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Purpose: Autosomal recessive dedicator of cytokinesis 8 (DOCK8-/-) and autosomal dominant signal transducer and activator of transcription 3 (STAT3+/-) deficiencies are inborn errors of immunity (IEI) disorders present with the classic features of eczema and create a dilemma during differentiation from atopic dermatitis (AD). Therefore, an appropriate approach is required for eczema to diagnose DOCK8-/- and STAT3+/- early. Here, we described a set of clinical and immunological variables, including atypical AD localizations and lymphocyte subsets, to differentiate DOCK8-/- or STAT3+/- from AD. Methods: This multicenter study involved 100 patients with DOCK8-/- and STAT3+/- and moderate/severe AD. We recruited disease manifestations, including detailed localizations of eczema, infections, and allergy. Principle Component analysis (PCA) was used to discriminate DOCK8-/- or STAT3+/- from AD. Results: There were 43 patients with DOCK8-/-, 23 with STAT3+/-, and 34 with AD. Pneumonia, severe infections, mucocutaneous candidiasis, and skin abscesses were commonly observed in DOCK8 and STAT3 deficiencies. Atypical skin involvement with neonatal rash, retro auricular, axillary, sacral, and genital eczema discriminate DOCK8-/- and STAT3+/- from AD with high specificity ranges between 73.5 and 94.1% and positive predictive index ranges between 55 and 93.1%. Together with using absolute numbers of CD3+, CD4+, and CD8+ T cells, the combined clinical and laboratory features showed perfect differentiation between DOCK8-/- or STAT3+/- and AD via PCA. Conclusions: The described features can be easily implemented by physicians providing early diagnosis of DOCK8 and STAT3 deficiencies.

Background: Inborn errors of immunity have been implicated in causing immune dysregulation, including allergic diseases. STAT6 is a key regulator of allergic responses. Objectives: This study sought to characterize a novel gain-of-function STAT6 mutation identified in a child with severe allergic manifestations. Methods: Whole-exome and targeted gene sequencing, lymphocyte characterization, and molecular and functional analyses of mutated STAT6 were performed. Results: This study reports a child with a missense mutation in the DNA binding domain of STAT6 (c.1114G>A, p.E372K) who presented with severe atopic dermatitis, eosinophilia, and elevated IgE. Naive lymphocytes from the affected patient displayed increased TH2- and suppressed TH1- and TH17-cell responses. The mutation augmented both basal and cytokine-induced STAT6 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reversed STAT6 hyperresponsiveness to IL-4, normalized TH1 and TH17 cells, suppressed the eosinophilia, and improved the patient\"s atopic dermatitis. Conclusions: This study identified a novel inborn error of immunity due to a STAT6 gain-of-function mutation that gave rise to severe allergic dysregulation. Janus kinase inhibitor therapy could represent an effective targeted treatment for this disorder.

Purpose: MALT1 deficiency is a combined immune deficiency characterized by recurrent infections, eczema, chronic diarrhea, and failure to thrive. Clinical and immunological characterizations of the disease have not been previously reported in large cohorts. We sought to determine the clinical, immunological, genetic features, and the natural history of MALT-1 deficiency. Methods: The clinical findings and treatment outcomes were evaluated in nine new MALT1-deficient patients. Peripheral lymphocyte subset analyses, cytokine secretion, and proliferation assays were performed. We also analyzed ten previously reported patients to comprehensively evaluate genotype/phenotype correlation. Results: The mean age of patients and disease onset were 33 ± 17 and 1.6 ± 0.7months, respectively. The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%). Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively. The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells. Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications. One patient received hematopoietic stem cell transplantation (HSCT) and five patients died as a complication of life-threatening infections. Analyzing this cohort with reported patients revealed overall survival in 58% (11/19), which was higher in patients who underwent HSCT (P = 0.03). Conclusion: This cohort provides the largest analysis for clinical and immunological features of MALT1 deficiency. HSCT should be offered as a curative therapeutic option for all patients at the early stage of life.

Background Obesity is a complex genetic-based pediatric disorder which triggers life-threatening conditions. Therefore, the understanding the molecular mechanisms of obesity has been a significant approach in medicine. Computational methods allow rapid and comprehensive pathway analysis, which is important for generation of diagnosis and treatment of obesity. Methods and results Aims of our study are to comprehensively investigate genetic characteristics of obesity in children with non-syndromic, early-onset (< 7 years), and severe obesity (BMI-SDS > 3) through computational approaches. First, the mutational analyses of 41 of obesity-related genes in 126 children with non-syndromic early-onset severe obesity and 76 healthy non-obese controls were performed using the next generation sequencing (NGS) technique, and the NGS data analyzed by using bioinformatics methods. Then, the relationship between pathogenic variants and anthropometric/biochemical parameters was further evaluated. Obtained results demonstrated that the 15 genes (ADIPOQ, ADRB2, ADRB3, IRS1, LEPR, NPY, POMC, PPARG, PPARGC1A, PPARGC1B, PTPN1, SLC22A1, SLC2A4, SREBF1 and UCP1) which directly related to obesity found linked together via biological pathways and/or functions. Among these genes, IRS1, PPARGC1A, and SLC2A4 stand out as the most central ones. Furthermore, 12 of non-synonymous pathogenic variants, including six novels, were detected on ADIPOQ (G90S and D242G), ADRB2 (V87M), PPARGC1A (E680G, A477T, and R656H), UCP1 (Q44R), and IRS1 (R302Q, R301H, R301C, H250P, and H250N) genes. Conclusion We propose that 12 of non-synonymous pathogenic variations detected on ADIPOQ, ADRB2, PPARGC1A, UCP1, and IRS1 genes might have a cumulative effect on the development and progression of obesity.

Royal jelly is a gelatinous nutrient secretion produced by the mandibular glands of young worker honey bees and has a critical role in honey bee life. In the honey bee colonies, queen and worker honey bees have very different morphologies and behaviors due to their diet in the larval period, despite having the same genome. In comparison, queen bees formed from larvae that feed royal jelly exclusively, and worker bees formed from larvae that feed on much less royal jelly. DNA methylation has been shown to play a critical role in the development of queen and worker honeybees. Alterations in DNA methylation, one of the epigenetic mechanisms defined as hereditable nucleotide modifications that occur in gene expression without changes in the DNA sequence, are closely related to many diseases, especially cancer. Hypermethylation of CpG islands located in the promoter regions of genes causes gene silencing and tumor suppressor genes epigenetically have silenced in cancer. The inactivation of tumor suppressor genes disrupts nearly all cellular pathways in cancer. In contrast to genetic alterations, gene silencing by epigenetic modifications may potentially be reversed and used in cancer treatment. Royal jelly, which causes epigenetic changes in bee colonies, has the potential to cause a change in cancer cells. In our study, royal jelly's effects on DNA methyltransferase enzyme and gene methylation of RASSF1A tumor suppressor were investigated in human cancer cell lines (HeLa, HT29, and A549), and modifications in the gene expression profile of royal jelly were determined by next generation sequencing.

Heat shock protein 90 (Hsp90) is a key chaperone that is abnormally expressed in cancer cells, and therefore, designing novel compounds to inhibit chaperone activities of the Hsp90 is a promising therapeutic approach for cancer drug discovery. Debio-0932 is a second-generation Hsp90 inhibitor that exhibited promising anticancer activity against a wide variety of cancer types with a strong binding affinity for Hsp90 and high oral bioavailability. Anticancer activities of the Debio-0932 were tested in MCF-7 and MDA-MB-231 cell lines. Molecular docking results indicated that Debio-0932 was selectively bound to the ATP binding pocket of the Hsp90 with an estimated free energy of binding − 7.24 kcal/mol. Antiproliferative activity of Debio-0932 was determined by XTT assay and Debio-0932 exhibited a cytotoxic effect on MCF-7 and MDA-MB-231 cells in a time and dose-depended manner. Apoptosis inducer role of Debio-0932 was evaluated in MCF-7 and MDA-MB-231 cells with fluorometric apoptosis/necrosis detection kit. Treatment with Debio-0932 stimulated apoptosis in both breast cancer cell lines. mRNA and protein expression levels of Bax, Bcl-2 and Casp-9 were determined in MCF-7 and MDA-MB-231 cells by RT-PCR and Western blotting respectively. Debio-0932 stimulated the down-regulation of anti-apoptotic protein Bcl-2 and the up-regulation of apoptotic protein Bax and cleavage of Casp-9 in cancer cells. Moreover, the anti-invasive potential of Debio-0932 was evaluated in endothelial cells (HUVEC) by wound-healing assay. Debio-0932 decreased the migration of HUVEC cells as compared to the control group. These results indicate that Debio-0932 is a promising compound to treat triple-negative breast cancer and hormone receptor-positive breast cancer, and their metastases.

Heat shock protein 90 (Hsp90) is a key chaperone that is abnormally expressed in cancer cells, and therefore, designing novel compounds to inhibit chaperone activities of the Hsp90 is a promising therapeutic approach for cancer drug discovery. Debio-0932 is a second-generation Hsp90 inhibitor that exhibited promising anticancer activity against a wide variety of cancer types with a strong binding affinity for Hsp90 and high oral bioavailability. Anticancer activities of the Debio-0932 were tested in MCF-7 and MDA-MB-231 cell lines. Molecular docking results indicated that Debio-0932 was selectively bound to the ATP binding pocket of the Hsp90 with an estimated free energy of binding - 7.24 kcal/mol. Antiproliferative activity of Debio-0932 was determined by XTT assay and Debio-0932 exhibited a cytotoxic effect on MCF-7 and MDA-MB-231 cells in a time and dose-depended manner. Apoptosis inducer role of Debio-0932 was evaluated in MCF-7 and MDA-MB-231 cells with fluorometric apoptosis/necrosis detection kit. Treatment with Debio-0932 stimulated apoptosis in both breast cancer cell lines. mRNA and protein expression levels of Bax, Bcl-2 and Casp-9 were determined in MCF-7 and MDA-MB-231 cells by RT-PCR and Western blotting respectively. Debio-0932 stimulated the down-regulation of anti-apoptotic protein Bcl-2 and the up-regulation of apoptotic protein Bax and cleavage of Casp-9 in cancer cells. Moreover, the anti-invasive potential of Debio-0932 was evaluated in endothelial cells (HUVEC) by wound-healing assay. Debio-0932 decreased the migration of HUVEC cells as compared to the control group. These results indicate that Debio-0932 is a promising compound to treat triple-negative breast cancer and hormone receptor-positive breast cancer, and their metastases.

Lung cancer is the leading cancer type of death rate. The lung adenocarcinoma subtype is responsible for almost half of the total lung cancer deaths. Despite the improvements in cancer treatment in recent years, lung adenocarcinoma patients' overall survival rate remains poor. Immunetherapy and chemotherapy are two of the most widely used options for the treatment of cancer. Although many cancer types initially respond to these treatments, the development of resistance is inevitable. The rapid development of drug resistance mainly characterizes lung adenocarcinoma. Despite being the subject of many studies in recent years, the resistance initiation and progression mechanism is still unclear. In this review, we have examined the role of the primary DNA repair pathways (non-homologous end joining (NHEJ) pathway, homologous-recombinant repair (HR) pathway, base excision repair (BER) pathway, and nucleotide excision repair (NER) pathway and transactivation mechanisms of tumor protein 53 (TP53) in drug resistance development. This review suggests that mentioned pathways have essential roles in developing the resistance against chemotherapy and immunotherapy in lung adenocarcinoma patients.

The mechanism behind the development and progression of cancer is complex and largely remained unknown. Recent studies suggest that interferon regulatory factors (IRF) 4 and 7 may play a significant role in carcinogenesis. Alterations on the expression profiles of the IRF4 and IRF7 directly induce pathogen susceptibility in the cell environment resulting in the activation of cancer-related factors required for a number of stages in metastatic cascade. In the present study, we have investigated the role of the IRF4 and IRF7 on the survival of patients with lung adenocarcinoma through genomics and interactome analyses using the data from The Cancer Genome Atlas (TCGA) database. In addition, the possible impact of the damaging mutations on the biological functions of the targeted proteins have been explored.

This research aims to investigate the interaction between phytohemagglutinin-L (PHA-L) and sialic acid, which is abundant on the breast cancer cell (MCF-7) surface and displays monosaccharide characteristics, by experimental and computational methods. Experimentally, CdSe/CdS nanoparticles (QDs) were synthesized; PHA-L was conjugated with QDs and labeled with 125I. Radiolabeling yield was found to be 97 ± 1.2 %. Afterwards, in vitro bioaffinities of radiolabeled PHA-L conjugated QDs have been investigated on MCF-7 cells and it has been observed that the cell incorporation increased with time. The results indicated that 125I labeled QD-PHA-L conjugates represent significant affinity on MCF-7 cells. In the second step of the study, the crystal structure of carbohydrate interaction surface of PHA-L was extracted from the crystal structure of PHA-L. The interactions between this surface and sialic acid were calculated by computational tools. These calculations revealed specific interactions between PHA-L and sialic acid. Semi-empirical methods, PM3 and AM1, were used in these calculations. Significant outcomes have been obtained from the experimental and computational studies and these results demonstrated that PHA-L may be an effective agent for imagining MCF-7 cells.

Objektif: Bu çalismanin amaci dogal menopozdaki hastalarda üç farkli hormon replasman tedavisinin (HRT) renal damarlar üzerine etkisini renal arter Doppler indeksleri ölçümü ile arastirmakti. Planlama: Otuz üç postmenapozal hastaya randomize olarak sirasiyla 0.625 mg konjuge equine östrojen (CEE) + 5 mg medroksiprogesteron asetat (MPA) (Grup I), 2 mg estradiol valerat (Grup II) ya da 2.5 mg Tibolon (Grup III) baslandi. Tedavi baslamadan önce ve baslangiçtan 70 gün sonra her hastaya sol interlobar renal arter Doppleri yapildi. Ortam: Kirikkale Üniversitesi Tip Fakültesi Kadin Hastaliklari ve Dogum ve Kirikkale Üniversitesi Tip Fakültesi Radyoloji Anabilim Dali Degerlendirme parametreleri: HRT baslangiç ve tedavi sonrasinda interlobar renal arter Doppler indeksleri ölçümü SONUÇ: Toplam 33 hastadan grup I’ den 11, grup II’ den 7 ve grup III’ den 9 hasta çalismaya dahil edildi. Bu 27 hastanin yas ortalamasi 49.44 ± 4.07 idi. Tüm hastalarin bazal pulsatilite (PI) ve resistivite indeks (RI) degerleri benzerdi. Yetmis günlük tedavi sonrasinda grup III’ teki hastalarin RI (p düsüs izlendi. Grup I’ deki hastalarin bazal ve tedavi sonrasi RI ve PI degerlerinde ise anlamli degisiklik olmadi. YORUM: Az sayida hastayla yapilmis olan bu çalismanin sonuçlari Tibolon ve estradiol valerat’in renal kan akimi üzerine olumlu etkileri olabilecegi ve östrojenle kombine kullanildiginda MPA’ in östrojenin vasküler etkilerini azaltici etki yaratabilecegini düsündürmekte ise de, bu yargiyi destekleyecek iyi planlanmis daha fazla hastayla yapilmis, uzun süreli çalismalara gereksinim vardir.

The purpose of this study was to compare the resistance indices (RIs) in the fetal interlobar renal arteries (IRAs) of third-trimester fetuses with or without pelvicaliceal dilatation of up to 10 mm and to compare them with those of the full-term healthy infants.Women with uncomplicated, low-risk, singleton third-trimester pregnancies were examined sonographically. The RIs in the IRAs were measured in the fetuses, who were stratified into 3 groups according to the anteroposterior diameter of the renal pelvic dilatation: group I, no dilatation; group II, 1-5-mm dilatation, and group III, 6-10-mm dilatation.In total, 178 women were examined. We could study both kidneys in 139 of the fetuses; in the other 39, only 1 kidney could be imaged perfectly. This yielded a total of 317 kidneys. Group I fetuses included 172 (54%); group II, 98 (31%); and group III, 47 (15%) of the kidneys. The mean (+/- standard deviation) RIs in the IRAs were 0.81 +/- 0.09, 0.80 +/- 0.07, and 0.80 +/- 0.06 in the 3 groups, respectively, with no statistically significant difference between the groups (p = 0.72). There was also no statistically significant difference between the RIs recorded in the right and left kidneys. The mean RI in the IRAs of the 34 infants who were available for follow-up 6-12 weeks after delivery was 0.73 +/- 0.07, which was significantly less than that recorded in the third-trimester fetuses (p = 0.005).The RI in the fetal IRA does not differ in fetuses with and without renal pelvic dilatation of up to 10 mm. Thus, an increase in the RI or an RI that significantly differs between the right and left kidneys should be investigated further for possible renal pathology.

An odd complication following routine breast augmentations was observed in two patients. Single-lumen, textured, high-profile, saline-filled mammary implants were placed in the submuscular plane and postoperative course was uneventful in the presented cases. Unilateral, gradual, and spontaneous swelling in one of the operated breasts was observed 6-14 months after surgery that prompted patients for examination. MRI showed regular external contours of the mammary implants without any evidence of rupture or extracapsular leakage. However, a substantially volumetric increase in the auto-inflated implant was noted since transverse diameter of the right breast implant was twice the left normal implant. All cases had to be re-operated and implants were explanted. Auto-inflated implants were checked and were found to be intact. Intraoperative findings included swelling of the implant and brown discoloration of the previously-transparent saline solution. Furthermore, composition of the fluid inside the expanded implant was found to have changed, possibly through an osmotic gradient. Several mechanisms such as osmotic swelling, defect at the valvular system of the implant, and inorganic salts yielded from texturization process in the shell are suggested but further research with more refined techniques should be done. The present study provides supplementary MRI and confirmatory clinical findings on this bizarre phenomenon and other factors apart from the disruption of the implant integrity may play a role.