Publications by authors named "Ryan O"

70 Publications

Modeling psychopathology: From data models to formal theories.

Psychol Methods 2021 Nov 4. Epub 2021 Nov 4.

Department of Psychology.

Over the past decade, there has been a surge of empirical research investigating mental disorders as complex systems. In this article, we investigate how to best make use of this growing body of empirical research and move the field toward its fundamental aims of explaining, predicting, and controlling psychopathology. We first review the contemporary philosophy of science literature on scientific theories and argue that fully achieving the aims of explanation, prediction, and control requires that we construct formal theories of mental disorders: theories expressed in the language of mathematics or a computational programming language. We then investigate three routes by which one can use empirical findings (i.e., data models) to construct formal theories: (a) using data models themselves as formal theories, (b) using data models to infer formal theories, and (c) comparing empirical data models to theory-implied data models in order to evaluate and refine an existing formal theory. We argue that the third approach is the most promising path forward. We conclude by introducing the abductive formal theory construction (AFTC) framework, informed by both our review of philosophy of science and our methodological investigation. We argue that this approach provides a clear and promising way forward for using empirical research to inform the generation, development, and testing of formal theories both in the domain of psychopathology and in the broader field of psychological science. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1037/met0000303DOI Listing
November 2021

Time to Intervene: A Continuous-Time Approach to Network Analysis and Centrality.

Psychometrika 2021 Jun 24. Epub 2021 Jun 24.

Utrecht University, Padualaan 14, 3584 CH,, Utrecht, The Netherlands.

Network analysis of ESM data has become popular in clinical psychology. In this approach, discrete-time (DT) vector auto-regressive (VAR) models define the network structure with centrality measures used to identify intervention targets. However, VAR models suffer from time-interval dependency. Continuous-time (CT) models have been suggested as an alternative but require a conceptual shift, implying that DT-VAR parameters reflect total rather than direct effects. In this paper, we propose and illustrate a CT network approach using CT-VAR models. We define a new network representation and develop centrality measures which inform intervention targeting. This methodology is illustrated with an ESM dataset.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11336-021-09767-0DOI Listing
June 2021

Recovering Within-Person Dynamics from Psychological Time Series.

Multivariate Behav Res 2021 Jun 21:1-32. Epub 2021 Jun 21.

Department of Methodology and Statistics, Utrecht University.

Idiographic modeling is rapidly gaining popularity, promising to tap into the within-person dynamics underlying psychological phenomena. To gain theoretical understanding of these dynamics, we need to make inferences from time series models about the underlying system. Such inferences are subject to two challenges: first, time series models will arguably always be misspecified, meaning it is unclear how to make inferences to the underlying system; and second, the sampling frequency must be sufficient to capture the dynamics of interest. We discuss both problems with the following approach: we specify a toy model for emotion dynamics as the true system, generate time series data from it, and then try to recover that system with the most popular time series analysis tools. We show that making straightforward inferences from time series models about an underlying system is difficult. We also show that if the sampling frequency is insufficient, the dynamics of interest cannot be recovered. However, we also show that global characteristics of the system can be recovered reliably. We conclude by discussing the consequences of our findings for idiographic modeling and suggest a modeling methodology that goes beyond fitting time series models alone and puts formal theories at the center of theory development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00273171.2021.1896353DOI Listing
June 2021

Oncological outcomes of laparoscopic versus open rectal cancer resections: meta-analysis of randomized clinical trials.

Br J Surg 2021 05;108(5):469-476

Department of Colorectal Surgery, St Vincent's University Hospital, Dublin, Ireland.

Background: The role of laparoscopic rectal cancer surgery has been questioned owing to conflicting reports on pathological outcomes from recent RCTs. However, it is unclear whether these pathological markers and the surgical approach have an impact on oncological outcomes. This study assessed oncological outcomes of laparoscopic and open rectal cancer resections.

Methods: A meta-analysis of RCTs was performed. Primary endpoints included oncological outcomes (disease-free survival (DFS), overall survival (OS), local recurrence). Secondary endpoints included surrogate markers for the quality of surgical resection.

Results: Twelve RCTs including 3744 patients (2133 laparoscopic, 1611 open) were included. There was no significant difference in OS (hazard ratio (HR) 0.87, 95 per cent c.i. 0.73 to 1.04; P = 0.12; I2 = 0 per cent) and DFS (HR 0.95, 0.81 to 1.11; P = 0.52; I2 = 0 per cent) between laparoscopic and open rectal resections. There was no significant difference in locoregional (odds ratio (OR) 1.03, 95 per cent c.i. 0.72 to 1.48; P = 0.86; I2 = 0 per cent) or distant (OR 0.87, 0.70 to 1.08; P = 0.20; I2 = 7 per cent) recurrence between the groups. Achieving a successful composite score (intact mesorectal excision, clear circumferential resection margin and distal margin) was significantly associated with improved DFS (OR 0.55, 0.33 to 0.74; P < 0.001; I2 = 0 per cent). An intact or acceptable mesorectal excision (intact mesorectal excision with or without superficial defects) had no impact on DFS. Finally, a positive CRM was associated with worse DFS.

Conclusion: Well performed surgery (laparoscopic or open) achieves excellent oncological outcomes with very little difference between the two modalities. The advantage and benefit of minimally invasive surgery should be assessed on an individual basis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bjs/znaa154DOI Listing
May 2021

Invisible Hands and Fine Calipers: A Call to Use Formal Theory as a Toolkit for Theory Construction.

Perspect Psychol Sci 2021 07 16;16(4):725-743. Epub 2021 Feb 16.

Psychological Methods Group, University of Amsterdam.

In recent years, a growing chorus of researchers has argued that psychological theory is in a state of crisis: Theories are rarely developed in a way that indicates an accumulation of knowledge. Paul Meehl raised this very concern more than 40 years ago. Yet in the ensuing decades, little has improved. We aim to chart a better path forward for psychological theory by revisiting Meehl's criticisms, his proposed solution, and the reasons his solution failed to meaningfully change the status of psychological theory. We argue that Meehl identified serious shortcomings in our evaluation of psychological theories and that his proposed solution would substantially strengthen theory testing. However, we also argue that Meehl failed to provide researchers with the tools necessary to construct the kinds of rigorous theories his approach required. To advance psychological theory, we must equip researchers with tools that allow them to better generate, evaluate, and develop their theories. We argue that formal theories provide this much-needed set of tools, equipping researchers with tools for thinking, evaluating explanation, enhancing measurement, informing theory development, and promoting the collaborative construction of psychological theories.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1745691620974697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273080PMC
July 2021

Surgical approach for rectal cancer: A network meta-analysis comparing open, laparoscopic, robotic and transanal TME approaches.

Eur J Surg Oncol 2021 02 26;47(2):285-295. Epub 2020 Jul 26.

School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland; Department of Surgery, Surgical Professorial Unit, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland.

Background: The optimal approach for total mesorectal excision (TME) of rectal cancer remains controversial.

Aim: To compare short- and long-term outcomes after open (OpTME), laparoscopic (LapTME), robotic (RoTME) and transanal TME (TaTME).

Methods: A systematic search of electronic databases was performed up to January 1, 2020 for randomized controlled trials (RCTs) comparing at least 2 TME strategies. A Bayesian arm-based random effect network meta-analysis (NMA) was performed, specifically, a mixed treatment comparison (MTC).

Results: 30 RCTs (and six updates) of 5586 patients with rectal cancer were included. No significant differences were identified in recurrence rates or survival rates. Operating time was shorter with OpTME (surface under the cumulative ranking curve [SUCRA] 0.96) compared to LapTME, RoTME and TaTME. Although OpTME was associated with the most blood loss (SUCRA 0.90) and had a slower recovery with increased length of stay (SUCRA 0.90) compared to the minimally invasive techniques, there was no difference in postoperative morbidity. OpTME was associated with a more complete TME specimen compared to LapTME (Risk Ratio [RR] 1.05, 95% Credible Interval [CrI] 1.01, 1.11), and TaTME had less involved CRMs (RR 0.173, 95% CrI 0.02, 0.76) versus LapTME. There were no differences between the modalities in terms of deep TME defects, DRM distance, or lymph node yield.

Conclusions: While OpTME was the most effective TME modality for short term histopathological resection quality, there was no difference in long-term oncologic outcomes. Minimally invasive approaches enhance postoperative recovery, at the cost of longer operating times. Technique selection should be based on individual tumour characteristics and patient expectations, as well as surgeon and institutional expertise.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejso.2020.06.037DOI Listing
February 2021

Factors Associated with Stroke Coding Quality: A Comparison of Registry and Administrative Data.

J Stroke Cerebrovasc Dis 2021 Feb 27;30(2):105469. Epub 2020 Nov 27.

Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia; Translational Public Health & Evaluation Division, Stroke & Ageing Research, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia. Electronic address:

Background: The International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Australian Modification (ICD-10-AM) codes are commonly used to identify patients with diseases or clinical conditions for epidemiological research. We aimed to determine the diagnostic agreement and factors associated with a clinician-assigned stroke diagnosis in a national registry and the ICD-10-AM codes recorded in government-held administrative data.

Materials And Methods: Data from 39 hospitals (2009-2013) participating in the Australian Stroke Clinical Registry (AuSCR) were linked and merged with person-level administrative data. The AuSCR clinician-assigned stroke diagnosis was the reference standard. Concordance was defined as agreement between the clinician-assigned diagnosis and the ICD-10-AM codes for acute stroke or transient ischemic attack (TIA) (ICD-10-AM codes: I61-I64, G45.9). Multivariable logistic regression was undertaken to assess factors associated with coded diagnostic concordance.

Results: A total of 14,716 patient admissions were included (46% female, 63% ischemic, 14% intracerebral hemorrhage [ICH], 18% TIA and 5% unspecified stroke based on the reference standard). Principal ICD-10-AM code concordance was ICH: 76.7%; ischemic stroke: 72.2%; TIA: 80.2%; unspecified stroke: 50.8%. Factors associated with a greater odds of ischemic stroke concordance included: treatment in a stroke unit (adjusted Odds Ratio, aOR:1.58; 95% confidence interval (CI) 1.37, 1.82); length of stay >4 days (aOR:1.30; 95% CI 1.17, 1.45); and discharge destination other than home (Residential care aOR:1.57; 95% CI 1.24, 1.96; Inpatient rehabilitation aOR:1.63; 95% CI 1.43, 1.86).

Conclusions: Diagnostic concordance varied based on stroke type. Future research to improve the quality of coding for stroke should focus on patients not treated in stroke units or with shorter lengths of stay where documentation in medical records may be limited.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105469DOI Listing
February 2021

Feedback of patient-reported outcomes to healthcare professionals for comparing health service performance: a scoping review.

BMJ Open 2020 11 23;10(11):e038190. Epub 2020 Nov 23.

Public Health and Health Services Research Group, Stroke Theme, Florey Institute of Neuroscience and Mental Health-Austin Campus, Heidelberg, Victoria, Australia

Objective: Patient-reported outcomes (PROs) provide self-reported patient assessments of their quality of life, daily functioning, and symptom severity after experiencing an illness and having contact with the health system. Feeding back summarised PROs data, aggregated at the health-service level, to healthcare professionals may inform clinical practice and quality improvement efforts. However, little is known about the best methods for providing these summarised data in a way that is meaningful for this audience. Therefore, the aim of this scoping review was to summarise the emerging approaches to PROs data for 'service-level' feedback to healthcare professionals.

Setting: Healthcare professionals receiving PROs data feedback at the health-service level.

Data Sources: Databases selected for the search were Embase, Ovid Medline, Scopus, Web of Science and targeted web searching. The main search terms included: 'patient-reported outcome measures', 'patient-reported outcomes', 'patient-centred care', 'value-based care', 'quality improvement' and 'feedback'. Studies included were those that were published in English between January 2009 and June 2019.

Primary And Secondary Outcome Measures: Data were extracted on the feedback methods of PROs to patients or healthcare providers. A standardised template was used to extract information from included documents and academic publications. Risk of bias was assessed using Joanna Briggs Institute Levels of Evidence for Effectiveness.

Results: Overall, 3480 articles were identified after de-duplication. Of these, 19 academic publications and 22 documents from the grey literature were included in the final review. Guiding principles for data display methods and graphical formats were identified. Seven major factors that may influence PRO data interpretation and use by healthcare professionals were also identified.

Conclusion: While a single best format or approach to feedback PROs data to healthcare professionals was not identified, numerous guiding principles emerged to inform the field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-038190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684821PMC
November 2020

Choosing between AR(1) and VAR(1) models in typical psychological applications.

PLoS One 2020 29;15(10):e0240730. Epub 2020 Oct 29.

Department of Psychological Methods, University of Amsterdam, Amsterdam, Netherlands.

Time series of individual subjects have become a common data type in psychological research. The Vector Autoregressive (VAR) model, which predicts each variable by all variables including itself at previous time points, has become a popular modeling choice for these data. However, the number of observations in typical psychological applications is often small, which puts the reliability of VAR coefficients into question. In such situations it is possible that the simpler AR model, which only predicts each variable by itself at previous time points, is more appropriate. Bulteel et al. (2018) used empirical data to investigate in which situations the AR or VAR models are more appropriate and suggest a rule to choose between the two models in practice. We provide an extended analysis of these issues using a simulation study. This allows us to (1) directly investigate the relative performance of AR and VAR models in typical psychological applications, (2) show how the relative performance depends both on n and characteristics of the true model, (3) quantify the uncertainty in selecting between the two models, and (4) assess the relative performance of different model selection strategies. We thereby provide a more complete picture for applied researchers about when the VAR model is appropriate in typical psychological applications, and how to select between AR and VAR models in practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240730PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595444PMC
December 2020

Comorbidity between depression and anxiety: assessing the role of bridge mental states in dynamic psychological networks.

BMC Med 2020 09 29;18(1):308. Epub 2020 Sep 29.

Department of Psychiatry, Interdisciplinary Center for Psychopathology and Emotion regulation (ICPE), University Medical Center Groningen (UMCG), University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands.

Background: Comorbidity between depressive and anxiety disorders is common. A hypothesis of the network perspective on psychopathology is that comorbidity arises due to the interplay of symptoms shared by both disorders, with overlapping symptoms acting as so-called bridges, funneling symptom activation between symptom clusters of each disorder. This study investigated this hypothesis by testing whether (i) two overlapping mental states "worrying" and "feeling irritated" functioned as bridges in dynamic mental state networks of individuals with both depression and anxiety as compared to individuals with either disorder alone, and (ii) overlapping or non-overlapping mental states functioned as stronger bridges.

Methods: Data come from the Netherlands Study of Depression and Anxiety (NESDA). A total of 143 participants met criteria for comorbid depression and anxiety (65%), 40 participants for depression-only (18.2%), and 37 for anxiety-only (16.8%) during any NESDA wave. Participants completed momentary assessments of symptoms (i.e., mental states) of depression and anxiety, five times a day, for 2 weeks (14,185 assessments). First, dynamics between mental states were modeled with a multilevel vector autoregressive model, using Bayesian estimation. Summed average lagged indirect effects through the hypothesized bridge mental states were compared between groups. Second, we evaluated the role of all mental states as potential bridge mental states.

Results: While the summed indirect effect for the bridge mental state "worrying" was larger in the comorbid group compared to the single disorder groups, differences between groups were not statistically significant. The difference between groups became more pronounced when only examining individuals with recent diagnoses (< 6 months). However, the credible intervals of the difference scores remained wide. In the second analysis, a non-overlapping item ("feeling down") acted as the strongest bridge mental state in both the comorbid and anxiety-only groups.

Conclusions: This study empirically examined a prominent network-approach hypothesis for the first time using longitudinal data. No support was found for overlapping mental states "worrying" and "feeling irritable" functioning as bridge mental states in individuals vulnerable for comorbid depression and anxiety. Potentially, bridge mental state activity can only be observed during acute symptomatology. If so, these may present as interesting targets in treatment, but not prevention. This requires further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12916-020-01738-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523307PMC
September 2020

Time to get personal? The impact of researchers choices on the selection of treatment targets using the experience sampling methodology.

J Psychosom Res 2020 Aug 5;137:110211. Epub 2020 Aug 5.

Department of Psychology, University of Pittsburgh, Pittsburgh, USA.

Objective: One of the promises of the experience sampling methodology (ESM) is that a statistical analysis of an individual's emotions, cognitions and behaviors in everyday-life could be used to identify relevant treatment targets. A requisite for clinical implementation is that outcomes of such person-specific time-series analyses are not wholly contingent on the researcher performing them.

Methods: To evaluate this, we crowdsourced the analysis of one individual patient's ESM data to 12 prominent research teams, asking them what symptom(s) they would advise the treating clinician to target in subsequent treatment.

Results: Variation was evident at different stages of the analysis, from preprocessing steps (e.g., variable selection, clustering, handling of missing data) to the type of statistics and rationale for selecting targets. Most teams did include a type of vector autoregressive model, examining relations between symptoms over time. Although most teams were confident their selected targets would provide useful information to the clinician, not one recommendation was similar: both the number (0-16) and nature of selected targets varied widely.

Conclusion: This study makes transparent that the selection of treatment targets based on personalized models using ESM data is currently highly conditional on subjective analytical choices and highlights key conceptual and methodological issues that need to be addressed in moving towards clinical implementation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychores.2020.110211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287646PMC
August 2020

Mortality and morbidity of stairlift injuries: Analysis of the UK TARN database.

Injury 2020 Jun 10;51(6):1306-1311. Epub 2020 Apr 10.

Department of Trauma and Orthopaedics, St George's University Hospitals NHS Foundation Trust, United Kingdom.

Aims: To investigate the incidence and pattern of injury in patients with a diagnosis of a fall from a stairlift.

Methods: Data was analysed from the Trauma Audit and Research Network (TARN) database from 2000 to 2018 for those recorded suffering stairlift related injuries between the ages of 40-100 years. Patient demographics, injury mechanism and pattern, mortality rate and height of fall were analysed.

Results: 1069 patients were identified in the initial search with 651 having an eligible mechanism of injury. The mean age was 82 (range 41.4-100.1) years. The most common site of injury was the limbs (49.2%) with the most severe injuries to the head (mean AIS 3.1). The mean ISS was 12.5 (Range 1-75). There was no relationship between height of fall and ISS (r 0.054 p = 0.4). Individuals were 78% more likely to have an ISS score of 15 or more if they had a head injury, (OR: 0.12; 95% CI: 0.06-0.24) and 79% more likely to have sustained an injury to the thorax (OR: 0.21; 95% CI: 0.11-0.41). Injury to the head was 95% more likely in individuals with an ISS score greater than 25 points or more (OR: 0.05; 95% CI: 0.01-0.16) and 69% more likely for those who sustain injury to the thorax. Individuals with an ISS score of 25 points or more were 18 times more likely to have sustained injury getting off their stair lift compared to any other method of falling from their stair lift. Mortality was associated with injuries to the thorax in those aged 70 years or below, injuries to the face, spine and limb for those aged 71-85 years and with head injury in those over 85 years. The overall mortality rate was 15.7%.

Conclusion: Falls from stairlifts commonly result in limb injuries and most severe injuries are sustained to the head. When patients fall getting off from astairlift, have injuries to their head or thorax they have a higher ISS. The overall mortality is 15.7%. Given the increasing use of stairlifts in our ageing population, strategies should be considered to make these safer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.injury.2020.04.004DOI Listing
June 2020

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy.

Cancer Biother Radiopharm 2020 Sep 7;35(7):497-510. Epub 2020 Apr 7.

Bayer AS, Oslo, Norway.

Targeted α therapy (TAT) offers the potential for the targeted delivery of potent α-particle-emitting radionuclides that emit high linear energy transfer radiation. This leads to a densely ionizing radiation track over a short path. Localized radiation induces cytotoxic, difficult-to-repair, clustered DNA double-strand breaks (DSBs). To date, radium-223 (Ra) is the only TAT approved for the treatment of patients with metastatic castration-resistant prostate cancer. Thorium-227 (Th), the progenitor nuclide of Ra, offers promise as a wider-ranging alternative due to the availability of efficient chelators, such as octadentate 3,2-hydroxypyridinone (3,2-HOPO). The 3,2-HOPO chelator can be readily conjugated to a range of targeting moieties, enabling the generation of new targeted thorium-227 conjugates (TTCs). This review provides a comprehensive overview of the advances in the preclinical development of TTCs for hematological cancers, including CD22-positive B cell cancers and CD33-positive leukemia, as well as for solid tumors overexpressing renal cell cancer antigen CD70, membrane-anchored glycoprotein mesothelin in mesothelioma, prostate-specific membrane antigen in prostate cancer, and fibroblast growth factor receptor 2. As the mechanism of action for TTCs is linked to the formation of DSBs, the authors also report data supporting combinations of TTCs with inhibitors of the DNA damage response pathways, including those of the ataxia telangiectasia and Rad3-related protein, and poly-ADP ribose polymerase. Finally, emerging evidence suggests that TTCs induce immunogenic cell death through the release of danger-associated molecular patterns. Based on encouraging preclinical data, clinical studies have been initiated to investigate the safety and tolerability of TTCs in patients with various cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/cbr.2020.3568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475103PMC
September 2020

Systematic review and meta-analysis comparing primary resection and anastomosis versus Hartmann's procedure for the management of acute perforated diverticulitis with generalised peritonitis.

Tech Coloproctol 2020 06 2;24(6):527-543. Epub 2020 Mar 2.

University College Dublin School of Medicine and Medical Science, Dublin, Ireland.

Background: Surgical strategies for acute perforated diverticulitis with generalised peritonitis remain controversial. This study aimed to meta-analyse trials comparing primary resection and anastomosis (PRA) to Hartmann's procedure (HP) for Hinchey III/IV diverticulitis.

Methods: A systematic literature search was conducted to identify observational studies and randomised control trials (RCTs) of patients with Hinchey III/IV diverticulitis undergoing sigmoidectomy that compared PRA to HP. The methodological quality of the included studies was assessed systematically (Newcastle-Ottawa, Jadad and Cochrane risk of bias scores) and a meta-analysis was performed.

Results: After removal of duplicates, 12 studies including 4 RCTs were identified. The analysis included 918 patients, of whom 367 (39.98%) underwent PRA. Both the initial stoma rate (risk ratio [RR] persistent stoma 0.43, 95% confidence interval [CI] 0.26, 0.71, p = 0.001; I = 99%, p < 0.0001) and the rate of permanent stoma after combining the first (emergency surgery) and second (stoma reversal) procedures were lower in the PRA group. There was no difference in in 30-day mortality; however, PRA resulted in a reduction in overall mortality as well as major complications after the initial operation (RR 0.67, 95% CI 0.46, 0.97, p = 0.03; I = 22%, p = 0.26), stoma reversal (RR 0.48, 95% CI 0.26, 0.92, p = 0.03; I = 0%, p = 0.58) and when combining both procedures (RR 0.67, 95% CI 0.51, 0.88, p = 0.005; I = 0%, heterogeneity p = 0.58). A subgroup analysis of stoma reversal rates using data from only RCTs were consistent (RR permanent stoma, 0.33, 95% CI 0.13, 0.85, p = 0.02; I = 77%, p = 0.004) with the findings of the overall analysis.

Conclusions: This meta-analysis demonstrates that PRA used in the management of haemodynamically stable patients with Hinchey grade III/IV diverticulitis leads to a lower overall persistent stoma rate, with reduced morbidity compared with the traditional management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10151-020-02172-2DOI Listing
June 2020

Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer.

Clin Cancer Res 2020 04 12;26(8):1985-1996. Epub 2019 Dec 12.

Bayer AG, Berlin, Germany.

Purpose: Prostate-specific membrane antigen (PSMA) is an attractive target for radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC). PSMA-targeted alpha therapy (TAT) has shown early signs of activity in patients with prostate cancer refractory to beta radiation. We describe a novel, antibody-based TAT, the PSMA-targeted thorium-227 conjugate PSMA-TTC (BAY 2315497) consisting of the alpha-particle emitter thorium-227 complexed by a 3,2-HOPO chelator covalently linked to a fully human PSMA-targeting antibody.

Experimental Design: PSMA-TTC was characterized for affinity, mode of action, and cytotoxic activity . Biodistribution, pharmacokinetics, and antitumor efficacy were investigated using cell line and patient-derived xenograft (PDX) models of prostate cancer.

Results: PSMA-TTC was selectively internalized into PSMA-positive cells and potently induced DNA damage, cell-cycle arrest, and apoptosis . Decrease in cell viability was observed dependent on the cellular PSMA expression levels. PSMA-TTC showed strong antitumor efficacy with T/C values of 0.01 to 0.31 after a single injection at 300 to 500 kBq/kg in subcutaneous cell line and PDX models, including models resistant to standard-of-care drugs such as enzalutamide. Furthermore, inhibition of both cancer and cancer-induced abnormal bone growth was observed in a model mimicking prostate cancer metastasized to bone. Specific tumor uptake and efficacy were demonstrated using various PSMA-TTC doses and dosing schedules. Induction of DNA double-strand breaks was identified as a key mode of action for PSMA-TTC both and .

Conclusions: The strong preclinical antitumor activity of PSMA-TTC supports its clinical evaluation, and a phase I trial is ongoing in mCRPC patients (NCT03724747).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-2268DOI Listing
April 2020

Synergistic Effect of a HER2 Targeted Thorium-227 Conjugate in Combination with Olaparib in a BRCA2 Deficient Xenograft Model.

Pharmaceuticals (Basel) 2019 Oct 15;12(4). Epub 2019 Oct 15.

Thorium Conjugate Research, Bayer AS, Oslo 0283, Norway.

Targeted thorium-227 conjugates (TTCs) represent a novel class of therapeutic radiopharmaceuticals for the treatment of cancer. TTCs consist of the alpha particle emitter thorium-227 complexed to a 3,2-hydroxypyridinone chelator conjugated to a tumor-targeting monoclonal antibody. The high energy and short range of the alpha particles induce potent and selective anti-tumor activity driven by the induction of DNA damage in the target cell. Methods: The efficacy of human epidermal growth factor receptor 2 (HER2)-TTC was tested in combination in vitro and in vivo with the poly ADP ribose polymerase (PARP) inhibitor (PARPi), olaparib, in the human colorectal adenocarcinoma isogenic cell line pair DLD-1 and the knockout variant DLD-1 BRCA2 -/- Results: The in vitro combination effects were determined to be synergistic in DLD-1 BRCA2 -/- and additive in DLD-1 parental cell lines. Similarly, the in vivo efficacy of the combination was determined to be synergistic only in the DLD-1 BRCA2 -/- xenograft model, with statistically significant tumor growth inhibition at a single TTC dose of 120 kBq/kg body weight (bw) and 50 mg/kg bw olaparib (daily, i.p. for 4 weeks), demonstrating comparable tumor growth inhibition to a single TTC dose of 600 kBq/kg bw. Conclusions: This study supports the further investigation of DNA damage response inhibitors in combination with TTCs as a new strategy for the effective treatment of mutation-associated cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ph12040155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958469PMC
October 2019

Preclinical Combination Studies of an FGFR2 Targeted Thorium-227 Conjugate and the ATR Inhibitor BAY 1895344.

Int J Radiat Oncol Biol Phys 2019 10 27;105(2):410-422. Epub 2019 Jun 27.

Bayer AS, Thorium Conjugate Research, Oslo, Norway.

Purpose: Fibroblast growth factor receptor 2 (FGFR2) has been previously reported to be overexpressed in several types of cancer, whereas the expression in normal tissue is considered to be moderate to low. Thus, FGFR2 is regarded as an attractive tumor antigen for targeted alpha therapy. This study reports the evaluation of an FGFR2-targeted thorium-227 conjugate (FGFR2-TTC, BAY 2304058) comprising an anti-FGFR2 antibody, a chelator moiety covalently conjugated to the antibody, and the alpha particle-emitting radionuclide thorium-227. FGFR2-TTC was assessed as a monotherapy and in combination with the DNA damage response inhibitor ATRi BAY 1895344.

Methods And Materials: The in vitro cytotoxicity and mechanism of action were evaluated by determining cell viability, the DNA damage response marker γH2A.X, and cell cycle analyses. The in vivo efficacy was determined using human tumor xenograft models in nude mice.

Results: In vitro mechanistic assays demonstrated upregulation of γH2A.X and induction of cell cycle arrest in several FGFR2-expressing cancer cell lines after treatment with FGFR2-TTC. In vivo, FGFR2-TTC significantly inhibited tumor growth at a dose of 500 kBq/kg in the xenograft models NCI-H716, SNU-16, and MFM-223. By combining FGFR2-TTC with the ATR inhibitor BAY 1895344, an increased potency was observed in vitro, as were elevated levels of γH2A.X and inhibition of FGFR2-TTC-mediated cell cycle arrest. In the MFM-223 tumor xenograft model, combination of the ATRi BAY 1895344 with FGFR2-TTC resulted in significant tumor growth inhibition at doses at which the single agents had no effect.

Conclusions: The data provide a mechanism-based rationale for combining the FGFR2-TTC with the ATRi BAY 1895344 as a new therapeutic approach for treatment of FGFR2-positive tumors from different cancer indications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2019.06.2508DOI Listing
October 2019

Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers.

Clin Cancer Res 2019 08 7;25(15):4723-4734. Epub 2019 May 7.

Bayer AS, Oslo, Norway.

Purpose: Targeted thorium-227 conjugates (TTC) represent a new class of molecules for targeted alpha therapy (TAT). Covalent attachment of a 3,2-HOPO chelator to an antibody enables specific complexation and delivery of the alpha particle emitter thorium-227 to tumor cells. Because of the high energy and short penetration range, TAT efficiently induces double-strand DNA breaks (DSB) preferentially in the tumor cell with limited damage to the surrounding tissue. We present herein the preclinical evaluation of a mesothelin (MSLN)-targeted thorium-227 conjugate, BAY 2287411. MSLN is a GPI-anchored membrane glycoprotein overexpressed in mesothelioma, ovarian, pancreatic, lung, and breast cancers with limited expression in healthy tissue.

Experimental Design: The binding activity and radiostability of BAY 2287411 were confirmed bioanalytically. The mode-of-action and antitumor potency of BAY 2287411 were investigated and in cell line and patient-derived xenograft models of breast, colorectal, lung, ovarian, and pancreatic cancer.

Results: BAY 2287411 induced DSBs, apoptotic markers, and oxidative stress, leading to reduced cellular viability. Furthermore, upregulation of immunogenic cell death markers was observed. BAY 2287411 was well-tolerated and demonstrated significant antitumor efficacy when administered via single or multiple dosing regimens . In addition, significant survival benefit was observed in a disseminated lung cancer model. Biodistribution studies showed specific uptake and retention of BAY 2287411 in tumors and enabled the development of a mechanistic pharmacokinetic/pharmacodynamic model to describe the preclinical data.

Conclusions: These promising preclinical results supported the transition of BAY 2287411 into a clinical phase I program in mesothelioma and ovarian cancer patients (NCT03507452).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-3476DOI Listing
August 2019

A squared standard error is not a measure of individual differences.

Proc Natl Acad Sci U S A 2019 04 19;116(14):6544-6545. Epub 2019 Mar 19.

Methodology and Statistics, Faculty of Social and Behavioural Sciences, Utrecht University, 3584 CH Utrecht, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1818033116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452686PMC
April 2019

Synergistic Effect of a Mesothelin-Targeted Th Conjugate in Combination with DNA Damage Response Inhibitors in Ovarian Cancer Xenograft Models.

J Nucl Med 2019 09 8;60(9):1293-1300. Epub 2019 Mar 8.

Thorium Conjugate Research, Bayer American Samoa, Oslo, Norway.

Targeted Th conjugates (TTCs) represent a new class of therapeutic radiopharmaceuticals for targeted α-therapy. They comprise the α-emitter Th complexed to a 3,2-hydroxypyridinone chelator conjugated to a tumor-targeting monoclonal antibody. The high energy and short range of the α-particles induce antitumor activity, driven by the induction of complex DNA double-strand breaks. We hypothesized that blocking the DNA damage response (DDR) pathway should further sensitize cancer cells by inhibiting DNA repair, thereby increasing the response to TTCs. This article reports the evaluation of the mesothelin (MSLN)-TTC conjugate (BAY 2287411) in combination with several DDR inhibitors, each of them blocking different DDR pathway enzymes. MSLN is a validated cancer target known to be overexpressed in mesothelioma, ovarian, lung, breast, and pancreatic cancer, with low expression in normal tissue. In vitro cytotoxicity experiments were performed on cancer cell lines by combining the MSLN-TTC with inhibitors of ataxia telangiectasia mutated, ataxia telangiectasia and Rad3-related (ATR), DNA-dependent protein kinase, and poly[adenosine diphosphate ribose] polymerase (PARP) 1/2. Further, we evaluated the antitumor efficacy of the MSLN-TTC in combination with DDR inhibitors in human ovarian cancer xenograft models. Synergistic activity was observed in vitro for all tested inhibitors (inhibitors are denoted herein by the suffix "i") when combined with MSLN-TTC. ATRi and PARPi appeared to induce the strongest increase in potency. Further, in vivo antitumor efficacy of the MSLN-TTC in combination with ATRi or PARPi was investigated in the OVCAR-3 and OVCAR-8 xenograft models in nude mice, demonstrating synergistic antitumor activity for the ATRi combination at doses demonstrated to be nonefficacious when administered as monotherapy. The presented data support the mechanism-based rationale for combining the MSLN-TTC with DDR inhibitors as new treatment strategies in MSLN-positive ovarian cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.118.223701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735281PMC
September 2019

Solution Thermodynamics and Kinetics of Metal Complexation with a Hydroxypyridinone Chelator Designed for Thorium-227 Targeted Alpha Therapy.

Inorg Chem 2018 Nov 29;57(22):14337-14346. Epub 2018 Oct 29.

Chemical Sciences Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States.

The solution chemistry of a chelator developed for Th targeted alpha therapy was probed. The compound of interest is an octadentate ligand comprising four N-methyl-3-hydroxy-pyridine-2-one metal-binding units, two tertiary amine groups, and one carboxylate arm appended for bioconjugation. The seven p K values of the ligand and the stability constants of complexes formed with Th(IV), Hf(IV), Zr(IV), Gd(III), Eu(III), Al(III), and Fe(III) were determined. The ligand exhibits extreme thermodynamic selectivity toward tetravalent metal ions with a ca. 20 orders of magnitude difference between the formation constant of the Th(IV) species formed at physiological pH, namely [ThL], and that of its Eu(III) analogue. Likewise, log β values of 41.7 ± 0.3 and 26.9 ± 0.3 (T = 25 °C) were measured for [ThL] and [FeL], respectively, highlighting the high affinity and selectivity of the ligand for Th ions over potentially competing endogenous metals. Single crystal X-ray analysis of the Fe(III) complex revealed a dinuclear 2:2 metal:chelator complex crystallizing in the space group P1̅. The formation of this dimeric species is likely favored by several intramolecular hydrogen bonds and the protonation state of the chelator in acidic media. L edge EXAFS data on the Th(IV) complexes of both the ligand and a monoclonal antibody conjugate revealed the expected mononuclear 1:1 metal:chelator coordination environment. This was also confirmed by high resolution mass spectrometry. Finally, kinetic experiments demonstrated that labeling the bioconjugated ligand with Th(IV) could be achieved and completed after 1 h at room temperature, reinforcing the high suitability of this chelator for Th targeted alpha therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.inorgchem.8b02430DOI Listing
November 2018

Engineering Kluyveromyces marxianus as a Robust Synthetic Biology Platform Host.

mBio 2018 09 25;9(5). Epub 2018 Sep 25.

Department of Molecular and Cell Biology, University of California, Berkeley, California, USA

Throughout history, the yeast has played a central role in human society due to its use in food production and more recently as a major industrial and model microorganism, because of the many genetic and genomic tools available to probe its biology. However, has proven difficult to engineer to expand the carbon sources it can utilize, the products it can make, and the harsh conditions it can tolerate in industrial applications. Other yeasts that could solve many of these problems remain difficult to manipulate genetically. Here, we engineered the thermotolerant yeast to create a new synthetic biology platform. Using CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats with Cas9)-mediated genome editing, we show that wild isolates of can be made heterothallic for sexual crossing. By breeding two of these mating-type engineered strains, we combined three complex traits-thermotolerance, lipid production, and facile transformation with exogenous DNA-into a single host. The ability to cross strains with relative ease, together with CRISPR-Cas9 genome editing, should enable engineering of isolates with promising lipid production at temperatures far exceeding those of other fungi under development for industrial applications. These results establish as a synthetic biology platform comparable to , with naturally more robust traits that hold potential for the industrial production of renewable chemicals. The yeast grows at high temperatures and on a wide range of carbon sources, making it a promising host for industrial biotechnology to produce renewable chemicals from plant biomass feedstocks. However, major genetic engineering limitations have kept this yeast from replacing the commonly used yeast in industrial applications. Here, we describe genetic tools for genome editing and breeding strains, which we use to create a new thermotolerant strain with promising fatty acid production. These results open the door to using as a versatile synthetic biology platform organism for industrial applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.01410-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156195PMC
September 2018

The International AIDS Society-Lancet Commission on the future of the HIV response and global health.

Lancet 2017 07;390(10092):344-345

the IAS, Geneva, Switzerland; Desmond Tutu HIV Research Foundation, University of Cape Town, Cape Town, South Africa.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(17)31874-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754741PMC
July 2017

The science of Durban, AIDS 2016.

J Int AIDS Soc 2017 06;20(1):21781

International AIDS Society, Geneva, Switzerland.

Introduction: The science presented at the 21st International AIDS Conference in Durban, South Africa, in July 2016, addressed the state of the field across basic, clinical, prevention, law and policy and implementation science.

Methods And Results: The AIDS response has seen remarkable achievements in scientific advances, in translation of those advances into prevention, treatment and care for affected individuals and communities, and in large scale implementation - reaching 18 million people with antiviral therapy by mid-year 2016. Yet incident HIV infections in adults remain stubbornly stable and are increasing in some regions and among adolescents and adults in some key populations, challenging current science, policy and programming. There have been important advances in both preventive vaccines and in cure research, but both areas require ongoing investment and innovation. Clinical research has flourished with new agents, regimens, delivery modes and diagnostics but has been challenged by aging and increasingly complex patient populations, long-term adherence challenges, co-infections and co-morbidities, and unresolved issues in TB management and epidemic control. It is an extraordinary period of innovation in prevention, yet the promise of new tools and combination approaches have yet to deliver epidemic HIV control.

Conclusions: Proven interventions, most notably pre-exposure prophylaxis, PrEP, have been limited in rollout and impact. Treatment as prevention has the promise to improve clinical outcomes but remains uncertain as a prevention tool to reduce population-level HIV incidence. The improvement of legal, policy and human rights environments for those most at risk for HIV acquisition and most at risk for lack of access to essential services; sexual and gender minorities, sex workers of all genders, people who inject drugs, and prisoners and detainees remain among the greatest unmet needs in HIV/AIDS. Failure to do better for these individuals and communities could undermine the HIV response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7448/IAS.20.1.21781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515038PMC
June 2017

A systematic review of Bayesian articles in psychology: The last 25 years.

Psychol Methods 2017 06;22(2):217-239

Department of Psychological Sciences, University of California, Merced.

Although the statistical tools most often used by researchers in the field of psychology over the last 25 years are based on frequentist statistics, it is often claimed that the alternative Bayesian approach to statistics is gaining in popularity. In the current article, we investigated this claim by performing the very first systematic review of Bayesian psychological articles published between 1990 and 2015 (n = 1,579). We aim to provide a thorough presentation of the role Bayesian statistics plays in psychology. This historical assessment allows us to identify trends and see how Bayesian methods have been integrated into psychological research in the context of different statistical frameworks (e.g., hypothesis testing, cognitive models, IRT, SEM, etc.). We also describe take-home messages and provide "big-picture" recommendations to the field as Bayesian statistics becomes more popular. Our review indicated that Bayesian statistics is used in a variety of contexts across subfields of psychology and related disciplines. There are many different reasons why one might choose to use Bayes (e.g., the use of priors, estimating otherwise intractable models, modeling uncertainty, etc.). We found in this review that the use of Bayes has increased and broadened in the sense that this methodology can be used in a flexible manner to tackle many different forms of questions. We hope this presentation opens the door for a larger discussion regarding the current state of Bayesian statistics, as well as future trends. (PsycINFO Database Record
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1037/met0000100DOI Listing
June 2017

Development of separation technology for the removal of radium-223 from targeted thorium conjugate formulations. Part II: purification of targeted thorium conjugates on cation exchange columns.

Drug Dev Ind Pharm 2017 Sep 27;43(9):1440-1449. Epub 2017 Apr 27.

a Bayer AS , Lysaker, Oslo , Norway.

Tumor targeting pharmaceuticals will play a crucial role in future pharma pipelines. The targeted thorium conjugate (TTC) therapeutic platform could provide real benefit to patients, whereby targeting moieties like monoclonal antibodies are radiolabelled with the alpha-emitting radionuclide thorium-227 (Th, t = 18.7 days). A potential problem could be the accumulation of the long-lived daughter nuclide radium-223 (Ra, t = 11.4 days) in the drug product during manufacturing and distribution. Therefore, the level of Ra must be standardized before administration to the patient. The focus in this study has been the removal of Ra, as the other progenies will have a very limited stay in the formulation. In this study, the purification of TTCs labeled with decayed Th has been explored. Columns packed with a strong cation exchange resin have been used to sequester Ra. The separation of TTC from Ra has been evaluated as influenced by both formulation and process parameters with a design of experiments (DOE) study; including citrate or acetate buffer, pH, buffer concentration, presence or absence of pABA + EDTA, resin amount and sodium chloride concentration. The aim was to achieve a separation with high sorption of Ra and accompanying low TTC sorption. The results were analyzed by multivariate analysis. Four regression models of TTC and Ra sorption from citrate and acetate buffered formulations were developed. The predictive accuracy of sorption in the four statistical models was given by standard deviations and confidence intervals. The TTC sorption in citrate and acetate buffered formulations was affected by the identical variables and the variation in TTC sorption was comparable for the two models. However, the DOE variables had a significantly stronger impact on the Ra sorption in citrate buffered formulations than the Ra sorption in acetate buffer. An optimal separation with a TTC sorption below 25% and Ra sorption above 90% can be achieved in both citrate and acetate buffered formulations. Stability studies of radiochemical purity (RCP) indicated that the measured Th values may be partly due to free Th and not TTC, but the results indicate that TTC stability may be controlled by optimizing formulation parameters. Hence, the sorption data and the regression models presented must be reviewed and further explored with regard to what is known about the stability of the TTC in the different buffered formulations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/03639045.2017.1318906DOI Listing
September 2017

Development of separation technology for the removal of radium-223 from targeted thorium conjugate formulations. Part I: purification of decayed thorium-227 on cation exchange columns.

Drug Dev Ind Pharm 2017 Feb 26;43(2):225-233. Epub 2016 Sep 26.

d Thorium Conjugate Research , Bayer AS, Lysaker, Oslo , Norway.

Targeted thorium conjugates (TTCs) are being explored as a potential future platform for specific tumor targeting pharmaceuticals. In TTCs, the alpha emitting radionuclide thorium-227 (Th) with a half-life of 18.697 d is labeled to targeting moieties, such as monoclonal antibodies (mAbs). The amount of daughter nuclide radium-223 (Ra, t=11.435 d) will increase during manufacture and distribution, and so a technology for purification is required to assure an acceptable level of Ra is administrated to the patient. Since Ra is the only progeny of Th with a long half-life (days), the progenies of Ra will have a very limited stay in the formulation once Ra is removed. The focus in this study has, therefore, been on the removal of Ra. In this study, the sorption and separation of Ra (radium(II)) and Th (thorium(IV)) on cation exchange columns has been evaluated as a purification method of decayed Th (i.e. prior to radiolabelling of a mAb and formation of TTC). The goal is to minimize the sorption of Th and maximize the sorption of Ra. Statistical experimental design with formulation and process parameters, including buffered formulations comprising citrate and acetate, at various concentrations and pH, presence of free radical scavenger and chelator, and resin amount have been evaluated for impact on the purification process. The studies have been interpreted by the aid of multivariate data analysis. The correlations between design of experimental variables and sorption are summarized by regression models. The predictive accuracy of radionuclide sorption was given by standard deviation and 95% confidence intervals originating from statistical cross validation. Experimental results and statistical models for citrate-buffered formulations verified reproducible and acceptable sorption levels of Ra and Th under selected conditions. For acetate-buffered formulations, prediction of Th sorption was influenced by complex variable relationships and hence a risk of obtaining irreproducibility. Fine-tuned variable levels showed, however, variable combinations predicting high sorption of Ra (>90%) and low sorption of Th (<3%) also for the acetate-buffered formulations. The optimal separation conditions should be decided based on tuning the variables levels for Ra in the citrate-buffered formulations, while for acetate, the optimal separation should be based on tuning variable levels for Th sorption. The ionic strength of the formulation also seemed to affect the radionuclide sorption. Labeling of an antibody-chelator conjugate with purified Th (i.e. preparation of TTC) was successful in the selected citrate-buffered formulations tested.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/03639045.2016.1234484DOI Listing
February 2017

In Vitro and In Vivo Efficacy of a Novel CD33-Targeted Thorium-227 Conjugate for the Treatment of Acute Myeloid Leukemia.

Mol Cancer Ther 2016 10 17;15(10):2422-2431. Epub 2016 Aug 17.

Thorium Conjugate Research, Bayer AS, Oslo, Norway.

The clinical efficacy of the first approved alpha pharmaceutical, Xofigo (radium-223 dichloride, RaCl), has stimulated significant interest in the development of new alpha-particle emitting drugs in oncology. Unlike radium-223 (Ra), the parent radionuclide thorium-227 (Th) is able to form highly stable chelator complexes and is therefore amenable to targeted radioimmunotherapy. We describe the preparation and use of a CD33-targeted thorium-227 conjugate (CD33-TTC), which binds to the sialic acid receptor CD33 for the treatment of acute myeloid leukemia (AML). A chelator was conjugated to the CD33-targeting antibody lintuzumab via amide bonds, enabling radiolabeling with the alpha-emitter Th. The CD33-TTC induced in vitro cytotoxicity on CD33-positive cells, independent of multiple drug resistance (MDR) phenotype. After exposure to CD33-TTC, cells accumulated DNA double-strand breaks and were arrested in the G phase of the cell cycle. In vivo, the CD33-TTC demonstrated antitumor activity in a subcutaneous xenograft mouse model using HL-60 cells at a single dose regimen. Dose-dependent significant survival benefit was further demonstrated in a disseminated mouse tumor model after single dose injection or administered as a fractionated dose. The data presented support the further development of the CD33-TTC as a novel alpha pharmaceutical for the treatment of AML. Mol Cancer Ther; 15(10); 2422-31. ©2016 AACR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-16-0251DOI Listing
October 2016

An efficient chelator for complexation of thorium-227.

Bioorg Med Chem Lett 2016 09 17;26(17):4318-21. Epub 2016 Jul 17.

The Department of Thorium Research, Bayer AS, Drammensveien 288, 0283 Oslo, Norway. Electronic address:

We present the synthesis and characterization of a highly efficient thorium chelator, derived from the octadentate hydroxypyridinone class of compounds. The chelator forms extremely stable complexes with fast formation rates in the presence of Th-227 (ambient temperature, 20min). In addition, mouse biodistribution data are provided which indicate rapid hepatobiliary excretion route of the chelator which, together with low bone uptake, supports the stability of the complex in vivo. The carboxylic acid group may be readily activated for conjugation through the ɛ-amino groups of lysine residues in biomolecules such as antibodies. This chelator is a critical component of a new class of Targeted Thorium Conjugates (TTCs) currently under development in the field of oncology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2016.07.034DOI Listing
September 2016
-->