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Older people with mental disorders represent a particularly vulnerable group in the health care system. Despite this, mental disorders in this group often remain undiagnosed or are not treated in accordance with guidelines, potentially due to a lack of knowledge or unfavorable attitudes regarding mental disorders in older individuals. Therefore, in an anonymous online survey of 1,284 participants (71.8% female, mean age 52.3 ± 18.0 years), we assessed knowledge and attitudes regarding mental health in old age in general and regarding dementia and late-life depression in particular. Regression analyses were conducted to determine predictors of higher knowledge and more favorable attitudes based on sociodemographic data. On average, participants answered 11 ± 2 out of 15 of the knowledge questions correctly. Items on the prevention of dementia, late-life depression symptoms, and associated suicide risk were most likely to be answered incorrectly. Participants showed less favorable attitudes towards people living with dementia than towards people with late-life depression, and higher knowledge scores were associated with more favorable attitudes. Our findings highlight a clear need for psychoeducation in the field of dementia and late-life depression, with a special emphasis on prevention-related knowledge. Fostering knowledge in this area is highly relevant, as it might positively influence attitudes towards older people with mental disorders, in turn facilitating health care and health-promoting behavior among older people., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Inc.)

Background: Treatment of major depressive disorder (MDD) in men is complicated by the endorsement of traditional masculinity ideologies (TMI) often leading to reluctance toward psychotherapy, therapy interfering processes, or premature termination. In addition, it has been shown that men with MDD have a significantly increased risk of being hypogonadal (e.g., total testosterone levels <12.1 nmoL/L). Therefore, it is recommended to examine depressed men with regard to their testosterone status and if hypogonadism is present to combine psychotherapy with testosterone treatment (TT)., Aim: This project aims to evaluate a male-specific psychotherapeutic program (MSPP) for MDD in depressed eugonadal and hypogonadal men receiving testosterone in comparison to a standard cognitive behavioral therapy (CBT) for MDD and a Waitlist., Methods: The study presents a 2×3 factorial study design. In total, 144 men aged between 25 and 50 will be stratified by testosterone status (eugonadal/hypogonadal) and then randomized into one of the three conditions (MSPP, CBT, or Waitlist). Additionally, a healthy control group of 100 men will be recruited, which will undergo only baseline assessments. Both standardized psychotherapy programs will encompass 18 sessions delivered in a weekly manner. Aligned with the TT-related medical visits of the 72 hypogonadal men, all participants will be followed up with clinical assessments and bio sampling at weeks 0, 6, 15, 24, and 36., Expected Results: Compared to Waitlist control groups, treatment groups are expected to be more effective and efficacious (depression score reduction of ≥50%) at week 24 and at the follow-up at week 36. The MSPP is expected to show higher effectiveness and efficacy for depressive symptoms and higher acceptability (lower dropout rate) as compared to CBT., Discussion: This study represents the first attempt to test a male-specific psychotherapy for MDD in a single-setting compared to standard CBT and a Waitlist control condition using randomized clinical trial methodology. In addition, the potential positive adjunct effect of psychotherapy to TT in reducing depressive burden and improving quality of life in hypogonadal depressed men represents a neglected research area and might introduce new hypogonadism screening procedures in depressed men and combined treatment approaches for depressed men suffering from hypogonadism. Limitations are the rigorous inclusion and exclusion criteria, which limit the generalizability of the study results to first episode treatment naïve depressed men., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT05435222., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Walther, Ehlert, Schneeberger, Eggenberger, Flückiger, Komlenac, Heald, Rice, Palm, Seidler, Ogrodniczuk, Oliffe, Rice, Kealy, Weber and Zimmermann.)

Treatment concepts in oncology are becoming increasingly personalized and diverse. Successively, changes in standards of care mandate continuous monitoring of patient pathways and clinical outcomes based on large, representative real-world data. The German Cancer Consortium's (DKTK) Clinical Communication Platform (CCP) provides such opportunity. Connecting fourteen university hospital-based cancer centers, the CCP relies on a federated IT-infrastructure sourcing data from facility-based cancer registry units and biobanks. Federated analyses resulted in a cohort of 600,915 patients, out of which 232,991 were incident since 2013 and for which a comprehensive documentation is available. Next to demographic data (i.e., age at diagnosis: 2.0% 0-20 years, 8.3% 21-40 years, 30.9% 41-60 years, 50.1% 61-80 years, 8.8% 81+ years; and gender: 45.2% female, 54.7% male, 0.1% other) and diagnoses (five most frequent tumor origins: 22,523 prostate, 18,409 breast, 15,575 lung, 13,964 skin/malignant melanoma, 9005 brain), the cohort dataset contains information about therapeutic interventions and response assessments and is connected to 287,883 liquid and tissue biosamples. Focusing on diagnoses and therapy-sequences, showcase analyses of diagnosis-specific sub-cohorts (pancreas, larynx, kidney, thyroid gland) demonstrate the analytical opportunities offered by the cohort's data. Due to its data granularity and size, the cohort is a potential catalyst for translational cancer research. It provides rapid access to comprehensive patient groups and may improve the understanding of the clinical course of various (even rare) malignancies. Therefore, the cohort may serve as a decisions-making tool for clinical trial design and contributes to the evaluation of scientific findings under real-world conditions., (© 2023. The Author(s).)

Astatine-211 ( 211 At) has physical properties that make it one of the top candidates for use as a radiation source for alpha particle-based radionuclide therapy, also referred to as targeted alpha therapy (TAT). Here, we summarize the main results of the completed clinical trials, further describe ongoing trials, and discuss future prospects., Competing Interests: PA, TB, KS, SP, EA, and SL are co-founders of Aprit Biotech AB. EA and SL are the co-founders of Atley Solutions AB. KS is the founder of Smerud Medical Research Group. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Albertsson, Bäck, Bergmark, Hallqvist, Johansson, Aneheim, Lindegren, Timperanza, Smerud and Palm.)

Intraperitoneal 211 At-based targeted α-therapy (TAT) may hold great promise as an adjuvant therapy after surgery and chemotherapy in epithelial ovarian cancer to eradicate any remaining undetectable disease. This implies that it will also be delivered to patients possibly already cured by the primary treatment. An estimate of long-term risks is therefore sought to determine whether the treatment is justified. Methods: Baseline data for risk estimates of α-particle irradiation were collected from published studies on excess cancer induction and mortality for subjects exposed to either 224 Ra treatments or Thorotrast contrast agent (25% ThO 2 colloid, containing 232 Th). Organ dosimetry for 224 Ra and Thorotrast irradiation were taken from the literature. These organ-specific risks were then applied to our previously reported dosimetry for intraperitoneal 211 At-TAT patients. Results: Risk could be estimated for 10 different organ or organ groups. The calculated excess relative risk per gray (ERR/Gy) could be sorted into 2 groups. The lower-ERR/Gy group, ranging up to a value of approximately 5, included trachea, bronchus, and lung, at 0.52 (95% CI, 0.21-0.82); stomach, at 1.4 (95% CI, -5.0-7.9); lymphoid and hematopoietic system, at 2.17 (95% CI, 1.7-2.7); bone and articular cartilage, at 2.6 (95% CI, 2.0-3.3); breast, at 3.45 (95% CI, -10-17); and colon, at 4.5 (95% CI, -3.5-13). The higher-ERR/Gy group, ranging from approximately 10 to 15, included urinary bladder, at 10.1 (95% CI, 1.4-23); liver, at 14.2 (95% CI, 13-16); kidney, at 14.9 (95% CI, 3.9-26); and lip, oral cavity, and pharynx, at 15.20 (95% CI, 2.73-27.63). Applying a typical candidate patient (female, age 65 y) and correcting for the reference population mortality rate, the total estimated excess mortality for an intraperitoneal 211 At-monoclonal antibody treatment amounted to 1.13 per 100 treated. More than half this excess originated from urinary bladder and kidney, 0.29 and 0.34, respectively. Depending on various adjustments in calculation and assumptions on competing risks, excess mortality could range from 0.11 to 1.84 per 100 treated. Conclusion: Published epidemiologic data on lifelong detriment after α-particle irradiation and its dosimetry allowed calculations to estimate the risk for secondary cancer after 211 At-based intraperitoneal TAT. Measures to reduce dose to the urinary organs may further decrease the estimated relative low risk for secondary cancer from 211 At-monoclonal antibody-based intraperitoneal TAT., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

The relationship between the spawning stock size and subsequent number of recruits is a central concept in fisheries ecology. The influence of habitat selection of spawning individuals on the stock-recruitment relationship is poorly known. Here we explore how each of four different spawner behaviors might influence the stock-recruitment relationship and estimates of its parameters in the two most commonly used stock-recruitment functions (Beverton-Holt and Ricker). Using simulated stock-recruitment data generated by four different spawner behaviors applied to multiple discrete habitats, we show that when spawners were distributed proportionally to local carrying capacities, there was small or no bias in estimated recruitment and stock-recruitment parameters. For an ideal free distribution of spawners, larger bias in the estimates of recruitment and stock-recruitment parameters was obtained, whereas a random and a stepwise spawner behavior introduced the largest bias. Using stock-recruitment data corresponding to a "realistic" range of population densities and adding measurement error (20%-60%) to the simulated stock-recruitment data generated larger variation in the estimation bias than what was introduced by the spawner behavior. Thus, for exploited stocks at low population density and where spawning stock size and recruitment cannot be observed perfectly, partial observation of the possible spawner abundance range and measurement error might be of higher concern for management., (© 2022 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Background: The aim of this study is to elucidate the difference in absorbed dose (D abs ) patterns in radiopharmaceutical therapies between alpha emitters ( 225 Ac) and beta emitters ( 177 Lu) when targeting cancer-associated fibroblasts (CAF) or tumor cells. Five spherical models with 3 mm diameter were created, representing spherical tumor masses that contain tumor clusters, interspersed with CAFs. The mean distance from a tumor cell to the nearest CAF (L mean ) varied throughout these models from 92 to 1030 µm. D abs calculations were performed while selecting either CAFs or tumor cells as sources, with Convolution/Superposition with 177 Lu and Monte Carlo simulations (GATE) with 225 Ac. Analyses were conducted with Dose Volume Histograms and efficacy ratios (ER), which represents the ratio of mean D abs that is deposited in the target volume., Results: 225 Ac is the most optimal radionuclide when CAFs are both targeted and irradiating themselves, as ERs increase from 1.5 to 3.7 when L mean increases from 92 to 1030 µm. With 177 Lu, these numbers vary from 1.2 to 2.7. Conversely, when CAFs are sources and tumors are targets with 225 Ac, ERs decreased from 0.8 to 0.1 when L mean increases from 92 to 1030 µm. With 177 Lu, these numbers vary from 0.9 to 0.3 CONCLUSION: When targeting CAFs to irradiate tumors, the efficacy of using 225 Ac decreases as the average size of the tumor clusters (or L mean ) increases. In such situations, 177 Lu will be more effective than 225 Ac when targeting CAFs due to the longer beta particle range., (© 2022. The Author(s).)

Background: Hospitalization is often stressful and burdensome for people living with dementia (PwD) and their informal caregivers (ICs). Day clinic treatment may provide a suitable alternative, but is often precluded by a diagnosis of dementia. Furthermore, it is often caregiver-based ratings that measure treatment success as the validity of self-reports in PwD is critically discussed. We therefore set out to examine the feasibility of psychobiological stress measures in PwD and ICs and to evaluate treatment trajectories considering both the day clinic context and the daily life of the dyads., Method: A total of 40 dyads of PwD (mean age: 78.15 ± 6.80) and their ICs (mean age: 63.85 ± 13.09) completed paper-and-pencil questionnaires (covering stress, depressive symptoms, and caregiver burden among others) in addition to the measurement of hair cortisol concentrations (HCC) at admission, discharge, and follow-up 6 months after day clinic treatment. As part of an ambulatory assessment, for 2 days at the beginning and 2 days at the end of the day clinic treatment, PwD and ICs collected six saliva samples per day for the analysis of salivary cortisol (sCort) and alpha-amylase (sAA)., Results: Paper-and-pencil questionnaires and HCC assessments were more feasible than the ambulatory assessment. We found discrepancies between subjective and physiological markers of stress in PwD. Whereas HCC decreased over time, self-reported stress increased. Child-parent dyads reported decreases in neuropsychiatric symptoms, associated burden, and self-reported stress from admission to follow-up. In daily life, both PwD and ICs showed characteristic diurnal profiles of sAA and sCort, however, we found no differences in summary indicators of salivary stress markers over time., Discussion: The psychobiological evaluation was feasible and added informative value, underlining the potential of physiological stress markers to complement self-reports on stress in PwD and to objectively evaluate treatment trajectories. In this sample, HCC was more feasible and acceptable as biological marker of stress compared to saliva samples. Concerning treatment trajectories, differential effects on the dyads were found, with child-parent dyads benefiting more from day clinic treatment compared to spousal dyads., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wuttke-Linnemann, Palm, Geschke, Skoluda, Bischoff, Nater, Endres and Fellgiebel.)

Objective: To determine the efficacy and resource utilization of through-and-through dissection of the soft palate for pharyngeal flap inset for velopharyngeal incompetence (VPI) of any indication., Design: Retrospective review., Setting: Tertiary care center., Patients: Thirty patients were included. Inclusion criteria were diagnosis of severe VPI based on perceptual speech assessment, confirmed by nasoendoscopy or videofluoroscopy; VPI managed surgically with modified pharyngeal flap with through-and-through dissection of the soft palate; and minimum 6 months follow-up. Patients with 22q11.2 deletion syndrome were excluded., Intervention: Modified pharyngeal flap with through-and-through dissection of the soft palate., Main Outcome Measure(s): Velopharyngeal competence and speech assessed using the Speech-Language Pathologist 3 scale., Results: The median preoperative speech score was 11 of 13 (range, 7 to 13), which improved significantly to a median postoperative score of 1 of 13 (range 0-7; P < .001). Velopharyngeal competence was restored in 25 (83%) patients, borderline competence in 3 (10%), and VPI persisted in 2 (7%) patients. Complications included 1 palatal fistula that required elective revision and 1 mild obstructive sleep apnea that did not require flap takedown. Median skin-to-skin operative time was 73.5 minutes, and median length of stay (LOS) was 50.3 hours., Conclusions: This technique allows direct visualization of flap placement and largely restores velopharyngeal competence irrespective of VPI etiology, with low complication rates. Short operative time and LOS extend the value proposition, making this technique not only efficacious but also a resource-efficient option for surgical management of severe VPI.

Draft genome sequences of Escherichia coli and Pseudomonas aeruginosa strains collected from clinical infections were used to determine the prevalence of newly emerging antibiotic resistance genes in Maine. Comparisons between cefepime-resistant and -susceptible E. coli strains and imipenem-resistant and -susceptible P. aeruginosa strains are being conducted.

Background: Informal caregivers are a particularly vulnerable population at risk for adverse health outcomes. Likewise, there are many scales available assessing individual caregiver burden and stress. Recently, resilience in caregivers gained increasing interest and scales started to assess resilience factors as well. Drawing on a homeostatic model, we developed a scale assessing both caregivers' stress and resilience factors. We propose four scales, two covering stress and two covering resilience factors, in addition to a sociodemographic basic scale. Based on the stress:resilience ratio, the individual risk of adverse health outcomes and suggestions for interventions can be derived. Methods: A total of 291 informal caregivers filled in the ResQ-Care as part of a survey study conducted during the second wave of the COVID-19 pandemic in Germany. Exploratory factor analysis was performed. Validity analyses were examined by correlations with the Brief Resilience Scale (BRS), the Perceived Stress Scale (PSS-4) and the Geriatric Depression Scale (GDS-15). Results: The data fitted our proposed four-factor solution well, explaining 43.3% of the variance. Reliability of each scale was at least acceptable with Cronbach's α ≥0.67 and MacDonald's ω ≥0.68 for all scales. The two strain scales weighed more than the resilience scales and explained 65.6% of the variance. Convergent and discriminant validity was confirmed for the BRS and PSS-4, whereas the GDS-15 correlation pattern was counterintuitive. Conclusion: The factor structure of the ResQ-Care scale was confirmed, with good indications of reliability and validity. Inconsistent correlations of the scales with the GDS-15 might be due to a reduced validity of GDS-15 assessment during the COVID-19 lockdown., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wuttke-Linnemann, Palm, Scholz, Geschke and Fellgiebel.)

Background: Sympatric speciation along ecological gradients has been studied repeatedly, in particular in freshwater fishes. Rapid post-glacial ecological divergence has resulted in numerous endemic species or ecologically distinct populations in lakes of the temperate zones. Here, we focus on the Baltic cisco (Coregonus albula) complex, to study the genetic similarity among two pairs of sympatric autumn- and spring-spawning populations from post-glacial German Lakes Stechlin and Breiter Luzin. For comparison, we included a similar pair of sympatric populations from the Swedish Lake Fegen. We wanted to explore potential genetic similarities between the three sympatric cisco population pairs in the three lakes, to evaluate whether the pairs may have emerged independently in the three lakes, or whether two different species may have colonized all three lakes independently. Furthermore, we considered allopatric C. albula populations from three Polish, three Finnish, and four Swedish locations, added one Siberian population of the sister species C. sardinella and a Swedish C. maraena (whitefish) population. By genotyping nine microsatellite markers in 655 individuals from these 18 populations, we wanted to elucidate how strongly the cisco populations differ across a larger geographical area within Europe. Finally, we compared the genetic differences between the spring- and autumn-spawning populations of ciscoes in the two German lakes to infer the potentially deteriorating effect of strong anthropogenic pressure on the lakes., Results: Dendrogram, Principal Coordinate Analysis and admixture analysis all indicated strong correspondence between population differentiation and geographical location for most cisco populations in Europe, including the Siberian population of C. sardinella. However, populations from some Swedish lakes deviated from this general pattern, by showing a distinct genetic structure. We found evidence for independent evolution of the three sympatric population pairs, because the populations co-occurring in the same lake were always most closely related. However, genetic differentiation was weak in the two German population pairs, but strong in the Swedish Lake Fegen, indicating that the weak differentiation in the German pairs reported earlier has eroded further., Conclusions: Our results suggest that the genetic differentiation at neutral genetic markers among populations of the Baltic cisco complex has evolved (and is maintained) by random genetic drift in isolated populations. However, earlier studies on the Swedish populations combining mitochondrial DNA and microsatellite data indicate that also post-glacial immigration from separate glacial refugia has shaped the present genetic population structure. The low neutral differentiation of the German sympatric pairs in contrast to the Swedish pair suggests that recent anthropogenic effects on the lakes in Germany may put the endemic spring-spawners at risk to extinction., (© 2021. The Author(s).)

Background and Aim: Andrographis paniculata and Eleutherococcus senticosus preparations and their fixed combination, called Kan Jang®, are traditionally used for relieving symptoms of upper-respiratory tract infections (URTIs). This study aimed to assess the efficacy of early intervention with Kan Jang® on the relief and duration of inflammatory symptoms during the acute phase of the disease., Experimental Procedure: A total of 179 patients with URTI symptoms received six Kan Jang® (daily dose of andrographolides: 60 mg) or placebo capsules a day for five consecutive days in this randomized, quadruple-blinded, placebo-controlled, two-parallel-group phase II study. The primary efficacy outcomes were the decrease in the acute-phase duration and the mean URTI symptoms score (sore throat, runny nose, nasal congestion, hoarseness, cough, headache, and fatigue)., Results: Early intervention with Kan Jang® significantly increased the recovery rate and reduced the number of sick leave days by >21% (0.64/day) relative to that observed in the placebo group (2.38 vs. 3.02 days, p = 0.0053). Kan Jang® significantly alleviated all URTI symptoms starting from the second day of treatment. A superior anti-inflammatory effect of Kan Jang® to that of placebo was also observed on the white blood cell count (p = 0.007) and erythrocyte sedimentation rate (p = 0.0258). Treatment with Kan Jang® was tolerated well., Conclusion: This study demonstrates that early intervention with Kan Jang® capsules reduces the recovery duration of patients by 21% and significantly relieves the severity of typical URTI symptoms., Competing Interests: Georg Wikman declares a conflict of interest because he is the president of SHI Research and Development AB. Staffan Palm, Panafarma Medical Consult AB, is an independent agreement contractor with the Swedish Herbal Institute. Alexander Panossian is self-employed at the research and development company Phytomed AB. He was the former Head of Research & Development at the Swedish Herbal Institute, Gothenburg, Sweden. He has no shares or financial interest in any pharmaceutical company. The other authors declare no conflicts of interest. The funder had no role in the design of the study; collection, analyses, or interpretation of data; writing of the manuscript, or decision to publish the results., (© 2021 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.)

The Advanced Topographic Laser Altimeter System (ATLAS) aboard the Ice, Cloud, and land Elevation Satellite-2 (ICESat-2) has been making very high resolution measurements of the Earth's surface elevation since October 2018. ATLAS uses photomultiplier tubes (PMTs) as detectors in photon counting mode, so that a single photon reflected back to the receiver triggers a detection within the ICESat-2 data acquisition system. However, one characteristic of ICESat-2 detected photons is the possible presence of afterpulses, defined as small amplitude pulses occurring after the primary signal pulse due to photon arrival. The disadvantage of these afterpulses is that they often confound the accurate measurements of low level signals following a large amplitude of signal and can degrade energy resolution and cause errors in pulse counting applications. This paper discusses and summarizes the after-pulsing effects exhibited by the ATLAS PMTs based on on-orbit measurements over different seasons and geographic regions. The potential impacts of these after-pulsing effects on altimetry and ocean subsurface retrievals are discussed., Competing Interests: The authors declare no conflicts of interest relevant to this study., (© 2021. The Authors. Earth and Space Science published by Wiley Periodicals LLC on behalf of American Geophysical Union.)

In the field of oncology, a close integration of cancer research and patient care is indispensable. Although an exchange of data between health care providers and other institutions such as cancer registries has already been established in Germany, it does not take advantage of internationally coordinated health data standards. Translational cancer research would also benefit from such standards in the context of secondary data use. This paper employs use cases from the German Cancer Consortium (DKTK) to show how this gap can be closed using a harmonised FHIR-based data model, and how to apply it to an existing federated data platform.

Intra-species genetic homogenization arising from anthropogenic impacts is a major threat to biodiversity. However, few taxa have sufficient historical material to systematically quantify long-term genetic changes. Using archival DNA collected over approximately 100 years, we assessed spatio-temporal genetic change in Atlantic salmon populations across the Baltic Sea, an area heavily impacted by hydropower exploitation and associated with large-scale mitigation stocking. Analysis was carried out by screening 82 SNPs in 1680 individuals from 13 Swedish rivers. We found an overall decrease in genetic divergence and diminished isolation by distance among populations, strongly indicating genetic homogenization over the past century. We further observed an increase in genetic diversity within populations consistent with increased gene flow. The temporal genetic change was lower in larger wild populations than in smaller wild and hatchery-reared ones, indicating that larger populations have been able to support a high number of native spawners in relation to immigrants. Our results demonstrate that stocking practices of salmon in the Baltic Sea have led to the homogenization of populations over the last century, potentially compromising their ability to adapt to environmental change. Stocking of reared fish is common worldwide, and our study is a cautionary example of the potentially long-term negative effects of such activities.

The relative role of genetic adaptation and phenotypic plasticity is of fundamental importance in evolutionary ecology [M. J. West-Eberhard, Proc. Natl. Acad. Sci. U.S.A. 102 (suppl. 1), 6543-6549 (2005)]. European eels have a complex life cycle, including transitions between life stages across ecological conditions in the Sargasso Sea, where spawning occurs, and those in brackish and freshwater bodies from northern Europe to northern Africa. Whether continental eel populations consist of locally adapted and genetically distinct populations or comprise a single panmictic population has received conflicting support. Here we use whole-genome sequencing and show that European eels belong to one panmictic population. A complete lack of geographical genetic differentiation is demonstrated. We postulate that this is possible because the most critical life stages-spawning and embryonic development-take place under near-identical conditions in the Sargasso Sea. We further show that within-generation selection, which has recently been proposed as a mechanism for genetic adaptation in eels, can only marginally change allele frequencies between cohorts of eels from different geographic regions. Our results strongly indicate plasticity as the predominant mechanism for how eels respond to diverse environmental conditions during postlarval stages, ultimately solving a long-standing question for a classically enigmatic species., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Introduction: Antibodies labeled with alpha-emitter astatine-211 have previously shown effective in intraperitoneal (i.p.) treatments of ovarian cancer. In the present work we explore the use of investigational farletuzumab, aimed at the folate receptor alpha. The aim was to evaluate the biodistribution and therapeutic effect of 211 At-farletuzumab in in-vitro and in-vivo experiments and, using models for radiation dosimetry, to translate the findings to expected clinical result. The activity concentration used for therapy in mice (170 kBq/mL) was chosen to be in agreement with an activity concentration that is anticipated to be clinically relevant in patients (200 MBq/L)., Methods: For biodistribution, using intravenous injections and mice carrying subcutaneous (s.c.) tumors, the animals were administered either 211 At-farletuzumab (n = 16); or with a combination of 125 I-farletuzumab and 211 At-MX35 (n = 12). At 1, 3, 10 and 22 h, mice were euthanized and s.c.-tumors and organs weighted and measured for radioactivity. To evaluate therapeutic efficacy, mice were inoculated i.p. with 2 × 10 6 NIH:OVCAR-3 cells. Twelve days later, the treatments were initiated by i.p.-administration. Specific treatment was given by 211 At-labeled farletuzumab (group A; n = 22, 170 kBq/mL) which is specific for OVCAR-3 cells. Control treatments were given by either 211 At-labeled rituximab which is unspecific for OVCAR-3 (group B; n = 22, 170 kBq/mL), non-radiolabeled farletuzumab (group C; n = 11) or PBS only (group D; n = 8)., Results: The biodistribution of 211 At-farletuzumab was similar to that with 125 I as radiolabel, and also to that of 211 At-labeled MX35 antibody. The tumor-free fraction (TFF) of the three control groups were all low (PBS 12%, unlabeled specific farletuzumab 9% and unspecific 211 At-rituximab 14%). TFF following treatment with 211 At-farletuzumab was 91%., Conclusion: The current investigation of intraperitoneal therapy with 211 At-farletuzumab, delivered at clinically relevant 211 At-mAb radioactivity concentrations and specific activities, showed a 6 to 10-fold increase (treated versus controls) in antitumor efficacy. This observation warrants further clinical testing., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Stig Palm, Tom Bäck, Lars Jacobsson, Sture Lindegren and Per Albertsson declare ownership in the Swedish commercial company Aprit Biotech AB. The data in this manuscript was derived prior to the declared ownership., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite the consensus around the clinical potential of the α-emitting radionuclide astatine-211 ( 211 At), there are only a limited number of research facilities that work with this nuclide. There are three main reasons for this: (1) Scarce availability of the nuclide. Despite a relatively large number of globally existing cyclotrons capable of producing 211 At, few cyclotron facilities produce the nuclide on a regular basis. (2) Lack of a chemical infrastructure, that is, isolation of 211 At from irradiated targets and the subsequent synthesis of an astatinated product. At present, the research groups that work with 211 At depend on custom systems for recovering 211 At from the irradiated targets. Setting up and implementing such custom units require long lead times to provide a proper working system. (3) The chemistry of 211 At. Compared with radiometals there are no well-established and generally accepted synthesis methods for forming sufficiently stable bonds between 211 At and the tumor-specific vector to allow for systemic applications. Herein we present an overview of the infrastructure of producing 211 At radiopharmaceuticals, from target to radiolabeled product including chemical strategies to overcome hurdles for advancement into clinical trials with 211 At.

Determining the origin of individuals in mixed population samples is key in many ecological, conservation and management contexts. Genetic data can be analyzed using genetic stock identification (GSI), where the origin of single individuals is determined using Individual Assignment (IA) and population proportions are estimated with Mixed Stock Analysis (MSA). In such analyses, allele frequencies in a reference baseline are required. Unknown individuals or mixture proportions are assigned to source populations based on the likelihood that their multilocus genotypes occur in a particular baseline sample. Representative sampling of populations included in a baseline is important when designing and performing GSI. Here, we investigate the effects of family sampling on GSI, using both simulated and empirical genotypes for Atlantic salmon (Salmo salar). We show that nonrepresentative sampling leading to inclusion of close relatives in a reference baseline may introduce bias in estimated proportions of contributing populations in a mixed sample, and increases the amount of incorrectly assigned individual fish. Simulated data further show that the induced bias increases with increasing family structure, but that it can be partly mitigated by increased baseline population sample sizes. Results from standard accuracy tests of GSI (using only a reference baseline and/or self-assignment) gave a false and elevated indication of the baseline power and accuracy to identify stock proportions and individuals. These findings suggest that family structure in baseline population samples should be quantified and its consequences evaluated, before carrying out GSI., (© 2019 The Authors. Molecular Ecology Resources published by John Wiley & Sons Ltd.)

Purpose: Targeted alpha therapy (TAT) is a promising treatment for micrometastatic and minimal residual cancer. We evaluated systemic α-radioimmunotherapy (α-RIT) of metastatic castration-resistant prostate cancer (mCRPC) using the α-particle emitter 211 At-labeled to the anti-PSCA A11 minibody. A11 is specific for prostate stem cell antigen (PSCA), a cell surface glycoprotein which is overexpressed in more than 90% of both localized prostate cancer and bone metastases., Methods: PC3-PSCA cells were implanted subcutaneously (s.c.) and intratibially (i.t) in nude mice. Efficacy of α-RIT (two fractions-14-day interval) was studied on s.c. macrotumors (0, 1.5 and 1.9 MBq) and on i.t. microtumors (~100-200 μm; 0, 0.8 or 1.5 MBq) by tumor-volume measurements. The injected activities for therapies were estimated from separate biodistribution and myelotoxicity studies., Results: Tumor targeting of 211 At-A11 was efficient and the effect on s.c. macrotumors was strong and dose-dependent. At 6 weeks, the mean tumor volumes for the treated groups, compared with controls, were reduced by approximately 85%. The separate myelotoxicity study following one single fraction showed reduced white blood cells (WBC) for all treated groups on day 6 after treatment. For the 0.8 and 1.5 MBq, the WBC reductions were transient and followed by recovery at day 13. For 2.4 MBq, a clear toxicity was observed and the mice were sacrificed on day 7. In the long-term follow-up of the 0.8 and 1.5 MBq-groups, blood counts on day 252 were normal and no signs of radiotoxicity observed. Efficacy on i.t. microtumors was evaluated in two experiments. In experiment 1, the tumor-free fraction (TFF) was 95% for both treated groups and significantly different (p < 0.05) from the controls at a TFF of 66%). In experiment 2, the difference in TFF was smaller, 32% for the treated group versus 20% for the controls. However, the difference in microtumor volume in experiment 2 was highly significant, 0.010 ± 0.003 mm 3 versus 3.79 ± 1.24 mm 3 (treated versus controls, respectively), i.e., a 99.7% reduction (p < 0.001). The different outcome in experiment 1 and 2 is most likely due to differences in microtumor sizes at therapy, or higher tumor-take in experiment 2 (where more cells were implanted)., Conclusion: Evaluating fractionated α-RIT with 211 At-labeled anti-PSCA A11 minibody, we found clear growth inhibition on both macrotumors and intratibial microtumors. For mice treated with multiple fractions, we also observed radiotoxicity manifested by progressive loss in body weight at 30 to 90 days after treatment. Our findings are conceptually promising for a systemic TAT of mCRPC and warrant further investigations of 211 At-labeled PSCA-directed vectors. Such studies should include methods to improve the therapeutic window, e.g., by implementing a pretargeted regimen of α-RIT or by altering the size of the targeting vector.

Using 10 polymorphic microsatellites and 1251 individual samples (some dating back to the early 1980s), genetic structure and effective population size in all native and introduced Swedish populations of the European wels catfish or Silurus glanis were studied. Levels of genetic variability and phylogeographic relationships were compared with data from a previous study of populations in other parts of Europe. The genetically distinct Swedish populations displayed comparably low levels of genetic variability and according to one-sample estimates based on linkage disequilibrium and sib ship-reconstruction, current local effective population sizes were lower than minimum levels recommended for short-term genetic conservation. In line with a previous suggestion of postglacial colonisation from a single refugium, all Swedish populations were assembled on a common branch in a star-shaped dendrogram together with other European populations. Two distinct subpopulations were detected in upper and lower habitats of River Emån, indicating that even minor dispersal barriers may restrict gene flow for wels in running waters. Genetic assignment of specimens encountered in the brackish Baltic Sea and in lakes where the species does not occur naturally indicated presence of long-distance sea dispersal and confirmed unauthorised translocations, respectively., (© 2019 The Fisheries Society of the British Isles.)

Targeted alpha therapy of disseminated cancer is an emerging technique where astatine-211 is one of the most promising candidate nuclides. Although astatine has been known for over 70 years, its chemistry is still largely unexplored, mainly due to the lack of stable or long-lived isotopes. However, substantial amounts of astatine-211 can be produced in cyclotrons by the bombardment of natural bismuth. The astatine can be recovered from the resulting irradiated target material through either wet extraction or dry-distillation. Chloroform has become an important intermediate solvent for the recovery of astatine after production, especially following dry distillation. In this work, the radiochemistry of astatine in chloroform was investigated using evaporation, solvent extraction, chromatographic methods and molecular modeling. The extraction of astatine in chloroform led to the formation of multiple astatine species, allowing for evaporation of the solvent to dryness without any loss of activity. Radiolysis products of chloroform were shown to play an important role in the speciation of astatine forming both reactive and kinetically stable compounds. It was hypothesized that reactions with chlorine, as well as trichloromethyl hydroperoxide, forming polar astatine compounds are important reactions under the current experimental conditions.

During the past 50 years, Fennoscandian populations of spring-spawning Baltic cisco ( Coregonus albula ), sympatric to common autumn-spawners, have declined or disappeared; for example, three out of four known spring-spawning populations in Sweden are regarded as extinct. Over the same period, the climate has changed and populations have been subject to other anthropogenic stressors. We compared historic (1960s) and recent (1990-2000s) morphological data from the still-existent sympatric cisco populations in Lake Fegen, Sweden. Phenotypic changes were found for spring-spawners making them more similar to the sympatric autumn-spawners that had remained virtually unchanged. Based on results for other salmoniform fishes, a phenotypically plastic response to increased temperature during early development appears unlikely. The recent material was also analyzed with microsatellite markers; long-term effective population size in spring-spawners was estimated to be about 20 times lower than autumn-spawners, with signs of long-term gene flow in both directions and a recent genetic bottleneck in spring-spawners. We suggest the change toward a less distinct phenotype in spring-spawners to reflect a recent increase in gene flow from autumn-spawners. Time since divergence was estimated to only c . 1,900 years (95% CI: 400-5,900), but still the Fegen populations represent the most morphologically and genetically distinct sympatric populations studied. Consequently, we hypothesize that less distinct population pairs can be even younger and that spring-spawning may have repeatedly evolved and disappeared in several lakes since the end of the last glaciation, concurrent with changed environmental conditions., Competing Interests: None declared., (© 2019 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

The use of nanobodies (Nbs) as vehicles in targeted alpha therapy (TAT) has gained great interest because of their excellent properties. They combine high in vivo affinity and specificity of binding with fast kinetics. This research investigates a novel targeted therapy that combines the α-particle emitter astatine-211 ( 211 At) and the anti-HER2 Nb 2Rs15d to selectively target HER2+ cancer cells. Two distinctive radiochemical methodologies are investigated using three different coupling reagents. The first method uses the coupling reagents, N -succinimidyl 4-(1,2-bis- tert -butoxycarbonyl)guanidinomethyl-3-(trimethylstannyl)benzoate (Boc 2 -SGMTB) and N -succinimidyl-3-(trimethylstannyl)benzoate ( m -MeATE), which are both directed to amino groups on the Nb, resulting in random conjugation. The second method aims at obtaining a homogeneous tracer population, via a site-specific conjugation of the N -[2-(maleimido)ethyl]-3-(trimethylstannyl)benzamide (MSB) reagent onto the carboxyl-terminal cysteine of the Nb. The resulting radioconjugates are evaluated in vitro and in vivo. 2Rs15d is labeled with 211 At using Boc 2 -SGMTB, m -MeATE, and MSB. After astatination and purification, the binding specificity of the radioconjugates is validated on HER2+ cells, followed by an in vivo biodistribution assessment in SKOV-3 xenografted mice. α-camera imaging is performed to determine uptake and activity distribution in kidneys/tumors. 2Rs15d astatination resulted in a high radiochemical purity >95% for all radioconjugates. The biodistribution studies of all radioconjugates revealed comparable tumor uptake (higher than 8% ID/g at 1 h). [ 211 At]SAGMB-2Rs15d showed minor uptake in normal tissues. Only in the kidneys, a higher uptake was measured after 1 h, but decreased rapidly after 3 h. Astatinated Nbs consisting of m -MeATE or MSB reagents revealed elevated uptake in lungs and stomach, indicating the presence of released 211 At. α-Camera imaging of tumors revealed a homogeneous activity distribution. The radioactivity in the kidneys was initially concentrated in the renal cortex, while after 3 h most radioactivity was measured in the medulla, confirming the fast washout into urine. Changing the reagents for Nb astatination resulted in different in vivo biodistribution profiles, while keeping the targeting moiety identical. Boc 2 -SGMTB is the preferred reagent for Nb astatination because of its high tumor uptake, its low background signals, and its fast renal excretion. We envision [ 211 At]SAGMB-2Rs15d to be a promising therapeutic agent for TAT and aim toward efficacy evaluation.

Eliminating microscopic residual disease with α-particle radiation is theoretically appealing. After extensive preclinical work with α-particle-emitting 211 At, we performed a phase I trial with intraperitoneal α-particle therapy in epithelial ovarian cancer using 211 At conjugated to MX35, the antigen-binding fragments-F(ab') 2 -of a mouse monoclonal antibody. We now present clinical outcome data and toxicity in a long-term follow-up with individual absorbed dose estimations. Methods: Twelve patients with relapsed epithelial ovarian cancer, achieving a second complete or nearly complete response with chemotherapy, received intraperitoneal treatment with escalating (20-215 MBq/L) activity concentrations of 211 At-MX35 F(ab') 2. Results: The activity concentration was escalated to 215 MBq/L without any dose-limiting toxicities. Most toxicities were low-grade and likely related to the treatment procedure, not clearly linked to the α-particle irradiation, with no observed hematologic toxicity. One grade 3 fatigue and 1 grade 4 intestinal perforation during catheter implantation were observed. Four patients had a survival of more than 6 y, one of whom did not relapse. At progression, chemotherapy was given without signs of reduced tolerability. Overall median survival was 35 mo, with a 1-, 2-, 5-, and 10-y survival of 100%, 83%, 50%, and 25%, respectively. Calculations of the absorbed doses showed that a lower specific activity is associated with a lower single-cell dose, whereas a high specific activity may result in a lower central dose in microtumors. Individual differences in absorbed dose to possible microtumors were due to variations in administered activity and the specific activity. Conclusion : No apparent signs of radiation-induced toxicity or decreased tolerance to relapse therapy were observed. The dosimetric calculations show that further optimization is advisable to increase the efficacy and reduce possible long-term toxicity., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease., Design: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry., Results: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10 -10 and 0.002 (OR allelic =1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33)., Conclusion: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

To improve the accuracy of chemoradiation therapy in anal cancer patients PET/CT is frequently used in the planning of radiation therapy. A systematic review was performed to assess impact on survival, quality of life, symptom score, change in target definition and treatment intention. Systematic literature searches were conducted in Medline, EMBASE, the Cochrane Library, and Centre for Reviews and Dissemination. Ten cross-sectional studies were identified. No data were available on survival or quality of life. The summary estimate of the proportion of patients in which PET/CT had an impact on the target definition, was 23% (95% CI 16;33). The corresponding summary estimate of a change in treatment intent from curative to palliative was 3% (95% CI 2;6). Almost one in four patients had a change in target definition, which supports the use of PET/CT in radiation therapy planning, but the consequence regarding survival and quality of life is still uncertain., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Intraperitoneally administered radiolabeled monoclonal antibodies (mAbs) have been tested in several clinical trials, often with promising results, but have never proven curative. Methods: We have previously presented simulations of clinically relevant amounts of intraperitoneal 90 Y-mAbs for treatment of minimal disease and shown that such treatments are unlikely to eradicate microtumors. Our previous model simulated the kinetics of intraperitoneally infused radiolabeled mAbs in humans and showed the benefit of instead using α-emitters such as 211 At. In the current work, we introduce penetration of mAbs into microtumors with radii of up to 400 μm. Calculations were performed using dynamic simulation software. To determine the radiation dose distribution in nonvascularized microtumors of various sizes after intraperitoneal 211 At-radioimmunotherapy, we used an in-house-developed Monte Carlo program for microdosimetry. Our aim was to find methods that optimize the therapy for as wide a tumor size range as possible. Results: Our results show that high-specific-activity radiolabeled mAbs that are bound to a tumor surface will penetrate slowly compared with the half-lives of 211 At and shorter-lived radionuclides. The inner-core cells of tumors with radii exceeding 100 μm may therefore not be sufficiently irradiated. For lower specific activities, the penetration rate and dose distribution will be more favorable for such tumors, but the dose to smaller microtumors and single cells will be low. Conclusion: Our calculations show that the addition of a boost with unlabeled mAb 1-5 h after therapy results in sufficient absorbed doses both to single cells and throughout microtumors up to approximately 300 μm in radius. This finding should also hold for other high-affinity mAbs and short-lived α-emitters., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The aim of this study was to compare the therapeutic efficacy of two different activity levels of the 213 Bi-labeled monoclonal antibody MX35 in an ovarian cancer model. Sixty female BALB/c (nu/nu) mice were inoculated intraperitoneally with human ovarian cancer cells (OVCAR-3). Two weeks later, 40 mice were injected intraperitoneal (i.p.) with 1 ml of 213 Bi-MX35, 3 MBq/mL (n = 20), or 9 MBq/mL (n = 20). An additional 20 mice received unlabeled MX35. Incidence of tumors and ascites was investigated 8 weeks after therapy. Body weight and white blood cell counts were monitored after treatment for possible signs of toxicity., Results: The tumor-free fraction of the animals treated with 3 MBq/mL of 213 Bi-MX35 was 0.55, whereas that of animals treated with 9 MBq/mL of 213 Bi-MX35 was 0.78. The control group treated with unlabeled MX35 had a tumor-free fraction of 0.15. No significant reduction in white blood cell counts or weight loss was observed., Conclusions: Tumor growth after i.p. treatment with 213 Bi-MX35 was significantly reduced compared to treatment with unlabeled MX35. Treatment with 9 MBq/mL of 213 Bi-MX35 resulted in higher tumor-free fraction compared with 3 MBq/mL of 213 Bi-MX35, but this difference was not statistically significant. No signs of toxicity were observed in the treated animals.

The bone marrow (BM) microenvironment provides critical physical cues for hematopoietic stem and progenitor cell (HSPC) maintenance and fate decision mediated by cell-matrix interactions. However, the mechanisms underlying matrix communication and signal transduction are less well understood. Contrary, stem cell culture is mainly facilitated in suspension cultures. Here, we used bone marrow-mimetic decellularized extracellular matrix (ECM) scaffolds derived from mesenchymal stromal cells (MSCs) to study HSPC-ECM interaction. Seeding freshly isolated HSPCs adherent (AT) and non-adherent (SN) cells were found. We detected enhanced expansion and active migration of AT-cells mediated by ECM incorporated stromal derived factor one. Probing cell mechanics, AT-cells displayed naïve cell deformation compared to SN-cells indicating physical recognition of ECM material properties by focal adhesion. Integrin αIIb (CD41), αV (CD51) and β3 (CD61) were found to be induced. Signaling focal contacts via ITGβ3 were identified to facilitate cell adhesion, migration and mediate ECM-physical cues to modulate HSPC function.

The goal of this study was to investigate whether targeted α-therapy can be used to successfully treat macrotumors, in addition to its established role for treating micrometastatic and minimal disease. We used an intravenous fractionated regimen of α-radioimmunotherapy in a subcutaneous tumor model in mice. We aimed to evaluate the absorbed dose levels required for tumor eradication and growth monitoring, as well as to evaluate long-term survival after treatment. Methods: Mice bearing subcutaneous tumors (50 mm 3 , NIH:OVCAR-3) were injected repeatedly (1-3 intravenous injections 7-10 d apart, allowing bone marrow recovery) with 211 At-MX35-F(ab') 2 at different activities (close to acute myelotoxicity). Mean absorbed doses to tumors and organs were estimated from biodistribution data and summed for the fractions. Tumor growth was monitored for 100 d and survival for 1 y after treatment. Toxicity analysis included body weight, white blood cell count, and hematocrit. Results: Effects on tumor growth after fractionated α-radioimmunotherapy with 211 At-MX35-F(ab') 2 was strong and dose-dependent. Complete remission (tumor-free fraction, 100%) was found for tumor doses of 12.4 and 16.4 Gy. The administered activities were high, and long-term toxicity effects (≤60 wk) were clear. Above 1 MBq, the median survival decreased linearly with injected activity, from 44 to 11 wk. Toxicity was also seen by reduced body weight. White blood cell count analysis after α-radioimmunotherapy indicated bone marrow recovery for the low-activity groups, whereas for high-activity groups the reduction was close to acute myelotoxicity. A decrease in hematocrit was seen at a late interval (34-59 wk after therapy). The main external indication of poor health was dehydration. Conclusion: Having observed complete eradication of solid tumor xenografts, we conclude that targeted α-therapy regimens may stretch beyond the realm of micrometastatic disease and be eradicative also for macrotumors. Our observations indicate that at least 10 Gy are required. This agrees well with the calculated tumor control probability. Considering a relative biological effectiveness of 5, this dose level seems reasonable. However, complete remission was achieved first at activity levels close to lethal and was accompanied by biologic effects that reduced long-term survival., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Unlabelled: A biokinetic model was constructed to evaluate and optimize various intraperitoneal radioimmunotherapies for micrometastatic tumors. The model was used to calculate the absorbed dose to both anticipated microtumors and critical healthy organs and demonstrated how intraperitoneal targeted radiotherapy can be optimized to maximize the ratio between them., Methods: The various transport mechanisms responsible for the biokinetics of intraperitoneally infused radiolabeled monoclonal antibodies (mAbs) were modeled using a software package. Data from the literature were complemented by pharmacokinetic data derived from our clinical phase I study to set parameter values. Results using the β-emitters (188)Re, (177)Lu, and (90)Y and the α-emitters (211)At, (213)Bi, and (212)Pb were compared. The effects of improving the specific activity, prolonging residence time by introducing an osmotic agent, and varying the activity concentration of the infused agent were investigated., Results: According to the model, a 1.7-L infused saline volume will decrease by 0.3 mL/min because of lymphatic drainage and by 0.7 mL/min because of the transcapillary convective component. The addition of an osmotic agent serves to lower the radiation dose to the bone marrow. Clinically relevant radioactivity concentrations of α- and β-emitters bound to mAbs were compared. For α-emitters, microtumors receive high doses (>20 Gy or 100 Sv [relative biological effect = 5]). Since most of the tumor dose originates from cell-bound radionuclides, an increase in the specific activity would further increase the tumor dose without affecting the dose to peritoneal fluid or bone marrow. For β-emitters, tumors will receive almost entirely nonspecific irradiation. The dose from cell-bound radiolabeled mAbs will be negligible by comparison. For the long-lived (90)Y, tumor doses are expected to be low at the maximum activity concentration delivered in clinical studies., Conclusion: According to the presented model, α-emitters are needed to achieve radiation doses high enough to eradicate microscopic tumors., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Effective treatment of metastasis is a great challenge in the treatment of different types of cancers. Targeted alpha therapy utilizes the short tissue range (50-100 μm) of α particles, making the method suitable for treatment of disseminated occult cancers in the form of microtumors or even single cancer cells. A promising radioactive nuclide for this type of therapy is astatine-211. Astatine-211 attached to tumor-specific antibodies as carrier molecules is a system currently under investigation for use in targeted alpha therapy. In the common radiolabeling procedure, astatine is coupled to the antibody arbitrarily on lysine residues. By instead coupling astatine to disulfide bridges in the antibody structure, the immunoreactivity of the antibody conjugates could possibly be increased. Here, the disulfide-based conjugation was performed using a new coupling reagent, maleimidoethyl 3-(trimethylstannyl)benzamide (MSB), and evaluated for chemical stability in vitro. The immunoconjugates were subsequently astatinated, resulting in both high radiochemical yield and high specific activity. The MSB-conjugate was shown to be stable with a long shelf life prior to the astatination. In a comparison of the in vivo distribution of the new immunoconjugate with other tin-based immunoconjugates in tumor-bearing mice, the MSB conjugation method was found to be a viable option for successful astatine labeling of different monoclonal antibodies.

Purpose: Ovarian cancer is often diagnosed at an advanced stage with dissemination in the peritoneal cavity. Most patients achieve clinical remission after surgery and chemotherapy, but approximately 70% eventually experience recurrence, usually in the peritoneal cavity. To prevent recurrence, intraperitoneal (i.p.) targeted α therapy has been proposed as an adjuvant treatment for minimal residual disease after successful primary treatment. In the present study, we calculated absorbed and relative biological effect (RBE)-weighted (equivalent) doses in relevant normal tissues and estimated the effective dose associated with i.p. administration of (211)At-MX35 F(ab')2., Methods and Materials: Patients in clinical remission after salvage chemotherapy for peritoneal recurrence of ovarian cancer underwent i.p. infusion of (211)At-MX35 F(ab')2. Potassium perchlorate was given to block unwanted accumulation of (211)At in thyroid and other NIS-containing tissues. Mean absorbed doses to normal tissues were calculated from clinical data, including blood and i.p. fluid samples, urine, γ-camera images, and single-photon emission computed tomography/computed tomography images. Extrapolation of preclinical biodistribution data combined with clinical blood activity data allowed us to estimate absorbed doses in additional tissues. The equivalent dose was calculated using an RBE of 5 and the effective dose using the recommended weight factor of 20. All doses were normalized to the initial activity concentration of the infused therapy solution., Results: The urinary bladder, thyroid, and kidneys (1.9, 1.8, and 1.7 mGy per MBq/L) received the 3 highest estimated absorbed doses. When the tissue-weighting factors were applied, the largest contributors to the effective dose were the lungs, stomach, and urinary bladder. Using 100 MBq/L, organ equivalent doses were less than 10% of the estimated tolerance dose., Conclusion: Intraperitoneal (211)At-MX35 F(ab')2 treatment is potentially a well-tolerated therapy for locally confined microscopic ovarian cancer. Absorbed doses to normal organs are low, but because the effective dose potentially corresponds to a risk of treatment-induced carcinogenesis, optimization may still be valuable., (Copyright © 2015 Elsevier Inc. All rights reserved.)

To facilitate multicentre clinical studies on targeted alpha therapy, it is necessary to develop an automated, on-site procedure for conjugating rare, short-lived, alpha-emitting radionuclides to biomolecules. Astatine-211 is one of the few alpha-emitting nuclides with appropriate chemical and physical properties for use in targeted therapies for cancer. Due to the very short range of the emitted α-particles, this therapy is particularly suited to treating occult, disseminated cancers. Astatine is not intrinsically tumour-specific; therefore, it requires an appropriate tumour-specific targeting vector, which can guide the radiation to the cancer cells. Consequently, an appropriate method is required for coupling the nuclide to the vector. To increase the availability of astatine-211 radiopharmaceuticals for targeted alpha therapy, their production should be automated. Here, we present a method that combines dry distillation of astatine-211 and a synthesis module for producing radiopharmaceuticals into a process platform. This platform will standardize production of astatinated radiopharmaceuticals, and hence, it will facilitate large clinical studies focused on this promising, but chemically challenging, alpha-emitting radionuclide. In this work, we describe the process platform, and we demonstrate the production of both astaine-211, for preclinical use, and astatine-211 labelled antibodies.

Many protein-misfolding diseases are caused by proteins carrying prion-like domains. These proteins show sequence similarity to yeast prion proteins, which can interconvert between an intrinsically disordered and an aggregated prion state. The natural presence of prions in yeast has provided important insight into disease mechanisms and cellular proteostasis. However, little is known about prions in other organisms, and it is not yet clear whether the findings in yeast can be generalized. Using bioinformatics tools, we show that Dictyostelium discoideum has the highest content of prion-like proteins of all organisms investigated to date, suggesting that its proteome has a high overall aggregation propensity. To study mechanisms regulating these proteins, we analyze the behavior of several well-characterized prion-like proteins, such as an expanded version of human huntingtin exon 1 (Q103) and the prion domain of the yeast prion protein Sup35 (NM), in D. discoideum. We find that these proteins remain soluble and are innocuous to D. discoideum, in contrast to other organisms, where they form cytotoxic cytosolic aggregates. However, when exposed to conditions that compromise molecular chaperones, these proteins aggregate and become cytotoxic. We show that the disaggregase Hsp101, a molecular chaperone of the Hsp100 family, dissolves heat-induced aggregates and promotes thermotolerance. Furthermore, prion-like proteins accumulate in the nucleus, where they are targeted by the ubiquitin-proteasome system. Our data suggest that D. discoideum has undergone specific adaptations that increase the proteostatic capacity of this organism and allow for an efficient regulation of its prion-like proteome.

The aim of this preclinical study was to evaluate the characteristics of the monoclonal antibody Rebmab200, which is a humanized version of the ovarian-specific murine antibody MX35. This investigation contributes to the foundation for future clinical α-radioimmunotherapy of minimal residual ovarian cancer with 211At-Rebmab200. Here, the biodistribution of 211At-Rebmab200 was evaluated, as was the utility of 99mTc-Rebmab200 for bioimaging. Rebmab200 was directly compared with its murine counterpart MX35 in terms of its in-vitro capacity for binding the immobilized NaPi2B epitope and live cells; we also assessed its biodistribution in nude mice carrying subcutaneous OVCAR-3 tumors. Tumor antigen and cell binding were similar between Rebmab200 and murine MX35, as was biodistribution, including normal tissue uptake and in-vivo tumor binding. We also demonstrated that 99mTc-Rebmab200 can be used for single-photon emission computed tomography of subcutaneous ovarian carcinomas in tumor-bearing mice. Taken together, our data support the further development of Rebmab200 for radioimmunotherapy and diagnostics.

Background: Endogenous opioids are implicated in the mechanism of action of alcohol and alcohol affects opioids in a number of brain areas, although little is known about alcohol's effects on opioids in the adolescent brain. One concern, in particular when studying young animals, is that alcohol intake models often are based on single housing that may result in alcohol effects confounded by the lack of social interactions. The aim of this study was to investigate short- and long-term alcohol effects on opioids and the influence of housing conditions on these effects., Methods: In the first part, opioid peptide levels were measured after one 24-hour session of single housing and 2-hour voluntary alcohol intake in adolescent and adult rats. In the second part, a model with a cage divider inserted during 2-hour drinking sessions was tested and the effects on opioids were examined after 6 weeks of adolescent voluntary intake in single-and pair-housed rats, respectively., Results: The effects of single housing were age specific and affected Met-enkephalin-Arg(6) Phe(7) (MEAP) in particular. In adolescent rats, it was difficult to distinguish between effects induced by alcohol and single housing, whereas alcohol-specific effects were seen in dynorphin B (DYNB), beta-endorphin (BEND), and MEAP levels in adults. Voluntary drinking affected several brain areas and the majority of alcohol-induced effects were not dependent on housing. However, alcohol effects on DYNB and BEND in the amygdala were dependent on housing. Housing alone affected MEAP in the cingulate cortex., Conclusions: Age-specific housing- and alcohol-induced effects on opioids were found. In addition, prolonged voluntary alcohol intake under different housing conditions produced several alcohol-induced effects independent of housing. However, housing-dependent effects were found in areas implicated in stress, emotionality, and alcohol use disorder. Housing condition and age may therefore affect the reasons and underlying mechanisms for drinking and could potentially affect the outcome of a number of end points in research on alcohol intake., (Copyright © 2014 The Authors Alcoholism: Clinical and Experimental Research published by Wiley Periodicals, Inc. on behalf of Research Society on Alcoholism.)

Presence of sympatric populations may reflect local diversification or secondary contact of already distinct forms. The Baltic cisco (Coregonus albula) normally spawns in late autumn, but in a few lakes in Northern Europe sympatric autumn and spring- or winter-spawners have been described. So far, the evolutionary relationships and taxonomic status of these main life history forms have remained largely unclear. With microsatellites and mtDNA sequences, we analyzed extant and extinct spring- and autumn-spawners from a total of 23 Swedish localities, including sympatric populations. Published sequences from Baltic ciscoes in Germany and Finland, and Coregonus sardinella from North America were also included together with novel mtDNA sequences from Siberian C. sardinella. A clear genetic structure within Sweden was found that included two population assemblages markedly differentiated at microsatellites and apparently fixed for mtDNA haplotypes from two distinct clades. All sympatric Swedish populations belonged to the same assemblage, suggesting parallel evolution of spring-spawning rather than secondary contact. The pattern observed further suggests that postglacial immigration to Northern Europe occurred from at least two different refugia. Previous results showing that mtDNA in Baltic cisco is paraphyletic with respect to North American C. sardinella were confirmed. However, the inclusion of Siberian C. sardinella revealed a more complicated pattern, as these novel haplotypes were found within one of the two main C. albula clades and were clearly distinct from those in North American C. sardinella. The evolutionary history of Northern Hemisphere ciscoes thus seems to be more complex than previously recognized.

Certain personality types and behavioral traits display high correlations to drug use and an increased level of dopamine in the reward system is a common denominator of all drugs of abuse. Dopamine response to drugs has been suggested to correlate with some of these personality types and to be a key factor influencing the predisposition to addiction. This study investigated if behavioral traits can be related to potassium- and amphetamine-induced dopamine response in the dorsal striatum, an area hypothesized to be involved in the shift from drug use to addiction. The open field and multivariate concentric square field™ tests were used to assess individual behavior in male Wistar rats. Chronoamperometric recordings were then made to study the potassium- and amphetamine-induced dopamine response in vivo. A classification based on risk-taking behavior in the open field was used for further comparisons. Risk-taking behavior was correlated between the behavioral tests and high risk takers displayed a more pronounced response to the dopamine uptake blocking effects of amphetamine. Behavioral parameters from both tests could also predict potassium- and amphetamine-induced dopamine responses showing a correlation between neurochemistry and behavior in risk-assessment and risk-taking parameters. In conclusion, the high risk-taking rats showed a more pronounced reduction of dopamine uptake in the dorsal striatum after amphetamine indicating that this area may contribute to the sensitivity of these animals to psychostimulants and proneness to addiction. Further, inherent dopamine activity was related to risk-assessment behavior, which may be of importance for decision-making and inhibitory control, key components in addiction.

Background: The prognostic significance of chest pain is well established in patients with coronary artery disease, but still ill defined in primary prevention. Therefore, the aim of our analysis was to assess the prognostic value of different forms of chest pain in a large cohort of primary care subjects under the conditions of contemporary modalities of care in primary prevention, including measurement of serum levels of the biomarker NT-pro-BNP., Design: We carried out a post-hoc analysis of the prospective DETECT cohort study., Methods: In a total of 5570 unselected subjects, free of coronary artery disease, within the 55,518 participants of the cross-sectional DETECT study, we assessed chest pain history by a comprehensive questionnaire and measured serum NT-pro-BNP levels. Three types of chest pain, which were any chest pain, exertional chest pain and classical angina, were defined. Major adverse cardiovascular events (MACEs = cardiovascular death, myocardial infarction, coronary revascularization procedures) were assessed during a 5-year follow-up period., Results: During follow-up, 109 subjects experienced a MACE. All types of reported chest pain were associated with an approximately three-fold increased risk for the occurrence of incident MACEs, even after adjusting for cardiovascular risk factors. Any form of reported chest pain had a similar predictive value for MACEs as a one-time measurement of NT-pro-BNP. However, adding a single measurement of NT-pro-BNP and the information on chest pain resulted in reclassification of approximately 40% of subjects, when compared with risk prediction based on established cardiovascular risk factors., Conclusions: In primary prevention, self-reported chest pain and a single measurement of NT-pro-BNP substantially improve cardiovascular risk prediction and allow for risk reclassification of approximately 40% of the subjects compared with assessing classical cardiovascular risk factors alone., (© The European Society of Cardiology 2012 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Adolescence is associated with high impulsivity and risk taking, making adolescent individuals more inclined to use drugs. Early drug use is correlated to increased risk for substance use disorders later in life but the neurobiological basis is unclear. The brain undergoes extensive development during adolescence and disturbances at this time are hypothesized to contribute to increased vulnerability. The transition from controlled to compulsive drug use and addiction involve long-lasting changes in neural networks including a shift from the nucleus accumbens, mediating acute reinforcing effects, to recruitment of the dorsal striatum and habit formation. This study aimed to test the hypothesis of increased dopamine release after a pharmacological challenge in adolescent rats. Potassium-evoked dopamine release and uptake was investigated using chronoamperometric dopamine recordings in combination with a challenge by amphetamine in early and late adolescent rats and in adult rats. In addition, the consequences of voluntary alcohol intake during adolescence on these effects were investigated. The data show a gradual increase of evoked dopamine release with age, supporting previous studies suggesting that the pool of releasable dopamine increases with age. In contrast, a gradual decrease in evoked release with age was seen in response to amphetamine, supporting a proportionally larger storage pool of dopamine in younger animals. Dopamine measures after voluntary alcohol intake resulted in lower release amplitudes in response to potassium-chloride, indicating that alcohol affects the releasable pool of dopamine and this may have implications for vulnerability to addiction and other psychiatric diagnoses involving dopamine in the dorsal striatum.

Causal links between early-life stress, genes and later psychiatric diagnoses are not possible to fully address in human studies. Animal models therefore provide an important complement in which conditions can be well controlled and are here used to study and distinguish effects of early-life stress and alcohol exposure. The objective of this study was to investigate the impact of rearing conditions on behaviour in young rats and if these changes could be followed over time and to examine interaction effects between early-life environment and adolescent alcohol drinking on behaviour and immunoreactive levels of the opioid peptides dynorphin B, met-enkephalin-Arg(6)Phe(7) and beta-endorphin. We employed a rodent model, maternal separation, to study the impact of rearing conditions on behaviour, voluntary alcohol consumption and alcohol-induced effects. The consequences of short, 15 min (MS 15), and long, 360 min (MS 360), maternal separation in combination with adolescent voluntary alcohol consumption on behaviour and peptides were examined. A difference in the development of risk taking behaviour was found between the MS15 and MS360 while the development of general activity was found to differ between intake groups. Beta-endorphin levels in the pituitary and the periaqueductal gray area was found to be higher in the MS15 than the MS360. Adolescent drinking resulted in higher dynorphin B levels in the hippocampus and higher met-enkephalin-Arg(6)Phe(7) levels in the amygdala. Amygdala and hippocampus are involved in addiction processes and changes in these brain areas after adolescent alcohol drinking may have consequences for cognitive function and drug consumption behaviour in adulthood. The study shows that individual behavioural profiling over time in combination with neurobiological investigations provides means for studies of causality between early-life stress, behaviour and vulnerability to psychiatric disorders.

Unlabelled: Targeted α-therapy (TAT) appears to be an ideal therapeutic technique for eliminating malignant circulating, minimal residual, or micrometastatic cells. These types of malignancies are typically infraclinical, complicating the evaluation of potential treatments. This study presents a method of ex vivo activity quantification with an α-camera device, allowing measurement of the activity taken up by tumor cells in biologic structures a few tens of microns., Methods: We examined micrometastases from a murine model of ovarian carcinoma after injection of a radioimmunoconjugate labeled with (211)At for TAT. At different time points, biologic samples were excised and cryosectioned. The activity level and the number of tumor cells were determined by combined information from 2 adjacent sections: one exposed to the α-camera and the other stained with hematoxylin and eosin. The time-activity curves for tumor cell clusters, comprising fewer than 10 cells, were derived for 2 different injected activities (6 and 1 MBq)., Results: High uptake and good retention of the radioimmunoconjugate were observed at the surface of tumor cells. Dosimetric calculations based on the measured time-integrated activity indicated that for an injected activity of 1 MBq, isolated tumor cells received at least 12 Gy. In larger micrometastases (≤ 100 μm in diameter), the activity uptake per cell was lower, possibly because of hindered penetration of radiolabeled antibodies; however, the mean absorbed dose delivered to tumor cells was above 30 Gy, due to cross-fire irradiation., Conclusion: Using the α-camera, we developed a method of ex vivo activity quantification at the cellular scale, which was further applied to characterize the behavior of a radiolabeled antibody administered in vivo against ovarian carcinoma. This study demonstrated a reliable measurement of activity. This method of activity quantification, based on experimentally measured data, is expected to improve the relevance of small-scale dosimetry studies and thus to accelerate the optimization of TAT.

The evolution of life-history traits is characterized by trade-offs between different selection pressures, as well as plasticity across environmental conditions. Yet, studies on local adaptation are often performed under artificial conditions, leaving two issues unexplored: (i) how consistent are laboratory inferred local adaptations under natural conditions and (ii) how much phenotypic variation is attributed to phenotypic plasticity and to adaptive evolution, respectively, across environmental conditions? We reared fish from six locally adapted (domesticated and wild) populations of anadromous brown trout (Salmo trutta) in one semi-natural and three natural streams and recorded a key life-history trait (body size at the end of first growth season). We found that population-specific reaction norms were close to parallel across different streams and Q ST was similar - and larger than F ST - within all streams, indicating a consistency of local adaptation in body size across natural environments. The amount of variation explained by population origin exceeded the variation across stream environments, indicating that genetic effects derived from adaptive processes have a stronger effect on phenotypic variation than plasticity induced by environmental conditions. These results suggest that plasticity does not "swamp" the phenotypic variation, and that selection may thus be efficient in generating genetic change.

Background: There is continuous debate to the use of biomarkers in the general practitioners office and to what degree the established biomarkers N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) and high-sensitive C-reactive protein (hs-CRP) might contribute to improved prediction of incident cardiovascular events., Objective: To evaluate the utility and 5-year predictive value of a single measurement of NT-pro-BNP and hs-CRP for incident cardiovascular events, and its added value beyond the contribution of conventional risk factors in primary care., Methods: Five year prospective longitudinal clinical epidemiological study in a nationwide sample of 4,775 primary care subjects (mean age 55.8 years, 62 % women) without coronary artery disease at baseline. Main outcome measures were incident major cardiovascular events and all-cause death., Results: During the 5 years of follow-up, 188 subjects (3.9 %) died or experienced a first major cardiovascular event. The addition of NT-pro-BNP, but not of hs-CRP to a prediction model with established cardiovascular risk factors improved the prediction of major cardiovascular events (increase in C statistic by 0.009; p = 0.008), and was associated with a significant improvement in net reclassification improvement (NRI = 23.6 %; p = 0.003)., Conclusion: In a primary care setting, one single measurement of NT-pro-BNP, but not of hs-CRP significantly improves the prediction of incident cardiovascular events.

Background: EuroSCORE and completeness of revascularization predicts long-term survival after multivessel PCI (MV-PCI). The SYNTAX-Score has also been proposed to predict clinical outcome. The prognostic impact of these scores to predict long-term survival after PCI has not yet been compared., Methods and Results: Long-term survival was assessed in 740 patients undergoing MV-PCI. We calculated EuroSCORE, SYNTAX-Score, STS-Score, the clinical SYNTAX-Score (CSS), and the "post-PCI residual SYNTAX-Score." Mean follow-up time was 4.5 ± 2.5 years. 341 patients (46%) were treated for ACS (STEMI N = 191; NSTEMI N = 150). 113 patients (15%) underwent PCI of left main coronary artery. The EuroSCORE was significantly lower for stable patients compared to patients with ACS (stable 4.1 ± 4.5, NSTEMI 13.9 ± 13.3, STEMI 18.1 ± 18.7, p < 0.001). The differences in the SYNTAX-Score were less obvious but even significant (stable 14.9 ± 8.6, NSTEMI 17.8 ± 9.9, STEMI 18.3 ± 9.0; p < 0.001). Patients in the highest tertiles of each risk score experienced a dramatically elevated mortality rate compared to the extremely low mortality rate in the lower tertiles (p log-rank <0.001). This comparison remained significant for the EuroSCORE and STS-Score but not for the SYNTAX-Score, when analysis was restricted to stable patients. The multivariate Cox-regression-analysis confirmed the logistic EuroSCORE, EuroSCORE II, and the STS-Score as independent predictors of long-term mortality, whereas the SYNTAX-Score (including residual form) and the CSS had no predictive value., Conclusion: The EuroSCORE and the STS-Score outperforms the SYNTAX-Score and the CSS in predicting long-term survival following MV-PCI. In addition, the residual SYNTAX-Score predicts long-term survival not independently., (© 2013, Wiley Periodicals, Inc.)

One major cause for discrepancies in results from animal experimental studies is the use of different animal strains and suppliers. We have previously reported that Wistar rats from five different suppliers display profound differences in ethanol intake and behavior. One of the neurobiological processes that could be underlying these differences is the endogenous opioid system, which has been implicated in the rewarding and reinforcing effects of alcohol. We therefore hypothesized that the differences between the supplier groups would also be evident in the endogenous opioid system. Radioimmunoassay was used to determine the levels of the opioid peptides Met-enkephalin-Arg(6)Phe(7) and dynorphin B in several brain areas of ethanol-drinking and ethanol naïve Wistar rats from five different suppliers. In the ethanol naïve animals, differences between the supplier groups were found in the pituitary gland, hypothalamus, frontal cortex, dorsal striatum and hippocampus. In the ethanol-drinking rats, differences were found in the same structures, with the addition of medial prefrontal cortex and substantia nigra. Correlations between ethanol intake and peptide levels were also found in several of the areas examined. The structures in which differences were found have all been implicated in the transition from drug use to addiction and these differences may lead to different propensities and vulnerability to this transition. Because the endogenous opioids have been suggested to be involved in a number of neurobiological disorders the results do not only have implications for research on alcohol or drug addiction, but many other fields as well., (Copyright © 2012 Elsevier Inc. All rights reserved.)