Biochemical control in intermediate- and high-risk prostate cancer after EBRT with and without brachytherapy boost.

PURPOSE: External beam radiotherapy (EBRT) with or without brachytherapy boost (BTB) has not been compared in prospective studies using guideline-recommended radiation dose and recommended androgen-deprivation therapy (ADT). In this multicenter retrospective analysis, we compared modern-day EBRT with BTB in terms of biochemical control (BC) for intermediate-risk (IR) and high-risk (HR) prostate cancer. METHODS: Patients were treated for primary IR or HR prostate cancer during 1999-2019 at three high-volume centers. Inclusion criteria were prescribed ≥ 76 Gy EQD2 (α/ß = 1.5 Gy) for IR and ≥ 78 Gy EQD2 (α/ß = 1.5 Gy) for HR as EBRT alone or with BTB. All HR patients received ADT and pelvic irradiation, which were optional in IR cases. BC between therapies was compared in survival analyses. RESULTS: Of 2769 initial patients, 1176 met inclusion criteria: 468 HR (260 EBRT, 208 BTB) and 708 IR (539 EBRT, 169 BTB). Median follow-up was 49 and 51 months for HR and IR, respectively. BTB patients with ≥ 113 Gy EQD2Gy experienced a stable, good BC outcome compared with BTB at lower doses. Patients treated with ≥ 113 Gy EQD2Gy also experienced significantly improved BC compared with EBRT (10-year BC failure rates after ≥ 113 Gy BTB and EBRT: respectively 20.4 and 41.8% for HR and 7.5 and 20.8% for IR). CONCLUSIONS: In patients with IR and HR prostate cancer, BTB with ≥ 113 Gy EQD2Gy offered a BC advantage compared with dose-escalated EBRT and lower BTB doses.

Structure-activity relationship and cytotoxicity of the new thiosemicarbazide derivatives and their Cu(II) complexes against prostate and melanoma cancer cells.

In this study, eighteen new ligands (B1-B18) containing a thiosemicarbazide core were synthesized and characterized in terms of physicochemical properties, molecular docking and in vitro biological activity. The structures of eleven ligands were investigated using X-Ray diffraction and Hirschfeld Surface analysis. To study the structure-activity relationship, the organic ligands contained pyridin-2-ylmethyl, pyridin-3-ylmethyl or pyridin-4-ylmethyl moieties and various substituents. Their pharmakokinetic profiles and molecular docking results suggest high potential as new drug candidates. The complexing ability of the selected organic ligands was also evaluated, yielding five new Cu(II) complexes (Cu(B1)Cl2, Cu(B4)Cl2, Cu(B10)Cl2, Cu(B17)Cl2, Cu(B18)Cl2). The obtained results suggest the formation of the polymeric structures. All organic ligands and Cu(II) complexes were tested for anticancer activity against prostate and melanoma cancer cells (PC-3, DU-145, LNCaP, A375, G-361, SK-MEL-28) and normal fibroblasts (BJ), as well as antimicrobial activity against six selected bateria strains. Among B1-B18 compounds, B3, B5, B9, B10, B12 and B14 exhibited cytotoxic activity. The studied Cu(II) complexes were in general more active, with Cu(B1)Cl2 exhibiting antincancer activity agains all three prostate cancer cells and Cu(B10)Cl2 reaching the IC50 value equal to 88 µM against G-361 melanoma cells. Several compounds also exhibited antimicrobial activity against gram-positive and gram-negative bacteria. It was found that the type of specific substituents, especially the presence of -chloro and -dichloro substituents had a greated impact on the cytotoxicity than the position of the nitrogen atom in the pyridylacetyl moiety.

Current trends in non-surgical management of Peyronie's disease-A narrative review.

Peyronie's disease (PD) is a connective tissue disorder affecting the tunica albuginea. It can cause pain and penile deformation, and its prevalence increases with age. Although surgery is the gold standard for the chronic phase of the disease, there are several conservative treatment methods available, and the optimal management of the acute phase of the disease remains a matter of debate. In this article, we aim to summarize the recent trends in research on the subject of non-surgical treatment of PD. The search was performed in PubMed, Scopus, and Web of Science databases and included studies in English published between 2012 and 2022 investigating the clinical outcomes of non-surgical PD management in humans. We have identified 20 distinct conservative treatment strategies. Among the oral therapeutics, only the use of phosphodiesterase type 5 inhibitors is currently recommended for clinical use in patients with concomitant erectile dysfunction. The use of collagenase from Clostridium histolyticum is supported by the best quality evidence in terms of intralesional injections for patients suffering from significant penile curvature; however, interferon alpha-2b can also be an option in such patients. Among other non-invasive methods, extracorporeal shockwaves can be useful for pain reduction, and penile traction therapy can lead to a reduction in penile curvature and plaque size. Despite a wide range of non-surgical methods available for PD treatment, the majority are not supported by sufficient scientific evidence, and the treatment efficacy is underwhelming. Further research on the subject of non-surgical management of PD is highly warranted.

Optimization of the Zebrafish Larvae Pentylenetetrazol-Induced Seizure Model for the Study of Caffeine and Topiramate Interactions.

Epilepsy is a common neurological disorder characterized by seizures that cause neurobiological and behavioral impairment. Caffeine (CAF), which is the most widely consumed stimulant in the world, is reported to influence epileptic seizures and antiepileptic drugs, especially topiramate (TPM). The aim of the study was to optimize the zebrafish larvae pentylenetetrazol-induced seizure model for the study of CAF and TPM interactions, which include the determination of dose space, and the delivery of an analytical method for monitoring CAF, TPM, and CAF metabolite paraxanthine (PAR) in Zebrafish larvae. Methods: The zebrafish larvae, 4 days post-fertilization, were incubated for 18 h with CAF, TPM, or CAF + TPM, with subsequent locomotor activity assessment. Seizures were evoked by adding PTZ solution to obtain a final concentration of 20 mM. Subsequently, the liquid chromatography-mass spectrometry (LC-MS/MS) analytical method was used to simultaneously assess the levels of both CAF and TPM in the larvae. CAF (50 mg/L) and TPM (75 µM) given separately decreased the average larvae locomotor activity compared to the PTZ group but, however, were not able to lower it to the control level. Co-administration of 25 mg/L CAF and 50 µM TPM suppressed the activity to the same level. Adding 25 µM TPM to 50 mg/L CAF decrease the measured CAF level in the larvae. Until proven otherwise, CAF consumption should be regarded as a potential determinant in the modulation of TPM's efficacy in the management of epileptic seizures. The optimized model will contribute to the standardization of studying CAF and TPM interactions and building the understanding of the molecular bases of the interaction.

LC-MS/MS-based quantification of tryptophan, kynurenine, and kynurenic acid in human placental, fetal membranes, and umbilical cord samples.

Tryptophan breakdown metabolites formed along the kynurenine pathway play a significant role in pregnancy and fetal development. To understand their involvement, it is crucial to quantify the levels of tryptophan (TRP), kynurenine (KYN), and kynurenic acid (KYNA) in relevant biological samples such as the placenta, fetal membranes, and umbilical cord. This study used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine TRP, KYN, and KYNA levels. The LC-MS/MS method was optimized for high sensitivity and specificity, demonstrating good reproducibility with a precision of < 10% CV and an accuracy of 85-115%. The lower limit of quantification for both TRP and KYN was 0.5 µg/ml, while for KYNA, it was 0.5 ng/mL. The method exhibited linearity within the examined range of concentrations in the homogenate, ranging from 0.5 to 30 µg/ml for TRP and KYN and from 0.5 to 25 ng/ml for KYNA. Using this method, we found significant differences in the concentrations of these substances in investigated maternal-fetal compartments. Placenta samples exhibited higher KYN and lower KYNA concentrations than the umbilical cord and fetal membrane, indicating a potentially important role for kynurenines in late pregnancy. Collectively, this finding may facilitate further research and provide inside into the involvement of the kynurenine pathway of TRP metabolism in fetal development.

Stereotactic management of arrhythmia - radiosurgery in treatment of ventricular tachycardia (SMART-VT). Results of a prospective safety trial.

BACKGROUND AND PURPOSE: Despite its increasing popularity, there are limited prospective data on stereotactic arrhythmia radioablation (STAR). In this trial, we assessed the safety and efficacy of STAR in patients with ventricular tachycardia (VT), focusing on early treatment-related grade ≥ 3 adverse events (AE). MATERIALS AND METHODS: This prospective trial was designed for adults with VT recurrence following catheter ablation (CA) despite adequate pharmacotherapy, or contraindications to CA. A single dose of 25 Gy was delivered to the arrhythmia substrate defined on electro-anatomic mapping and cardiac-gated CT. The primary endpoint was safety, defined as two or fewer treatment-related grade ≥ 3 AEs during the first three months in 11 patients. Additional endpoints included treatment efficacy, clinical and biological markers of cardiac injury, and quality of life. RESULTS: Eleven patients with a median age of 67 years, structural heart disease, and a clinically significant recurrence of VT despite adequate pharmacotherapy and 1-4 previous CAs were enrolled between 2020/09 and 2022/10. Following the treatment, one patient developed a possibly treatment-related grade ≥ 3 AE, a grade 4 heart failure exacerbation at 87 days, which resolved after conservative treatment. There was a total 84.3% reduction in VT burden in 10 evaluable patients; however, VT recurrence was eventually observed in eight, and three patients required additional CAs. Three deaths due to unrelated causes were recorded. CONCLUSIONS: STAR appears to be safe and efficient. It is a promising treatment for selected patients; however, long-term outcomes remain to be evaluated, and controlled trials comparing STAR with standards of care are missing.

Lipidomic characteristics of three edible cold-pressed oils by LC/Q-TOF for simple quality and authenticity assurance.

Distinguishing oil samples from each other is challenging but it is crucial for ensuring food quality, and for detecting and preventing the possible adulteration of these products. Lipidomic profiling is believed to provide sufficient information to get fit-to-purpose confidence of oil identification as well as to deliver oil-specific lipid features which could be used as targets for routine authenticity testing of camelina, flax, and hemp oil in food control laboratories. Conducted di- and triacylglycerol profiling by LC/Q-TOFMS yielded successful differentiation of the oils. A marker panel consisting of 27 lipids (both DAGs and TAGs) useful for quality verification and authenticity assurance of the oils was established. Moreover, sunflower, rapeseed, and soybean oils were analysed as potential adulterants. We identified 6 lipid markers (DAGs 34:6, 35:2, 40:1, 40:2, 42:2, and TAG 63:1) which can be used for revealing the adulteration of camelina, hemp, and flax seed oils with these oils.

Pork liver tissue-specific peptide markers for food authenticity testing and adulteration detections.

A liquid chromatography-mass spectrometry bottom-up proteomic approach was applied for the detection and identification of proteins from liver tissues. We identified 74 unique pork liver peptide markers that are resistant to the thermal processing of food. These peptides are derived from 43 proteins, which perform various functions in the liver. Roasted and sterilised pâté-type products with a pork liver content ranging from 6% to 51% were examined to select the most reliable pork liver peptide markers that survive unmodified in complex processed food matrices. Of the 74 specific heat-stable peptides detected in pure liver tissue, five (GDAPEEEVSLSK, ALTAELEAVGK, TFYLNVLNEEER, AQFGQPEILLGTIPGTGGTQR and VIAPGFNALEQILQSTAGK) were the best candidates to confirm the presence of liver tissue in highly processed meat products. We have identified unique tissue-specific markers that enable rapid and specific identification of pork liver in processed food and may contribute to the development of new methods for testing food authenticity.

Histopathological Examination of an Explanted Heart in a Long-Term Responder to Cardiac Stereotactic Body Radiotherapy (STereotactic Arrhythmia Radioablation).

Cardiac stereotactic body radiotherapy is an emerging treatment method for recurrent ventricular tachycardia refractory to invasive treatment methods. The single-fraction delivery of 25 Gy was assumed to produce fibrosis, similar to a post-radiofrequency ablation scar. However, the dynamics of clinical response and recent preclinical findings suggest a possible different mechanism. The data on histopathological presentation of post-radiotherapy hearts is scarce, and the authors provide significantly different conclusions. In this article, we present unique data on histopathological examination of a heart explanted from a patient who had a persistent anti-arrhythmic response that lasted almost a year, until a heart failure exacerbation caused a necessity of a heart transplant. Despite a complete treatment response, there was no homogenous transmural fibrosis in the irradiated region, and the overall presentation of the heart was similar to other transplanted hearts of patients with advanced heart failure. In conclusion, our findings support the theorem of functional changes as a source of the anti-arrhythmic mechanism of radiotherapy and show that durable treatment response can be achieved in absence of transmural fibrosis of the irradiated myocardium.

Shotgun Lipidomic Analysis for Differentiation of Niche Cold Pressed Oils.

The fast-growing food industry is bringing significant number of new products to the market. To protect consumers' health and rights, it is crucial that food control laboratories are able to ensure reliable quality testing, including product authentication and detection of adulterations. In our study, we applied a fast and eco-friendly method based on shotgun-lipidomic mass spectrometry for the authentication of niche edible oils. Comprehensive lipid profiles of camelina (CA), flax (FL) and hemp (HP) seed oils were obtained. With the aid of principal component analysis (PCA), it was possible to detect and distinguish each of them based on their lipid profiles. Lipidomic markers characteristic ofthe oils were also identified, which can be used as targets and expedite development of new multiplexed testing methods.

Sensitivity to negative and positive feedback as a stable and enduring behavioural trait in rats.

RATIONALE: According to psychological theories, cognitive distortions play a pivotal role in the aetiology and recurrence of mood disorders. Although clinical evidence for the coexistence of depression and altered sensitivity to performance feedback is relatively coherent, we still do not know whether increased or decreased sensitivity to positive or negative feedback is associated with 'pro-depressive' profile in healthy subjects. OBJECTIVE: Our research has been designed to answer this question, and here, we present the first steps in that direction. METHODS: Using a rat version of the probabilistic reversal-learning (PRL) paradigm, we evaluated how sensitivity to negative and positive feedback influences other cognitive processes associated with mood disorders, such as motivation in the progressive ratio schedule of reinforcement (PRSR) paradigm, hedonic status in the sucrose preference (SP) test, locomotor and exploratory activity in the open field (OF) test, and anxiety in the light/dark box (LDB) test. RESULTS: The results of our study demonstrated for the first time that in rodents, sensitivity to negative and positive feedback could be considered a stable and enduring behavioural trait. Importantly, we also showed that these traits are independent of each other and that trait sensitivity to positive feedback is associated with cognitive flexibility in the PRL test. The computational modelling results also revealed that in animals classified as sensitive to positive feedback, the α learning rates for both positive and negative reward prediction errors were higher than those in animals classified as insensitive. We observed no statistically significant interactions between sensitivity to negative or positive feedback and the parameters measured in the PRSR, SP, OF or LDB tests. CONCLUSIONS: Further studies using animal models of depression based on chronic stress should reveal whether sensitivity to feedback is a latent trait that when interacts with stressful life events, could produce correlates of depressive symptoms in rats.

Using rodents to model abnormal sensitivity to feedback in depression.

Depressive disorder accounts for a substantial proportion of psychiatric problems across the globe and has a devastating impact on quality of life and occupational function. Psychological models of depression emphasize the causal role of cognitive distortions in this disease, and cognitive problems have been included in the diagnostic criteria for depressive episodes. Here, we focus on recent progress in preclinical modelling of aberrations in one of the most important neurocognitive mechanisms involved in the manifestation of depression - abnormal sensitivity to positive and negative feedback. First, we summarize the recent advances in understanding neurocognitive mechanisms of aberrant feedback sensitivity in depression and underlying neurobiological substrates. Second, by combining behavioural, neurochemical, neuroanatomical and pharmacological approaches, we evaluate the translational value of the probabilistic reversal-learning (PRL) task, a behavioural paradigm that enables investigation of correlates of feedback sensitivity in humans and animals. Finally, we identify and discuss directions for future investigation, including cognitive biomarkers of depression and resilience to stress based on feedback sensitivity and personalized treatment targets.