances of the parameter estimates in random effects meta-regression inference. This method treats the assumed covariance matrix of the effect measure variables as a working covariance matrix. Using an example of meta-analysis data from clinical trials of a vaccine, the robust variance estimation approach is illustrated in comparison with two other methods of variance estimation. A simulation study is presented, comparing the three methods of variance estimation in terms of bias and coverage probability. We find that, despite the seeming suitability of the robust estimator for random effects meta-regression, the improved variance estimator of Knapp and Hartung (2003 Knapp , G. , Hartung , J. ( 2003 ) Improved tests for a random effects meta-regression with a single covariate . Stat. Med. 22 : 2693 – 2710 . [PUBMED] [INFOTRIEVE] [CROSSREF] [Crossref], [PubMed], [Web of Science ®] , [Google Scholar]) yields the best performance among the three estimators, and thus may provide the best protection against errors in the estimated weights.     

A Consistency Approach for Evaluation of Biosimilar Products

Recently, biosimilars have attracted much attention from sponsors and regulatory authorities, while patents on early biological products will soon expire in the next few years. The European Medicines Agency (EMEA) of the European Union (EU) published a guideline on similar biological medicinal products for approval of these products in 2005 European Medicines Agency . ( 2005 ). Guideline on Similar Biological Medicinal Products. The European Medicines Agency Evaluation of Medicines for Human Use. EMEA/CHMP/437/04. London: EMEA. Available at: http://www.emea.europa.eu/docs/en_GB/document-library/Scientific_guideline/2009/09/WC500003517.pdf  [Google Scholar]. Based on the foundational principles of the EMEA guideline, biosimilars are expected to be similar, not identical, to the innovator biologics they seek to copy. In this article, we develop a consistency approach for assessment of similarity between a biosimilar product and the innovator biologic. A method for sample size determination for conducting a clinical trial to assess the biosimilar product is also proposed. A numerical example is given to illustrate applications of the proposed approach in different scenarios.     

Radiosensitising agents for the radiotherapy of cancer: advances in traditional and hypoxia targeted radiosensitisers

Background: Radiotherapy is utilised for the treatment of ～ 50% of patients with solid tumours, but its efficacy is limited by normal tissue toxicity and by the intrinsic or acquired radioresistance of many tumours. The combination of radiotherapy with chemotherapeutic agents that preferentially sensitise tumour cells to its cytotoxic effects has thus long been considered as a strategy to enhance cancer therapy. However, current chemoradiotherapy protocols remain highly unsatisfactory. Therefore, continuing efforts are being conducted to identify improved radiosensitising agents. Objective: To survey the patent literature and associated peer-reviewed publications of the past 4 years pertaining to the development of novel radiosensitising agents, with a focus on anticancer drugs traditionally used as radiosensitisers and on agents targeting radioresistant hypoxic tumour cells. Methods: Patents were searched with a set of relevant keywords using several search engines (ep.espacenet.com/, www.freepatentsonline.com/, patft.uspto.gov/). A Medline search on the same topics was performed in parallel. Results/conclusion: A total of 37 patents/applications were retrieved. Of these, 14 concern the use of conventional anticancer cytotoxic drugs for tumour radiosensitisation. The other patents mostly disclose novel hypoxic radiosensitisers, bioreductive drugs and inhibitors of hypoxia-inducible factor-1. Whether these advances will translate into clinically valuable radiosensitisers is, however, unclear.