Risk of chronic thromboembolic pulmonary hypertension after splenectomy.

OBJECTIVES: The purpose of the clinical study was to evaluate the risk of chronic thromboembolic pulmonary hypertension (CTEPH) after splenectomy and to analyze some biochemical and coagulation parameters. BACKGROUND: CTEPH caused by incomplete resolution of thromboemboli and irreversible remodeling of the pulmonary arteries is a progressive, and without treatment a fatal disease. Although the definite etiopathophysiology is not quite perfectly researched, numerous clinical conditions associated with CTEPH as history of pulmonary embolism, infected ventriculoatrial shunts or permanent intravascular devices, high-dose thyroid hormone replacement, malignancy and chronic inflammatory diseases, including osteomyelitis, inflammatory bowel diseases, are well accepted. These factors also include splenectomy. METHODS: We performed a prospective follow-up of patients after splenectomy in the period of 5 years (2017-2022). The study population consisted of 62 adult post-splenectomy patients, who were divided into 3 groups based on the cause of the splenectomy - trauma, haematologic diseases, and others. The study population was analyzed in terms of gender, age, cause of splenectomy, blood group, clinical risk factors and thrombophilic conditions. Some basic haemocoagulation parameters and selected coagulation and biochemical parameters were analyzed. All patients underwent screening echocardiography, symptomatic patients repeatedly. In the presence of pulmonary hypertension (PH) unexplained by other diseases, patients underwent ventilation/perfusion lung scan performed to confirm/exclude perfusion defects typical for CTEPH. If PH and perfusion defects persisted despite effective 3-month anticoagulation therapy, patients underwent right heart catheterization to confirm/exclude CTEPH. RESULTS: The study confirmed a higher incidence of CTEPH after splenectomy compared to published data, the 5-year cumulative incidence was 3.2 %. Other detected clinical risk factors did not affect the incidence of thromboembolism/CTEPH after splenectomy. In our study, the strongest factor in terms of the incidence of thromboembolism/CTEPH after splenectomy was the presence of a thrombophilia detected before the screening echocardiography. Tested haemocoagulation and biochemical parameters in small patient subgroup had no impact on the incidence of thromboembolism/CTEPH - however, the limiting factor was a small patient subgroup. CONCLUSION: The results of the study suggest that the incidence of thromboembolism after splenectomy was consistent with the present data, but the incidence of CTEPH after splenectomy was significantly higher. This suggests that post-splenectomy condition may be an independent risk factor for CTEPH and may imply different management of these patients in the future (Tab. 5, Ref. 18).

The performance and limitations of PCA3, TMPRSS2:ERG, HOXC6 and DLX1 urinary markers combined in the improvement of prostate cancer diagnostics.

BACKGROUND: Prostate cancer (PCa) is the second most commonly diagnosed cancer in men. To date, the role of the combined application of long non-coding RNAs (PCA3, DLX1, HOXC6, TMPRSS2:ERG) for obtaining the most accurate method of detection of PCa has not yet been comprehensively investigated. METHODS: In total 240 persons were included in the retrospective study. Among them were 150 patients with confirmed PCa, 30 patients with benign prostatic hyperplasia, 30 patients with active chronic prostatitis and 30 healthy volunteers. In all patients, the urine samples were collected prior to biopsy or treatment. Polymerase chain reaction with reverse transcription was performed to detect the expression level of PCA3, HOXC6, DLX1 and the presence of the TMPRSS2:ERG transcript. RESULTS: PCA3 was detected in urine samples in all cases. Using a PCA3 score of 56 allowed the differentiation between PCa and all other cases with a sensitivity of 61% and specificity of 96% (p < 0.001) while a PCA3 score threshold value of 50 resulted in a differentiation between clinically significant PCa (ISUP grades 2-5) and all other cases with a sensitivity of 93% and specificity of 93% (p < 0.001). The TMPRSS2:ERG expression in urine was detected exclusively in the group of patients with PCa and only in 16% of all cases. CONCLUSIONS: PCA3 score detected in urine demonstrated moderate sensitivity and good specificity in differentiation between PCa and non-PCa and high sensitivity and specificity in differentiation between clinically significant PCa and non-PCa.

Flavonoids attenuate cancer metabolism by modulating Lipid metabolism, amino acids, ketone bodies and redox state mediated by Nrf2.

Metabolic reprogramming of cancer cells is a common hallmark of malignant transformation. The preference for aerobic glycolysis over oxidative phosphorylation in tumors is a well-studied phenomenon known as the Warburg effect. Importantly, metabolic transformation of cancer cells also involves alterations in signaling cascades contributing to lipid metabolism, amino acid flux and synthesis, and utilization of ketone bodies. Also, redox regulation interacts with metabolic reprogramming during malignant transformation. Flavonoids, widely distributed phytochemicals in plants, exert various beneficial effects on human health through modulating molecular cascades altered in the pathological cancer phenotype. Recent evidence has identified numerous flavonoids as modulators of critical components of cancer metabolism and associated pathways interacting with metabolic cascades such as redox balance. Flavonoids affect lipid metabolism by regulating fatty acid synthase, redox balance by modulating nuclear factor-erythroid factor 2-related factor 2 (Nrf2) activity, or amino acid flux and synthesis by phosphoglycerate mutase 1. Here, we discuss recent preclinical evidence evaluating the impact of flavonoids on cancer metabolism, focusing on lipid and amino acid metabolic cascades, redox balance, and ketone bodies.

Kidney manifestations of mitochondrial disorders.

Mitochondria are intracellular organelles involved in a number of key biologic processes in the cell, including energy production, redox signaling, calcium homeostasis, inflammation, senescence, innate immune response, and mitophagy. Mitochondrial cytopathies include a heterogeneous group of diseases that are characterized by impaired oxidative phosphorylation, leading to multi-organ involvement and progressive clinical deterioration. Mitochondrial cytopathies can result from mitochondrial or nuclear DNA mutations. Mitochondrial defects play an important role in the pathogenesis of nephropathies as tubular syndromes, interstitial nephritis, focal and segmental glomerulosclerosis and diabetic nephropathy. The role of mitochondria in a pathogenesis of nephrotoxicity and kidney carcinogenesis is also discussed (Tab. 2, Fig. 7, Ref. 100). Keywords: mitochondrial nephropathy, interstitial nephritis, glomerulosclerosis, diabetic nephropathy, nephrotoxicity, mitochondrial cytopathies.

Systemic treatment of the metastatic renal cell carcinoma: usefulness of the apparent diffusion coefficient of diffusion-weighted MRI in prediction of early therapeutic response.

Accurate prediction of early treatment response to systemic therapy (ST) with tyrosine kinase inhibitors (TKI) in patients with metastatic renal cell carcinoma (mRCC) could help avoid ineffective and expensive treatment with serious side effects. Neither RECIST v.1.1 nor Choi criteria successfully discriminate between patients with mRCC who received ST having a short or long time to progression (TTP). There is no biomarker, which is able to predict early therapeutic response to TKIs application in patients with mRCC. The goal of our study was to investigate the potential of apparent diffusion coefficient (ADC) of diffusion-weighted imaging (DWI) of MRI in prediction of early therapeutic response to ST with pazopanib in patients with mRCC. The retrospective study enrolled 32 adult patients with conventional mRCC who received pazopanib (mean duration-7.5 ± 3.45). The mean duration of follow-up was 11.85 ± 4.34 months. In all patients as baseline examination and 1 month after treatment, 1.5T MRI including DWI sequence was performed followed by ADC measurement of the main renal lesion. For assessment of the therapeutic response, RECIST 1.1 is used. Partial response (PR), stable disease (SD) and progressive disease (PD) were observed in 12 (37.50%), 10 (31.25%) and 10 (31.25%) cases with mean TTP of 10.33 ± 2.06 months (95% confidence interval, CI = 9.05-11.61), 7.40 ± 2.50 months (95% CI = 5.61-9.19) and 4.20 ± 1.99 months (95% CI = 2.78-5.62) accordingly (p < 0.05). There was no difference in change of main lesions' longest size 1 month after ST in patients with PR, SD and PD. Comparison of mean ADC values before and 1 month after systemic treatment showed significant decrease by 19.11 ± 10.64% (95% CI = 12.35-25.87) and by 7.66 ± 6.72% (95% CI = 2.86-12.47) in subgroups with PR and SD, respectively (p < 0.05). There was shorter TTP in patients with mRCC if ADC of the main renal lesion 1 month after the ST increased from the baseline less than 1.73% compared to patients with ADC levels above this threshold: 5.29 ± 3.45 versus 9.50 ± 2.04 months accordingly (p < 0.001). Overall, our findings highlighted the use of ADC as a predictive biomarker for early therapeutic response assessment. Use of ADC will be effective and useful for reliable prediction of responders and non-responders to systemic treatment with pazopanib.

MicroRNA-15a tissue expression is a prognostic marker for survival in patients with clear cell renal cell carcinoma.

None of the currently investigated molecular markers demonstrated sufficient accuracy in prognostication of the renal cell carcinoma (RCC) oncologic outcomes; thus, none of them has been recommended for the application in the routine clinical practice. The role of miR-15a as a potential prognostic marker for RCC is still not unveiled. The aim of our study was to assess the expression of miR-15a in tumor tissues of the patients with RCC and to evaluate the possibility of its usage as a prognostic molecular biomarker of this disease. The retrospective included 64 adult patients with clear cell RCC (ccRCC) in whom radical or partial nephrectomy was conducted. After deparaffinization of formalin-fixed paraffin-embedded (FFPE) ccRCC specimens, the tissue expression of miR-15a was measured using the reverse transcription and quantitative polymerase chain reaction in the real time. For the reference, the expression of miR-15a was estimated in 15 FFPE tissue specimens of the normal renal parenchyma. Survival analysis involved all cases of non-metastatic RCCs (n = 57). Five-year cancer-specific survival (CSS) was estimated by means of the Kaplan-Meier method and was calculated from the date of surgery to the date of death. Patients with the RCC were characterized by significantly upregulated tumor tissue mean levels of miR-15a compared to the healthy controls: 0.10 ± 2.62 relative units (RU) versus 4.84E - 03 ± 3.11E - 03 RU (p < 0.001). Overexpression of miR-15a was strongly associated with poor histologic prognostic features of ccRCC. Poorly differentiated tumors tend to have more pronounced upregulation of miR-15a compared to highly differentiated lesions: Mean expression values were 4.57 ± 3.19 RU for Fuhrman grade 4 versus 0.02 ± 0.01 RU for Fuhrman grade 1 (p < 0.001). The metastatic involvement of the regional lymphatic nodules (N +) was associated with significantly upregulated miRNA-15a in comparison with N - cases: Mean expression values were 4.92 ± 2.80 RU versus 1.10 ± 2.29 RU, respectively (p < 0.001). In patients with miR-15a expression in RCC tissues ≤ 0.10 RU, mean 5-year CSS was significantly longer compared to patients with expression levels above this threshold: 92.31% (mean duration of survival-59.88 ± 0.12 months) versus 54.8% (mean duration of survival-49.74 ± 2.16 months), respectively (p < 0.001). The tissue expression of miR-15a could be used as a potential prognostic molecular biomarker for conventional RCC.

MicroRNA-15a expression measured in urine samples as a potential biomarker of renal cell carcinoma.

INTRODUCTION: Currently, there is no accurate diagnostic molecular biomarker for renal cell carcinoma (RCC). The aim of this study was to assess the expression of microRNA-15a (miR-15a) in urine of patients with RCC and to evaluate its potential as a diagnostic molecular biomarker. MATERIALS AND METHODS: In total, 67 patients with solid renal tumors were enrolled: clear-cell RCC (ccRCC, n = 22), papillary RCC (pRCC, n = 16), chromophobe RCC (chRCC, n = 14), oncocytoma (n = 8), papillary adenoma (n = 2) and angiomyolipoma (n = 5). MiRNA-15a expression levels measurement in urine were performed using qPCR. Urine of 15 healthy volunteers without kidney pathology was used as control. RESULTS: We observed a difference in mean miR-15a expression values in groups of pre-operative patients with RCC, benign renal tumors and healthy persons (2.50E-01 ± 2.72E-01 vs 1.32E-03 ± 3.90E-03 vs 3.36E-07 ± 1.04E-07 RFU, respectively, p < 0.01). There was no difference in miR-15a expression between ccRCC, pRCC and chRCC (p > 0.05). Direct association between RCC size and miR-15a expression values was obtained (Pearson correlation coefficient-0.873). On the 8th day after nephrectomy, mean expression value in patients with RCC decreased by 99.53% (p < 0.01). MiR-15a expression differentiated RCC from benign renal tumors with 98.1% specificity, 100% sensitivity at a cut-off value of 5.00E-06 RFU, with AUC-0.955. CONCLUSIONS: MiR-15a expression measured in urine may be used as diagnostic molecular biomarker for RCC.

Melatonin and breast cancer: Evidences from preclinical and human studies.

The breast cancer affects women with high mortality and morbidity worldwide. The risk is highest in the most developed world but also is markedly rising in the developing countries. It is well documented that melatonin has a significant anti-tumor activities demonstrated on various cancer types in a plethora of preclinical studies. In breast cancer, melatonin is capable to disrupt estrogen-dependent cell signaling, resulting in a reduction of estrogen-stimulated cells, moreover, it's obvious neuro-immunomodulatory effect in organism was described. Several prospective studies have demonstrated the inverse correlation between melatonin metabolites and the risk of breast cancer. This correlation was confirmed by observational studies that found lower melatonin levels in breast cancer patients. Moreover, clinical studies have showed that circadian disruption of melatonin synthesis, specifically night shift work, is linked to increased breast cancer risk. In this regard, proper light/dark exposure with more selective use of light at night along with oral supplementation of melatonin may have benefits for high-risk women. The results of current preclinical studies, the mechanism of action, and clinical efficacy of melatonin in breast cancer are reviewed in this paper. Melatonin alone or in combined administration seems to be appropriate drug for the treatment of early stages of breast cancer with documented low toxicity over a wide range of doses. These and other issues are also discussed.

Differential diagnosis of the small renal masses: role of the apparent diffusion coefficient of the diffusion-weighted MRI.

INTRODUCTION: Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and more than 90% of neoplasms arising from the kidney. Uninformative percutaneous kidney biopsies vary from 10 to 23%. As a result, 7.5-33.6% of partial nephrectomies in patients with small renal masses (SRM) are performed on benign renal tumors. The aim of this study was to assess the feasibility of the apparent diffusion coefficient (ADC) of the diffusion-weighted imaging (DWI) of MRI, as RCC imaging biomarker for differentiation of SRM. METHOD: Adult patients (n = 158) with 170 SRM were enrolled into this study. The control group were healthy volunteers with normal clinical and radiologic findings (n = 15). All participants underwent MRI with DWI sequence included. RESULTS: Mean ADC values of solid RCC (1.65 ± 0.38 × 10-3 mm2/s) were lower than healthy renal parenchyma (2.47 ± 0.12 × 10-3 mm2/s, p < 0.05). There was no difference between mean ADC values of ccRCC, pRCC and chRCC (1.82 ± 0.22 × 10-3 vs 1.61 ± 0.07 × 10-3 vs 1.46 ± 0.09 × 10-3 mm2/s, respectively, p = ns). An inverse relationship between mean ADC values and Fuhrman grade of nuclear atypia of solid ccRCCs was observed: grade I-1.92 ± 0.11 × 10-3 mm2/s, grade II-1.84 ± 0.14 × 10-3 mm2/s, grade III-1.79 ± 0.10 × 10-3 mm2/s, grade IV-1.72 ± 0.06 × 10-3 mm2/s. This was significant (p < 0.05) only between tumors of I and IV grades. Significant difference (p < 0.05) between mean ADC values of solid RCCs, benign renal tumors and renal cysts was observed (1.65 ± 0.38 × 10-3 vs 2.23 ± 0.18 × 10-3 vs 3.15 ± 0.51 × 10-3 mm2/s, respectively). In addition, there was a significant difference (p < 0.05) in mean ADC values between benign cysts and cystic RCC (3.36 ± 0.35 × 10-3 vs 2.83 ± 0.21 × 10-3 mm2/s, respectively). CONCLUSION: ADC maps with b values of 0 and 800 s/mm2 can be used as an imaging biomarker, to differentiate benign SRM from malignant SRM. Using ADC value threshold of 1.75 × 10-3 mm2/s allows to differentiate solid RCC from solid benign kidney tumors with 91% sensitivity and 89% specificity; ADC value threshold of 2.96 × 10-3 mm2/s distinguishes cystic RCC from benign renal cysts with 90% sensitivity and 88% specificity. However, the possibility of differentiation between ccRCC histologic subtypes and grades, utilizing ADC values, is limited.

Polymorphism rs2073618 of the osteoprotegerin gene as a potential marker of subclinical carotid atherosclerosis in Caucasians with type 2 diabetes mellitus.

BACKGROUND: The OPG/RANKL/RANK (osteoprotegerin/receptor-activator of nuclear factor κB ligand/receptor-activator of nuclear factor κB) axis has been recently linked to the development of atherosclerosis and plaque destabilization. We have investigated whether polymorphism rs2073618 of the OPG gene is associated with subclinical markers of carotid atherosclerosis in subjects with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: 595 subjects with T2DM were enrolled in the cross-sectional study. Subclinical markers of carotid atherosclerosis (carotid intima media thickness, plaque thickness, and plaques presence) were assessed with ultrasound at the time of recruitment. Genotyping for rs2073618 (a missense variant located in exon I of the OPG gene) was performed, and OPG serum levels were determined by ELISA. RESULTS: Compared to the GG genotype, the CC genotype of the rs2073618 polymorphism had a significantly increased risk for the presence of carotid plaque (OR = 2.54, 95 % CI = 1.22-5.28, p = 0.01). No statistically significant difference could be detected (p = 0.68) upon comparing median values of serum OPG levels among studied genotype groups in subjects with T2DM. Multivariable linear regression analyses in T2DM subjects demonstrated that GC and CC genotypes (p = 0.03 and p = 0.003), together with statin therapy (p = 0.009), were independent predictors of the number of carotid segments with plaques. CONCLUSIONS: Despite the fact that OPG rs2073618 genotypes failed to predict the serum OPG levels as there was no statistical difference among compared genotypes, our results demonstrate that the rs2073618 polymorphism could be a possible genetic marker for the prediction of increased risk for carotid plaque burden as a measure of advanced subclinical atherosclerosis in T2DM subjects.

Immunomodulatory effects of stem cells: Therapeutic option for neurodegenerative disorders.

Stem cells have the capability of self-renewal and can differentiate into different cell types that might be used in regenerative medicine. Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) currently lack effective treatments. Although stem cell therapy is still on the way from bench to bedside, we consider that it might provide new hope for patients suffering with neurodegenerative diseases. In this article, we will give an overview of recent studies on the potential therapeutic use of mesenchymal stem cells (MSCs), neural stem cells (NSCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and perinatal stem cells to neurodegenerative disorders and we will describe their immunomodulatory mechanisms of action in specific therapeutic modalities.

Angiomodulators in cancer therapy: New perspectives.

The formation of new blood vessels plays a crucial for the development and progression of pathophysiological changes associated with a variety of disorders, including carcinogenesis. Angiogenesis inhibitors (anti-angiogenics) are an important part of treatment for some types of cancer. Some natural products isolated from marine invertebrates have revealed antiangiogenic activities, which are diverse in structure and mechanisms of action. Many preclinical studies have generated new models for further modification and optimization of anti-angiogenic substances, and new information for mechanistic studies and new anti-cancer drug candidates for clinical practice. Moreover, in the last decade it has become apparent that galectins are important regulators of tumor angiogenesis, as well as microRNA. MicroRNAs have been validated to modulate endothelial cell migration or endothelial tube organization. In the present review we summarize the current knowledge regarding the role of marine-derived natural products, galectins and microRNAs in tumor angiogenesis.

Renal cell carcinoma: applicability of the apparent coefficient of the diffusion-weighted estimated by MRI for improving their differential diagnosis, histologic subtyping, and differentiation grade.

BACKGROUND: Renal cell carcinoma (RCC) represents the most common malignant epithelial neoplasm of the kidney. Accurate assessment of the renal masses, defining the histologic subtype and the grade of differentiation of the tumor, is vital to ensure an adequate case management as well as for staging and prognosis. Recently, diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI) tends to be increasingly appealing for the clinicians as an imaging procedure of choice for the diagnosis and staging of the RCC, which is predetermined by several advantages over CT. The goal of the survey was to assess the applicability of the apparent diffusion coefficient (ADC) of the DWI MRI for the differential diagnostics, histologic subtyping, and defining the grade of differentiation of the RCC. METHODS: The study enrolled 288 adult patients with renal lesions: 188 patients with solid RCC-126 patients with clear cell subtype (ccRCC), 32 patients with papillary RCC (pRCC), 30 patients with chromophobe RCC (chRCC); 27 patient with cystic form or RCC (Bosniak cyst, category IV); 32 patients with renal angiomyolipoma (AML); 25 patients with renal oncocytoma (OC); and 16 patients with the renal abscess (AB). In total, 245 lesions were pathologically verified. As a reference, 19 healthy volunteers were included into the study. All patients underwent MRI of the kidneys, involving DWI with subsequent evaluation of the ADC. RESULTS: There was a reliable difference (p < 0.05) in mean ADC values between the normal renal parenchyma (NRP), solid RCC of different histologic subtypes and grades, cystic RCC, and benign renal lesions. The mean ADC values obtained in the result of the study were (×10-3 mm2/s): 2.47 ± 0.12 in NRP, 1.63 ± 0.29 in all solid RCCs, 1.82 ± 0.22 in solid ccRCC (1.92 ± 0.11-Fuhrman grade I, 1.84 ± 0.14-Fuhrman grade II, 1.79 ± 0.10-Fuhrman grade III, 1.72 ± 0.06-Fuhrman grade IV), 1.61 ± 0.07 in pRCC, 1.46 ± 0.09 in chRCC, 2.68 ± 0.11 in cystic RCC, 2.13 ± 0.08 in AML, 2.26 ± 0.06 in OC, and 3.30 ± 0.07 in AB. CONCLUSION: The data received in our study demonstrate a substantial restriction of diffusion of hydrogen molecules in tissues of ccRCC in comparison with the healthy renal parenchyma preconditioned by the greater density of tumor. A statistically significant difference in mean ADC values of ccRCC with different grades of nuclear pleomorphism by Fuhrman was observed: Low-grade tumors showed higher mean ADC values compared to high-grade tumors. The modality of the MRI DWI along with ADC measurement allows to reliably differentiate between the solid RCC of main histologic subtypes and grades, cystic RCC, and the benign renal lesions.

IRAP inhibition using HFI419 prevents moderate to severe acetylcholine mediated vasoconstriction in a rabbit model.

Coronary artery vasospasm (constriction) caused by reduced nitric oxide bioavailability leads to myocardial infarction. Reduced endothelial release of nitric oxide by the neurotransmitter acetylcholine, leads to paradoxical vasoconstriction as it binds to smooth muscle cell M3 receptors. Thus, inhibition of coronary artery vasospasm will improve clinical outcomes. Inhibition of insulin regulated aminopeptidase has been shown to improve vessel function, thus we tested the hypothesis that HFI419, an inhibitor of insulin regulated aminopeptidase, could reduce blood vessel constriction to acetylcholine. The abdominal aorta was excised from New Zealand white rabbits (n=15) and incubated with 3mM Hcy to induce vascular dysfunction in vitro for 1h. HFI419 was added 5min prior to assessment of vascular function by cumulative doses of acetylcholine. In some rings, vasoconstriction to acetylcholine was observed in aortic rings after pre-incubation with 3mM homocysteine. Incubation with HFI419 inhibited the vasoconstrictive response to acetylcholine, thus improving, but not normalizing, vascular function (11.5±8.9% relaxation vs 79.2±37% constriction, p<0.05). Similarly, in another group with mild vasoconstriction, HFI419 inhibited this effect (34.9±4.6% relaxation vs 11.1±5.2%, constriction, p<0.05). HFI419 had no effect on control aorta or aorta with mild aortic dysfunction. The present study shows that HFI419 prevents acetylcholine mediated vasoconstriction in dysfunctional blood vessels. HFI419 had no effect on normal vasodilation. Our results indicate a therapeutic potential of HFI419 in reducing coronary artery vasospasm.