Factors affecting onset of puberty in Denizli province in Turkey

The relationship between the possible factors affecting pubertal onset and pubertal timing was investigated in the Denizli province in Turkey. A total number of 3311 subjects (1562 girls, 1749 boys) aged 6-16.5 years participated in this study. Body mass index (BMI) was calculated. Pubertal stages were assessed according to methods of Marshall and Tanner. Testicular volume was determined using Prader orchidometer. Menarcheal age was recorded. All parents and students completed different questionnaires on demographic variables affecting pubertal timing such as socioeconomic conditions, psychosocial factors, exercise, nutritional status, chronic diseases, migration and birth weight. Using distribution percentiles of pubertal stages according to age, the relation between pubertal timing and factors affecting puberty was investigated. There was no significant association between exercise, birth weight, migration, chronic disease, and socioeconomic status and age of puberty onset. Menarcheal age of overweight and obese girls was significantly lower than that of girls with normal weight. In-family stress was the cause of early puberty in girls and of delayed puberty in boys

The Significance of Lung Ultrasonography in Children with COVID-19

Introduction:The infection of new Coronavirus disease-2019 (COVID-19) continues to affect both adults and children worldwide. Although there are studies of adult patients with COVID-19 that defined ultrasound findings, there is limited data available on the diagnostic use of ultrasonography in children. This study is aimed to evaluate the results of bedside lung ultrasonography (LUS) performed in pediatric patients with COVID-19.Methods:The study included pediatric patients who were diagnosed with COVID-19. All lung areas were visualized on LUS and evaluated together with demographic, clinical, and laboratory data, and chest X-ray (CXR) findings.Results:An evaluation was made of 102 pediatric patients, comprising 54 girls and 48 boys with a mean age of 9.65±4.78 (min 35 days-max 17) years. Forty-six percent of the patients had respiratory system symptoms, 36% were asymptomatic, and 18% had symptoms other than in the respiratory system. Pathologic findings were determined on CXR in 36% of patients, and on LUS in 57%. The difference in the detection rate of pathologic findings between LUS and CXR was statistically significant (p=0.001). Pathology was observed on LUS in 29 of 65 patients with normal CXR. The sensitivity rate for detecting pathology in patients with respiratory symptoms was 49% on CXR and 77% on LUS (p=0.001).Conclusion:We determined that the sensitivity of LUS is higher than CXR in demonstrating lung involvement in patients with COVID-19 with respiratory symptoms. LUS may be helpful in the evaluation of pediatric patients with COVID-19 but more studies are needed to prove its feasibility in children

Evaluation of frequencies of HLA-A, B and DR in thracian population and examination of its relationship with Balkan populations

Amaç: Bu çalışmada Trakya bölgesinde yaşayan Türk popülasyonunun insan lökosit antijenleri (HLA) allel dağılımları belirlendi. Çalışma Planı: Çalışma grubu, üç kuşaktır Trakya bölgesinde yaşayan ve benzer linguistik özellikler gösteren 105 doku vericisinden oluşturuldu. HLAA, B ve DRB1 allellerinin genotiplendirmesinde Polimeraz zincir reaksiyonu-sekans spesifik primer (PZR-SSP) yöntemi kullanıldı. Tüm alleler içinde en sık gözlenenler HLA-A*02 (%20.5), HLA-B*35 (%22.9), HLA-DR*11 (%17.6) oldu. Bulgular: HLA allellerinin frekansları, HLA gen bölgesinin fazla polimorfik yapısından dolayı popülasyonlar arasında farklılık göstermektedir. Dağılımdaki bu farklılıklar ve benzerlikler toplumların birbirleriyle akrabalıklarını ortaya koymada en tercih edilen genetik yaklaşımlardan biridir. Sonuç: Bu çalışmada da diğer Türk popülasyonları ile farklı Balkan popülasyonları arasındaki akrabalıkları belirlemek amacıyla HLA-DR frekansları karşılaştırıldı. Trakya Türklerinin Balkan popülasyonlarına benzer bir HLA-DR dağılımı sergilediği görüldü.Objectives: In this study, human leukocyte antigen (HLA) allel frequencies of Thracian Turkish population were determined. Study Design: The study group consisted of 105 tissue donors who live in Thrace region of Turkey for three generations and have similar linguistic features. Polymerase chain reaction-sequencespecific primer (PCR-SSP) method was used for genotyping of HLA-A, B and DRB1 alleles. The most frequent HLA alleles were HLA-A*02 (20.5%), HLA-B*35 (22.9%) and HLA-DR*11 (17.6%). Results: Conclusion: In this study also, HLA-DR allel frequencies were compared in order to determine the relationship between other Turkish populations and Balkan populations. It is observed that Thracian Turkish population has similar HLA-DR distributions with Balkan populations

Epithelial to mesenchymal transition is associated with rapamycin resistance

Rapamycin analogues have antitumor efficacy in several tumor types, however few patients demonstrate tumor regression. Thus, there is a pressing need for markers of intrinsic response/resistance and rational combination therapies. We hypothesized that epithelial-to-mesenchymal transition (EMT) confers rapamycin resistance. We found that the epithelial marker E-cadherin protein is higher in rapamycin sensitive (RS) cells and mesenchymal breast cancer cell lines selected by transcriptional EMT signatures are less sensitive to rapamycin. MCF7 cells, transfected with constitutively active mutant Snail, had increased rapamycin resistance (RR) compared to cells transfected with wild-type Snail. Conversely, we transfected two RR mesenchymal cell lines—ACHN and MDA-MB-231—with miR-200b/c or ZEB1 siRNA to promote mesenchymal-to-epithelial transition. This induced E-cadherin expression in both cell lines, and ACHN demonstrated a significant increase in RS. Treatment of ACHN and MDA-MB-231 with trametinib modulated EMT in ACHN cells in vitro. Treatment of MDA-MB-231 and ACHN xenografts with trametinib in combination with rapamycin resulted in significant growth inhibition in both but without an apparent effect on EMT. Future studies are needed to determine whether EMT status is predictive of sensitivity to rapalogs and to determine whether combination therapy with EMT modulating agents can enhance antitumor effects of PI3K/mTOR inhibitors

Efficacy of futibatinib, an irreversible fibroblast growth factor receptor inhibitor, in FGFR-altered breast cancer.

Several alterations in fibroblast growth factor receptor (FGFR) genes have been found in breast cancer; however, they have not been well characterized as therapeutic targets. Futibatinib (TAS-120; Taiho) is a novel, selective, pan-FGFR inhibitor that inhibits FGFR1-4 at nanomolar concentrations. We sought to determine futibatinib\u27s efficacy in breast cancer models. Nine breast cancer patient-derived xenografts (PDXs) with various FGFR1-4 alterations and expression levels were treated with futibatinib. Antitumor efficacy was evaluated by change in tumor volume and time to tumor doubling. Alterations indicating sensitization to futibatinib in vivo were further characterized in vitro. FGFR gene expression between patient tumors and matching PDXs was significantly correlated; however, overall PDXs had higher FGFR3-4 expression. Futibatinib inhibited tumor growth in 3 of 9 PDXs, with tumor stabilization in an FGFR2-amplified model and prolonged regression (\u3e 110 days) in an FGFR2 Y375C mutant/amplified model. FGFR2 overexpression and, to a greater extent, FGFR2 Y375C expression in MCF10A cells enhanced cell growth and sensitivity to futibatinib. Per institutional and public databases, FGFR2 mutations and amplifications had a population frequency of 1.1%-2.6% and 1.5%-2.5%, respectively, in breast cancer patients. FGFR2 alterations in breast cancer may represent infrequent but highly promising targets for futibatinib

Cyclin E overexpression sensitizes triple negative breast cancer to Wee1 kinase Inhibition

Purpose: Poor prognosis in triple-negative breast cancer (TNBC) is due to an aggressive phenotype and lack of biomarker-driven targeted therapies. Overexpression of cyclin E and phosphorylated-CDK2 are correlated with poor survival in TNBC patients, and the absence of CDK2 desensitizes cells to inhibition of Wee1 kinase, a key cell cycle regulator. We hypothesize that cyclin E expression can predict response to therapies, which include the Wee1 kinase inhibitor, AZD1775. Experimental Design: Mono and combination therapies with AZD1775 were evaluated in TNBC cell lines and multiple patient derived xenograft (PDX) models with different cyclin E expression profiles. The mechanism(s) of cyclin E-mediated replicative stress were investigated following cyclin E induction or CRISPR/Cas9 knockout by a number of assays in multiple cells lines. Results: Cyclin E overexpression (1) is enriched in TNBCs with high recurrence rates, (2) sensitizes TNBC cell lines and PDX models to AZD1775, (3) leads to CDK2-dependent activation of DNA replication stress pathways and (4) increases Wee1 kinase activity. Moreover, treatment of cells with either CDK2 inhibitors or carboplatin leads to transient transcriptional induction of cyclin E (in cyclin E-low tumors) and result in DNA replicative stress. Such drug mediated cyclin E induction in TNBC cells and PDX models sensitizes them to AZD1775 in a sequential treatment combination strategy. Conclusions: Cyclin E is a potential biomarker of response (1) for AZD1775 as monotherapy in cyclin E high TNBC tumors and (2) for sequential combination therapy with CDK2 inhibitor or carboplatin followed by AZD1775 in cyclin E low TNBC tumors

Oxidative Phosphorylation Is a Metabolic Vulnerability in Chemotherapy-Resistant Triple-Negative Breast Cance

Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pretreatment biopsies from patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of OXPHOS signature. IACS-10759, a novel inhibitor of OXPHOS, stabilized growth in multiple TNBC patient-derived xenografts (PDX). On gene expression profiling, all of the sensitive models displayed a basal-like 1 TNBC subtype. Expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen to identify synthetic lethal targets in tumors treated with IACS-10759 found several potential targets, including CDK4. We validated the antitumor efficacy of the combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 in vitro and in vivo. In addition, the combination of IACS-10759 and multikinase inhibitor cabozantinib had improved antitumor efficacy. Taken together, our data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens. SIGNIFICANCE: These findings suggest that triple-negative breast cancer is highly reliant on OXPHOS and that inhibiting OXPHOS may be a novel approach to enhance efficacy of several targeted therapies

Pubertal stages according to age and factors of affecting puberty in school children in Denizli province

Amaç: Son yıllarda normal pubertal gelişimin zamanlaması konusuna ilgi artmıştır. Bu çalışmada pubertal gelişimde yüzyılın eğiliminin olası etkisini araştırmak üzere, Denizli'de yaşayan okul çocuklarının pubertal durumları değerlendirildi. Metod: Çalışmada kırsal ve kentsel bölgede yaşayan 6-16.5 yaş arasında 1562 kız, 1749 erkek çocuk yer aldı. Kilo ve boy ölçüldü, VK hesaplandı. Pubertal evreler Tanner metodu ile değerlendirildi. Testis hacimleri orşidometre ile ölçüldü. Menarş yaşı kaydedildi. Çalışmaya katılan tüm çocuklara puberteyi etkileyen demografik özellikler araştırmak için bir anket uygulandı. Bulgular : Kızlarda meme gelişim evreleri için ortalama yaşlar, M1'de 7.74 ± 1.08, M2'de 10.16 ± 0.97, M3'de 11.72 ± 1.29, M4'de 12.97 ± 1.17, M5'de 13.66 ± 0.89 olarak bulundu. Pubik kıllanma evreleri için ortalama yaşlar, PK1'de 8.72 ± 1.50, PK2'de 10.57 ± 1.39, PK3'de 12.12 ± 1.10, PK4'de 13.10 ± 1.04, PK5'de 13.87 ± 0.83 olarak bulundu. Ortalama menarş yaşı 12.41 yaştı. Normal çocuklarla ile karşılaştırıldığında, menarş yaşının fazla kilolu ve obez çocuklarda daha erkene kaydığı görüldü. Erkeklerde testis hacmine göre değerlendirilen maturasyon evrelerindeki ortalama yaşlar, G1'de 8.70 ± 1.38, G2'de 11.76 ± 1.28, G3'de 12.81 ± 1.0, G4'de 13.17 ± 0.87, G5'de 13.87 ± 0.98 olarak bulundu. Erkeklerde pubik kıllanma evrelerindeki ortalama yaşlar PK1'de 9.39 ± 1.81, PK2'de 12.02 ± 1.33, PK3'de için 13.05 ± 0.88, PK4'de 13.42 ± 0.87, PK5'de 14.02 ± 0.92 olarak bulundu. Egzersiz, doğum ağırlığı, göç, kronik hastalık, sosyoekonomik durum ile puberte başlama zamanı arasında anlamlı bir ilişkiye rastlanmadı. Aile içi stresin kızlarda erken erkeklerde gecikmiş puberteye neden olduğu görüldü. 90 Sonuçlar : Bu çalışmada, ortalama puberte başlama yaşının erkeklerde literatürdeki birçok çalışmada bildirilen yaşlara benzer, kızlarda ise daha erken olduğu görülmüştür. Puberte başlama zamanınını en fazla etkileyen faktörün aile içi stres olduğu saptanmıştır.Aim: Timing of normal pubertal maturation has received increased attention over the past several years. To investigate the pubertal development of school children living in Denizli, in order to look for possible secular trends in pubertal development. Methods: A total number of 1562 girls and 1749 boys (aged 6 - 16.5 years) from both urban and rural schools were included in this study. Weight and height were measured and body mass index was calculated. Pubertal stages were assessed by clinical examination according to methods of Tanner. Testicular volume was determined using an orchidometer. Menarcheal age was recorded. All participants completed a questionnaire on demographic variables affecting pubertal timing. Results: In girls, the mean ages at breast stage (B) were 7.74 ± 1.08 years for B1, 10.16 ± 0.97 for B2, 11.72 ± 1.29 for B3, 12.97 ± 1.17 for B4, and 13.66 ± 0.89 for B5. The mean ages at pubic hair stage (PH) were 8.72 ± 1.50 years for PH1, 10.57 ± 1.39 for PH2, 12.12 ± 1.10 for PH3, 13.10 ± 1.04 for PH4, and 13.87 ± 0.83 for PH5. The mean age at menarche was 12.4 years. Menarcheal age was earlier in overweight and obese children compared with that in normal children. In boys, the mean ages at each maturity stage according to testis volume (G) were 8.70 ± 1.38 years for G1, 11.76 ± 1.28 for G2, 12.81 ± 1.0 for G3, 13.17 ± 0.87 for G4, and 13.87 ± 0.98 for G5. The mean ages at PH in boys were 9.39 ± 1.81 years for PH1, 12.02 ± 1.33 for PH2, 13.05 ± 0.88 for PH3, 13.42 ± 0.87 for PH4, and 14.02 ± 0.92 for PH5. No significant correlation was found between exercise, obesity, birth weight, migration, chronic diseases, socioeconomic status and pubertal onset. Stressful situations in family were the causes of delayed puberty in boys, but of precocicity in girls. 92 Conclusions: In this study, while the mean age at onset of puberty in boys was comparable to that of other populations in the world, girls are found to start pubertal development earlier than those of other populations. It was concluded that stressful situations in family were the factors affecting puberty onset the most