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1.
Int J Obes (Lond) ; 42(4): 641-647, 2018 04.
Article in English | MEDLINE | ID: mdl-29064476

ABSTRACT

BACKGROUND/OBJECTIVES: It is well known that increased abdominal fat is associated with cardiovascular (CV) risk. Perirenal fat has been recently associated with CV risk in adults. However, studies with children are lacking. We investigated the relationship of perirenal fat and other abdominal fat depots (including preperitoneal, intra-abdominal and subcutaneous fat) with carotid intima-media thickness (cIMT-a surrogate marker of CV risk) in prepubertal children, so as to identify novel markers that can be easily assessed and used in the early prevention of cardiovascular disease. SUBJECTS/METHODS: Subjects were 702 asymptomatic prepubertal Caucasian children (418 lean, 142 overweight and 142 obese) who were recruited in a primary care setting. Ultrasound measurements (perirenal, preperitoneal, intra-abdominal and subcutaneous fat and cIMT), clinical (body mass index (BMI) and systolic blood pressure) and metabolic parameters (insulin resistance (HOMA-IR), high molecular weight (HMW) adiponectin and serum lipids) were assessed. RESULTS: Perirenal fat was associated with diverse metabolic and CV risk factors in all the studied subjects. However, in overweight and obese children, perirenal fat was mostly associated with cIMT (P<0.001) and was the only fat depot that showed independent associations with cIMT in multivariate analyses (overweight chidren: ß=0.250, P=0.003, r2=12.8%; obese children: ß=0.254, P=0.002, r2=15.5%) after adjusting for BMI, gender, age and metabolic parameters. Perirenal fat was also the only fat depot that showed independent associations with HMW-adiponectin in obese children (ß=-0.263, P=0.006, r2=22.8%). CONCLUSIONS: Perirenal fat is the main abdominal fat depot associated with cIMT, especially in overweight and obese children, and may thus represent a helpful parameter for assessing CV risk in the pediatric population.


Subject(s)
Abdominal Fat/diagnostic imaging , Carotid Intima-Media Thickness/statistics & numerical data , Adiponectin/blood , Blood Pressure/physiology , Child , Cohort Studies , Female , Humans , Male , Obesity/epidemiology , Overweight/epidemiology , Risk Factors
2.
Leukemia ; 29(1): 96-106, 2015 Jan.
Article in English | MEDLINE | ID: mdl-24781018

ABSTRACT

Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), especially for the poor prognostic subgroup of NOTCH1-mutated patients. Here, we report that the γ-secretase inhibitor PF-03084014 inhibits the constitutive Notch activation and induces selective apoptosis in CLL cells carrying NOTCH1 mutations. Combination of PF-03084014 with fludarabine has a synergistic antileukemic effect in primary NOTCH1-mutated CLL cells, even in the presence of the protective stroma. At transcriptional level, PF-03084014 plus fludarabine treatment induces the upregulation of the proapoptotic gene HRK and the downmodulation of MMP9, IL32 and RAC2 genes that are related to invasion and chemotaxis. PF-03084014 also overcomes fludarabine-mediated activation of nuclear factor-κB signaling. Moreover, this combination impairs angiogenesis and CXCL12-induced responses in NOTCH1-mutated CLL cells, in particular those related to tumoral migration and invasion. Importantly, all these collaborative effects are specific for NOTCH1 mutation and do not occur in unmutated cases. In conclusion, we provide evidence that Notch is a therapeutic target in CLL cases with NOTCH1-activating mutations, supporting the use of Notch pathway inhibitors in combination with chemotherapy as a promising approach for the treatment of these high-risk CLL patients.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Neoplasm Invasiveness/prevention & control , Neoplasm Metastasis/prevention & control , Neovascularization, Pathologic/prevention & control , Receptor, Notch1/genetics , Tetrahydronaphthalenes/pharmacology , Valine/analogs & derivatives , Vidarabine/analogs & derivatives , Aged , Enzyme Inhibitors/pharmacology , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Male , Middle Aged , Mutation , Tumor Cells, Cultured , Valine/pharmacology , Vidarabine/pharmacology
3.
Leukemia ; 26(6): 1429-32, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22182921
4.
Curr Drug Targets ; 11(7): 769-80, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20370650

ABSTRACT

Programmed cell death, commonly associated with the term apoptosis, is an integrated intracellular program that plays a critical role in lymphoid tissue homeostasis. Alterations in this highly regulated process is a common feature of most lymphoid malignancies, thus facilitating tumor escape from traditional chemotherapeutic agents whose main endpoint is the induction of tumor cell death. In the last years, enormous progress has been made in understanding the deregulated signals that could lead to ineffective apoptosis in B lymphoid tumors. Consequently, several new strategies have been designed to modulate the key molecules of life-and-death decisions. Numerous novel approaches are being validated and some of them have progressed to clinical testing or have even been approved in a record time. In this review we will focus on current therapies that have demonstrated to trigger efficiently cell death in B lymphoid neoplasms, either by directly targeting the intracellular apoptotic machinery or by modulating different factors involved in its regulation.


Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Cell Death/drug effects , Drug Delivery Systems/methods , Hematologic Neoplasms/drug therapy , Lymphoma, B-Cell/drug therapy , Apoptosis/drug effects , Humans , Models, Biological , Signal Transduction/drug effects
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