👤 Ferdi Öztürk

Setmelanotide is a recently approved medication for patients over two years of age with monogenic obesity that emerges from POMC, LEPR, PCSK1 mutations, or Bardet-Biedl syndrome. While primarily targeting melanocortin-4 receptors (MC4R), setmelanotide also weakly stimulates melanocortin-1 receptors (MC1R), which may affect pigmentation. Clinical outcomes of this treatment modality remain limited due to the rarity of disorders mentioned above. We present a 12-year-old boy with a homozygous LEPR mutation who experienced skin hyperpigmentation shortly after the initiation of setmelanotide treatment. By the third month of treatment, gradual darkening of nevi was noted. At six-month follow-up, two nevi were excised due to pigmentation changes, and histopathology revealed dysplastic features in both. This case raises concerns about potential MC1R-mediated melanocytic activity during setmelanotide treatment. Therapy was temporarily discontinued. To our knowledge, this is the first reported pediatric case with LEPR-related monogenic obesity developing dysplastic nevi during setmelanotide use. Show less

Obesity is a serious health problem that progressively affects individuals’ lives with comorbidities, such as heart disease, stroke, and diabetes mellitus. Since its prevalence has increased, particularly in children less than five years old, its genetic and environmental causes should be determined for prevention and control of the disease. The aim of this study was to detect underlying genetic risk factors in a family with an exclusively breastfed obese infant. A three-generation family was recruited to be evaluated for obesity. Detailed examinations along with body mass index (BMI) calculations were performed on available family members. Whole exome sequencing (WES) was performed on a 7-month-old obese infant. Bioinformatic analyses were performed on the Genomize SEQ platform with variant filtering at minor allele frequencies <1% for all normal populations. Sanger sequencing was applied in variant confirmation and family segregation. Neuro-motor developmental features were normal and genetic syndromes were excluded from the index. Early-onset severe obesity (+4.25 standard deviation score weight-for-height) was evident in index case; his father and grandmother were also obese (BMIs 38.1 kg/m This study confirmed the paternal inheritance of all potentially deleterious obesity-related variants. The cumulative effect of individual variants might explain the obesity phenotype in this family. The infant is recommended to be followed up periodically due to increased risk for later childhood obesity. Show less

Imidazole derivatives display extensive applications in pharmaceutical chemistry and have been investigated as bioactive compounds for medicinal chemistry. In this study, besides the starting materials ( Show less

Blood vessels in tumors are often dysfunctional. This impairs the delivery of therapeutic agents to and distribution among the cancer cells. Subsequently, treatment efficacy is reduced, and dose escalation can increase adverse effects on non-malignant tissues. The dysfunctional vessel phenotypes are attributed to aberrant pro-angiogenic signaling, and anti-angiogenic agents can ameliorate traits of vessel dysfunctionality. However, they simultaneously reduce vessel density and thereby impede drug delivery and distribution. Exploring possibilities to improve vessel functionality without compromising vessel density in the tumor microenvironment, we evaluated transcription factors (TFs) involved in epithelial-mesenchymal transition (EMT) as potential targets. Based on similarities between EMT and angiogenic activation of endothelial cells, we hypothesized that these TFs, Snai1 in particular, might serve as key regulators of vessel dysfunctionality. In vitro, experiments demonstrated that Snai1 (similarly Slug and Twist1) regulates endothelial permeability, permissiveness for tumor cell transmigration, and tip/stalk cell formation. Endothelial-specific, heterozygous knock-down of Snai1 in mice improved vascular quality in implanted tumors. This resulted in better oxygenation and reduced metastasis. Notably, the tumors in Snai1KD mice responded significantly better to chemotherapeutics as drugs were transported into the tumors at strongly increased rates and more homogeneously distributed. Thus, we demonstrate that restoring vessel homeostasis without affecting vessel density is feasible in malignant tumors. Combining such vessel re-engineering with anti-cancer drugs allows for strategic treatment approaches that reduce treatment toxicity on non-malignant tissues. Show less

Tricho-rhino-phalangeal syndrome (TRPS) is a rare, autosomal dominant disorder characterized by typical craniofacial features, ectodermal and skeletal findings. TRPS type 1 (TRPS1) is caused by pathogenic variations in the TRPS1 gene, which relates to the vast majority of cases. TRPS type 2 (TRPS2) is a contiguous gene deletion syndrome involving loss of functional copies of the TRPS1, RAD21, and EXT1. Herein, we reported the clinical and genetic spectrum of seven TRPS patients with a novel variant. We also reviewed the musculoskeletal and radiological findings in the literature. Seven Turkish patients (three female, four male) from five unrelated families aged between 7 to 48 years were evaluated. The clinical diagnosis was confirmed by either molecular karyotyping or TRPS1 sequencing analysis via next-generation sequencing. Both TRPS1 and TRPS2 patients had some common distinctive facial features and skeletal findings. All patients had a bulbous nose with hypoplastic alae nasi, brachydactyly, short metacarpals and phalanges in variable stages. Low bone mineral density (BMD) was identified in two TRPS2 family members presenting with bone fracture, and growth hormone deficiency was detected in two patients. Skeletal X-ray imaging revealed cone-shaped epiphysis of the phalanges in all, and multiple exostoses were present in three patients. Cerebral hamartoma, menometrorrhagia and long bone cysts were among the new/rare conditions. Three pathogenic variants in TRPS1 were identified in four patients from three families, including a frameshift (c.2445dup, p.Ser816GlufsTer28), one missense (c.2762G > A), and a novel splice site variant (c.2700+3A > G). We also reported a familial inheritance in TRPS2 which is known to be very rare. Our study contributes to the clinical and genetic spectrum of patients with TRPS while also providing a review by comparing with previous cohort studies. Show less

Lung cancer continues to be a major health problem worldwide owing to its incidence, and causes physical, psychological, social, and economic problems. Activated cytotoxic T cells (ACTC) are positively correlated with the tumor microenvironment (TME), improving the prognosis of cancer patients. Recently, ACTC-derived exosomes (ACTC-dExo) were implicated in this effect by inhibiting mesenchymal stem cells, which may promote metastasis in the TME. Exosomes are thought to be advantageous for the specific delivery of drugs to cancer cells because they have the characteristics of natural liposomes, are nanosized, and remain largely stable in the blood due to the protein and lipid content they carry on their membranes. In this study, we aimed to determine the cytotoxic and metastatic inhibitory effects of ACTC-dExo in A549 cells in vitro. Cytotoxic CD8 Show less

Congenital myasthenic syndromes (CMS) are composed of numerous hereditary disorders involving genetic mutations in proteins essential to the integrity of neuromuscular transmission. The symptoms of CMS vary according to the age at onset of symptoms, and the type and severity of muscle weakness. Effective treatment and genetic counseling depend upon the underlying pathogenic molecular mechanism and subtype of CMS. A retrospective and cross-sectional study was performed with 16 patients with a genetically confirmed diagnosis of CMS to share our experience with clinical symptoms, demographic data, genetic variants, and treatments applied. Sixteen patients with a specific CMS genetic diagnosis (three novel mutations) were identified, including CHRNE (n = 7), DOK7 (n = 2), AGRN (n = 2), RAPSN (n = 1), CHRNA1 (n = 1), CHRNB1 (n = 1), CHAT (n = 1), and SCN4A (n = 1). Age at onset of symptoms ranged from the neonatal period to 12 years. Genetic diagnosis was confirmed between the ages of three months and 17 years. A significant delay was determined between the onset of symptoms and genetic diagnosis of the disease. This study highlights the importance of genetic testing in CMS. Due to the rarity of CMS, more cases will be recognized and reported as the use of laboratory and genetic testing accelerates. We hope that our experience will grow and contribute further to the literature as clinical follow-up and treatment increase. Show less

The aim of this study was to investigate the effects of the CETP gene rs289714 polymorphism on the serum lipid profile and other metabolic parameters in Turkish patients with coronary artery disease (CAD). The CETP rs289714 variant was examined in 104 patients with CAD and 77 controls using the polymerase chain reaction-restriction fragment length polymorphism method. The CETP rs289714 genotype and allele distribution was not statistically different between the groups (p>0.05). The body mass index (BMI) values in men with CAD were higher in patients with the G allele compared with those carrying the AA genotype (p=0.05). Logistic regression analysis showed that the G allele in male CAD patients was a risk factor for a BMI of ≥ 27 kg/m2 (odds ratio: 0.269, 95% confidence interval: 0.075–0.966; p=0.044). The G allele in female patients was associated with lower HDL-C levels than the AA genotype (p=0.049). The results suggest that the CETP rs289714 polymorphism may cause risk for the development of CAD due to its effects on high-density lipoprotein cholesterol values in female patients and BMI in male patients. Show less