Valdoltra and osteoarticular tuberculosis among Slovenians--the 100th anniversary of the Valdoltra Hospital

The 100th anniversary of the hospital in Valdoltra, Slovenia, on the northeastern Adriatic coast near the Italian frontier--where borders have frequently changed (the town has belonged to Austria-Hungary, Italy, Yugoslavia, and Slovenia) and which experienced military occupation in the interwar period--offers an opportunity to review the professional path of this institution. The hospital was established in 1909 as an act of charity by the Trieste Friends of Children Society due to the high incidence of scrofula as well as bone and extrapulmonary tuberculosis among Trieste children. With 270 beds, it provided medical assistance to sick children and also later to adults. After the First World War, its management was assumed by the Italian Red Cross, which built an additional wing in 1934 and increased the hospital's capacity to 340 beds. After Italy's capitulation, German soldiers occupied the hospital and left it in shambles at the end of the war. In September 1945, the hospital was renovated and taken over by the Slovenian healthcare system; 400 beds were again available for treating bone tuberculosis patients. This did not last for long. By 1947, after the Treaty of Peace with Italy was signed and Valdoltra became the central Yugoslav institution for treating bone tuberculosis, the hospital had to be relocated to Rovinj, Croatia due to the political division of the Trieste region into Zones A and B. Only in 1952 did the hospital return to Valdoltra and continue its mission. In the twentieth century, tuberculosis was treated similarly everywhere until antitubercular agents were discovered. At first, conservative climatic and hygiene-dietary methods, orthopedic aids, plaster corsets, and physiotherapy were used to treat bone tuberculosis. This was followed by surgical treatment, which came into vogue after 1945, when it was supported by antibiotic treatment, and (postoperative) physiotherapy and rehabilitation. Chemotherapeutic agents and preventive outpatient BCG-vaccination proved successful in curing bone tuberculosis and other forms of tuberculosis, and the number of consumptive patients continued to decrease. The Valdoltra hospital has preserved its tradition of treating osteoarticular pathologies and has been the main Slovenian orthopedic hospital since 1961.     

Robustness of Treatment Planning for Electrochemotherapy of Deep-Seated Tumors

Treatment of cutaneous and subcutaneous tumors with electrochemotherapy has become a regular clinical method, while treatment of deep-seated tumors is still at an early stage of development. We present a method for preparing a dedicated patient-specific, computer-optimized treatment plan for electrochemotherapy of deep-seated tumors based on medical images. The treatment plan takes into account the patient’s anatomy, tissue conductivity changes during electroporation and the constraints of the pulse generator. Analysis of the robustness of a treatment plan made with this method shows that the effectiveness of the treatment is not affected significantly by small single errors in electrode positioning. However, when many errors occur simultaneously, the resulting drop in effectiveness is larger, which means that it is necessary to be as accurate as possible in electrode positioning. The largest effect on treatment effectiveness stems from uncertainties in dielectric properties and electroporation thresholds of treated tumors and surrounding tissues, which emphasizes the need for more accurate measurements and more research. The presented methods for treatment planning and robustness analysis allow quantification of the treatment reproducibility and enable the setting of suitable safety margins to improve the likelihood of successful treatment of deep-seated tumors by electrochemotherapy.     

Lacustrine basin to delta evolution in the Zagorje Basin,a Pannonian sub-basin (Late Miocene: Pontian,NW Croatia)

Pontian deposits of the Zagorje Basin constitute a coarsening-upward succession, which reflects the infilling style of this Pannonian sub-basin, i.e. the progradation of clastic systems into the brackish lake. Six facies differentiated correspond to lake floor, channelled slope, distal and proximal pro-delta, distal and proximal mouth bars, and lagoon/bay to swamp and alluvial environments. The deposition in the mouth-bar area was dominated by frictional forces. The upper-stage plane-bed sands are the main mouth-bar facies, which is uncommon in the geological record. The main factors for the origin of such bars include an abundant sand supply by the high-energy fluvial system(s), low-energy of the receiving basin and shallow depositional depth. Prolonged, catastrophic floods generated sustained hyperpycnal flows, which bypassed the mouth-bar area and fed the slope/pro-delta. The high ratio between sediment supply and subsidence rate resulted in a fast moving progradational wave, which involved the entire SW Pannonian Basin, including the Zagorje Basin.     

Numerical optimization of gene electrotransfer into muscle tissue

Background  

Electroporation-based gene therapy and DNA vaccination are promising medical applications that depend on transfer of pDNA into target tissues with use of electric pulses. Gene electrotransfer efficiency depends on electrode configuration and electric pulse parameters, which determine the electric field distribution. Numerical modeling represents a fast and convenient method for optimization of gene electrotransfer parameters. We used numerical modeling, parameterization and numerical optimization to determine the optimum parameters for gene electrotransfer in muscle tissue.     

Systems Modelling of NHEJ Reveals the Importance of Redox Regulation of Ku70/80 in the Dynamics of DNA Damage Foci

The presence of DNA double-stranded breaks in a mammalian cell typically activates the Non-Homologous End Joining (NHEJ) pathway to repair the damage and signal to downstream systems that govern cellular decisions such as apoptosis or senescence. The signalling system also stimulates effects such as the generation of reactive oxygen species (ROS) which in turn feed back into the damage response. Although the overall process of NHEJ is well documented, we know little of the dynamics and how the system operates as a whole. We have developed a computational model which includes DNA Protein Kinase (DNA-PK) dependent NHEJ (D-NHEJ) and back-up NHEJ mechanisms (B-NHEJ) and use it to explain the dynamic response to damage induced by different levels of gamma irradiation in human fibroblasts. Our work suggests that the observed shift from fast to slow repair of DNA damage foci at higher levels of damage cannot be explained solely by inherent stochasticity in the NHEJ system. Instead, our model highlights the importance of Ku oxidation which leads to increased Ku dissociation rates from DNA damage foci and shifts repair in favour of the less efficient B-NHEJ system.     

Towards treatment planning and treatment of deep-seated solid tumors by electrochemotherapy

Background  

Electrochemotherapy treats tumors by combining specific chemotherapeutic drugs with an intracellular target and electric pulses, which increases drug uptake into the tumor cells. Electrochemotherapy has been successfully used for treatment of easily accessible superficial tumor nodules. In this paper, we present the first case of deep-seated tumor electrochemotherapy based on numerical treatment planning.     

Clinicopathological and prognostic significance of osteopontin expression in patients with prostate cancer: a systematic review and meta-analysis

Background: Evaluation of the feasibility for osteopontin (OPN) to serve as a biomarker in the prognosis and clinical-pathological features of prostate cancer (PCA) patients.Methods: The original publications related to OPN and PCA were comprehensively searched in the online databases, including PubMed, Embase, Cochrane Library, Web of Science, Medline, Wanfang and China National Knowledge Infrastructure up to August 2019. Results were analyzed by Revman 5.3 and Stata 12.0.Results: A total of 21 studies were included in the analysis and the result showed that the positive OPN expression group had a lower overall survival than the negative expression group (univariate: hazards ratio (HR) = 2.32, 95% confidence interval (95% CI) [1.74, 3.10], multivariate: HR = 2.41, 95% CI [1.63, 3.57]) and a lower biochemical relapse-free survival than the negative group (univariate: HR = 1.42, 95% CI [0.92, 2.17], multivariate: HR = 1.61, 95% CI [1.39, 1.87]). In addition, there was a higher expression level of OPN in PCA tissues than in normal prostate tissues (OR = 46.55, 95% CI [12.85, 168.59], P<0.00001) and benign prostatic hyperplasia (BPH) tissues (OR = 11.07, 95% CI [3.43, 35.75], P<0.0001). Moreover, OPN positive expression was also related to high Gleason score (OR = 2.64, 95% CI [1.49, 4.70], P=0.0009), high TNM stage (OR = 3.15, 95% CI [1.60, 6.20, P=0.0009), high Whitmore–Jewett stage (OR = 2.53, 95% CI [1.06, 6.03], P=0.04), high lymph node (OR = 3.69, 95% CI [1.88, 7.23], P=0.0001), and distant metastasis (OR = 8.10, 95% CI [2.94, 22.35], P=0.01). There was no difference observed in the differentiation of PCA (OR = 1.79, 95% CI [0.39, 8.33], P=0.46).Conclusion: OPN could be recognized as a promising diagnostic and prognostic biomarker for PCA patients.     

Integrated Stochastic Model of DNA Damage Repair by Non-homologous End Joining and p53/p21- Mediated Early Senescence Signalling

Unrepaired or inaccurately repaired DNA damage can lead to a range of cell fates, such as apoptosis, cellular senescence or cancer, depending on the efficiency and accuracy of DNA damage repair and on the downstream DNA damage signalling. DNA damage repair and signalling have been studied and modelled in detail separately, but it is not yet clear how they integrate with one another to control cell fate. In this study, we have created an integrated stochastic model of DNA damage repair by non-homologous end joining and of gamma irradiation-induced cellular senescence in human cells that are not apoptosis-prone. The integrated model successfully explains the changes that occur in the dynamics of DNA damage repair after irradiation. Simulations of p53/p21 dynamics after irradiation agree well with previously published experimental studies, further validating the model. Additionally, the model predicts, and we offer some experimental support, that low-dose fractionated irradiation of cells leads to temporal patterns in p53/p21 that lead to significant cellular senescence. The integrated model is valuable for studying the processes of DNA damage induced cell fate and predicting the effectiveness of DNA damage related medical interventions at the cellular level.