Systematic coarse-graining using structural information : applications to lipid membranes

Within last 20 years, advances in computational power and methodology have made computer simulations an integral part of studies of biomolecular systems. Simulations on all-atom level are routinely used to study, e.g., microscopic details of lipid aggregates and proteins. However, many phenomena are still outside the reach of all-atom simulations, and coarser models are needed. Detailed information from all-atom models can provide input data for parameterizing coarse-grained (CG) models. Techniques for such parameterization are called systematic coarse-graining methods, and can be based, e.g., on matching forces or structural information between the two resolutions. The main part of this dissertation employs inverse Monte Carlo (IMC) for constructing CG models for a lipid membrane containing dipalmitoylphosphatidylcholine (DPPC) and cholesterol. Three 2D models are constructed at different levels of resolution, in each case matching the radial distribution functions (RDFs) of the CG model to those from atom-scale simulations. The main results are the presence of cholesterol-rich and cholesterol-poor domains at intermediate cholesterol concentrations and the presence of strong tail density fluctuations at low cholesterol concentrations. The former agrees with the experimental studies of the system, while the latter was confirmed through atom-scale simulations. Accurate quantitative studies were restricted by transferability problems in all the CG models; hence, focus is on comparing the different models and critical discussion of the RDF inversion as a basis for coarse-graining. The IMC method is also improved by increasing its tolerance to statistical noise, as well as through inclusion of a virial pressure constraint and generalization to models where particles have internal degrees of freedom. The dissertation also discusses the analysis of individual lipid conformations from atom-scale simulations using self-organizing maps (SOMs), as well as the use of SOMs in coarse-graining. Atomistic simulations provide a vast amount of data, and direct analysis may be difficult. SOM, an unsupervised machine learning method, is studied as an alternative to more traditional analysis. Focus is on determining good parameters for the method and on qualitative analysis based on the good visualization properties of SOM. The internal dynamics of the molecules are also analyzed using SOMs for visualization. A bilayer of palmitoyllinoleoyl-PC (PLPC) is used as a model system

The risk of inguinal hernia repair after radical prostatectomy - a population-based cohort study

Objectives A nationwide population-based register study will evaluate the risk of postoperative inguinal hernia repair after primary curative-intent treatment of prostate carcinoma (PCa). Background Several previous studies have suggested an increased risk of inguinal hernia repair after prostatectomy. Only a few studies have compared the risk by PCa treatment modalities. Methods Data were collected between the years 1998 and 2016 from the national hospital discharge database HILMO and between the years 1998 and 2015 from the Finnish cancer registry to identify all men with prostate cancer with data on primary treatment available and information on inguinal hernia diagnoses and procedures among them. The risk of inguinal hernia repair among men managed with prostatectomy was compared to those treated with radiation therapy. Participants treated with prostatectomy were analyzed as a whole and separately stratified into subgroups managed with mini-invasive or open surgery. Multivariate Cox regression with adjustment for age and comorbidities was used for analysis. Results A total of 7207 cases of PCa were included in the study. 4595 men were treated with radical prostatectomy and 2612 with radiation therapy. Overall, the risk of hernia repair was higher among men treated with prostatectomy compared to men who received radiation therapy as the primary PCa treatment (HR 1.42, 95% CI 1.14-1.77). The risk did not differ markedly by the prostatectomy method. Conclusion Prostate cancer treatment with prostatectomy is associated with an increased risk of inguinal hernia surgery than external beam radiation therapy treatment. This risk should be taken into account when planning PCa treatment.Peer reviewe

Coarse-Grained Model for Phospholipid/Cholesterol Bilayer

We construct a coarse-grained (CG) model for dipalmitoylphosphatidylcholine (DPPC)/cholesterol bilayers and apply it to large-scale simulation studies of lipid membranes. Our CG model is a two-dimensional representation of the membrane, where the individual lipid and sterol molecules are described by point-like particles. The effective intermolecular interactions used in the model are systematically derived from detailed atomic-scale molecular dynamics simulations using the Inverse Monte Carlo technique, which guarantees that the radial distribution properties of the CG model are consistent with those given by the corresponding atomistic system. We find that the coarse-grained model for the DPPC/cholesterol bilayer is substantially more efficient than atomistic models, providing a speed-up of approximately eight orders of magnitude. The results are in favor of formation of cholesterol-rich and cholesterol-poor domains at intermediate cholesterol concentrations, in agreement with the experimental phase diagram of the system. We also explore the limits of the novel coarse-grained model, and discuss the general validity and applicability of the present approach

The risk of inguinal hernia repair after radical prostatectomy - a population-based cohort study

Objectives A nationwide population-based register study will evaluate the risk of postoperative inguinal hernia repair after primary curative-intent treatment of prostate carcinoma (PCa). Background Several previous studies have suggested an increased risk of inguinal hernia repair after prostatectomy. Only a few studies have compared the risk by PCa treatment modalities. Methods Data were collected between the years 1998 and 2016 from the national hospital discharge database HILMO and between the years 1998 and 2015 from the Finnish cancer registry to identify all men with prostate cancer with data on primary treatment available and information on inguinal hernia diagnoses and procedures among them. The risk of inguinal hernia repair among men managed with prostatectomy was compared to those treated with radiation therapy. Participants treated with prostatectomy were analyzed as a whole and separately stratified into subgroups managed with mini-invasive or open surgery. Multivariate Cox regression with adjustment for age and comorbidities was used for analysis. Results A total of 7207 cases of PCa were included in the study. 4595 men were treated with radical prostatectomy and 2612 with radiation therapy. Overall, the risk of hernia repair was higher among men treated with prostatectomy compared to men who received radiation therapy as the primary PCa treatment (HR 1.42, 95% CI 1.14-1.77). The risk did not differ markedly by the prostatectomy method. Conclusion Prostate cancer treatment with prostatectomy is associated with an increased risk of inguinal hernia surgery than external beam radiation therapy treatment. This risk should be taken into account when planning PCa treatment.Peer reviewe

Prostate Cancer–specific Survival After Radical Prostatectomy Is Improved Among Metformin Users but Not Among Other Antidiabetic Drug Users

Publisher Copyright: © 2021 The Author(s)Background: Metformin has been linked to improved survival among diabetic prostate cancer (PCa) patients, while hyperinsulinemia and insulin usage has been related to worse prognosis. Objective: To evaluate the association of metformin and other antidiabetic drugs with PCa death and androgen deprivation therapy (ADT). Design, setting, and participants: The study cohort included 14 424 men who underwent radical prostatectomy in Finland during 1995–2013. Cases were identified, and clinical data were collected from patient files and national registries using personal identification numbers. Intervention: Information on the use of each antidiabetic drug during 1995–2014 was collected from prescription registry of the Social Insurance Institution of Finland. Outcome measurements and statistical analysis: The risks of PCa death and initiation of ADT were analyzed by antidiabetic drug use with the Cox regression method. Each antidiabetic drug group was analyzed separately to model simultaneous usage. Pre- and postdiagnostic uses were analyzed separately. Results and limitations: Prediagnostic use of antidiabetic drugs in general had no association with the risk of PCa death. Prediagnostic use of metformin was related to a reduced risk of ADT initiation (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.59–0.96), while high-dose insulin users had an increased risk. Overall, antidiabetic drug use after PCa diagnosis was associated with an elevated risk of PCa death. Only postdiagnostic metformin use was associated with reduced risks of PCa death (HR 0.47, 95% CI 0.30–0.76) and ADT initiation compared with nonusers. Study limitations are missing information on glycemic control, smoking, living or exercise habits, prostate-specific antigen, and Gleason score. Conclusions: Among surgically treated PCa patients, use of metformin was associated with improved disease-specific survival, while insulin and insulin secretagogues were associated with poor survival. Metformin might be a favorable diabetes treatment among men with PCa. Patient summary: In this Finnish nationwide study, we found that the risks of prostate cancer death and cancer progression are lowered among metformin users, but not among other antidiabetic drug users. Metformin might be a favorable treatment choice for diabetes in men with prostate cancer.Peer reviewe

Role of Lipids and Lipid Metabolism in Prostate Cancer Progression and the Tumor’s Immune Environment

Modulation of lipid metabolism during cancer development and progression is one of the hallmarks of cancer in solid tumors; its importance in prostate cancer (PCa) has been demonstrated in numerous studies. Lipid metabolism is known to interact with androgen receptor signaling, an established driver of PCa progression and castration resistance. Similarly, immune cell infiltration into prostate tissue has been linked with the development and progression of PCa as well as with disturbances in lipid metabolism. Immuno-oncological drugs inhibit immune checkpoints to activate immune cells’ abilities to recognize and destroy cancer cells. These drugs have proved to be successful in treating some solid tumors, but in PCa their efficacy has been poor, with only a small minority of patients demonstrating a treatment response. In this review, we first describe the importance of lipid metabolism in PCa. Second, we collate current information on how modulation of lipid metabolism of cancer cells and the surrounding immune cells may impact the tumor’s immune responses which, in part, may explain the unimpressive results of immune-oncological treatments in PCa

Hyperuricemia Is Not an Independent Predictor of Erectile Dysfunction

Introduction: Erectile dysfunction (ED) is strongly associated with physiological and metabolic disturbances, and hyperuricemia has been proposed to predict the onset of ED.Aim: To investigate if hyperuricemia is an independent predictor for ED when all relevant confounding factors are taken into account.Methods: This is a cross-sectional study of men aged between 45 and 70 years. The population was well characterized for established cardiovascular risk factors, metabolic syndrome, as well as kidney function, depression, and socioeconomic factors. Analysis was limited to 254 men with complete data and also serum uric acid (SUA) measurements were available. This included 150 men with and 104 without ED. The presence and severity of ED was evaluated using International Index of Erectile Function-5 questionnaire. Risk of ED by SUA level was calculated using univariate and multivariable-adjusted logistic regression. Effect modification by participant characteristics were evaluated in subgroup analyses.Main outcome measures: The main outcome measures of this study are prevalence and severity of erectile dysfunction.Results: Patients with ED (59% of the study population) were older than men without ED (59 vs 54 years) and had lower serum testosterone (14.3, 95% CI 11.3-17.3 vs 15.1 nmol/l, 95% CI 12.1-18.8, respectively). Regarding all other variables, the groups were comparable. No significant difference was found for SUA by ED. SUA was not associated with ED risk in univariate or multivariable analysis (multivariable-adjusted OR 1.14, 95% CI 0.59-2.19, P = .7) for SUA level higher than median compared with median or lesser (OR 1.00, 95% CI 0.997-1.006, P = .7 for continuous variable). No subgroup analysis modified the association. After multivariable adjustment age, education level and depression were statistically significant predictors of ED.Conclusions: Elevated SUA was not found to be an independent risk factor for ED. Metabolic syndrome, glomerular filtration rate, or cardiovascular risk factors did not modify this result. ED cannot be predicted based on the level of SUA. A Tuokko, T Murtola, P Korhonen, et al. Hyperuricemia Is Not an Independent Predictor of Erectile Dysfunction.</p

Inverse Association between Statin Use and Cancer Mortality Relates to Cholesterol Level

Statins have been associated with a decreased cancer mortality. However, cholesterol level as such may modify the risk of cancer death. To clarify the complex interplay between statins, cholesterol level, and cancer mortality, we conducted a comprehensive analysis to separate the effects of cholesterol level and statin medication on cancer mortality. Our study population consisted of 16,924 men participating in the Finnish Randomized Study of Screening for Prostate Cancer with at least one cholesterol measurement during follow-up (1996–2017). Cox proportional regression was used to estimate hazard ratios. In total, 1699 cancer deaths were observed during the median follow-up of 19 years. When statins’ association with the risk of cancer death was estimated without adjustment for cholesterol level, statin use was associated with a lowered cancer mortality (HR 0.87; 95% CI 0.79–0.97) compared to non-users. However, with further adjustment for total cholesterol level, statin use was no longer associated with a lower cancer mortality (HR 1.08; 95% CI 0.97–1.20). Upon stratified analysis, statin use was associated with a decreased cancer mortality only if the total cholesterol level decreased after the initiation of statin use (HR 0.66; 95% CI 0.58–0.76). The inverse association between statin use and cancer mortality is limited to men with a reduction in total cholesterol level after the commencement of statins, i.e., statin use is associated with a lowered cancer mortality only if the total cholesterol level decreases. This suggests that the effect of statin use on cancer mortality relates to the decreased total cholesterol level