Calcitriol promotes M2 polarization of tumor-associated macrophages in 4T1 mouse mammary gland cancer via the induction of proinflammatory cytokines.

Our research found that vitamin D3 (VD3) treatment increased lung metastasis in mice with 4T1 murine breast cancer (BC). This study aims to investigate the impact of VD3 on the activation of tumor-associated macrophages (TAMs) in BC. Mice bearing 4T1, E0771, 67NR BC cells, and healthy mice, were fed diets with varying VD3 contents (100-deficient, 1000-normal, and 5000 IU/kg-elevated). Some mice in the 1000 and 100 IU/kg groups received calcitriol. We studied bone metastasis and characterized TAMs and bone marrow-derived macrophages (BMDMs). 4T1 cells had higher bone metastasis potential in the 5000 IU/kg and calcitriol groups. In the same mice, an elevated tumor osteopontin level and M2 polarization of TAMs (MHCIIlow CD44high phenotype) were observed. Gene expression analysis confirmed M2 polarization of 4T1 (but not 67NR) TAMs and BMDMs, particularly in the 100 IU + cal group (increased Mrc1, Il23, and Il6). This polarization was likely due to COX-2/PGE2 induction in 4T1 calcitriol-treated cells, leading to increased proinflammatory cytokines like IL-6 and IL-23. Future studies will explore COX-2/PGE2 as a primary mediator of calcitriol-stimulated inflammation in the BC microenvironment, especially relevant for BC patients with VD3 deficiency and supplementation.

Dual effect of vitamin D3 on breast cancer-associated fibroblasts.

BACKGROUND: Cancer-associated fibroblasts (CAFs) play an important role in the tumor microenvironment. Despite the well-known in vitro antitumoral effect of vitamin D3 (VD3), its impact on breast CAFs is almost unknown. In this study, we analyzed the ex vivo effects of calcitriol on CAFs isolated from breast cancer tissues. METHODS: CAFs were cultured with 1 and 10 nM calcitriol and their phenotype; gene expression, protein expression, and secretion were assessed. Calcitriol-treated CAFs-conditioned media (CM) were used to analyze the effect of CAFs on the migration and protein expression of MCF-7 and MDA-MB-231 cells. RESULTS: Tumor tissues from VD3-deficient patients exhibited lower levels of ß-catenin and TGFß1, along with higher levels of CYP24A1 compared to VD3-normal patients. In VD3-deficient patients, CAF infiltration was inversely associated with CYP24A1 levels and positively correlated with OPN levels. Calcitriol diminished CAFs' viability, but this effect was weaker in premenopausal and VD3-normal patients. Calcitriol reduced mRNA expression of CCL2, MMP9, TNC, and increased PDPN, SPP1, and TIMP1. It also decreased the secretion of CCL2, TNC, and the activity of MMP-2, while increasing cellular levels of TIMP1 in CAFs from all patient groups. In nonmetastatic and postmenopausal patients, PDPN surface expression increased, and CAFs CM from these groups decreased MCF-7 cell migration after ex vivo calcitriol treatment. In premenopausal and VD3-deficient patients, calcitriol reduced IDO1 expression in CAFs. Calcitriol-treated CAFs CM from these patients decreased OPN expression in MCF-7 and/or MDA-MB-231 cells. However, in premenopausal patients, calcitriol-treated CAFs CM also decreased E-cadherin expression in both cell lines. CONCLUSION: The effects of calcitriol on breast CAFs, both at the gene and protein levels, are complex, reflecting the immunosuppressive or procancer properties of CAFs. The anticancer polarization of CAFs following ex vivo calcitriol treatment may result from decreased CCL2, TNC (gene and protein), MMP9, and MMP-2, while the opposite effect may result from increased PDPN, TIMP1 (gene and protein), and SPP1. Despite these multifaceted effects of calcitriol on molecule expression, CAFs' CMs from nonmetastatic and postmenopausal patients treated ex vivo with calcitriol decreased the migration of MCF-7 cells.

Electrical Parameters as Diagnostics of Fresh Engine Oil Condition-Correlation with Test Voltage Frequency.

The aim of this study was to assess whether electrical parameters (capacitance and conductivity) of fresh engine oils-tested over a wide range of measurement voltage frequencies-can be used for oil quality assessment and its identification, based on physicochemical properties. The study encompassed 41 commercial engine oils with different quality ratings (American Petroleum Institute (API) and European Automobile Manufacturers' Association (ACEA)). As part of the study, the oils were tested for their total base number (TBN) and total acid number (TAN), as well as their electrical parameters, including impedance magnitude, phase shift angle, conductance, susceptance, capacitance and quality factor. Next, the results for all of the samples were examined for correlations between the mean electrical parameters and the test voltage frequency. A statistical analysis (k-means and agglomerative hierarchical clustering) was applied to group oils with similar readings, drawing on the values for all electrical parameters to produce group oils with the highest similarity to each other into clusters. The results show that the electrical-based diagnostics of fresh engine oils can serve as a highly selective method for identifying oil quality, offering much higher resolution than assessments based on the TBN or the TAN. This is further supported by the cluster analysis, with five clusters generated for electrical parameters of the oils, compared to only three generated for TAN- and TBN-based measurements. Out of all the tested electrical parameters, capacitance, impedance magnitude and quality factor were found to be the most promising for diagnostic purposes. The value of electrical parameters of fresh engine oils is mostly dependent on the test voltage frequency (with the exception of capacitance). The correlations identified in the course of the study can be used to select for those frequency ranges that offer the highest diagnostic utility.

Modulation of Fibroblast Activity via Vitamin D3 Is Dependent on Tumor Type-Studies on Mouse Mammary Gland Cancer.

Vitamin D3 and its analogs are known to modulate the activity of fibroblasts under various disease conditions. However, their impact on cancer-associated fibroblasts (CAFs) is yet to be fully investigated. The aim of this study was to characterize CAFs and normal fibroblasts (NFs) from the lung of mice bearing 4T1, 67NR, and E0771 cancers and healthy mice fed vitamin-D3-normal (1000 IU), -deficient (100 IU), and -supplemented (5000 IU) diets. The groups receiving control (1000 IU) and deficient diets (100 IU) were gavaged with calcitriol (+cal). In the 4T1-bearing mice from the 100 IU+cal group, increased NFs activation (increased α-smooth muscle actin, podoplanin, and tenascin C (TNC)) with a decreased blood flow in the tumor was observed, whereas the opposite effect was observed in the 5000 IU and 100 IU groups. CAFs from the 5000 IU group of E0771-bearing mice were activated with increased expression of podoplanin, platelet-derived growth factor receptor ß, and TNC. In the 100 IU+cal group of E0771-bearing mice, a decreased blood flow was recorded with decreased expression of fibroblast growth factor 23 (FGF23) and C-C motif chemokine ligand 2 (CCL2) in tumors and increased expression of TNC on CAFs. In the 67NR model, the impact of vitamin D3 on blood flow or CAFs and lung NFs was not observed despite changes in plasma and/or tumor tissue concentrations of osteopontin (OPN), CCL2, transforming growth factor-ß, vascular endothelial growth factor, and FGF23. In healthy mice, divergent effects of vitamin D3 supplementation/deficiency were observed, which lead to the creation of various body microenvironments depending on the mouse strain. Tumors developing in such microenvironments themselves modified the microenvironments by producing, for example, higher concentrations of OPN and stromal-cell-derived factor 1 (4T1), which influences the response to vitamin D3 supplementation/deficiency and calcitriol administration.

Alcohol and Cardiovascular Diseases-Do the Consumption Pattern and Dose Make the Difference?

Excessive consumption of alcohol is not only a social problem, but it also significantly increases the morbidity and mortality rates of many societies. A correlation has been demonstrated between alcohol consumption and increased mortality from cancer, accidents and injuries, liver cirrhosis and other causes. Alcohol abuse increases the incidence of hemorrhagic stroke and the risk of ischemic stroke, induces serious arrhythmias, adversely affects blood pressure and damages the heart muscle. The dose and way of drinking alcohol play a crucial role in assessing whether this drink allows people to maintain health or whether it is a great health and social threat. The beneficial effects of low and moderate doses of alcohol on the occurrence of cardiovascular diseases have been shown in many population studies and meta-analyses in which the effect of U-shaped or J-shaped curves relating alcohol intake to cardiovascular mortality was observed, especially in ischemic heart disease. However, due to the fact that alcohol consumption is associated with many health hazards, it is not recommended to consume it as a preventive action of cardiovascular diseases. Moreover, recent studies suggest that association of low-to-moderate alcohol consumption with the reduction in cardiovascular risk is a result of lifestyle changes and that any reduction in alcohol consumption is in fact beneficial in terms of general health.

Micro-RNAs in Response to Active Forms of Vitamin D3 in Human Leukemia and Lymphoma Cells.

Non-coding micro-RNA (miRNAs) regulate the protein expression responsible for cell growth and proliferation. miRNAs also play a role in a cancer cells' response to drug treatment. Knowing that leukemia and lymphoma cells show different responses to active forms of vitamin D3, we decided to investigate the role of selected miRNA molecules and regulated proteins, analyzing if there is a correlation between the selected miRNAs and regulated proteins in response to two active forms of vitamin D3, calcitriol and tacalcitol. A total of nine human cell lines were analyzed: five leukemias: MV-4-1, Thp-1, HL-60, K562, and KG-1; and four lymphomas: Raji, Daudi, Jurkat, and U2932. We selected five miRNA molecules-miR-27b, miR-32, miR-125b, miR-181a, and miR-181b-and the proteins regulated by these molecules, namely, CYP24A1, Bak1, Bim, p21, p27, p53, and NF-kB. The results showed that the level of selected miRNAs correlates with the level of proteins, especially p27, Bak1, NFκB, and CYP24A1, and miR-27b and miR-125b could be responsible for the anticancer activity of active forms of vitamin D3 in human leukemia and lymphoma.

The Impact of Exosomes/Microvesicles Derived from Myeloid Dendritic Cells Cultured in the Presence of Calcitriol and Tacalcitol on Acute B-Cell Precursor Cell Lines with MLL Fusion Gene.

Vitamin D analogs (VDAs) may directly inhibit the growth of normal and malignant (derived from acute lymphoblastic leukemia (ALL)) B cells, as both types of cells express vitamin D receptor (VDR). We performed anti-proliferative, morphology tests and phenotyping to evaluate the sensitivity of monocytes and iDCs (immature myeloid-derived dendritic cells) on calcitriol and tacalcitol treatment, phenotyping, morphology, and size distribution measurement to determine the characteristics of microvesicles (MVs) and exosomes (EXs) derived from them and, finally, phenotyping and Elisa test to determine the effects of VDAs on modulation of the phenotype of B cells through extracellular vesicles (EVs) released by iDCs. Our results confirmed that both SC cells and iDCs were sensitive to the VDAs and showed altered surface expression of markers associated with monocyte differentiation, which was resulting in the phenotypic changes in EVs derived from them. We also showed that obtained EVs could change the morphology and phenotype of ALL-B-derived precursor cells in a different way, depending on their origin. The differential effect of VDAs on ALL-B cells, which was associated with increased or decreased expression of CD27, CD24, CD38, and CD23 expression, was observed. Hence, further studies to explain the modulation in the composition of EVs by VDAs are required.

Polymorphism of VDR Gene and the Sensitivity of Human Leukemia and Lymphoma Cells to Active Forms of Vitamin D.

The active forms of vitamin D3 (calcitriol and tacalcitol) coupled to the vitamin D receptor (VDR) are known to exhibit anti-cancer properties. However, not all cancer cells are sensitive to the active forms of vitamin D3 and its analogs. The study aimed to determine whether polymorphism of VDR is responsible for the sensitivity of human leukemia and lymphoma cells to calcitriol and tacalcitol. The impact of calcitriol and tacalcitol on the proliferation and morphology of nine different leukemia and lymphoma cell lines was determined. Only MV-4-11, Thp-1, and HL-60 cell lines sensitive to proliferation inhibition by calcitriol and tacalcitol showed morphology changes. Subsequently, the levels of the VDR and 1,25D3-MARRS proteins of calcitriol and tacalcitol binding receptors and the VDR receptor polymorphism in human leukemia and lymphoma cells were ascertained. Contrary to the current understanding, higher levels of VDR are not responsible for the greater sensitivity of cells to calcitriol and tacalcitol. Importantly, we first showed that sensitivity to calcitriol and tacalcitol in leukemias and lymphomas could be determined by the VDR polymorphism. The FokI polymorphism and the presence of the "bat" haplotype were observed only in the sensitive cells.

Resveratrol and cardiovascular system-the unfulfilled hopes.

INTRODUCTION: Resveratrol is a natural polyphenolic compound with a stilbene structure endowed with multiple health-promoting effects. Among phenolic compounds, resveratrol is assigned a leading role in the health-promoting effects of red wine. METHODS: The aim of the study was to assess the effect of resveratrol on the cardiovascular system in the experimental and clinical studies conducted so far. Moreover, the paper discusses the results of the most recent meta-analyses assessing resveratrol's therapeutic effect on the cardiovascular system in humans. RESULTS: In animal and preclinical studies, resveratrol has demonstrated a wide physiological and biochemical spectrum of activity, including antioxidant, anti-inflammatory, antiplatelet, and anticoagulant activities, which translated into its health-promoting effects on the cardiovascular system. The performed meta-analyses allow to confirm such an impact, however, after the assessment with the use of the SYRCLE's tool, these studies are burdened with a high risk of bias, and the results are not clearly presented. CONCLUSION: Despite numerous articles and clinical studies, the convincing beneficial mechanisms of resveratrol as well as its health-promoting effects in cardiovascular diseases have not been clearly confirmed in humans. Therefore, there is a need for further clinical studies, especially randomized, double-blind, placebo-controlled trials to objectively confirm the possible health-promoting effects of this substance and to determine both the efficacy and safety, and possible therapeutic potential.

Vitamin D Metabolite Profile in Cholecalciferol- or Calcitriol-Supplemented Healthy and Mammary Gland Tumor-Bearing Mice.

To analyze if the prometastatic activity of calcitriol (active vitamin D3 metabolite), which was previously observed in a 4T1 breast cancer model, is also found in other breast cancers, and to assess the impact of various schemes of vitamin D supply, we used 4T1 and E0771 mouse metastatic and 67NR nonmetastatic cells in this study. BALB/c and C57BL/6 healthy and tumor-bearing mice were exposed to a control (1000 IU), low- (100 IU), and high- (5000 IU) vitamin D3 diets. Additionally, from day 7 of tumor transplantation, the 1000 and 100 IU groups were gavaged with calcitriol (+cal). After 8 weeks of feeding, plasma levels of 25(OH)D3, 24,25(OH)2D3, and 3-epi-25(OH)D3 were significantly lower in calcitriol-treated and vitamin D-deficient groups than in the control, whereas the levels of all metabolites were increased in the 5000 IU group. The ratio of 25(OH)D3:24,25(OH)2D3 was increased in both calcitriol-treated groups, whereas the ratio of 25(OH)D3:3-epi-25(OH)D3 was increased only in the 100 IU group but decreased in the 5000 IU group. In contrast to E0771, 4T1 lung metastasis was accelerated in all vitamin D-supplemented mice, as well as in the deficient group with an increased inflammatory response. 67NR tumor growth was transiently inhibited in the 1000 IU+cal group, but single metastases were observed in the 5000 and 100 IU groups. Based on the results, we conclude that various schemes of vitamin D supply and vitamin D deficiency led to similar metabolite profiles irrespective of the mice strain and tumor burden. However, depending on the type of breast cancer, different effects on tumor growth and metastasis were noticed.

Protein Disulphide Isomerase A1 Is Involved in the Regulation of Breast Cancer Cell Adhesion and Transmigration via Lung Microvascular Endothelial Cells.

Cancer cell cross-talk with the host endothelium plays a crucial role in metastasis, but the underlying mechanisms are still not fully understood. We studied the involvement of protein disulphide isomerase A1 (PDIA1) in human breast cancer cell (MCF-7 and MDA-MB-231) adhesion and transendothelial migration. For comparison, the role of PDIA1 in proliferation, migration, cell cycle and apoptosis was also assessed. Pharmacological inhibitor, bepristat 2a and PDIA1 silencing were used to inhibit PDIA1. Inhibition of PDIA1 by bepristat 2a markedly decreased the adhesion of breast cancer cells to collagen type I, fibronectin and human lung microvascular endothelial cells. Transendothelial migration of breast cancer cells across the endothelial monolayer was also inhibited by bepristat 2a, an effect not associated with changes in ICAM-1 expression or changes in cellular bioenergetics. The silencing of PDIA1 produced less pronounced anti-adhesive effects. However, inhibiting extracellular free thiols by non-penetrating blocker p-chloromercuribenzene sulphonate substantially inhibited adhesion. Using a proteomic approach, we identified that ß1 and α2 integrins were the most abundant among all integrins in breast cancer cells as well as in lung microvascular endothelial cells, suggesting that integrins could represent a target for PDIA1. In conclusion, extracellular PDIA1 plays a major role in regulating the adhesion of cancer cells and their transendothelial migration, in addition to regulating cell cycle and caspase 3/7 activation by intracellular PDIA1. PDIA1-dependent regulation of cancer-endothelial cell interactions involves disulphide exchange and most likely integrin activation but is not mediated by the regulation of ICAM-1 expression or changes in cellular bioenergetics in breast cancer or endothelial cells.

Insulin enhancement of the antitumor activity of chemotherapeutic agents in colorectal cancer is linked with downregulating PIK3CA and GRB2.

The present state of cancer chemotherapy is unsatisfactory. New anticancer drugs that marginally improve the survival of patients continue to be developed at an unsustainably high cost. The study aimed to elucidate the effects of insulin (INS), an inexpensive drug with a convincing safety profile, on the susceptibility of colon cancer to chemotherapeutic agents: 5-fluorouracil (FU), oxaliplatin (OXA), irinotecan (IRI), cyclophosphamide (CPA) and docetaxel (DOC). To examine the effects of insulin on cell viability and apoptosis, we performed an in vitro analysis on colon cancer cell lines Caco-2 and SW480. To verify the results, we performed in vivo analysis on mice bearing MC38 colon tumors. To assess the underlying mechanism of the therapy, we examined the mRNA expression of pathways related to the signaling downstream of insulin receptors (INSR). Moreover, we performed Western blotting to confirm expression patterns derived from the genetic analysis. For the quantification of circulating tumor cells in the peripheral blood, we used the maintrac method. The results of our study show that insulin-pretreated colon cancer cells are significantly more susceptible to commonly used chemotherapeutics. The apoptosis ratio was also enhanced when INS was administered complementary to the examined drugs. The in vivo study showed that the combination of INS and FU resulted in significant inhibition of tumor growth and reduction of the number of circulating tumor cells. This combination caused a significant downregulation of the key signaling substrates downstream of INSR. The results indicate that the downregulation of PIK3CA (phosphatidylinositol 3-kinase catalytic subunit alpha), which plays a critical role in cell signaling and GRB2 (growth factor receptor-bound protein 2), a regulator of cell proliferation and differentiation may be responsible for the sensitizing effect of INS. These findings were confirmed at protein levels by Western blotting. In conclusion, these results suggest that INS might be potentially applied to clinical use to enhance the therapeutic effectiveness of chemotherapeutic drugs. The findings may become a platform for the future development of new and inexpensive strategies for the clinical chemotherapy of tumors.

Calcitriol Analogues Decrease Lung Metastasis but Impair Bone Metabolism in Aged Ovariectomized Mice Bearing 4T1 Mammary Gland Tumours.

Calcitriol and its analogues are considered drugs supporting the anticancer treatment of breast cancer and preventing the osteoporosis that results from the development of cancer or from chemotherapy or hormone therapy. Following the orthotopic implantation of 4T1 mammary carcinoma cells into aged ovariectomized (OVX) mice, we evaluated the effects of calcitriol and its two analogues, PRI-2191 and PRI-2205, on metastatic spread and bone homeostasis. Calcitriol and its analogues temporarily inhibited the formation of metastases in the lungs. Unexpectedly, only mice treated with calcitriol analogues showed a deterioration of bone-related parameters, such as bone column density, marrow column density and the CaPO4 coefficient. These findings correlated with an increased number of active osteoclasts differentiated from bone marrow-derived macrophages in mice treated with the analogues. Interestingly, in the tumours from mice treated with PRI-2191 and PRI-2205, the expression of Tnfsf11 (RANKL) was increased. On the other hand, osteopontin (OPN) levels in plasma and tumour tissue, as well as TRAC5b levels in tumours, were diminished by calcitriol and its analogues. Despite a similar action of both analogues towards bone metabolism, their impact on vitamin D metabolism differed. In particular, PRI-2191 and calcitriol, not PRI-2205 treatment significantly diminished the levels of both 25(OH)D3 and 24,25(OH)2D3. In conclusion, though there is evident antimetastatic activity in old OVX mice, signs of increased bone metabolism and deterioration of bone mineralization during therapy with calcitriol analogues were observed.

Temporal inhibition of mouse mammary gland cancer metastasis by CORM-A1 and DETA/NO combination therapy.

Carbon monoxide and nitric oxide are two of the most important vasoprotective mediators. Their downregulation observed during vascular dysfunction, which is associated with cancer progression, leads to uncontrolled platelet activation. Therefore, the aim of our studies was to improve vasoprotection and to decrease platelet activation during progression of mouse mammary gland cancer by concurrent use of CO and NO donors (CORM-A1 and DETA/NO, respectively). Methods: Mice injected intravenously with 4T1-luc2-tdTomato or orthotopically with 4T1 mouse mammary gland cancer cells were treated with CORM-A1 and DETA/NO. Ex vivo aggregation and activation of platelets were assessed in the blood of healthy donors and breast cancer patients. Moreover, we analyzed the compounds' direct effect on 4T1 mouse and MDA-MB-231 human breast cancer cells proliferation, adhesion and migration in vitro. Results: We have observed antimetastatic effect of combination therapy, which was only transient in orthotopic model. During early stages of tumor progression concurrent use of CORM-A1 and DETA/NO demonstrated vasoprotective ability (decreased endothelin-1, sICAM and sE-selectin plasma level) and downregulated platelets activation (decreased bound of fibrinogen and vWf to platelets) as well as inhibited EMT process. Combined treatment with CO and NO donors diminished adhesion and migration of breast cancer cells in vitro and inhibited aggregation as well as TGF-ß release from breast cancer patients' platelets ex vivo. However, antimetastatic effect was not observed at a later stage of tumor progression which was accompanied by increased platelets activation and endothelial dysfunction related to a decrease of VASP level. Conclusion: The therapy was shown to have antimetastatic action and resulted in normalization of endothelial metabolism, diminution of platelet activation and inhibition of EMT process. The effect was more prominent during early stages of tumor dissemination. Such treatment could be applied to inhibit metastasis during the first stages of this process.

Combination Therapy with DETA/NO and Clopidogrel Inhibits Metastasis in Murine Mammary Gland Cancer Models via Improved Vasoprotection.

Vascular endothelial dysfunction and platelet activation play a key role in tumor metastasis, and therefore, both of these processes are considered important therapeutic targets in cancer. The aim of our studies was to analyze antimetastatic activity of combination therapy using nitric oxide donor DETA/NO and antiplatelet drug clopidogrel. Nitric oxide acts as a vasoprotective mediator, while clopidogrel inhibits ADP-mediated platelet aggregation. 4T1-luc2-tdTomato cell line transplanted intravenously (i.v.) and 4T1 cell line transplanted orthotopically were used as metastatic mammary gland cancer models. Moreover, antiaggregation action of compounds was tested ex vivo on the blood samples taken from breast cancer patients. We have shown that in selected dosage regimes, DETA/NO combined with clopidogrel significantly reduced lung metastatic foci formation in an i.v. model, and such inhibition was transiently observed also in an orthotopic model. The antimetastatic effect was correlated with a significant increase of prostacyclin (PGI2) metabolite and reduction of endothelin-1, sE-selectin, sI-CAM, and TGF-ß plasma levels as well as decreased V-CAM expression on the endothelium. Combination therapy decreased fibrinogen binding to the resting platelets at the early stage of tumor progression (day 14). However, at the later stages (days 21 and 28), the markers of platelet activation were detected (increased JON/A antibody bound, P-selectin level, binding of fibrinogen, and vWf). Decreased aggregation as well as a lower release of TGF-ß were detected in platelets incubated ex vivo with compounds tested from metastatic breast cancer patients. Although combination therapy increases E-cadherin, the increase of N-cadherin and α-SMA in tumor tissue was also observed. The results showed that at the early stages of tumor progression, combined therapy with DETA/NO and clopidogrel improves vasoprotective and antiplatelet activity. However, in advanced tumors, some adverse effects toward platelet activation can be observed.

Calcitriol and Its Analogs Establish the Immunosuppressive Microenvironment That Drives Metastasis in 4T1 Mouse Mammary Gland Cancer.

In our previous study, calcitriol and its analogs PRI-2191 and PRI-2205 stimulated 4T1 mouse mammary gland cancer metastasis. Therefore, we aimed to analyze the inflammatory response in 4T1-bearing mice treated with these compounds. Gene expression analysis of the splenocytes and regional lymph nodes demonstrated prevalence of the T helper lymphocytes (Th2) response with an increased activity of regulatory T (Treg) lymphocytes in mice treated with these compounds. We also observed an increased number of mature granulocytes and B lymphocytes and a decreased number of TCD4⁺, TCD4⁺CD25⁺, and TCD8⁺, as well as natural killer (NK) CD335⁺, cells in the blood of mice treated with calcitriol and its analogs. Among the splenocytes, we observed a significant decrease in NK CD335⁺ cells and an increase in TCD8⁺ cells. Calcitriol and its analogs decreased the levels of interleukin (IL)-1ß and IL-10 and increased the level of interferon gamma (IFN-γ) in the plasma. In the tumor tissue, they caused an increase in the level of IL-10. Gene expression analysis of lung tissue demonstrated an increased level of osteopontin (Spp1) and transforming growth factor ß (TGF-ß) mRNA. The expression of Spp1 was also elevated in lymph nodes. Calcitriol and its analogs caused prevalence of tumor-conducive changes in the immune system of 4T1 tumor-bearing mice, despite the induction of some tumor-disadvantageous effects.

Melanoma cell adhesion molecule as an emerging biomarker with prognostic significance in systolic heart failure.

BACKGROUND: Melanoma cell adhesion molecule (MCAM) is a marker of endothelial damage. MCAM diagnostic and prognostic value was assessed in chronic heart failure (CHF). MATERIALS & METHODS: 130 CHF patients and 32 controls were included in the study. Telephone follow-up lasted one year. End points were: death from all causes, and hospitalization with CHF exacerbation. RESULTS: MCAM was higher in patients than in controls (p = 0.01). Receiver operator curve analysis revealed that MCAM may serve as a predictor of death (area under the curve: 0.8404; p < 0.002). Patients with MCAM above 500 ng/ml had worse prognosis (p = 0.03). NT-proBNP and age were independent predictors of death in multivariate analysis. CONCLUSION: The increased MCAM indicates endothelial damage in CHF and may serve as a marker of worse prognosis in these patients.

[Angina pectoris due to coronary-subclavian steal syndrome caused by the LIMA graft in the patient after CABG with the use of the right and left mammary artery]. / Dlawica piersiowa niestabilna spowodowana zespolem podkradania wiencowo-podobojczykowego przez LIMA z jednoczesnym krytycznym zwezeniem RIMA u pacjenta po CABG z uzyciem dwóch tetnic piersiowych wewnetrznych.

We present a case of a patient with unstable angina pectoris two years after coronary artery by-pass graft surgery with the use of the right and left mammary artery. The symptoms were caused by the critical RIMA stenosis and coronary-subclavian steal syndrome through the LIMA graft. Unsuccessful attempt of percutaneous angioplasty of the closed left subclavian artery was made. The angioplasty of the proximal part of the RIMA with the implantation of a drug eluting stent followed by the angioplasty of both left circumflex artery and obtuse marginal artery with the implantation of bare metal stents was performed. These procedures resulted in disappearance of anginal symptoms. Neurological examination did not reveal any signs of vertebrobasilar steal.