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In vitro therapeutic efficacy studies are commonly conducted in cell monolayers. However, three-dimensional (3D) tumor spheroids are known to better represent in vivo tumors. This study used [ 177 Lu]Lu-PSMA-I&T, an already clinically applied radiopharmaceutical for targeted radionuclide therapy against metastatic castrate-resistant prostate cancer, to demonstrate the differences in the radiobiological response between 2D and 3D cell culture models of the prostate cancer cell lines PC-3 (PSMA negative) and LNCaP (PSMA positive). After assessing the target expression in both models via Western Blot, cell viability, reproductive ability, and growth inhibition were assessed. To investigate the geometric effects on dosimetry for the 2D vs. 3D models, Monte Carlo simulations were performed. Our results showed that PSMA expression in LNCaP spheroids was highly preserved, and target specificity was shown in both models. In monolayers of LNCaP, no short-term (48 h after treatment), but only long-term (14 days after treatment) radiobiological effects were evident, showing decreased viability and reproductive ability with the increasing activity. Further, LNCaP spheroid growth was inhibited with the increasing activity. Overall, treatment efficacy was higher in LNCaP spheroids compared to monolayers, which can be explained by the difference in the resulting dose, among others.

[ 177 Lu]Lu-PSMA I&T is widely used for the radioligand therapy of metastatic castration-resistant prostate cancer (mCRPC). Since this kind of therapy has gained a large momentum in recent years, an upscaled production process yielding multiple patient doses in one batch has been developed. During upscaling, the established production method as well as the HPLC quality control were challenged. A major finding was a correlation between the specific activity and the formation of a pre-peak, presumably caused by radiolysis. Hence, nonradioactive reference standards were irradiated with an X-ray source and the formed pre-peak was subsequently identified as a deiodination product by UPLC-MS. To confirm the occurrence of the same deiodinated side product in the routine batch, a customized deiodinated precursor was radiolabeled and analyzed with the same HPLC setup, revealing an identical retention time to the pre-peak in the formerly synthesized routine batches. Additionally, further cyclization products of [ 177 Lu]Lu-PSMA I&T were identified as major contributors to radiochemical impurities. The comparison of two HPLC methods showed the likelihood of the overestimation of the radiochemical purity during the synthesis of [ 177 Lu]Lu-PSMA I&T . Finally, a prospective cost reduction through an optimization of the production process was shown.

Radiation therapy is one of the most effective tools in cancer therapy. However, success varies individually, necessitating improved understanding of radiobiology. Three-dimensional (3D) tumor spheroids are increasingly gaining attention, being a superior in vitro cancer model compared to 2D cell cultures. This in vitro study aimed at comparing radiation responses in 2D and 3D cell culture models of different human cancer cell lines (PC-3, LNCaP and T-47D) irradiated with varying doses (1, 2, 4, 6, 8 or 20 Gy) of X-ray beams. Radiation response was analyzed by growth analysis, various cell viability assays (e.g., clonogenic assay, resazurin assay) and amount of DNA damage (γH2AX Western Blot). Results showed decreasing cell proliferation with the increase of radiation doses for all cell lines in monolayers and spheroids of LNCaP and T-47D. However, significantly lower radiosensitivity was detected in spheroids, most pronounced in PC-3, evincing radiation resistance of PC-3 spheroids up to 8 Gy and significant growth inhibition only by a dose escalation of 20 Gy. Cell line comparison showed highest radiosensitivity in LNCaP, followed by T-47D and PC-3 in 2D, whereas, in 3D, T-47D showed highest sensitivity. The results substantiate the significant differences in radiobiological response to X-rays between 2D and 3D cell culture models.

Physical activity (PA) has been shown to associate with many health benefits but studies with metabolome-wide associations with PA are still lacking. Metabolome studies may deepen the mechanistic understanding of PA on the metabolic pathways related to health outcomes. The aim of the present study was to study the association of accelerometer based sedentary time (SB) and PA with metabolome measures. SB and PA were measured by a hip-worn accelerometer in 314 young adult men (age: mean 28, standard deviation 7 years). Metabolome was analyzed from fasting serum samples consisting of 66 metabolome measures (nuclear magnetic resonance-based metabolomics). The associations were analyzed using a single and compositional approach with regression analysis. The compositional analysis revealed that 4 metabolome variables were significantly (γ: 0.32−0.44, p ≤ 0.002), and 13 variables with a trend towards significance (p < 0.05), associated with SB with varying metabolic pathways. Trends towards significant associations (p < 0.05) were observed with 5 variables with moderate-to-vigorous and 1 variable with light intensity PA with varying metabolic pathways. The present study revealed possible mechanistic pathways relevant for the interaction between especially SB but also PA of moderate-to-vigorous intensity with ketone bodies and amino acid concentration related to exercised-induced energy production and lipid metabolism.

Personalized treatment of cancer patients demands specific and validated biomarkers for tumor diagnosis and therapy. The development and validation of such require translational preclinical models that recapitulate human diseases as accurately as possible. Moreover, there is a need for convergence of different (pre)clinical disciplines that openly share their knowledge and methodologies. This review sheds light on the differential perception of biomarkers and gives an overview of currently used models in tracer development and approaches for biomarker discovery.

This study examined the impact of high adherence to a neuromuscular training (NMT) warm-up on the risk of lower extremity (LE) injuries in children's soccer. Twenty U11-U14 youth clubs ( n = 92 teams, 1409 players) were randomized into intervention ( n = 44 teams) and control ( n = 48 teams) groups. The intervention group was advised to perform an NMT warm-up 2 to 3 times a week for 20 weeks. Team adherence, injuries, and exposure were registered throughout the follow-up. Primary outcomes were the incidence of soccer-related acute LE injuries and the prevalence of overuse LE injuries. Intervention teams conducted mean 1.7 (SD 1.0) NMT warm-ups weekly through follow-up. The seasonal trend for adherence declined significantly by -1.9% (95% CI -0.8% to -3.1%) a week. There was no difference in the incidence of acute injuries nor the prevalence of overuse LE injuries in high team adherence group ( n = 17 teams) compared to controls. However, the risk for acute noncontact LE injuries was 31% lower in the high team adherence group compared to controls (IRR 0.69, 95% CI 0.49 to 0.97). In an efficacy analysis ( n = 7 teams), there was a significant reduction of 47% in the rate of noncontact LE injuries (IRR 0.53, 95% CI 0.29 to 0.97). In conclusion, teams conducted NMT warm-up sessions regularly, but with a declining trend. A greater protective effect was seen in teams with the highest adherence to the NMT warm-up.

We developed and validated a prognostic index to predict survival from prostate cancer (PCa) based on the Finnish randomized screening trial (FinRSPC). Men diagnosed with localized PCa ( N = 7042) were included. European Association of Urology risk groups were defined. The follow-up was divided into three periods (0-3, 3-9 and 9-20 years) for development and two corresponding validation periods (3-6 and 9-15 years). A multivariable complementary log-log regression model was used to calculate the full prognostic index. Predicted cause-specific survival at 10 years from diagnosis was calculated for the control arm using a simplified risk score at diagnosis. The full prognostic index discriminates well men with PCa with different survival. The area under the curve (AUC) was 0.83 for both the 3-6 year and 9-15 year validation periods. In the simplified risk score, patients with a low risk score at diagnosis had the most favorable survival, while the outcome was poorest for the patients with high risk scores. The prognostic index was able to distinguish well between men with higher and lower survival, and the simplified risk score can be used as a basis for decision making.

Limited data are available regarding strength and endurance training adaptations to occupational physical performance during deployment. This study assessed acute training-induced changes in neuromuscular (electromyography; EMG) and metabolic (blood lactate, BLa) responses during a high-intensity military simulation test (MST), performed in the beginning (PRE) and at the end (POST) of a six-month crisis-management operation. MST time shortened (145 ± 21 vs. 129 ± 16 s, -10 ± 7%, p < 0.001) during the operation. Normalized muscle activity increased from PRE to POST in the hamstring muscles by 87 ± 146% (116 ± 52 vs. 195 ± 139%EMG MVC , p < 0.001) and in the quadriceps by 54 ± 81% (26 ± 8 vs. 40 ± 20%EMG MVC , p < 0.001). In addition, higher acute BLa values were measured after MST during POST. Changes in BLa and EMG suggested an increased neural input and metabolic rate during POST MST, likely leading to faster performance times at the end of the operation. High EMG values throughout the different phases of MST suggested that despite the anaerobic nature of the test, the soldiers were able to maintain their voluntary muscle activation level until the end of the test. This indicates only limited neural fatigue during the two-minute high-intensity military specific performance. While learning effect may explain some part of the improvement in the MST performance times, combined strength and endurance training three times per week may improve neuromuscular performance in occupationally relevant tasks.

Decreases in aerobic fitness during military operations have been observed in several studies. Thus, differences in training adaptations during a 6-month crisis-management operation were compared by using the change in endurance performance as the outcome measure. Sixty-six male soldiers volunteered for the study, consisting of pre-post assessments of blood biomarkers, body composition, physical performance, and the military simulation test (MST) performance. Physical training volume was self-reported. After the follow-up, the data were divided based on individual changes in endurance performance. Endurance performance was improved in the high-responder group (HiR, n = 25) and maintained or decreased in the low-responder group (LoR n = 24). During the operation, the LoR group decreased while the HiR group increased their endurance training frequency from the pre-deployment level (Δ 28 ± 57% vs. -40 ± 62%, p = 0.004). Fat mass decreased (-7.6 ± 11.7% vs. 14.2 ± 20.4%, p < 0.001), and 1-min push-up (27.7 ± 21.9% vs. 11.7 ± 26.1%, p = 0.004) and MST performance improved (-13.6 ± 6.8% vs. -7.5 ± 6.5%, p = 0.006) more in the HiR group. No differences were observed in the changes of other physical performance test results or analyzed biomarkers. In conclusion, soldiers who were initially leaner and fitter in terms of lower body strength and power were more likely to decrease their aerobic fitness during the operation.

Background and Objectives: There is lack of knowledge on whether mothers' gestational diabetes (GDM) risk is related to their physical activity (PA) or their children's PA and body composition. We aimed to examine the difference in (1) change in self-reported PA from pre-pregnancy to seven-year follow-up and (2) accelerometer-based PA at seven years after delivery between the mothers having GDM risk (GDMRyes-mothers) and not having GDM risk (GDMRno-mothers). Furthermore, we examined the difference in children's PA and/or body composition at six years of age according to their mothers' GDM risk. Materials and Methods: The study included 199 Finnish women. GDM risk factors were screened at the beginning of pregnancy, and the women were classified as GDMRyes-mothers if they had at least one GDM risk factor (body mass index ≥25 kg/m 2 ; age ≥40 years; family history of diabetes; GDM, signs of glucose intolerance, or newborn's macrosomia (≥4500 g) in earlier pregnancy) or as GDMRno-mothers if they had no risk factors. Mothers' PA was assessed by self-reporting at 8-12 gestational weeks concerning pre-pregnancy PA and at a follow-up seven years after the delivery. Moreover, mothers' and their children's PA was measured using a triaxial Hookie AM20-accelerometer at seven years after delivery. Children's body composition was assessed using a TANITA bioelectrical impedance device. Adjusted linear regression analyses were applied. Results: GDMRno-mothers increased their self-reported PA more than GDMRyes-mothers from pre-pregnancy to the seven-year follow-up. Concerning women's measured PA as well as children's PA and body composition at seven years after delivery, the differences were non-significant between GDMRyes-mothers and GDMRno-mothers. However, of the GDM risk factors, mothers' pre-pregnancy body mass index was positively related to unhealthier body composition in boys at six years of age. Conclusion: Health promotion should be targeted at women with GDM risk factors, in particular overweight women, in enhancing women's PA in the long term and their children's healthy body composition.