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Kaufman oculocerebrofacial syndrome is a rare autosomal recessive disorder which represents a phenotype mainly involving craniofacial and neurodevelopmental manifestations due to UBE3B gene mutations. The vast majority of the affected individuals exhibit microcephaly, eye abnormalities, and typical facial gestalt including blepharophimosis, ptosis, telecanthus, upslanting palpebral fissures, dysplastic ears, and micrognathia. We encountered 2 siblings in whom severe psychomotor delay, distinctive facial features, hearing loss, and respiratory distress were observed. Some clinical manifestations of the patients, including epibulbar dermoid, microtia, and multiple preauricular tags, were reminiscent of the oculoauriculovertebral spectrum. However, 2 affected siblings exhibited a similar clinical picture consisting of microcephaly, severe developmental and cognitive disabilities, failure to thrive, and dysmorphic features, which were not fully consistent with oculoauriculovertebral spectrum. Also, hypoplastic nails, considered as a core manifestation of Coffin-Siris syndrome, were present in our patients. Therefore, whole-exome sequencing was carried out in order to identify the underlying genetic alterations, contributing to the complex phenotype shared by the 2 siblings. A homozygous pathogenic mutation was found in both affected siblings in the UBE3B gene which caused Kaufman oculocerebrofacial syndrome. Kaufman oculocerebrofacial syndrome should be considered among the autosomal recessive causes of blepharophimosis-mental retardation syndromes, particularly in populations with a high rate of consanguineous marriages, even if there are dysmorphic facial features that are not typically associated with the phenotype.

Background A number of inborn errors of metabolism caused by abnormal protein trafficking that lead to endoplasmic reticulum storage diseases (ERSD) have been defined in the last two decades. One such disorder involves biallelic mutations in the gene encoding endoplasmic reticulum resident co-chaperone DNAJC3 (P58IPK ) that leads to diabetes in the second decade of life, in addition to multiple endocrine dysfunction and nervous system involvement. Objective The aim of this study was to define the natural history of this new form of diabetes, especially the course of abnormalities related to glucose metabolism. Methods Whole-exome and Sanger sequencing was used to detect DNAJC3 defect in two patients. Detailed analysis of their clinical history as well as biochemical, neurological and radiological studies were carried out to deduce natural history of neurological and endocrine phenotype. Results DNAJC3 defect led to beta-cell dysfunction causing hyperinsulinemichypoglycemia around 2 years of age in both patients, which evolved into diabetes with insulin deficiency in the second decade of life, probably due to beta cell loss. Endocrine phenotype involved severe early-onset growth failure due to growth hormone deficiency, and hypothyroidism of central origin. Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life. Conclusion Biallelic loss-of-function in the ER co-chaperone DNAJC3 leads to a new form of diabetes with early onset hyperinsulinemic hypoglycemia evolving into insulin deficiency as well as severe growth failure, hypothyroidism and diffuse neurodegeneration.

In contrast to the mouse, functional assets of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in the human spleen remain to be better elucidated. Here, we report that the spleen in gastric and pancreatic cancer adopts an immune regulatory character, harbors excessive amount of PMN-MDSC, and anatomically enables their interaction with T cells. Compared to the peripheral blood, the spleen from cancer patients contained significantly higher levels of low-density PMN-MDSC, but not early-stage MDSC (e-MDSC) and monocytic-MDSC (M-MDSC). Low-density fraction of polymorphonuclear (PMN) cells was enriched in immature myeloid cells and displayed higher levels of CD10, CD16, and ROS than their blood-derived counterparts. They were also positive for PD-L1, LOX-1, and pSTAT3. The white pulp and periarteriolar lymphoid sheath (PALS) were strategically surrounded by PMN cells that were in contact with T cells. Unlike those from the blood, both low-density and normal-density PMN cells from the human spleen suppressed T cell proliferation and IFN-γ production. Independent of clinical grade, high PMN-MDSC percentages were associated with decreased survival in gastric cancer. In summary, our results outline the immune regulatory role of the spleen in cancer where neutrophils acquire MDSC functions and feasibly interact with T cells.

Advances in omics technologies have made it possible to unravel biomarkers from different biological levels. Intensive studies have been carried out to uncover the dysregulations in psoriasis and to identify molecular signatures associated with the pathogenesis of psoriasis. In this review, we presented an overview of the current status of the omics-driven biomarker research and emphasized the transcriptomic, epigenomic, proteomic, metabolomic, and glycomic signatures proposed as psoriasis biomarkers. Furthermore, insights on the limitations and future directions of the current biomarker discovery strategies were discussed, which will continue to comprehend broader visions of psoriasis research, diagnosis, and therapy especially in the context of personalized medicine.

Introduction: BRAF(V600E) activating mutation is the most frequent genetic abnormality in the pathogenesis of papillary thyroid carcinoma. We aimed to evaluate the association between BRAF(V600E )mutation and well-established prognostic clinicopathological characteristics as well as iodine exposure. Material and methods: From 2000 to 2012, the data of PTC patients admitted to Dr. Lutfi Kirdar Kartal Education and Research Hospital in Turkey were reviewed retrospectively. Clinicopathological parameters were collected. BRAF(V600E) mutation was analysed by DNA sequencing method in tumour specimens. We hypothesised that BRAF(V600E) mutation prevalence is positively correlated with prolonged iodine exposure and expected to be higher in the second half of the recruitment period due to the increment in time spent from the iodisation process of the table salt in our country. Thus, iodine exposure was categorised as short-term (2000-2006) and long-term (2006-2012). Results: A total of 197 patients were accrued. The study population predominantly consisted of conventional variant. A statistically significant relationship was observed between BRAF(V600E) mutation presence and age (p = 0.03), conventional variant PTC (p = 0.00002), T4 stage (p= 0.002), vascular invasion (p= 0.036), thyroid capsule invasion (p < 0.00001), extrathyroidal tissue invasion (p < 0.00001), and lymph node metastasis (p < 0.00001). When categorised as long-term and short-term, iodine exposure was not statistically significantly related with BRAF(V600E) mutation; however, there were far more PTC cases in the long-term group (86.3% vs. 13.7%). Conclusion: We revealed that BRAF(V600E) mutation is associated with adverse clinicopathological parameters. There appeared to be no relation between long-term iodine exposure and BRAF(V600E). Research Fund of the Tekirdag Namik Kemal University [NKUBAP.01, YL.16.021] This work was supported by a grant of the Research Fund of the Tekirdag Namik Kemal University (Project number: NKUBAP.01.YL.16.021).

Cancer as the leading cause of death worldwide has many issues that still need to be addressed. Since the alterations on the glycan compositions or/and structures (i.e., glycosylation, sialylation, and fucosylation) are common features of tumorigenesis, glycomics becomes an emerging field examining the structure and function of glycans. In the past, cancer studies heavily relied on genomics and transcriptomics with relatively little exploration of the glycan alterations and glycoprotein biomarkers among individuals and populations. Since glycosylation of proteins increases their structural complexity by several orders of magnitude, glycome studies resulted in highly dynamic biomarkers that can be evaluated for cancer diagnosis, prognosis, and therapy. Glycome not only integrates our genetic background with past and present environmental factors but also offers a promise of more efficient patient stratification compared with genetic variations. Therefore, studying glycans holds great potential for better diagnostic markers as well as developing more efficient treatment strategies in human cancers. While recent developments in glycomics and associated technologies now offer new possibilities to achieve a high-throughput profiling of glycan diversity, we aim to give an overview of the current status of glycan research and the potential applications of the glycans in the scope of the personalized medicine strategies for cancer. WOS:000628899900003 33404348 Q2

Non-functioning pituitary adenomas (NFPAs) are tumors with clinically challenging features since they have insidious progression. A complex network of gene interactions is thought to have roles in tumor formation and progression. Therefore, revealing the genetic network behind NFPA tumorigenesis is not only essential to attain further knowledge of tumor biology, but also plays a fundamental role in the development of efficacious treatment strategies. Differential co-expression network analysis is an outstanding approach for elucidation of groups of genes which show distinct co-expression patterns among phenotypes. In this study, we carried out a differential co-expression network analysis of NFPA-associated transcriptome dataset (n=40) considering invasive (n=22) and non-invasive (n=18) phenotypes. Furthermore, we identified differentially co-expressed and co-regulated mRNA modules, which might be considered as potential systems biomarkers for NFPA prognosis and invasiveness. As a result, we have identified a novel 13-gene module, including CEACAM6, CYP4B1, EIF2S2, HID1, IFFO1, MYO18A, PDCD2, SGIP1, SWSAP1 and four unknown genes (A_24_P127621, A_24_P255786, A_24_P683553, and A_24_P916979), which was able to categorize the patients into two groups as invasive and non-invasive NFPA with distinct prognosis. The prognostic core module genes were associated with progression and prognosis of brain and glandular based cancers as well. Furthermore, these module genes were also expressed in blood, salivary gland, and spinal cord tissues. These results may provide the evidence on featured gene module which might play a prominent role in NFPA prognosis and sub-typing as effective biomarkers and therapeutic targets in the future.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease, more commonly COVID-19 has emerged as a world health pandemic. There are couples of treatment methods for COVID-19, however, well-established drugs and vaccines are urgently needed to treat the COVID-19. The new drug discovery is a tremendous challenge; repurposing of existing drugs could shorten the time and expense compared with de novo drug development. In this study, we aimed to decode molecular signatures and pathways of the host cells in response to SARS-CoV-2 and the rapid identification of repurposable drugs using bioinformatics and network biology strategies. We have analyzed available transcriptomic RNA-seq COVID-19 data to identify differentially expressed genes (DEGs). We detected 177 DEGs specific for COVID-19 where 122 were upregulated and 55 were downregulated compared to control (FDR, Highlights • Molecular transcriptomes alterations of the lung epithelial cells in response to SARS-CoV-2 were detected. • Significant molecular pathways altered in COVID-19 revealed. • Hub proteins were detected as novel drug targets for COVID-19. • Molecular regulatory signatures were identified. • Repurposable drugs were identified for COVID-19.

Metabolic systems engineering is being used to redirect microbial metabolism for the overproduction of chemicals of interest with the aim of transforming microbial hosts into cellular factories. In this study, a genome-based metabolic systems engineering approach was designed and performed to improve biopolymer biosynthesis capability of a moderately halophilic bacterium Halomonas smyrnensis AAD6T producing levan, which is a fructose homopolymer with many potential uses in various industries and medicine. For this purpose, the genome-scale metabolic model for AAD6T was used to characterize the metabolic resource allocation, specifically to design metabolic engineering strategies for engineered bacteria with enhanced levan production capability. Simulations were performed in silico to determine optimal gene knockout strategies to develop new strains with enhanced levan production capability. The majority of the gene knockout strategies emphasized the vital role of the fructose uptake mechanism, and pointed out the fructose-specific phosphotransferase system (PTSfru) as the most promising target for further metabolic engineering studies. Therefore, the PTSfru of AAD6T was restructured with insertional mutagenesis and triparental mating techniques to construct a novel, engineered H. smyrnensis strain, BMA14. Fermentation experiments were carried out to demonstrate the high efficiency of the mutant strain BMA14 in terms of final levan concentration, sucrose consumption rate, and sucrose conversion efficiency, when compared to the AAD6T. The genome-based metabolic systems engineering approach presented in this study might be considered an efficient framework to redirect microbial metabolism for the overproduction of chemicals of interest, and the novel strain BMA14 might be considered a potential microbial cell factory for further studies aimed to design levan production processes with lower production costs.

Ecballium elaterium, common name squirting cucumber juice is used for the symptomatic treatment of rhinosinusitis in folk medicine. There are reports of allergic reactions of this plant in the literature. It has strong anti-inflammatory effect and people in the eastern Mediterranean region widely use this fruit juice for rhinitis and sinusitis. We presented a case of uvular edema caused by this plant.

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) lack robust diagnostics and prognostic biomarkers. Metabolomics is a postgenomics field that offers fresh insights for biomarkers of common complex as well as rare diseases. Using data on metabolite-disease associations published in the previous decade (2006-2016) in PubMed, ScienceDirect, Scopus, and Web of Science, we identified 101 metabolites as putative biomarkers for these three neurodegenerative diseases. Notably, uric acid, choline, creatine, L-glutamine, alanine, creatinine, and N-acetyl-L-aspartate were the shared metabolite signatures among the three diseases. The disease-metabolite-pathway associations pointed out the importance of membrane transport (through ATP binding cassette transporters), particularly of arginine and proline amino acids in all three neurodegenerative diseases. When disease-specific and common metabolic pathways were queried by using the pathway enrichment analyses, we found that alanine, aspartate, glutamate, and purine metabolism might act as alternative pathways to overcome inadequate glucose supply and energy crisis in neurodegeneration. These observations underscore the importance of metabolite-based biomarker research in deciphering the elusive pathophysiology of neurodegenerative diseases. Future research investments in metabolomics of complex diseases might provide new insights on AD, PD, and ALS that continue to place a significant burden on global health.