Non-HDL-cholesterol in dyslipidemia: Review of the state-of-the-art literature and outlook.

Dyslipidemia refers to unhealthy changes in blood lipid composition and is a risk factor for atherosclerotic cardiovascular diseases (ASCVD). Usually, low-density lipoprotein-cholesterol (LDL-C) is the primary goal for dyslipidemia management. However, non-high-density lipoprotein cholesterol (non-HDL-C) has gained attention as an alternative, reliable goal.

Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive () Acute Lymphoblastic Leukemia (ALL).

Ph+ () B-ALL was considered to be high risk, but recent advances in -targeting TKIs has shown improved outcomes in combination with backbone chemotherapy. Nevertheless, new treatment strategies are needed, including approaches without chemotherapy for elderly patients. LIMK1/2 acts downstream from various signaling pathways, which modifies cytoskeleton dynamics via phosphorylation of cofilin.

A multiparametric niche-like drug screening platform in acute myeloid leukemia.

Functional precision medicine in AML often relies on short-term in vitro drug sensitivity screening (DSS) of primary patient cells in standard culture conditions. We designed a niche-like DSS assay combining physiologic hypoxia (O 3%) and mesenchymal stromal cell (MSC) co-culture with multiparameter flow cytometry to enumerate lymphocytes and differentiating (CD11/CD14/CD15+) or leukemic stem cell (LSC)-enriched (GPR56+) cells within the leukemic bulk. After functional validation of GPR56 expression as a surrogate for LSC enrichment, the assay identified three patterns of response, including cytotoxicity on blasts sparing LSCs, induction of differentiation, and selective impairment of LSCs.

Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia.

By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures.

Synergy of FLT3 inhibitors and the small molecule inhibitor of LIM kinase1/2 CEL_Amide in FLT3-ITD mutated Acute Myeloblastic Leukemia (AML) cells.

Patients with FLT3-ITD mutated (FLT3-ITD+) Acute Myeloid Leukemia (AML), have frequently relapsed or refractory disease and FLT3-ITD+ inhibitors have limited efficacy. Rho kinases (ROCK) are constitutively activated by FLT3-ITD+ in AML via PI3 kinase and Rho GTPase. Upon activation by ROCK, LIM kinases (LIMK) inactivate cofilin by phosphorylation which affects cytoskeleton dynamics, cell growth and apoptosis.

Does an Optimal Relationship Between Injury Risk and Workload Represented by the "Sweet Spot" Really Exist? An Example From Elite French Soccer Players and Pentathletes.

Objective: To examine the relationships between the occurrence and severity of injuries using three workload ratios (ACWR, EWMA, REDI) in elite female soccer players and international male and female pentathletes.

Materials And Methods: Female soccer players in the U16 to U18 national French teams ( = 24) and international athletes ( = 12, 4 women and 8 men) in the French modern pentathlon team were monitored throughout an entire season. The Acute Chronic Workload Ratio (ACWR), the Exponentially Weighted Moving Averages (EWMA), and the Robust Exponential Decreasing Index (REDI) were calculated for internal load by the ROE method in soccer and external load in pentathlon.

BET inhibitors impair leukemic stem cell function only in defined oncogenic subgroups of acute myeloid leukaemias.

Bromodomain and Extra-Terminal inhibitors (BETi) such as OTX015 are active in Acute Myeloid Leukaemias (AML). Their activity on Leukemic Stem Cells (LSCs) is less documented. We interrogated the anti-LSC activity of OTX015 in a niche-like long-term culture in 26 primary AML samples and validated our findings in vivo.

Natural Killer Lymphocytes Are Dysfunctional in Kidney Transplant Recipients on Diagnosis of Cancer.

Background: The incidence of cancer is increased after solid organ transplantation. Natural killer (NK) cells are key effectors of the tumor immune response.

Methods: We conducted a cross sectional multicentre matched case-control study including 42 kidney transplant recipients (KTRs) on diagnosis of cancer and 41 KTRs without cancer.

BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells.

The bromodomain (BRD) and extraterminal (BET) proteins including BRD2, BRD3 and BRD4 have been identified as key targets for leukemia maintenance. A novel oral inhibitor of BRD2/3/4, the thienotriazolodiazepine compound OTX015, suitable for human use, is available. Here we report its biological effects in AML and ALL cell lines and leukemic samples.

Effect of eprosartan-based antihypertensive therapy on coronary heart disease risk assessed by Framingham methodology in Canadian patients with diabetes: results of the POWER survey.

Objective: As part of the Physicians' Observational Work on Patient Education According to their Vascular Risk (POWER) survey, we used Framingham methodology to examine the effect of an eprosartan-based regimen on total coronary heart disease (CHD) risk in diabetic patients recruited in Canada.

Methods: Patients with new or uncontrolled hypertension (sitting systolic blood pressure [SBP] >140 mmHg with diastolic blood pressure <110 mmHg) were identified at 335 Canadian primary care practices. Initial treatment consisted of eprosartan 600 mg/day, which was later supplemented with other antihypertensives as required.

Natural killer cell dysfunction in uremia: the role of oxidative stress and the effects of dialysis.

Immune deficiency is one of the numerous consequences of chronic renal failure. We can hypothesize that an abnormal natural killer (NK) cell response is present in patients with end-stage renal disease (ESRD). To characterize the immune defect in ESRD patients, we performed a NK cell subset analysis in 66 patients with ESRD treated by hemodialysis or peritoneal dialysis.

Natural killer cell function, an important target for infection and tumor protection, is impaired in type 2 diabetes.

Patients with Type 2 diabetes (T2D) are highly susceptible to infection and have an increased incidence of some tumors, possibly due to immune system dysfunction. In the innate cellular immune system, Natural Killer (NK) lymphocytes are important effectors responsible for controlling infections and combating tumor development. We analyzed NK cell subsets in 51 patients with long-standing T2D.

Effect of eprosartan-based therapy on systolic blood pressure and total cardiovascular risk in a large international population: preliminary report of the observational POWER study.

Background: Estimation of total cardiovascular risk is useful for developing preventive strategies for individual patients. The POWER (Physicians' Observational Work on Patient Education According to their Vascular Risk) survey, a 6-month, open-label, multinational, post-marketing observational evaluation of eprosartan, an angiotensin II receptor blocker, was undertaken to assess the efficacy and safety of eprosartan-based therapy in the treatment of high arterial blood pressure in a large population recruited from 16 countries with varying degrees of baseline cardiovascular risk, and the effect of eprosartan-based therapy on total cardiovascular risk, as represented by the SCORE (Systematic Coronary Risk Assessment) or Framingham risk equations.

Methods: Participating physicians recruited > 29,000 hypertensive patients whom they considered to be candidates (according to specified criteria) for treatment with eprosartan 600 mg/day, with other drugs added at the discretion of the physician.

Blood pressure responses to hypertension treatment and trends in cognitive function in patients with initially difficult-to-treat hypertension: a retrospective subgroup analysis of the Observational Study on Cognitive Function and SBP Reduction (OSCAR) study.

The Observational Study on Cognitive Function and SBP Reduction (OSCAR) provided opportunities to examine the influence of eprosartan on trends in cognitive performance in a large population of patients with difficult-to-treat hypertension (DTTH). A total of 4649 patients diagnosed retrospectively with DTTH, defined as systolic/diastolic blood pressure (SBP/DBP) ≥140/90 mm Hg despite use of at least 3 antihypertensive drugs during the month preceding the baseline visit comprised the intention-to-treat (ITT) cohort. The patients were given eprosartan-based antihypertension therapy (EBT; 600 mg/d).

Eprosartan-based hypertension therapy, systolic arterial blood pressure and cognitive function: analysis of Middle East data from the OSCAR study.

Background: Studies have indicated a relationship between hypertension and cognitive function. The possible effect of antihypertensive therapy on cognitive disorders is therefore a matter of interest.

Materials And Methods: The Observational Study on Cognitive function And SBP Reduction (OSCAR) was an open-label, multinational trial designed to evaluate the impact of eprosartan-based antihypertensive therapy on cognitive function in patients with essential hypertension.

Advanced glycation end products regulate extracellular matrix protein and protease expression by human glomerular mesangial cells.

Advanced glycation end products (AGEs) may play a role in the pathogenesis of diabetic nephropathy, by modulating extracellular matrix turnover. AGEs are known to activate specific membrane receptors, including the receptor for AGE (RAGE). In the present study, we analyzed the various receptors for AGEs expressed by human mesangial cells and we studied the effects of glycated albumin and of carboxymethyl lysine on matrix protein and remodelling enzyme synthesis.

Acute graft-versus-host disease transiently impairs thymic output in young patients after allogeneic hematopoietic stem cell transplantation.

Long-term T-cell reconstitution after hematopoietic stem cell transplantation (HSCT) is dependent on patient thymic function and affected by graft-versus-host disease (GVHD). To assess the impact of acute GVHD (aGVHD) on thymic function, we followed a cohort of 93 patients who received HSCT from a human histocompatibility leukocyte antigen-identical sibling, mainly for hematologic malignancies. Thymic output was measured by signal-joint T-cell receptor excision circles (sjTREC) real-time polymerase chain reaction.

Oxidative stress mediates a reduced expression of the activating receptor NKG2D in NK cells from end-stage renal disease patients.

To characterize the immune defect of patients with end-stage renal disease (ESRD), we performed NK cell subset analysis in 66 patients with ESRD treated by hemodialysis (n = 59) or peritoneal dialysis (n = 7). Compared with healthy blood donors, patients undergoing chronic dialysis showed a profound decrease in NKG2D(+) cells within both the CD8(+) T cell (58% vs 67%, p = 0.03) and NK cell (39% vs 56%, p = 0.

NKG2D ligands expression and NKG2D-mediated NK activity in Sezary patients.

Sezary syndrome (SS) is a rare lymphoma characterized by the clonal expansion in the skin and in blood of CD4(+)CD158k(+) T cells. Natural killer (NK) activation against tumors in leukemia models is partly based on the recognition of the target through the NKG2D/NKG2D ligands interactions. We analyzed ex vivo SS malignant lymphocytes for the expression of the NKG2D ligands such as the major histocompatibility complex class I-related molecules (MIC) A and B and the UL16 binding proteins (ULBP).

Effects of hypertension therapy based on eprosartan on systolic arterial blood pressure and cognitive function: primary results of the Observational Study on Cognitive function And Systolic Blood Pressure Reduction open-label study.

Background: Recent studies have indicated a relationship between hypertension and cognitive function but therapeutic trials of antihypertensive therapy on the prevention of cognitive disorders have produced controversial findings.

Methods: The Observational Study on Cognitive function And Systolic Blood Pressure Reduction is an open-label trial in 28 countries designed to evaluate the impact of eprosartan-based therapy on cognitive function. The Mini-Mental State Examination was used as a global tool for the comprehensive assessment of cognitive function, with an intention to treat a cohort of 25 745 hypertensive patients aged at least 50 years during a follow-up interval of 6 months.

A novel approach to treatment of hypertension in diabetic patients - a multicenter, double-blind, randomized study comparing the efficacy of combination therapy of Eprosartan versus Ramipril with low-dose Hydrochlorothiazide and Moxonidine on blood pressure levels in patients with hypertension and associated diabetes mellitus type 2 - rationale and design [ISRCTN55725285].

Hypertension and diabetes mellitus are closely interrelated and coexist in as many as two-thirds of patients with type 2 diabetes. The consequent risk of such an association is an accelerated development of atherosclerotic cardiovascular disease and nephropathy complications.In choosing an antihypertensive agent, effectiveness needs to be accompanied by favourable metabolic, cardioprotective, and nephroprotective properties.

Type 1 plasminogen activator inhibitor deficiency aggravates the course of experimental glomerulonephritis through overactivation of transforming growth factor beta.

Type 1 plasminogen activator inhibitor (PAI-1) is the primary inhibitor of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Whereas PAI-1 is not expressed in normal kidneys, it is strongly induced in glomerular diseases and thus could promote the local accumulation of fibrin. To study the role of PAI-1 in the development of inflammatory glomerular injury, passive antiglomerular basement membrane (GBM) glomerulonephritis (GN) was induced in PAI-1 knockout mice and in wild-type mice of the same genetic background.

Induction of urokinase receptor expression in nephrotoxic nephritis.

The urokinase receptor (uPAR) is a multifunctional molecule involved in pericellular, fibrinolytic, and proteolytic activities, as well as in cell adhesion and chemotaxis and may play a role in the pathogenesis of tissue remodeling occurring during glomerulonephritis. We analyzed sequentially the expression of uPAR by immunohistochemistry and in situ hybridization in an accelerated model of nephrotoxic nephritis in rats. A strong induction of uPAR mRNA expression was observed in glomeruli as soon as 1 h after nephrotoxic serum injection.

Prognostic value of plasminogen activator inhibitor type 1 mRNA in microdissected glomeruli from transplanted kidneys.

Background: Plasminogen activator inhibitor type 1 (PAI-1) exerts antifibrinolytic and profibrotic activities. Inside the glomerulus, PAI-1 is mainly synthesized by mesangial cells. We hypothesized that thrombin, via its receptor protease activated receptor type 1 (PAR-1), present on the membrane of glomerular cells, is an important mediator of PAI-1 synthesis.