Microenvironmental IL1 1 β promotes metastatic colonisation of breast cancer cells in the bone via activation of Wnt-dependent cancer stem cell activity

Dissemination of tumour cells to the bone marrow is an early event in breast cancer, however cells may lie dormant for many years before bone metastases develop. Treatment for bone metastases is not curative, therefore new adjuvant therapies which prevent the colonisation of disseminated cells into metastatic lesions are required. There is evidence that cancer stem cells (CSCs) within breast tumours are capable of metastasis, but the mechanism by which these colonise bone is unknown. Here, we establish that bone marrow-derived IL1β stimulates breast cancer cell colonisation in the bone by inducing intracellular NFkB and CREB signalling in breast cancer cells, leading to autocrine Wnt signalling and CSC colony formation. Importantly, we show that inhibition of this pathway prevents both CSC colony formation in the bone environment, and bone metastasis. These findings establish that targeting IL1β-NFKB/CREB-Wnt signalling should be considered for adjuvant therapy to prevent breast cancer bone metastasis

COMPARATIVE ASSESSMENT OF EFFECT OF COMBINED DRUGS OF ACE INHIBITOR AND DIURETIC (“NOLIPREL FORTE” AND “CAPOZIDE”) ON CARDIOVASCULAR REMODELING IN HYPERTENSIVE PATIENTS

Aim. To assess antihypertensive efficacy and effect on cardio-vascular remodeling of combined drugs of ACE inhibitor and diuretic, “Noliprel forte” (NF) and “Capozide” (CA), in hypertensive high risk patients.Material and methods. 50 hypertensive (II grade) patients (25 men and 25 women, 19-65 years old) with high cardio-vascular risk took part in comparative opened randomized study. No one of patients received antihypertensive therapy before study. All patients were randomized for therapy with one of combined drug of ACE inhibitors and diuretic. 25 patients took NF (perindopril 4 mg and indapamide 1,25 mg), and 25 patients -CA (captopril 50 mg and hydrochlorothiazide 25 mg). Duration of observation period was 6 months. Before study, after 3 and 6 months of therapy ambulatory blood pressure monitoring (ABPM), echocardiography, cardiac and vessel Dopplerography, ultrasound scanning of general carotid arteries with detection of intima-media thickness (IMT), pulse wave speed (PWS) were held in all patients. Blood bio-chemical analysis was done also.Results. After 3 months 2 patients in NF group and 4 ones in CA group were required to reinforce of ther-apy with additional administration of perindoprile 4 mg and captopril 50 mg respectively. As a result of 6-month of therapy in NF group systolic dlood pressure (BP) decreased in 14,0% (р<0,001) and diastolic BP – на 12,9% (р<0,001). CA reduced systolic BP by 17,9% (р<0,0001) and diastolic BP – by 17,5% (р<0,001). 76% and 70% of patients in NF and CA groups, respectively, reached target BP level. Positive dynamic of daily profile of BP was observed according to ABPM data. Cerebral blood flow did not worsen despite of BP decrease. Both drugs decreased in thickness of inter-ventricular septum and left ventricular mass. Besides, NF decreased in thickness of left ventricular posterior wall. Both drugs reduced in IMT and decreased in PWS. NF therapy did not change of blood biochemical parameters. CA therapy, opposite, resulted in significant growth of plasma uric acid by 39,6%.Conclusion. 6-month therapy with NF showed high antihypertensive efficacy for both of drugs, which did not accompany with cerebral blood flow disturbances. Both drugs also showed an ability for positive effect on cardio-vascular remodeling (with NF priority), improvement of artery wall elasticity. NF, unlike CA, did not increase in plasma uric acid level

COMPARATIVE ASSESSMENT OF EFFECT OF COMBINED DRUGS OF ACE INHIBITOR AND DIURETIC (“NOLIPREL FORTE” AND “CAPOZIDE”) ON CARDIOVASCULAR REMODELING IN HYPERTENSIVE PATIENTS

Aim. To assess antihypertensive efficacy and effect on cardio-vascular remodeling of combined drugs of ACE inhibitor and diuretic, “Noliprel forte” (NF) and “Capozide” (CA), in hypertensive high risk patients.Material and methods. 50 hypertensive (II grade) patients (25 men and 25 women, 19-65 years old) with high cardio-vascular risk took part in comparative opened randomized study. No one of patients received antihypertensive therapy before study. All patients were randomized for therapy with one of combined drug of ACE inhibitors and diuretic. 25 patients took NF (perindopril 4 mg and indapamide 1,25 mg), and 25 patients -CA (captopril 50 mg and hydrochlorothiazide 25 mg). Duration of observation period was 6 months. Before study, after 3 and 6 months of therapy ambulatory blood pressure monitoring (ABPM), echocardiography, cardiac and vessel Dopplerography, ultrasound scanning of general carotid arteries with detection of intima-media thickness (IMT), pulse wave speed (PWS) were held in all patients. Blood bio-chemical analysis was done also.Results. After 3 months 2 patients in NF group and 4 ones in CA group were required to reinforce of ther-apy with additional administration of perindoprile 4 mg and captopril 50 mg respectively. As a result of 6-month of therapy in NF group systolic dlood pressure (BP) decreased in 14,0% (р&lt;0,001) and diastolic BP – на 12,9% (р&lt;0,001). CA reduced systolic BP by 17,9% (р&lt;0,0001) and diastolic BP – by 17,5% (р&lt;0,001). 76% and 70% of patients in NF and CA groups, respectively, reached target BP level. Positive dynamic of daily profile of BP was observed according to ABPM data. Cerebral blood flow did not worsen despite of BP decrease. Both drugs decreased in thickness of inter-ventricular septum and left ventricular mass. Besides, NF decreased in thickness of left ventricular posterior wall. Both drugs reduced in IMT and decreased in PWS. NF therapy did not change of blood biochemical parameters. CA therapy, opposite, resulted in significant growth of plasma uric acid by 39,6%.Conclusion. 6-month therapy with NF showed high antihypertensive efficacy for both of drugs, which did not accompany with cerebral blood flow disturbances. Both drugs also showed an ability for positive effect on cardio-vascular remodeling (with NF priority), improvement of artery wall elasticity. NF, unlike CA, did not increase in plasma uric acid level.</p

Mutation status of refractory to imatinib patients with chronic myeloid leukemia

Mutation status of 36 chronic myeloid leukemia (CML) patients in chronic phase with primary and secondary imatinib resistance was analyzed. BCR-ABL mutations identified by direct DNA sequencing. BCR-ABL kinase domain mutations were detected in 30.5 % (11 of 36) of those patients. Most of identified mutations were missense mutations: Q252H, M244V, G250E, Y253F/H, E255K/V, T315I, M351T, F359V, F359C, F486S. Patients with BCR-ABL mutations have significantly lower 4-year event-free survival compared with CML patients without mutations (18 % vs. 53 %; р = 0.003). The results can be used as reference information in deciding on therapy in imatinib resistant CML patients with clinically relevant BCR-ABL mutations

Mutation status of refractory to imatinib patients with chronic myeloid leukemia

Mutation status of 36 chronic myeloid leukemia (CML) patients in chronic phase with primary and secondary imatinib resistance was analyzed. BCR-ABL mutations identified by direct DNA sequencing. BCR-ABL kinase domain mutations were detected in 30.5 % (11 of 36) of those patients. Most of identified mutations were missense mutations: Q252H, M244V, G250E, Y253F/H, E255K/V, T315I, M351T, F359V, F359C, F486S. Patients with BCR-ABL mutations have significantly lower 4-year event-free survival compared with CML patients without mutations (18 % vs. 53 %; р = 0.003). The results can be used as reference information in deciding on therapy in imatinib resistant CML patients with clinically relevant BCR-ABL mutations.</p

The Role of IL-1beta in the Early Tumor Cell-Induced Angiogenic Response

Item does not contain fulltextIn this study, we assessed the involvement of IL-1beta in early angiogenic responses induced by malignant cells using Matrigel plugs supplemented with B16 melanoma cells. We found that during the angiogenic response, IL-1beta and vascular endothelial growth factor (VEGF) interact in a newly described autoinduction circuit, in which each of these cytokines induces the other. The IL-1beta and VEGF circuit acts through interactions between bone marrow-derived VEGF receptor 1(+)/IL-1R1(+) immature myeloid cells and tissue endothelial cells. Myeloid cells produce IL-1beta and additional proinflammatory cytokines, which subsequently activate endothelial cells to produce VEGF and other proangiogenic factors and provide the inflammatory microenvironment for angiogenesis and tumor progression. These mechanisms were also observed in a nontumor early angiogenic response elicited in Matrigel plugs by either rIL-1beta or recombinant VEGF. We have shown that IL-1beta inhibition stably reduces tumor growth by limiting inflammation and inducing the maturation of immature myeloid cells into M1 macrophages. In sharp contrast, only transient inhibition of tumor growth was observed after VEGF neutralization, followed by tumor recurrence mediated by rebound angiogenesis. This occurs via the reprogramming of VEGF receptor 1(+)/IL-1R1(+) cells to express hypoxia inducible factor-1alpha, VEGF, and other angiogenic factors, thereby directly supporting proliferation of endothelial cells and blood vessel formation in a paracrine manner. We suggest using IL-1beta inhibition as an effective antitumor therapy and are currently optimizing the conditions for its application in the clinic

Non-redundant properties of IL-1alpha and IL-1beta during acute colon inflammation in mice

Item does not contain fulltextOBJECTIVE: The differential role of the IL-1 agonists, IL-1alpha, which is mainly cell-associated versus IL-1beta, which is mostly secreted, was studied in colon inflammation. DESIGN: Dextran sodium sulfate (DSS) colitis was induced in mice globally deficient in either IL-1alpha or IL-1beta, and in wild-type mice, or in mice with conditional deletion of IL-1alpha in intestinal epithelial cells (IECs). Bone marrow transplantation experiments were performed to assess the role of IL-1alpha or IL-1beta of myeloid versus colon non-hematopoietic cells in inflammation and repair in acute colitis. RESULTS: IL-1alpha released from damaged IECs acts as an alarmin by initiating and propagating colon inflammation, as IL-1alpha deficient mice exhibited mild disease symptoms with improved recovery. IL-1beta is involved in repair of IECs and reconstitution of the epithelial barrier during the resolution of colitis; its deficiency correlates with disease exacerbation. Neutralisation of IL-1alpha in control mice during acute colitis led to alleviation of clinical and histological manifestations, whereas treatment with rIL-1Ra or anti-IL-1beta antibodies was not effective. Repair after colitis correlated with accumulation of CD8 and regulatory T cells in damaged crypts. CONCLUSIONS: The role of IL-1alpha and IL-1beta differs in DSS-induced colitis in that IL-1alpha, mainly of colon epithelial cells is inflammatory, whereas IL-1beta, mainly of myeloid cell origin, promotes healing and repair. Given the dissimilar functions of each IL-1 agonistic molecule, an IL-1 receptor blockade would not be as therapeutically effective as specific neutralising of IL-1alpha, which leaves IL-1beta function intact

The multicenter experience with bendamustine in the treatment of relapsed and refractory multiple myeloma

Relapsed and refractory (R/R) multiple myeloma (MM) constitutes a specific and unmet medical need. Median survival ranges from as little as 6 to 9 months, and responses to treatment are characteristically short. In patients with R/R MM after therapy of bortezomib and/or immunomodulators a bendamustine-based treatment can be used as “salvage”.In this retrospective analysis we have identified 32 patients with R/R MM by means of case research, have been bendamustine-based treated at Hematological Clinics of Russian Federation since 2011. Median age was 67 (43–81) years, the female/male ratio was 2.5:1. After in median 2 (1–7) lines of prior therapy patients received in median 3 (1–9) cycles of bendamustine-based therapy. Bendamustine dosage was 70–120 mg/m2 /day on 2 days of each 28-day cycle until progressive disease or intolerability. Overall rate response was 56.2 %: 21.9 % partial response, stable disease 34.4 %. Median time to progression was 5.3 (0.8–18.0) months and median overall survival was 25.4 (0.8–47.1) months. Hematologic toxicity was in 53.2 % of patients