Survey of Pharmaceutical Industry's Best Practices around In Vitro Transporter Assessment and Implications for Drug Development: Considerations from the International Consortium for Innovation and Quality for Pharmaceutical Development Transporter Working Group.

The International Consortium for Innovation and Quality in Pharmaceutical Development Transporter Working Group had a rare opportunity to analyze a crosspharma collation of in vitro data and assay methods for the evaluation of drug transporter substrate and inhibitor potential. Experiments were generally performed in accordance with regulatory guidelines. Discrepancies, such as not considering the impact of preincubation for inhibition and free or measured in vitro drug concentrations, may be due to the retrospective nature of the dataset and analysis. Lipophilicity was a frequent indicator of crosstransport inhibition (P-gp, BCRP, OATP1B, and OCT1), with high molecular weight (MW ≥500 Da) also common for OATP1B and BCRP inhibitors. A high level of overlap in in vitro inhibition across transporters was identified for BCRP, OATP1B1, and MATE1, suggesting that prediction of DDIs for these transporters will be common. In contrast, inhibition of OAT1 did not coincide with inhibition of any other transporter. Neutrals, bases, and compounds with intermediate-high lipophilicity tended to be P-gp and/or BCRP substrates, whereas compounds with MW <500 Da tended to be OAT3 substrates. Interestingly, the majority of in vitro inhibitors were not reported to be followed up with a clinical study by the submitting company, whereas those compounds identified as substrates generally were. Approaches to metabolite testing were generally found to be similar to parent testing, with metabolites generally being equally or less potent than parent compounds. However, examples where metabolites inhibited transporters in vitro were identified, supporting the regulatory requirement for in vitro testing of metabolites to enable integrated clinical DDI risk assessment. SIGNIFICANCE STATEMENT: A diverse dataset showed that transporter inhibition often correlated with lipophilicity and molecular weight (>500 Da). Overlapping transporter inhibition was identified, particularly that inhibition of BCRP, OATP1B1, and MATE1 was frequent if the compound inhibited other transporters. In contrast, inhibition of OAT1 did not correlate with the other drug transporters tested.

Tissue distribution and retention drives efficacy of rapidly clearing VHL-based PROTACs.

BACKGROUND: Proteolysis-targeting chimeras (PROTACs) are being developed for therapeutic use. However, they have poor pharmacokinetic profiles and their tissue distribution kinetics are not known. METHODS: A typical von Hippel-Lindau tumor suppressor (VHL)-PROTAC 14C-A947 (BRM degrader)-was synthesized and its tissue distribution kinetics was studied by quantitative whole-body autoradiography (QWBA) and tissue excision in rats following IV dosing. Bile duct-cannulated (BDC) rats allowed the elucidation of in vivo clearance pathways. Distribution kinetics was evaluated in the tissues and tumors of mice to support PK-PD correlation. In vitro studies enabled the evaluation of cell uptake mechanisms and cell retention properties. RESULTS: Here, we show that A947 quickly distributes into rat tissues after IV dosing, where it accumulates and is retained in tissues such as the lung and liver although it undergoes fast clearance from circulation. Similar uptake/retention kinetics enable tumor growth inhibition over 2-3 weeks in a lung cancer model. A947 quickly excretes in the bile of rats. Solute carrier (SLC) transporters are involved in hepatocyte uptake of PROTACs. Sustained BRM protein degradation is seen after extensive washout that supports prolonged cell retention of A947 in NCI-H1944 cells. A947 tissue exposure and pharmacodynamics are inversely correlated in tumors. CONCLUSIONS: Plasma sampling for VHL-PROTAC does not represent the tissue concentrations necessary for efficacy. Understanding of tissue uptake and retention could enable less frequent IV administration to be used for therapeutic dosing.

Proteolysis-targeting chimeras (PROTACs) are a type of potential cancer medicine designed to target proteins primarily present in tumours. There is limited data on how it is absorbed, distributed, metabolised and excreted from tissues. Here, we studied the tissue distribution of synthetic PROTAC molecules labelled with radioactivity following intravenous injection in rodent models. We find that PROTAC can rapidly distribute to target tumour tissues and its prolonged retention within the tumour cells can contribute to prevention of further tumour growth, as demonstrated in the lung cancer model. These findings suggest the evaluation of PROTAC therapeutic effectiveness directly from tumour tissues provides more relevant assessment than sampling from blood circulation, which may have implications for a reduction in intravenous dosing.

Can period-related symptoms predict menstrual manipulation among Australian female cyclists?

This study explored the extent of menstrual manipulation and its associated impact on period-related symptoms and training disruptions in Australian Female Cyclists. 205 female cyclists, from recreational to elite level, participated in an online "Female Cyclist Questionnaire (FCQ)". The FCQ utilised a series of validated questionnaires to obtain demographic information and menstrual function of the respondents, and to investigate their menstrual manipulation habits and perceptions on how their period-related symptoms affected their well-being, mood, energy and training tolerance. More than 80% of the cyclists reported that their period-related symptoms impacted upon training and 41% made training adjustments based on these symptoms. Two-thirds of respondents thought their training should be phase-controlled yet only half discussed their hormonal cycles with their coaches. Menstrual manipulation was predicted by reduced "workout tolerance" in these cyclists (odds ratio = 0.632). Half of the respondents reported compromised ability to tolerate high-intensity interval training with period-related symptoms. Period pain, increased irritability, lower energy levels and more sugar cravings were commonly reported but did not predict menstrual manipulation. The data indicated that period-related symptoms are present in Australian female cyclists across all levels of participation. However, the perceived impact to training and subsequent behavioural changes varied among individuals.

Using the Dynamic Well-Stirred Model to Extrapolate Hepatic Clearance of Organic Anion-Transporting Polypeptide Transporter Substrates without Assuming Albumin-Mediated Hepatic Drug Uptake.

Extrapolating in vivo hepatic clearance from in vitro uptake data is a known challenge, especially for organic anion-transporting polypeptide transporter (OATP) substrates, and the well-stirred model (WSM) commonly yields systematic underpredictions for those anionic drugs, hypothetically due to "albumin-mediated hepatic drug uptake". In the present study, we demonstrate that the WSM incorporating the dynamic free fraction (f D), a measure of drug protein binding affinity, performs reasonably well in predicting hepatic clearance of OATP substrates. For a selection of anionic drugs, including atorvastatin, fluvastatin, pravastatin, rosuvastatin, pitavastatin, cerivastatin, and repaglinide, this dynamic well-stirred model (dWSM) correctly predicts hepatic plasma clearance within 2-fold error for six out of seven OATP substrates examined. The geometric mean of clearance ratios between the predicted and the observed values falls in the range of 1.21-1.38. As expected, the WSM with unbound fraction (f u) systematically underpredicts hepatic clearance with greater than 2-fold error for five out of seven drugs, and the geometric mean of clearance ratios between the predicted and the observed values is in the range of 0.20-0.29. The results suggest that, despite its simplicity, the dWSM operates well for transporter-mediated uptake clearance, and that clearance under-prediction of OATP substrates may not necessarily be associated with the chemical class of the anionic drugs, nor is it a result of albumin-mediated hepatic drug uptake as currently hypothesized. Instead, the superior prediction power of the dWSM confirms the utility of the dynamic free fraction in clearance prediction and the importance of drug plasma binding kinetics in hepatic uptake clearance. SIGNIFICANCE STATEMENT: The traditional well-stirred model (WSM) consistently underpredicts organin anion-transporting polypeptide transporter (OATP)-mediated hepatic uptake clearance, hypothetically due to the albumin-mediated hepatic drug uptake. In this manuscript, we apply the dynamic WSM to extrapolate hepatic clearance of the OATP substrates, and our results show significant improvements in clearance prediction without assuming albumin-mediated hepatic drug uptake.

A Prospective Randomised Trial to Determine the Effect of a Reduced Versus Standard Dose of Enzalutamide on Side Effects in Frail Patients with Prostate Cancer.

BACKGROUND AND OBJECTIVE: Enzalutamide is a potent androgen receptor signalling inhibitor, effectively used for the treatment of different stages of prostate cancer. Side effects occur frequently at the registered dose, whilst a lower dose might be equally effective. Therefore, the aim of this study is to determine the effect of a reduced dose of enzalutamide on side effects in frail patients with prostate cancer. METHODS: This multicentre randomised trial compared the standard enzalutamide dose of 160 mg once daily (OD) with a reduced dose of 120 mg OD in frail patients with prostate cancer. Fatigue, cognitive side effects, and depressive symptoms were measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire, Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire, and Geriatric Depression Scale-15 (GDS-15). Linear mixed-effect models were used to study differences in side effects over time between both groups. KEY FINDINGS AND LIMITATIONS: In total, 52 patients were included in the analysis (25 reduced dose and 27 standard dose). Patients treated with the reduced dose had significantly lower fatigue after 24 wk than those with the standard dose (difference FACIT-Fatigue 6.2; 95% confidence interval 1.4-11.0; p = 0.01). Patients treated with the reduced dose showed stable fatigue, cognitive side effects, and depressive symptoms over time, whilst patients with the standard dose showed significantly worse side effects after 24 wk than at baseline. CONCLUSIONS AND CLINICAL IMPLICATIONS: A reduced dose of enzalutamide results in less fatigue, cognitive side effects, and depressive symptoms in frail patients with prostate cancer than the standard dose, without any indication of interference with efficacy endpoints. PATIENT SUMMARY: In this report, we looked at the side effects of enzalutamide at two dose levels. We found that, in frail patients, three tablets a day result in less fatigue than four tablets a day. Patients treated with four tablets a day showed an increase in fatigue, cognitive side effects, and depression. We conclude that a lower dose of three tablets can be used to alleviate side effects without indications for less efficacy.

Effects of In-Exercise Carbohydrate Supplementation on Prolonged High-Intensity Exercise Performance in Oral Contraceptive Users.

PURPOSE: To examine the impact of oral contraceptive (OC) phases on performance, physiological, and subjective responses to prolonged, intensive exercise when carbohydrate (CHO) stores are reduced. METHODS: Ten well-trained female cyclists using monophasic OC completed 4 identical trials (>150 min) under conditions of in-trial 60-g·h-1 CHO supplementation (CHO+) or placebo (CHO-) during the sugar- (SUG) and active-pill (ACT) phases of their OC cycle. Each trial comprised two 400-kcal time trials (TT) separated by 1 hour of submaximal cycling at first ventilatory threshold. RESULTS: Change in completion time from TT1 to TT2 was minimized in CHO+ compared with CHO- (4.06 [2.55] vs 6.08 [5.33] min; P = .019, effect size = -0.36). An interaction effect of OC and CHO was observed for time to complete TT (P = .006), mean TT power (P = .002), mean TT heart rate (P = .002), and posttrial emotional balance (P = .020) and negative emotional state (P = .033). In ACT, mean TT power and heart rate were higher in CHO+ when compared with CHO-, resulting in faster TTs in CHO+ and improved posttrial emotional well-being. When CHO was not supplemented, TT power and heart rate were higher in SUG when compared with ACT, resulting in faster TTs in SUG and improved posttrial emotional balance. CONCLUSION: CHO depletion during ACT negatively influenced TT performance and emotional well-being when compared with SUG. Irrespective of OC pill phase, CHO supplementation should be prioritized to sustain performance and improve postexercise recovery-stress balance.

Introducing the Dynamic Well-Stirred Model for Predicting Hepatic Clearance and Extraction Ratio.

The well-stirred model (WSM) incorporating the fraction of unbound drug (fu) to account for the effect of plasma binding on intrinsic clearance has been widely used for predicting hepatic clearance under the assumption that drug protein binding reaches equilibrium instantaneously. Our theoretical analysis reveals that the effect of protein binding on intrinsic clearance is better accounted for with the dynamic free fraction (fD), a measure of drug protein binding affinity, which leads to a putative dynamic well-stirred model (dWSM) without the instantaneous equilibrium assumption. Using recombinant CYP3A4 as the in vitro clearance system, we demonstrate that the binding effect of albumin on the intrinsic clearance of both highly bound midazolam and highly free verapamil is fully corrected by their corresponding fD values, respectively. On the other hand, fu only corrects the binding effect of albumin on the intrinsic clearance of verapamil, and yields severe over-correction of the intrinsic clearance of midazolam. The results suggest that the traditional WSM is suitable for highly free drugs like verapamil but not necessarily for highly bound drugs such as midazolam due to the violation of the instantaneous equilibrium assumption or under-estimating the true free drug concentration. In comparison, the dWSM incorporating fD holds true as long as drug elimination follows steady-state kinetics, and hence, it is more broadly applicable to drugs with different protein binding characteristics. Here we demonstrate with 36 diverse drugs, that the dWSM significantly improves the accuracy of predicting human hepatic clearance and liver extraction ratio from in vitro microsomal clearance data, highlighting the importance of drug plasma protein binding kinetics in addressing the under-prediction of hepatic clearance by the WSM.

Fatigue Resistance Is Altered during the High-Hormone Phase of Eumenorrheic Females but Not Oral Contraceptive Users.

PURPOSE: This study aimed to examine the effect of ovarian hormones and their synthetic equivalents on substrate utilization and fatigue resistance during a race-specific cycling protocol. METHODS: Seventeen well-trained female cyclists (nine eumenorrheic females, eight oral contraceptive users) completed two experimental trials, in a randomized order, in their low- (follicular/sugar pill) and high-hormone (luteal/active pill) phases. Each 91-min trial consisted of a 45-min moderate-intensity component (submaximal cycling, or SMC) followed by 6 min of high-intensity (HIT) and then a fatigue resistance test (FRT): 6 × 1-min all-out efforts with 1-min active recovery. Meals, comprising carbohydrate (CHO) intake of 8 g·kg -1 body mass, were standardized 24-h pretrial. An electrolyte-only solution was provided ad libitum during each trial. RESULTS: In eumenorrheic females, a large reduction in average power during FRT was observed in the luteal phase (277 ± 31 vs 287 ± 33 W; P = 0.032). Greater CHO ox (~ 4%, P = 0.020) during SMC and ventilatory inefficiencies during SMC and HIT (~7%, P < 0.001) were also observed in the luteal phase. In contraceptive users, despite some phasal changes in cardiorespiratory and metabolic data in SMC (~6% higher blood glucose and ~2% higher minute ventilation in active pill phase), none of the performance parameters in the FRT were different. CONCLUSIONS: Fatigue resistance was compromised only in high-hormone phase of the menstrual cycle, with eumenorrheic females likely susceptible because of increased CHO utilization during SMC. Hormone-induced ventilatory inefficiencies may also have increased metabolic demand. These findings emphasize the need to maintain CHO availability for power production, particularly in high-hormone phases.

Artificial Intelligence for Quantitative Modeling in Drug Discovery and Development: An Innovation and Quality Consortium Perspective on Use Cases and Best Practices.

Recent breakthroughs in artificial intelligence (AI) and machine learning (ML) have ushered in a new era of possibilities across various scientific domains. One area where these advancements hold significant promise is model-informed drug discovery and development (MID3). To foster a wider adoption and acceptance of these advanced algorithms, the Innovation and Quality (IQ) Consortium initiated the AI/ML working group in 2021 with the aim of promoting their acceptance among the broader scientific community as well as by regulatory agencies. By drawing insights from workshops organized by the working group and attended by key stakeholders across the biopharma industry, academia, and regulatory agencies, this white paper provides a perspective from the IQ Consortium. The range of applications covered in this white paper encompass the following thematic topics: (i) AI/ML-enabled Analytics for Pharmacometrics and Quantitative Systems Pharmacology (QSP) Workflows; (ii) Explainable Artificial Intelligence and its Applications in Disease Progression Modeling; (iii) Natural Language Processing (NLP) in Quantitative Pharmacology Modeling; and (iv) AI/ML Utilization in Drug Discovery. Additionally, the paper offers a set of best practices to ensure an effective and responsible use of AI, including considering the context of use, explainability and generalizability of models, and having human-in-the-loop. We believe that embracing the transformative power of AI in quantitative modeling while adopting a set of good practices can unlock new opportunities for innovation, increase efficiency, and ultimately bring benefits to patients.

Clinical and morphological features of large-cell neuroendocrine carcinomas and small-cell lung carcinomas expressing the DLL3 and ASCL1 oncoproteins.

Intratumoral similarities and differences between large-cell neuroendocrine carcinomas (LCNECs) and small-cell lung carcinomas (SCLCs) are determined partially by the Notch signaling pathway, which controls the switch from neuroendocrine to slight/non-neuroendocrine cell fate. LCNECs are divided into two subgroups according to genomic alterations: type I LCNECs exhibit a neuroendocrine profile characterized by achaete-scute homolog 1 (ASCL1)high/delta-like protein 3 (DLL3)high/NOTCHlow and type II LCNECs show the pattern ASCL1low/DLL3low/NOTCHhigh. Here, we used immunohistochemistry, transmission electron microscopy, and digital analysis to examine the role of the Notch ligand DLL3 as an immunomarker of the neuroendocrine state and ASCL1 as a regulator of cell-cell interactions in SCLCs and LCNECs. High DLL3 and ASCL1 expression was associated with atypical submicroscopic characteristics involving nuclear size, chromatin arrangement, Golgi apparatus, and endoplasmic reticulum, and was characteristic of type I LCNECs with similarity to SCLCs, whereas low DLL3 and ASCL1 expression was found in both SCLCs and type II LCNECs. In patients diagnosed at an early stage who did not have metastasis and who underwent chemotherapy, DLL3high and ASCL1high SCLCs and type I LCNECs were associated with a better prognosis and a lower risk of death. The present findings suggested that DLL3/ASCL1 are potential therapeutic targets and prognostic indicators in patients with SCLCs or LCNECs.

Standardisation of the C:N ratio in ileal digesta changes relationships among fermentation end-products during in vitro hindgut fermentation in pigs.

Undigested proteins that become available for the microbiota in the hindgut can be used as building blocks for bacterial cells, or can enter various catabolic pathways. Degradation via protein fermentation pathways is least preferred, as several fermentation end-products released can be toxic for the host. Directing microbial protein metabolism towards protein synthesis or degradative pathways that result in less toxic end-products, for example through nutritional interventions, is an interesting strategy for improving health. We studied variation in protein fermentation patterns, resulting from variation in substrate composition. Ileal digesta, obtained from cannulated pigs fed different protein sources, were subjected to fermentation in vitro under different conditions; (1) ileal digesta were fermented as-is, (2) ileal digesta were fermented after standardisation to a constant high C:N ratio, by addition of high fermentable carbohydrates and (3) ileal digesta samples were incubated under limiting N concentrations. Gas production was monitored as an indirect measure of microbial activity, and fermentation end-products at different points in time were analysed by gas chromatography and high resolution mass spectrometry. Using principal component analysis, we identified patterns in protein fermentation end-products and related them to the composition of ileal digesta. Protein-associated fermentation end-product concentrations of e.g. isovaleric-, isobutyric-, phenylacetic acid and p-cresol were negatively affected by the available amount of high fermentable carbohydrates combined with a high C:N ratio. The aforementioned fermentation end-products positively correlated with NH3 concentrations and negatively with short-chain fatty acid (SCFA) concentrations. Standardisation to a constant high C:N ratio changed their relationship; isovaleric-, isobutyric-, phenylacetic acid and p-cresol lost their correlation with NH3 concentrations, became positively correlated with SCFA concentrations, and now showed a positive correlation with available amounts of high fermentable carbohydrates. Our observations demonstrate an important role of the C:N ratio in the relationship between fermentation end-products. At constant C:N, protein fermentation end-products correlate with end-products of carbohydrate fermentation and NH3, often considered as a proxy for protein fermentation, loses its predictive power.

Diagnostic and societal impact of implementing the syncope guidelines of the European Society of Cardiology (SYNERGY study).

BACKGROUND: Syncope management is fraught with unnecessary tests and frequent failure to establish a diagnosis. We evaluated the potential of implementing the 2018 European Society of Cardiology (ESC) Syncope Guidelines regarding diagnostic yield, accuracy and costs. METHODS: A multicentre pre-post study in five Dutch hospitals comparing two groups of syncope patients visiting the emergency department: one before intervention (usual care; from March 2017 to February 2019) and one afterwards (from October 2017 to September 2019). The intervention consisted of the simultaneous implementation of the ESC Syncope Guidelines with quick referral routes to a syncope unit when indicated. The primary objective was to compare diagnostic accuracy using logistic regression analysis accounting for the study site. Secondary outcome measures included diagnostic yield, syncope-related healthcare and societal costs. One-year follow-up data were used to define a gold standard reference diagnosis by applying ESC criteria or, if not possible, evaluation by an expert committee. We determined the accuracy by comparing the treating physician's diagnosis with the reference diagnosis. RESULTS: We included 521 patients (usual care, n = 275; syncope guidelines intervention, n = 246). The syncope guidelines intervention resulted in a higher diagnostic accuracy in the syncope guidelines group than in the usual care group (86% vs.69%; risk ratio 1.15; 95% CI 1.07 to 1.23) and a higher diagnostic yield (89% vs. 76%, 95% CI of the difference 6 to 19%). Syncope-related healthcare costs did not differ between the groups, yet the syncope guideline implementation resulted in lower total syncope-related societal costs compared to usual care (saving €908 per patient; 95% CI €34 to €1782). CONCLUSIONS: ESC Syncope Guidelines implementation in the emergency department with quick referral routes to a syncope unit improved diagnostic yield and accuracy and lowered societal costs. TRIAL REGISTRATION: Netherlands Trial Register, NTR6268.

New Methodology for Determining Plasma Protein Binding Kinetics Using an Enzyme Reporter Assay Coupling with High-Resolution Mass Spectrometry.

Determination of drug binding kinetics in plasma is important yet extremely challenging. Accordingly, we introduce "dynamic free fraction" as a new binding parameter describing drug-protein binding kinetics. We demonstrate theoretically and experimentally that the dynamic free fraction can be determined by coupling the drug binding assay with a reporter enzyme in combination with high-resolution mass spectrometry measuring the relative initial steady-state rates of enzymatic reactions in the absence and presence of matrix proteins. This novel and simple methodology circumvents a long-standing challenge inherent in existing methods for determining binding kinetics constants, such as kon and koff, and enables assessment of the impact of protein binding kinetics on pharmaceutical properties of drugs. As demonstrated with nine model drugs, the predicted liver extraction ratio, a measure of efficiency of drug removal by the liver, correlates significantly better to the observed extraction ratio when using the dynamic free fraction (fD) in place of the unbound fraction (fu) of the drug in plasma. Similarly, the in vivo hepatic clearance of these drugs, a measure of liver drug elimination, is highly comparable to the clearance values calculated with the dynamic free fraction (fD), which is markedly better than those calculated with the unbound fraction (fu). In contrast to the prevailing view, these results indicate that protein binding kinetics is an important pharmacokinetic property of a drug. As plasma protein binding is one of the most important drug properties, this new methodology may represent a breakthrough and could have a real impact on the field.

Dihydropyrimidine dehydrogenase phenotype in peripheral blood mononuclear cells is related to adverse events of fluoropyrimidine-therapy.

PURPOSE: The primary objective of this study was to determine if dihydropyrimidine dehydrogenase (DPD) activity measured in peripheral blood mononuclear cells (PBMCs) is related to adverse events during fluoropyrimidine therapy. METHODS: A retrospective cohort study was conducted. The study population included 481 patients who received fluoropyrimidine treatment and for whom relevant patient characteristics were known and adverse events were noted in the electronic health records. Factors besides DPD phenotype that could affect the incidence of adverse events were corrected for using log regression. These log regression models were used to identify an association between the DPD phenotype measured in PBMCs and adverse events. RESULTS: Patients with a decreased DPD activity measured in PBMCs suffered more adverse events. Results from log regression data show that this effect remains significant after correcting for dosage, chemotherapy regimen and relevant patient characteristics. CONCLUSION: A significant correlation was found between reduced DPD enzyme activity in PBMCs and adverse events. The findings in this paper support further exploring DPD phenotyping as a method for preventing fluoropyrimidine-related adverse events. Further assessment of DPD phenotyping will require clinical validation in a prospective study.

The Self-Regulation Assessment (SeRA) questionnaire: development and exploratory analyses of a new patient-reported outcome measure for rehabilitation.

PURPOSE: To develop and explore underlying dimensions of the Self-Regulation Assessment (SeRA) and psychometric features of potential components. Further, to identify associations between the SeRA and disability-management self-efficacy, type of diagnosis, and type of rehabilitation. MATERIALS AND METHODS: Based on a previously developed model of self-regulation, expert and patient opinions, and cognitive interviews, a list of 22 items on self-regulation (the SeRA) was constructed. The SeRA was included in a cross-sectional survey among a multi-diagnostic group of 563 former rehabilitation patients. Exploratory analyses were conducted. RESULTS: Respondents had a mean age of 56.5 (SD 12.7) years. The largest diagnostic groups were chronic pain disorder and brain injury. Four components were found within the SeRA, labelled as "insight into own health condition," "insight into own capabilities," "apply self-regulation," and "organization of help." Cronbach's alpha was high (total scale: 0.93, subscales: range 0.85-0.89). Only scores on the first subscale showed a ceiling effect. Subscale three showed the highest correlation with a self-efficacy measure. Small differences in SeRA total scores (range 71.6-78.1) were found between different diagnostic groups. CONCLUSION: The SeRA is a new self-regulation measure with four subscales. Further research is needed to establish the validity and reliability of the SeRA. IMPLICATIONS FOR REHABILITATIONThe Self-Regulation Assessment (SeRA) was developed to provide a comprehensive measurement of self-regulation among rehabilitation populations.The SeRA could potentially be used to identify persons with self-regulation problems at the start of rehabilitation treatment and measure outcomes of rehabilitation for self-regulation.The SeRA could potentially be used to help analyse outcomes of rehabilitation practice as well as evaluate interventions on self-regulation.

Clinical and morphological features of large-cell neuroendocrine carcinomas and small-cell lung carcinomas expressing the DLL3 and ASCL1 oncoproteins

Abstract Intratumoral similarities and differences between large-cell neuroendocrine carcinomas (LCNECs) and small-cell lung carcinomas (SCLCs) are determined partially by the Notch signaling pathway, which controls the switch from neuroendocrine to slight/non-neuroendocrine cell fate. LCNECs are divided into two subgroups according to genomic alterations: type I LCNECs exhibit a neuroendocrine profile characterized by achaete‐scute homolog 1 (ASCL1)high/delta-like protein 3 (DLL3)high/NOTCHlow and type II LCNECs show the pattern ASCL1low/DLL3low/NOTCHhigh. Here, we used immunohistochemistry, transmission electron microscopy, and digital analysis to examine the role of the Notch ligand DLL3 as an immunomarker of the neuroendocrine state and ASCL1 as a regulator of cell-cell interactions in SCLCs and LCNECs. High DLL3 and ASCL1 expression was associated with atypical submicroscopic characteristics involving nuclear size, chromatin arrangement, Golgi apparatus, and endoplasmic reticulum, and was characteristic of type I LCNECs with similarity to SCLCs, whereas low DLL3 and ASCL1 expression was found in both SCLCs and type II LCNECs. In patients diagnosed at an early stage who did not have metastasis and who underwent chemotherapy, DLL3high and ASCL1high SCLCs and type I LCNECs were associated with a better prognosis and a lower risk of death. The present findings suggested that DLL3/ASCL1 are potential therapeutic targets and prognostic indicators in patients with SCLCs or LCNECs.