The molecular mechanisms linking metabolic syndrome to endometrial and breast cancers

The metabolic syndrome represents a plethora of cardio-metabolic risk factors including obesity, arterial hypertension, atherogenic dyslipidemia, hyperglycemia, accompanied by pro-inflammatory and pro-thrombotic state. The metabolic syndrome is one of the key risk factors for certain types of cancer. Among these malignancies, breast cancer and endometrial neoplasms require special attention. Incriminated major causes for the development of breast and endometrial cancer in metabolic syndrome patients are: the pro-inflammatory status and related cytokines, adipokine imbalances, hyperestrogenism, growth factors, disturbances in cancer microenvironment, insulin resistance and hyperinsulinemia. The metabolic syndrome consists of molecular dysregulations that create a pro-oncogenic status. Our review aims at providing a better understanding of the mechanisms underlying the link between the metabolic syndrome and endometrial and breast cancer

Rheumatoid Arthritis and CLOVES Syndrome: A Tricky Diagnosis

The PI3K/AKT/mTOR signaling pathway is significantly activated in rheumatoid arthritis. In addition, somatic activating mutations of the PI3K/AKT/mTOR pathway may result in PIK3CA-related overgrowth spectrum diseases, including CLOVES (Congenital Lipomatous Overgrowth, Vascular malformation, Epidermal nevi, Skeletal abnormalities/Scoliosis) syndrome. We describe the case of a young female patient, with anti-citrullinated peptide antibodies-positive rheumatoid arthritis, referred for persistent finger pain and stiffness. Examination revealed discrete macrodactyly involving two fingers, scoliosis, asymmetrical calves, venectasias, a shoulder nevus and triangular feet with a “sandal gap” between two toes. These mild dysmorphic features with early-onset and the history of surgeries for thoracic lipoma and venous malformation were strongly suggestive of CLOVES syndrome. Confirmatory mutation analysis was not performed, as blood or saliva testing is not contributive for tissue-specific localized effects in the PIK3CA-related overgrowth spectrum. Nevertheless, lack of detection of a PIK3CA mutation does not exclude the diagnosis in patients fulfilling clinical criteria. Due to the patient’s wish to plan a pregnancy, therapy consisted in sulfasalazine and hydroxychloroquine, along with orthotic correction of leg length discrepancy. Overgrowth syndromes and arthritis may share common pathways. Mild macrodactyly should be differentiated from dactylitis. Diagnosing patients with minimal dysmorphic features within the PI3K-related overgrowth spectrum may help design better care strategies, in the quest for personalized medicine

Frail Silk: Is the Hughes-Stovin Syndrome a Behçet Syndrome Subtype with Aneurysm-Involved Gene Variants?

Hughes-Stovin syndrome is a rare disease characterized by thrombophlebitis and multiple pulmonary and/or bronchial aneurysms. The etiology and pathogenesis of HSS are incompletely known. The current consensus is that vasculitis underlies the pathogenic process, and pulmonary thrombosis follows arterial wall inflammation. As such, Hughes-Stovin syndrome may belong to the vascular cluster with lung involvement of Behçet syndrome, although oral aphtae, arthritis, and uveitis are rarely found. Behçet syndrome is a multifactorial polygenic disease with genetic, epigenetic, environmental, and mostly immunological contributors. The different Behçet syndrome phenotypes are presumably based upon different genetic determinants involving more than one pathogenic pathway. Hughes-Stovin syndrome may have common pathways with fibromuscular dysplasias and other diseases evolving with vascular aneurysms. We describe a Hughes-Stovin syndrome case fulfilling the Behçet syndrome criteria. A MYLK variant of unknown significance was detected, along with other heterozygous mutations in genes that may impact angiogenesis pathways. We discuss the possible involvement of these genetic findings, as well as other potential common determinants of Behçet/Hughes-Stovin syndrome and aneurysms in vascular Behçet syndrome. Recent advances in diagnostic techniques, including genetic testing, could help diagnose a specific Behçet syndrome subtype and other associated conditions to personalize the disease management

Allelic distribution of BDNF Val66Met polymorphism in healthy Romanian volunteers

Population stratification of functional gene polymorphisms is a potential confounding factor in genetic association studies. The Val66Met (rs6265) single-nucleotide polymorphism in the brain-derived neurotrophic factor gene (BDNF) exhibits one of the highest variabilities in terms of allelic distribution between populations. The present study reports the distribution of BDNF Val66Met alleles in a sample of healthy volunteers (N = 1124) selected from the Romanian population. Frequencies were 80.74% for the Val allele and 19.26% for the Met allele. The data from this study extends efforts to map the allelic distribution of BDNF Val66Met in populations around the world and emphasizes that population stratification should be controlled for in future studies that report phenotypic associations in samples from different populations

Anemia in Sports: A Narrative Review

Recent years have brought about new understandings regarding the pathogenesis of anemia in sports. From hemodilution and redistribution considered to contribute to the so-called “sports anemia” to iron deficiency caused by increased demands, dietary restrictions, decreased absorption, increased losses, hemolysis, and sequestration, to genetic determinants of different types of anemia (some related to sport), the anemia in athletes deserves a careful and multifactorial approach. Dietary factors that reduce iron absorption (e.g., phytate, polyphenols) and that augment iron’s bioavailability (e.g., ascorbic acid) should be considered. Celiac disease, more prevalent in female athletes, may underlie an unexplained iron deficiency anemia. Iron loss during exercise occurs in several ways: sweating, hematuria, gastrointestinal bleeding, inflammation, and intravascular and extravascular hemolysis. From a practical point of view, assessing iron status, especially in the athletes at risk for iron deficiency (females, adolescents, in sports with dietary restrictions, etc.), may improve the iron balance and possibly the performance. Hemoglobin and serum ferritin are measures that are easily employable for the evaluation of patients’ iron status. Cutoff values should probably be further assessed with respect to the sex, age, and type of sport. A healthy gut microbiome influences the iron status. Athletes at risk of iron deficiency should perform non-weight-bearing, low-intensity sports to avoid inducing hemolysis

A novel common large genomic deletion and two new missense mutations identified in the Romanian phenylketonuria population

The mutation spectrum for the phenylalanine hydroxylase (PAH) gene was investigated in a cohort of 84 hyperphenylalaninemia (HPA) patients from Romania identified through newborn screening or neurometabolic investigations. Differential diagnosis identified 81 patients with classic PAH deficiency while 3 had tetrahydropterin-cofactor deficiency and/or remained uncertain due to insufficient specimen. PAH-genetic analysis included a combination of Sanger sequencing of exons and exon–intron boundaries, MLPA and NGS with genomic DNA, and cDNA analysis from immortalized lymphoblasts. A diagnostic efficiency of 99.4% was achieved, as for one allele (out of a total of 162 alleles) no mutation could be identified. The most prevalent mutation was p.Arg408Trp which was found in ~ 38% of all PKU alleles. Three novel mutations were identified, including the two missense mutations p.Gln226Lys and p.Tyr268Cys that were both disease causing by prediction algorithms, and the large genomic deletion EX6del7831 (c.509 + 4140_706 + 510del7831) that resulted in skipping of exon 6 based on PAH-cDNA analysis in immortalized lymphocytes. The genomic deletion was present in a heterozygous state in 12 patients, i.e. in ~ 8% of all the analyzed PKU alleles, and might have originated from a Romanian founder

Oral Microbiome: Getting to Know and Befriend Neighbors, a Biological Approach

The oral microbiome, forming a biofilm that covers the oral structures, contains a high number of microorganisms. Biofilm formation starts from the salivary pellicle that allows bacterial adhesion–colonization–proliferation, co-aggregation and biofilm maturation in a complex microbial community. There is a constant bidirectional crosstalk between human host and its oral microbiome. The paper presents the fundamentals regarding the oral microbiome and its relationship to modulator factors, oral and systemic health. The modern studies of oral microorganisms and relationships with the host benefits are based on genomics, transcriptomics, proteomics and metabolomics. Pharmaceuticals such as antimicrobials, prebiotics, probiotics, surface active or abrasive agents and plant-derived ingredients may influence the oral microbiome. Many studies found associations between oral dysbiosis and systemic disorders, including autoimmune diseases, cardiovascular, diabetes, cancers and neurodegenerative disorders. We outline the general and individual factors influencing the host–microbial balance and the possibility to use the analysis of the oral microbiome in prevention, diagnosis and treatment in personalized medicine. Future therapies should take in account the restoration of the normal symbiotic relation with the oral microbiome

Gene–Environment Interactions in Irrational Beliefs: The Roles of Childhood Adversity and Multiple Candidate Genes

Cognitive behavioral therapy is based on the view that maladaptive thinking is the causal mechanism of mental disorders. While this view is supported by extensive evidence, very limited work has addressed the factors that contribute to the development of maladaptive thinking. The present study aimed to uncover interactions between childhood maltreatment and multiple genetic differences in irrational beliefs. Childhood maltreatment and irrational beliefs were assessed using multiple self-report instruments in a sample of healthy volunteers (N = 452). Eighteen single-nucleotide polymorphisms were genotyped in six candidate genes related to neurotransmitter function (COMT; SLC6A4; OXTR), neurotrophic factors (BDNF), and the hypothalamic–pituitary–adrenal axis (NR3C1; CRHR1). Gene–environment interactions (G×E) were first explored in models that employed one measure of childhood maltreatment and one measure of irrational beliefs. These effects were then followed up in models in which either the childhood maltreatment measure, the irrational belief measure, or both were substituted by parallel measures. Consistent results across models indicated that childhood maltreatment was positively associated with irrational beliefs, and these relations were significantly influenced by COMT rs165774 and OXTR rs53576. These results remain preliminary until independent replication, but they represent the best available evidence to date on G×E in a fundamental mechanism of psychopathology

DNA Methylation and Micro-RNAs: The Most Recent and Relevant Biomarkers in the Early Diagnosis of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a frequently encountered cancer type, and its alarming incidence is explained by genetic and epigenetic alterations. Epigenetic changes may represent diagnostic and prognostic biomarkers of HCC. In this review we discussed deoxyribonucleic acid (DNA) hypomethylation, DNA hypermethylation, and aberrant expression of small non-coding ribonucleic acid (RNA), which could be useful new biomarkers in the early diagnosis of HCC. We selected the articles on human subjects published in English over the past two years involving diagnostic markers detected in body fluids, cancer diagnosis made on histopathological exam, and a control group of those with benign liver disease or without liver disease. These biomarkers need further investigation in clinical trials to develop clinical applications for early diagnosis and management of HCC