Miracle-dz/UniFAR-FTUs huggingface dataset:
Noonan syndrome, PTPN11 mutations, and brain tumors. A clinical report and review of the literature

Noonan syndrome (NS), an autosomal dominant disorder, is characterized by short stature, congenital heart defects, developmental delay, and facial dysmorphism. PTPN11 mutations are the most common cause of NS. PTPN11 encodes a non‐receptor protein tyrosine phosphatase, SHP2. Hematopoietic malignancies and solid tumors are associated with NS. Among solid tumors, brain tumors have been described in children and young adults but remain rather rare. We report a 16‐year‐old boy with PTPN11‐related NS who, at the age of 12, was incidentally found to have a left temporal lobe brain tumor and a cystic lesion in the right thalamus. He developed epilepsy 2 years later. The temporal tumor was surgically resected because of increasing crises and worsening radiological signs. Microscopy showed nodules with specific glioneuronal elements or glial nodules, leading to the diagnosis of dysembryoplastic neuroepithelial tumor (DNT). Immunohistochemistry revealed positive nuclear staining with Olig2 and pERK in small cells. SHP2 plays a key role in RAS/MAPK pathway signaling which controls several developmental cell processes and oncogenesis. An amino‐acid substitution in the N‐terminal SHP2 domain disrupts the self‐locking conformation and leads to ERK activation. Glioneuronal tumors including DNTs and pilocytic astrocytomas have been described in NS. This report provides further support for the relation of DNTs with RASopathies and for the implication of RAS/MAPK pathways in sporadic low‐grade glial tumors including DNTs. © 2017 Wiley Periodicals, Inc.
DIABETES MELITUS TIPE 2

Abstract Type 2 Diabetes Mellitus is a metabolic disorder that is marked by the rise in blood sugar due to a decrease in insulin secretion by pancreatic beta cells and insulin function ordisorder (insulin resistance). Results Health Researchin 2008, showed the incidence of diabetes mellitus in Indonesia reached 57%, while the incidence in type 2 diabetes mellitus World is 95%. Risk factors of diabetes mellitus type 2, namely age, gender, obesity, hypertension, genetics, diet, smoking, alcohol, lack ofactivity, waist circumference, . Treatment done by the use of oral medication hyperglycemia and insulin as well as life style modification storeduce the incidence and microvascular and macrovascular complications of diabetes mellitus type 2. Keywords: Definition, diabetes mellitus type 2, risk factors, treatment Abstrak Diabetes Mellitus Tipe 2 adalah penyakit gangguan metabolik yang di tandai oleh kenaikan gula darah akibat penurunan sekresi insulin oleh sel beta pankreas dan atau ganguan fungsi insulin (resistensi insulin). Hasil Riset Kesehatan Dasar pada tahun 2008, menunjukan angka kejadian Diabetes Melitus di Indonesia mencapai 57% sedangkan kejadian di Dunia diabetes melitus tipe 2 adalah 95%. Faktor resiko dari Diabetes melitus tipe 2 yaitu usia, jenis kelamin,obesitas,hipertensi, genetik,makanan,merokok,alkohol,kurang aktivitas,lingkar perut, . Penatalaksanaan dilakukan dengan cara penggunaan obat oral hiperglikemi dan insulin serta modifikasi gaya hidup untuk mengurangi kejadian dan komplikasi mikrovaskular maupun makrovaskular dari Diabetes melitus tipe 2 . Kata kunci : Definisi, diabetes Melitus tipe 2, faktor resiko, penatalaksanaan
Characterization of recombinant prolyl aminopeptidase from Aspergillus oryzae

Aims: Prolyl aminopeptidase (PAP) degrades only amino‐terminal proline from peptides. The food‐grade fungus Aspergillus oryzae produces this enzyme only in small amounts. In this paper, we present efficient production of recombinant PAP with an overexpression system of A. oryzae and characterization of its biochemical properties.
β-Catenin and Peroxisome Proliferator-activated Receptor-δ Coordinate Dynamic Chromatin Loops for the Transcription of Vascular Endothelial Growth Factor A Gene in Colon Cancer Cells*

Background: Mechanism of VEGFA transcription by complex interplay of β-catenin and PPAR-δ remains elusive. Results: The VEGFA promoter was dynamically occupied by β-catenin, TCF-4, and PPAR-δ. β-Catenin also bound downstream region of the VEGFA gene. Conclusion: β-Catenin is responsible for the formation of chromatin loops, which is relieved by PPAR-δ activation. Significance: Proposed mechanism could provide clues for VEGFA-mediated colon cancer cell initiation. Vascular endothelial growth factor A (VEGFA) mRNA is regulated by β-catenin and peroxisome proliferator activated receptor δ (PPAR-δ) activation in colon cancer cells, but the detailed mechanism remains to be elucidated. As chromatin loops are generally hubs for transcription factors, we tested here whether β-catenin could modulate chromatin looping near the VEGFA gene and play any important role for PPAR-δ activated VEGFA transcription. First, we identified the far upstream site as an important site for VEGFA transcription by luciferase assay and chromatin immunoprecipitation in colorectal carcinoma HCT116 cells. Chromatin conformation capture analysis also revealed the chromatin loops formed by the β-catenin bindings on these sites near the VEGFA gene. Dynamic association and dissociation of β-catenin/TCF-4/PPAR-δ on the far upstream site and β-catenin/NF-κB p65 on the downstream site were also detected depending on PPAR-δ activation. Interestingly, β-catenin-mediated chromatin loops were relieved by PPAR-δ activation, suggesting a regulatory role of β-catenin for VEGFA transcription. Based on these data, we propose a model for PPAR-δ-activated VEGFA transcription that relies on β-catenin-mediated chromatin looping as a prerequisite for the activation. Our findings could extend to other β-catenin regulated target genes and could provide a general mechanism and novel paradigm for β-catenin-mediated oncogenesis.
A Study on the Measurement of Bacterial Contamination of MRI Examination Equipment and Disinfection Conditions

Abstract In radiology department, where patients with a variety of diseases receive their tests, there is a large possibility of cross contamination of nosocomial infection. Magnetic resonance imaging (MRI) tests take particularly more time than other tests do, which increases the possibility of being exposed to cross contamination. Therefore, this research examines the status of MRI equipment sterilization and investigates the bacterial distribution on head coils, which have the most frequent contact with patients, patient fixation blocks, and bores, which are confined spaces. The status of MRI equipment disinfection was examined by a survey targeting 150 employees, and the distribution of bacteria was measured in ten medical facilities. The result of bacterial distribution tests on MRI equipment showed various bacteria, including Staphylococcus, Acinetobacter, Sphingomona, Pantoea agglomeranss, Micrococcus, Bacillus, Saprophyticus, Brevundimona, and Myroidesspecies. The result of examining the stat us of MRI room disinfection showed that the disinfections of the head coil, block, and bore were implemented well, and the largest proportion was carried out once a day in the morning. The time and implementation of disinfection by the disinfection manager showed that they were implemented well when the manager was the MRI room examiner. The disinfection after examining a patient using an appropriate disinfectant is mandatory to prevent cross contamination.
Growth characteristics and endocrine abnormalities in 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2DS) has a wide range of clinical features including endocrine abnormalities. We aimed to characterize growth patterns, hypoparathyroidism, and thyroid dysfunction of individuals with 22q11.2DS. Anthropometric and laboratory measurements were obtained from the charts of 48 individuals (males=28, 8.0±6.8 visits/participant) followed at a national 22q11.2DS clinic between 2009 and 2016. Age at diagnosis was 4.3±4.9 years and age at last evaluation 11.2±7.2 years. Median height‐SDS was negative at all ages. Height‐SDS at last visit was correlated to the midparental height‐SDS (r=0.52 P=0.002). Yet, participants did not reach their target height, with a difference of 1.06±1.07 SD (P <0.0001). Height‐SDS at last visit of participants with a heart defect was lower compared to participants with a normal heart (−1.5±1.4 vs. −0.6±0.8, P=0.036), with lower height‐SDS in the subgroup of participants with severe heart defects (−2.1±1.6, P=0.009). Mean IGF1‐SDS was low (−0.99±1.68) but was not correlated with height‐SDS. Thirteen patients (27%) had hypoparathyroidism: 10 presented during infancy and 3 during adolescence. Five patients (10.4%, female=4) had thyroid abnormalities. In conclusions, individuals with 22q11.2 DS have a distinct growth pattern consisting of growth restriction at all ages, resulting in final adult height in the low‐normal range. Hypoparathyroidism is common and may present during the neonatal period as well as later in life. Thyroid abnormalities may present during childhood, adolescence, or adulthood.
Mammalian Alteration/Deficiency in Activation 3 (Ada3) Is Essential for Embryonic Development and Cell Cycle Progression*

Background: Ada3 is a core component of HAT containing coactivator complexes. Results: Germline deletion of Ada3 is embryonic lethal, and cell deletion leads to abnormal cell cycle progression. Conclusion: Ada3 is a critical protein at organismic and cellular level. Significance: This study describes a novel role of Ada3, a component of HAT complexes, as a critical regulator of cell survival. Ada3 protein is an essential component of histone acetyl transferase containing coactivator complexes conserved from yeast to human. We show here that germline deletion of Ada3 in mouse is embryonic lethal, and adenovirus-Cre mediated conditional deletion of Ada3 in Ada3FL/FL mouse embryonic fibroblasts leads to a severe proliferation defect which was rescued by ectopic expression of human Ada3. A delay in G1 to S phase of cell cycle was also seen that was due to accumulation of Cdk inhibitor p27 which was an indirect effect of c-myc gene transcription control by Ada3. We further showed that this defect could be partially reverted by knocking down p27. Additionally, drastic changes in global histone acetylation and changes in global gene expression were observed in microarray analyses upon loss of Ada3. Lastly, formation of abnormal nuclei, mitotic defects and delay in G2/M to G1 transition was seen in Ada3 deleted cells. Taken together, we provide evidence for a critical role of Ada3 in embryogenesis and cell cycle progression as an essential component of HAT complex.
Alu‐mediated deletion of PIGL in a Patient with CHIME syndrome

CHIME syndrome is a rare autosomal recessive neuroectodermal disorder associated with biallelic mutations in PIGL. To date, six molecularly confirmed cases of CHIME syndrome have been reported. Here, we report the seventh patient with biallelic PIGL mutations associated with CHIME syndrome and describe the first characterization of an intragenic deletion in PIGL. Our characterization of the deletion breakpoint junction demonstrated that the breakpoints occurred within Alu repeats and the deletion was most likely mediated by a microhomology event. Analysis of PIGL genomic sequences for repetitive elements demonstrated that Alu repeats represent ∼34% of its intronic sequence, suggesting that the genomic architecture may predispose the gene to disease‐causing copynumber changes. Taken together, these findings indicate that patients with a clinical diagnosis of CHIME syndrome and a single identifiable mutation in PIGL warrant further investigation for copynumber changes involving PIGL.
Effects of sour cherry juice on blood glucose and some cardiovascular risk factors improvements in diabetic women: A pilot study

Purpose – Some studies on anthocyanins have revealed their antioxidant activity and beneficial effects for diabetes control and reducing the risk of coronary heart diseases. It has been found that sour cherries contain high levels of anthocyanins that possess insulin‐releasing stimulatory properties on pancreatic β‐cells in vitro. The purpose of this paper is to investigate whether concentrated sour cherry juice (CSCJ) beneficially alters serum glucose and some cardiovascular risk factors in diabetes type 2 subjects.Design/methodology/approach – In this quasi‐experimental study, 19 diabetic women with FBS ≥ 110 mg/dl were recruited from patients referred to the Diabetes Clinic of Shariati Hospital. Subjects were asked to consume 40 g of CSCJ daily for 6 weeks. Before the onset of the study (week 0) and after 6 weeks, weight and blood pressure measurements were done and fasting blood samples were drawn. FBS, hemoglobin A1c (HbA1c) and blood lipid profiles were measured. In addition, a 24‐hour food record w.
Polymorphic Fibrillation of the Destabilized Fourth Fasciclin-1 Domain Mutant A546T of the Transforming Growth Factor-β-induced Protein (TGFBIp) Occurs through Multiple Pathways with Different Oligomeric Intermediates*

Background: Corneal dystrophies are linked to aggregation of mutants of transforming growth factor β-induced Protein (TGFBIp) leading to blindness. Results: Depending on concentration, the fourth fasciclin-1 domain carrying the A546T substitution follows different fibrillation pathways involving different oligomeric intermediates. Conclusion: Aggregate species forming under different conditions have different biochemical properties. Significance: Understanding the molecular events causing aggregation is crucial for development of possible drugs. Mutations in the transforming growth factor β-induced protein (TGFBIp) are linked to the development of corneal dystrophies in which abnormal protein deposition in the cornea leads to a loss of corneal transparency and ultimately blindness. Different mutations give rise to phenotypically distinct corneal dystrophies. Most mutations are located in the fourth fasciclin-1 domain (FAS1–4). The amino acid substitution A546T in the FAS1–4 domain is linked to the development of lattice corneal dystrophy with amyloid deposits in the superficial and deep stroma, classifying it as an amyloid disease. Here we provide a detailed description of the fibrillation of the isolated FAS1–4 domain carrying the A546T substitution. The A546T substitution leads to a significant destabilization of FAS1–4 and induces a partially folded structure with increased surface exposure of hydrophobic patches. The mutation also leads to two distinct fibril morphologies. Long straight fibrils composed of pure β-sheet structure are formed at lower concentrations, whereas short and curly fibrils containing a mixture of α-helical and β-sheet structures are formed at higher concentrations. The formation of short and curly fibrils is preceded by the formation of a small number of oligomeric species with high membrane permeabilization potential and rapid fibril formation. The long straight fibrils are formed more slowly and through progressively bigger oligomers that lose their membrane permeabilization potential as fibrillation proceeds beyond the lag phase. These different fibril classes and associated biochemical differences may lead to different clinical symptoms associated with the mutation.
HUBUNGAN PENGETAHUAN IBU TENTANG KANKER SERVIKS DENGAN KEIKUTSERTAAN IBU MELAKUKAN IVA TEST DI KELURAHAN JEBRES SURAKARTA

Latar belakang: Kanker leher rahim (serviks) merupakan ancaman penyakit yang menakutkan bagi wanita. Pasien kanker rahim di seluruh dunia diperkirakan terjadi sekitar 500 ribu kasus baru, 270 ribu diantaranya meninggal setiap tahunnya. Kanker serviks dapat dicegah, salah satunya dengan Metode Inspeksi Visual dengan Asam Asetat (IVA), yaitu metode screening yang praktis, murah, dan memungkinkan dilakukan di Indonesia. Pada tahun 2009-2011 terdapat tiga orang meninggal karena kanker serviks di Kelurahan Jebres, namun dari 1207 wanita usia produktif hanya enam orang yang mengikuti IVA test diadakan oleh Puskesmas pada bulan Mei 2011. Tujuan: Menganalisis hubungan antara pengetahuan tentang kanker serviks dengan keikutsetaan ibu melakukan IVA Test di Kelurahan Jebres Surakarta. Metode: Penelitian observasional analitik menggunakan pendekatan cross sectional. Subjek penelitian adalah ibu usia 30-50 tahun sebanyak 66 responden dengan pengambilan sampel menggunakan cluster random sampling. Hasil: Hasil uji Chi Square dengan taraf signiﬁkansi (α=0,05) didapatkan nilai hitung (13.073) > tabel (5.991) dengan Pvalue = 0,000 (p<0,05) sehingga Ho ditolak dan Ha diterima. Simpulan: Terdapat hubungan antara pengetahuan tentang kanker serviks dengan keikutsertaan ibu melakukan IVA Test di Kelurahan Jebres Surakarta. Kata Kunci: Pengetahuan, Kanker Serviks, IVA Test
Tripartite Motif Containing 28 (Trim28) Can Regulate Cell Proliferation by Bridging HDAC1/E2F Interactions*

Background: Trim28 appears up-regulated in many cancers. Results: In early stage lung tumors high Trim28 correlates with increased overall survival and Trim28 reduces cell proliferation in model lung cancer cell lines through E2F interactions. Conclusion: Trim28 may have a tumor suppressing role in the early stages of lung cancer. Significance: These results suggest a complex role for Trim28 in lung cancer. Trim28 is a poorly understood transcriptional co-factor with pleiotropic biological activities. Although Trim28 mRNA is found in many studies to be up-regulated in both lung and breast cancer tissues relative to normal adjacent tissue, we found that within a panel of early-stage lung adenocarcinomas high levels of Trim28 protein correlate with better overall survival. This surprising observation suggests that Trim 28 may have anti-proliferative activity within tumors. To test this hypothesis, we used shRNAi to generate Trim28-knockdown breast and lung cancer cell lines and found that Trim28 depletion led to increased cell proliferation. Likewise, overexpression of Trim28 led to decreased cell proliferation. Confocal microscopy indicated co-localization of E2F3 and E2F4 with Trim28 within the cell nucleus, and co-immunoprecipitation assays demonstrated that Trim28 can bind both E2F3 and E2F4. Trim28 overexpression inhibited the transcriptional activity of E2F3 and E2F4, whereas Trim28 deficiency enhanced their activity. Co-immunoprecipitations further indicated that Trim28 bridges an interaction between E2Fs 3 and 4 and HDAC1. Promoter-reporter assays demonstrated that the ability of HDAC1 to repress E2F3 and E2F4-driven transcription is dependent on Trim28. Trim28 depletion increased E2F3 and E2F4 DNA binding activity, as measured by chromatin-immunoprecipitation (ChIP) assays while simultaneously reducing HDAC1 binding. Finally, ChIP-ReChIP experiments demonstrated that Trim/E2F complexes exist on several E2F-regulated promoters. Taken together, these results suggest that Trim28 has anti-proliferative activity in lung cancers via repression of members of the E2F family that are critical for cell proliferation.
Phenotypic expression of 19q13.32 microdeletions: Report of a new patient and review of the literature

The phenotypic manifestations of microdeletions in the 19q13.32 region are still poorly known. In this paper we report a patient who presented with hypotonia, developmental delay, facial dysmorphism, micrognathia, kyphoscoliosis, and buried penis. Chromosomal microarray revealed an interstitial 327 kb de novo microdeletion in the 19q13.32 region comprising eight genes (ARGHAP35, NPAS1, TMEM160, ZC3H4, SAE1, BBC3, MIR3190, and MIR3191). Previously reported cases of microdeletions in the 19q13.32 region were reviewed and compared to our patient, highlighting the common features of a possible 19q13.32 microdeletion syndrome.
Precise Regulation of Porcupine Activity Is Required for Physiological Wnt Signaling

Background: Wnts control development and differentiation; their secretion may be regulated. Results: All Wnt activity absolutely requires post-translational modification by the O-acyltransferase PORCN, whose abundance or activity modulates signaling tightly and over a large dynamic range. Conclusion: Subtle changes in PORCN activity have major consequences and cause the human disease focal dermal hypoplasia. Significance: PORCN is a key regulator of all Wnt signaling. Gradients of diverse Wnt proteins regulate development, renewal, and differentiation. Porcupine (PORCN) is a membrane-bound O-acyltransferase that is required for post-translational modification of all Wnts to enable their transport, secretion, and activity. Mutations in PORCN are associated with focal dermal hypoplasia (FDH), whereas gene deletion causes embryonic lethality in mice. To study the protein in more detail, zinc finger nucleases were used to edit the PORCN genomic locus, establishing two HT1080 fibrosarcoma clones null for PORCN activity that facilitate the study of PORCN structure and function. We establish that PORCN is a key non-redundant node for the regulation of global Wnt signaling because PORCN null cells are completely incapable of autocrine Wnt signaling. The strength of Wnt signaling is exquisitely sensitive to PORCN expression, with a dynamic range of at least 3 orders of magnitude, suggesting that PORCN activity is a key modulator of all Wnt ligand activity. Consistent with this, we find that multiple FDH-associated mutants have only subtle alterations in enzyme activity yet are associated with a severe FDH phenotype. These studies support an essential regulatory role of PORCN in shaping Wnt signaling gradients.
A tumor profile in Patau syndrome (trisomy 13)

Individuals with trisomic conditions like Down syndrome and Edwards syndrome are prone to certain types of malignancy. However, for Patau syndrome (constitutional trisomy 13), which occurs in 1/10,000–1/20,000 live births, the tumor profile has not been well characterized. An awareness of susceptibility to malignancies can improve care of affected individuals, as well as further our understanding of the contribution of trisomy to carcinogenesis. Therefore, we conducted an extensive review of the literature; we found 17 malignancies reported in individuals with Patau syndrome. These comprised eight embryonic tumors, three leukemias, two malignant germ cell tumors, two carcinomas, a malignant brain tumor, and a sarcoma. Benign tumors were mainly extragonadal teratomas. The small number of reported malignant tumors suggests that there is not an increased risk of cancer in the context of trisomy 13. The tumor profile in Patau syndrome differs from that observed in Edwards syndrome (trisomy 18) and Down syndrome (trisomy 21), suggesting that the supernumerary chromosome 13 could promote particular tumor formations as it does particular malformations. No general and direct relationships of tumor occurrence with organ weight, congenital malformations, histological changes, or presence of tumor suppressor genes on chromosome 13 were observed. However, some tumors were found in tissues whose growth and development are controlled by genes mapping to chromosome 13. Recent reports of successful outcomes following surgical treatment and adapted chemotherapy indicate that treatment of cancer is possible in Patau syndrome.
Usefulness of resistant gene markers for predicting treatment outcome on second‐line anti‐tuberculosis drugs

Aim: Mutations in rrs [nucleotide (nt) 1401], gyrA gene (codons 90, 91 or 94), tlyA, ethA and thyA genes of Mycobacterium tuberculosis (MTB) were evaluated for their usefulness in predicting treatment outcome of kanamycin (KM), capreomycin (CPM), ofloxacin (OFX), ethionamide (ETH) and para‐aminosalicylic acid (PAS).