An autopsy case of sudden death due to pulmonary arterial hypertension (PAH) in a 5-year-old boy whose cause of death was not determined during autopsy, but was later determined by postmortem examination, is presented. The boy developed convulsions that subsequently stopped, but remained unconscious. He was transported to hospital by ambulance, but died soon after. The boy had been found to have right ventricular overload on ECG 2 weeks earlier. A plan had been made to consult a doctor for a specialist visit 2 months later. During autopsy, significant abnormalities or injuries were not observed on the body's external surface. Internal examination showed congested organs, and the blood remaining in the body was dark red with fluidity. The heart was significantly enlarged (146 g), with nearly equivalent thickness of the left and right ventricles, showing right ventricular hypertrophy. Obvious macroscopic abnormalities were not observed at the origin and main trunk of the pulmonary artery. The lungs were slightly swollen (right lung 100 g, left lung 95 g), severely congested, and edematous. A postmortem CT scan displayed some patchy shadows in both lungs; however, no significant abnormalities were detected. Histopathological examination suggested a diagnosis of PAH. Three genes (BMPR2, ALK1, and ENG) were tested, revealing a heterozygous insertion of five nucleotides, TTTCC, between nucleotides 2677 and 2678 within exon 12 of the BMPR2 gene. Therefore, the subject was considered to have had heritable PAH due to a BMPR2 gene mutation.

Fibroblast-to-myofibroblast (FibroMF) differentiation is crucial for embryogenesis and organ fibrosis. Although transforming growth factor-β (TGFβ) is the primary mediator of FibroMF differentiation, the type-I receptor (TGFβRI) responsible for this has not yet been confirmed. In the current study, we investigated the ALK1 and ALK5 expressions in TGFβ1-stimulated NIH 3T3 fibroblasts to compare with the data from the gene expression omnibus (GEO) repository. In our results, whereas TGFβ1 treatment promoted FibroMF differentiation accompanied by increased ALK5 expression and reduced ALK1 expression. TGFβ1-induced FibroMF differentiation and increased α-smooth muscle actin (αSMA) and ALK5 expression were inhibited by co-treatment with ALK5 inhibitor SB431542. GEO database analysis indicated increased ALK5 expression and reduced ALK1 expression in fibrotic compared to normal mouse or human tissues correlating to organ fibrosis progression. Finally, the inhibitors of Akt, mTOR, and β-catenin suppressed TGFβ1-induced ALK5 expression indicating that the Akt pathway promotes FibroMF differentiation via ALK5 expression and fibrosis.

Anorectal Hodgkin lymphoma (HL) is rare, mainly described in human immunodeficiency virus (HIV) patients with exceptional cases reported in immunocompetents. We report the case of a middle age HIV male, presenting with intestinal occlusion. Rectosigmoidoscopy showed multiple anorectal nodular and ulceronecrotic masses. The biopsy specimens revealed a diffuse polymorphous inflammatory infiltrate in the lamina propria, associated with CD30, CD20, CD3, CD15, and ALK1 scattered large Hodgkin and/or Reed Sternberg -like cells stained by LMP1 antibody and EBER. A diagnosis of EBV-associated atypical lymphoproliferative disease mimicking HL was made. These lesions remained stable for 2 years without treatment then disappeared leaving a mucosal scar. A later control biopsy showed a condylomatous lesion, without lymphoid lesion, suggesting a sexually acquired infection. Eight years later, the complete resolution of the lesion without any treatment is a strong argument against a malignant lymphoid process and raises doubts as to the reality of isolated anorectal HL in immunocompetent participants.

Hereditary haemorrhagic telangiectasia or Rendu-Osler-Weber syndrome is a rare genetic autosomic dominant disorder with an estimated prevalence of one in 3000-5000 individuals. This multisystemic vascular dysplasia is determined by the mutation of two main genes which are endoglin (ENG) or HHT1 and ALK1 or HHT2. These mutations induce the vascular disorders which cause recurrent epistaxis and eventually multiple telangiectasias and arteriovenous visceral malformations (AVM). We report the case of an 11-year-old boy who developed severe hypoxaemia due to multiple pulmonary arteriovenous malformations.

The t (2;5) (p23; q35) translocation associated with CD30-positive anaplastic large-cell lymphoma (ALCL) creates a hybrid gene encoding the chimeric nucleolar protein nucleophosmin-anaplastic lymphoma kinase (NFMALK) protein, which can be demonstrated by immunostaining with ALK1 monoclonal antibody. In this study, 40 specimens of ALCL from 6 pediatric, 34 adult patients, were immunostained with monoclonal antibodies against CD30 (Ber-H2), EMA, CD45 (LCA), CD3, CD20 (L26), CD15, and ALK1 antigens, and results were correlated with histopathologic features. The mean age of the pediatric and adult patients was 10-years and 38-years, respectively. ALK1 was positive in 14 cases (35%) representing 83% of pediatric and 26% of adult patients, statistically significantly higher in the pediatric group (p= 0.01). Considering the better prognosis attributed to cases with t (2;5), it is interesting to note that the percentage of ALK1-positive cases is significantly higher in pediatric patients with coexpression of EMA, compared to adults.

Anaplastic large cell lymphoma (ALCL) is a well-recognized subtype of non-Hodgkin lymphoma in childhood. Several series report experience with the diagnosis and management of pediatric ALCL, the average age at diagnosis being 8 to 16 years, with a reported range of 1 to 15 years. We present a case of ALCL affecting a 5-month-old infant in whom the diagnosis was confirmed by the nuclear and cytoplasmic immunohistochemical expression of ALK1, in addition to the presence of classical t(2;5)(p23;q35) translocation detected using reverse transcriptase-polymerase chain reaction. This is the youngest case of ALCL thus far reported and hence expands the spectrum of infantile lymphoproliferative disorders.

Anaplastic lymphoma kinase ( ALK) gene aberrations-such as mutations, amplifications, and copy number gains-represent a major genetic predisposition to neuroblastoma (NB). This study aimed to evaluate the correlation between ALK gene copy number status, ALK protein expression, and clinicopathological parameters. We retrospectively retrieved 30 cases of poorly differentiated NB and constructed tissue microarrays (TMAs). ALK copy number changes were assessed by fluorescence in situ hybridization (FISH) assays, and ALK immunohistochemistry (IHC) testing was performed using three different antibodies (ALK1, D5F3, and 5A4 clones). ALK amplification and copy number gain were observed in 10% (3/30) and 53.3% (16/30) of the cohort, respectively. There were positive correlations between ALK copy number and IHC-positive rate in ALK1 and 5A4 antibodies ( P < 0.001 and P = 0.019, respectively). ALK1, D5F3, and 5A4 antibodies equally showed 100% sensitivity in detecting ALK amplification. However, the sensitivity for detecting copy number gain differed among the three antibodies, with 75% sensitivity in D5F3 and 0% sensitivity in ALK1. ALK-amplified NBs were correlated with synchronous MYCN amplification and chromosome 1p deletion. ALK IHC positivity was frequently observed in INSS stage IV and high-risk group patients. In conclusion, this study identified that an increase in the ALK copy number is a frequent genetic alteration in poorly differentiated NB. ALK-amplified NBs showed consistent ALK IHC positivity with all kinds of antibodies. In contrast, the detection performance of ALK copy number gain was antibody dependent, with the D5F3 antibody showing the best sensitivity.

Alternative splicing is an important gene regulation process to distribute proteins in health and diseases. Extra Domain A+ Fibronectin (EDA+Fn) is an alternatively spliced form of fibronectin (Fn) protein, present in the extra cellular matrix (ECM) and a recognised marker of various pathologies. TGFβ1 has been shown to induce alternative splicing of EDA+Fn in many cell types. Podocytes are spectacular cell type and play a key role in filtration and synthesise ECM proteins in renal physiology and pathology. In our previous study we have demonstrated expression and alternative splicing of EDA+Fn in basal condition in human podocytes culture. TGFβ1 further induced the basal expression and alternative splicing of EDA+Fn through Alk5 receptor and SR proteins. In this study, we have investigated TGFβ1 mediated signalling involved in alternative splicing of EDA+Fn in human podocytes. We have performed western blotting to characterise the expression of the EDA+Fn protein and other signalling proteins and RT-PCR to look for signalling pathways involved in regulation of alternative splicing of EDA+Fn in conditionally immortalised human podocytes culture.We have used TGFβ1 as a stimulator and SB431542, SB202190 and LY294002 for inhibitory studies. In this work, we have demonstrated in human podocytes culture TGFβ1 2.5ng/ml induced phosphorylation of Smad1/5/8, Smad2 and Smad3 via the ALK5 receptor. TGFβ1 significantly induced the PI3K/Akt pathway and the PI3K/Akt pathway inhibitor LY294002 significantly downregulated basal as well as TGFβ1 induced alternative splicing of EDA+Fn in human podocytes. In addition to this, TGFβ1 significantly induced the p38 MAP kinase signalling pathway and p38 MAP kinase signalling pathway inhibitor SB202190 downregulated the TGFβ1-mediated alternative splicing of EDA+Fn in human podocytes. The results with PI3K and p38 MAP kinase signalling pathway suggest that inhibiting PI3K signalling pathway downregulated the basal alternative splicing of EDA+Fn in human podocytes and its the inhibition of p38 Map Kinase signalling pathway which had specifically downregulated the TGFβ1 mediated alternative splicing of EDA+Fn in human podocytes culture. Activation of TGFβ1-mediated Smad1/5/8 via Alk5 receptor suggests that TGFβ1 signalling pathway involved Alk5/Alk1 receptor axis signalling in human podocytes.

Equine degenerative suspensory ligament desmitis (DSLD) in Peruvian Paso horses typically presents at 7-15 years and is characterized by lameness, focal disorganization of collagen fibrils, and chondroid deposition in the body of the ligament. With the aim of developing a test for disease risk (that can be used to screen horses before breeding) we have quantified the expression of 76 TGFβ-signaling target genes in adipose-derived stromal fibroblasts (ADSCs) from six DSLD-affected and five unaffected Paso horses. Remarkably, 35 of the genes showed lower expression (p<0.05) in cells from DSLD-affected animals and this differential was largely eliminated by addition of exogenous TGFβ1. Moreover, TGFβ1-mediated effects on expression were prevented by the TGFβR1/2 inhibitor LY2109761, showing that the signaling was via a TGFβR1/2 complex. The genes affected by the pathology indicate that it is associated with a generalized metabolic disturbance, since some of those most markedly altered in DSLD cells (ATF3, MAPK14, ACVRL1 (ALK1), SMAD6, FOS, CREBBP, NFKBIA, and TGFBR2) represent master-regulators in a wide range of cellular metabolic responses.

The bone morphogenetic protein (BMP) signaling gradient is central for dorsoventral patterning in amphibian embryos. This gradient is established through the interaction of several BMPs and BMP antagonists and modulators, some secreted by Spemann's organizer, a cluster of cells coordinating embryonic development. Anti-dorsalizing morphogenetic protein (ADMP), a BMP-like transforming growth factor beta ligand, negatively affects the formation of the organizer, although it is robustly expressed within the organizer itself. Previously, we proposed that this apparent discrepancy may be important for the ability of ADMP to scale the BMP gradient with embryo size, but how this is achieved is unclear.

Here we report that ADMP acts in the establishment of the organizer via temporally and mechanistically distinct signals. At the onset of gastrulation, ADMP is required to establish normal organizer-specific gene expression domains, thus displaying a dorsal, organizer-promoting function. The organizer-restricting, BMP-like function of ADMP becomes apparent slightly later, from mid-gastrula. The organizer-promoting signal of ADMP is mediated by the activin A type I receptor, ACVR1 (also known as activin receptor-like kinase-2, ALK2). ALK2 is expressed in the organizer and is required for organizer establishment. The anti-organizer function of ADMP is mediated by ACVRL1 (ALK1), a putative ADMP receptor expressed in the lateral regions flanking the organizer that blocks expansion of the organizer. Truncated ALK1 prevents the organizer-restricting effects of ADMP overexpression, suggesting a ligand-receptor interaction. We also present a mathematical model of the regulatory network controlling the size of the organizer.

We show that the opposed, organizer-promoting and organizer-restricting roles of ADMP are mediated by different receptors. A self-regulating network is proposed in which ADMP functions early through ALK2 to expand its own expression domain, the organizer, and later functions through ALK1 to restrict this domain. These effects are dependent on ADMP concentration, timing, and the spatial localization of the two receptors. This self-regulating temporal switch may control the size of the organizer and the genes expressed within in response to genetic and external stimuli during gastrulation.

Culturing articular chondrocytes under physiological oxygen tension exerts positive effects on their extracellular matrix synthesis. The underlying molecular mechanisms which enhance the chondrocytic phenotype are, however, still insufficiently elucidated. The TGF-β superfamily of growth factors, and the prototypic TGF-β isoforms in particular, are crucial in maintaining matrix homeostasis of these cells. We employed a feedback-controlled table-top bioreactor to investigate the role of TGF-β in microtissues of human chondrocytes over a wider range of physiological oxygen tensions (i.e., physoxia). We compared 1%, 2.5%, and 5% of partial oxygen pressure (pO₂) to the 'normoxic' 20%. We confirmed physoxic conditions through the induction of marker genes (PHD3, VEGF) and oxygen tension-dependent chondrocytic markers (SOX9, COL2A1). We identified 2.5% pO₂ as an oxygen tension optimally improving chondrocytic marker expression (ACAN, COL2A1), while suppressing de-differentiation markers (COL1A1,COL3A1). Expression of TGF-β isoform 2 (TGFB2) was, relatively, most responsive to 2.5% pO₂, while all three isoforms were induced by physoxia. We found TGF-β receptors ALK1 and ALK5 to be regulated by oxygen tension on the mRNA and protein level. In addition, expression of type III co-receptors betaglycan and endoglin appeared to be regulated by oxygen tension as well. R-Smad signaling confirmed that physoxia divergently regulated phosphorylation of Smad1/5/8 and Smad2/3. Pharmacological inhibition of canonical ALK5-mediated signaling abrogated physoxia-induced COL2A1 and PAI-1 expression. Physoxia altered expression of hypertrophy markers and that of matrix metalloproteases and their activity, as well as expression ratios of specific proteins (Sp)/Krüppel-like transcription factor family members SP1 and SP3, proving a molecular concept of ECM marker regulation. Keeping oxygen levels tightly balanced within a physiological range is important for optimal chondrocytic marker expression. Our study provides novel insights into transcriptional regulations in chondrocytes under physoxic in vitro conditions and may contribute to improving future cell-based articular cartilage repair strategies.

Hereditary hemorrhagic telangiectasia (HTT, or Osler-Weber-Rendu disease) is a constitutional vascular dysplasia characterized by hemorrhagic manifestations, cutaneous or mucosal telangiectases and visceral shunting due to arteriovenous malformations. In France, its prevalence varies from 1/6,000 to 1/8,500. The diagnosis is clinical and based on the common triad: chronic epistaxis, responsible for anemias, cutaneous or mucosal telangiectases (on typical locations) and the hereditary nature of these signs inheredited in an autosomal dominant way. Penetrance is almost complete at 50 years. Visceral complications produce highly variable manifestations: pulmonary arteriovenous malformations may be manifested by brain abscess or transient ischemic attacks, signs of chronic hypoxia or hemorrhagic rupture; neurological arteriovenous malformations can produce signs of compression or be hemorrhagic; hepatic arteriovenous malformations, which remain latent for a long time, become clinically severe in a limited proportion of patients; hemorrhagic, digestive arteriovenous malformations worsen chronic anemia. HHT is a genetic disorder; two genes (ALK1 and ENG) involved in the signaling pathway of the transforming growth factor-beta have been identified so far. Vascular homeostasis of capillaries is impaired, which leads to an accumulation in time of successive and progressive telangiectases and arteriovenous fistulas. Disease management consists in anemia management, as well as in epistaxis prevention and treatment. The management of arteriovenous malformations lies on early detection and the possibility to occlude them with interventional radiology.

Lymphomas are a heterogeneous group of diseases that encompass malignant disorders of B-cells, T-cells, or natural killer cells. B-cell lymphomas represent approximately 80-85% of cases. Transformation of B-cell lymphomas from a low grade to a higher grade within the same lineage is a well-described phenomenon. The most common and well-known transformation is from follicular lymphoma to diffuse large B-cell lymphoma. However, the transformation of B-cell lymphomas to T-cell lymphomas is extremely rare. In this article, we report a case of grade I follicular lymphoma (B-cell lymphoma) that transformed into anaplastic large cell lymphoma CD30+ ALK1- (T-cell lymphoma). This article reported a case with a unique particular combination of morphology and immunophenotype in the same patient. In addition, we report a remarkable response with complete remission following treatment with Brentuximab vedotin (anti-CD30 antibody-drug conjugate) and high-dose methotrexate. The patient achieved this durable response despite the aggressive presentation.

Primary pulmonary hypertension (PPH) consisting of hereditary pulmonary arterial hypertension and idiopathic pulmonary arterial hypertension is an obstructive pulmonary hypertension caused by primary pulmonary artery hyperplasia. Both environmental and genetic factors are involved in the pathogenesis of PPH. Genes associated with TGF-β signaling pathway including BMPR2, ALK1, ENG, SMAD8 and other genes including NFU1, CAV1, KCNK3 and TopBPl have been associated with PPH. In this review, the function and mechanism of the above genes in the pathogenesis PPH are summarized.

An anaplastic large cell lymphoma which fulfills all the criteria required for its inclusion among the soft tissue forms is reported. We point out in this case, in addition to its low frequency in adults, the severe systemic involvement of the disorder with out generalization, the lack of expression of the ALK1 protein, frequently positive in the generalized forms and the absence of response to polichiomiotherapy. We think that this case emphasizes the heterogenicity if the disorder on the clinical pathologycal relation ship of this kind of lymphomas.

CONCLUSIONS

Anaplastic large cell lymphoma of the breast is a rare malignancy associated with prosthetic breast implants. We present a case of a woman with no prior history of breast implants who developed anaplastic lymphoma kinase-1 negative anaplastic large cell lymphoma on a background of a previous benign cyst aspiration.

Central nervous system involvement is an uncommon complication of systemic non-Hodgkin lymphomas. The majority of these cases concern B-cell lymphomas. We report a case of systemic T-cell anaplastic large cell lymphoma CD30+ ALK- with CNS involvement at the time of diagnosis and unusual MRI characteristics resembling acute disseminated encephalomyelitis.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a widespread disease causing obstruction of the nasal cavity. Its cause remains unclear. The transforming growth-factor beta (TGF-β) superfamily and their receptors, termed Activin receptor-like kinases (ALKs), have recently been suggested to play a role in local airway inflammation, but have so far not been evaluated in human nasal epithelial cells (HNECs) from CRSwNP patients. We demonstrated that ALK1-7 were expressed in the nasal polyp epithelium, and the expression of ALK1-6 was markedly elevated in polyps compared to nasal mucosa from healthy controls. Stimulation with the ALK ligand TGF-β1 decreased Ki67 expression in HNECs from CRSwNP patients, not evident in controls. Likewise, TGF-β1, Activin A and Activin B, all ALK ligands, decreased IL-8 release and Activin A and Activin B reduced ICAM1 expression on HNECs from CRSwNP patients, not seen in controls. Pre-stimulation with TGF-β1, Activin A, BMP4 and Activin B attenuated a TNF-α-induced ICAM1 upregulation on HNECs of CRSwNP. No effect was evident in controls. In conclusion, an increased expression of ALK1-6 was found on polyp epithelial cells and ligand stimulation appeared to reduce proliferation and local inflammation in polyps.

The transcription factor "Kruppel-like factor 4" (KLF4) is a central player in the field of pluripotent stem cell biology. In particular, it was put under the spotlight as one of the four factors of the cocktail originally described for reprogramming into induced pluripotent stem cells (iPSCs). In contrast, its possible functions in native tissue stem cells remain largely unexplored. We recently published that KLF4 is a regulator of "stemness" in human keratinocytes. We show that reducing the level of expression of this transcription factor by RNA interference or pharmacological repression promotes the ex vivo amplification and regenerative capacity of two types of cells of interest for cutaneous cell therapy: native keratinocyte stem and progenitor cells from adult epidermis, which have been used for more than three decades in skin graft bioengineering, and keratinocytes generated by the lineage-oriented differentiation of embryonic stem cells (ESCs), which have potential for the development of skin bio-bandages. At the mechanistic level, KLF4 repression alters the expression of a large set of genes involved in TGF-β1 and WNT signaling pathways. Major regulators of TGF-β bioavailability and different TGF-β receptors were targeted, notably modulating the ALK1/Smad1/5/9 axis. At a functional level, KLF4 repression produced an antagonist effect on TGFβ1-induced keratinocyte differentiation.

Keywords: ESC-derived keratinocytes; KLF4; TGF-β1; WNT; adult epidermal keratinocytes; skin grafts; stemness.

ALK positive histiocytosis is a relatively new histiocytic proliferation disease with a characteristic gene translocation involving fusion of the ALK gene with different partners, mostly KIF5B. We report a case of ALK-positive histiocytosis with literature review. A 27-year-old male patient presented mainly with progressive lower limb weakness. Imaging studies showed an intradural extramedullary enhancing lesion at the L3 level. A 1.5 cm mass was excised from the sensory nerve root in the filum terminale at the level of L3. Histologic examination showed infiltration of the nerve by numerous histiocytes with moderate to abundant eosinophilic to clear-foamy and variably-vacuolated cytoplasm with irregular-to-smooth contoured nuclei. The histiocytes were positive for CD68 and ALK1 and negative for S100 and CD1a. KIF5B-ALK fusion was detected by real time-polymerase chain reaction. The patient is asymptomatic nine months after surgical excision. This is the first reported localized case occurring in the nerve root of an adult patient, thus expanding the clinical manifestations of this disease. An integrated histological, immunohistochemical and molecular approach is recommended for diagnosis. We recommend performing ALK1 immunohistochemical stain on all histiocytosis cases to increase awareness and detection of this newly described entity.

Cardiovascular diseases are associated to risk factors as obesity, hypertension and diabetes. The transforming growth factor-β1 receptors ALK1 and endoglin regulate blood pressure and vascular homeostasis. However, no studies relate the association of ALK1 and endoglin polymorphisms with cardiovascular risk factors. We analysed the predictive value of the ALK1 and endoglin polymorphisms on cardiovascular target organ damage in hypertensive and diabetic patients in 379 subjects with or without hypertension and diabetes in a Primary Care setting. The ALK1 rs2071219 polymorphism (AA genotype) is associated with a lower presence of diabetic retinopathy and with the absence of altered basal glycaemia. Being carrier of the ALK1 rs3847859 polymorphism (G allele) is associated with lower basal heart rate and with higher LDL-cholesterol levels. The endoglin rs3739817 polymorphism (AA genotype) is associated with higher levels of LDL-cholesterol, and being carrier of the endoglin rs10987759 polymorphism (C allele) is associated with higher haemoglobin levels and with an increased heart rate. Summarizing, several ALK1 and endoglin gene polymorphisms increase the risk of cardiovascular events. The analysis of these polymorphisms in populations at risk, in combination with the determination of other parameters and biomarkers, could implement the diagnosis and prognosis of susceptibility to cardiovascular damage.

Background: Brain arteriovenous malformations (AVMs) are a relatively infrequent vascular pathology of unknown etiology that, despite their rarity, cause the highest number of hemorrhagic strokes under the age of 30 years. They pose a challenge to all forms of treatment due to their variable morphology, location, size, and, last but not least, evolving nature. MicroRNAs (miRNAs) are non-coding RNA strands that may suppress the expression of target genes by binding completely or partially to their complementary sequences. Single nucleotide polymorphisms (SNPs), as the name implies, are variations in a single nucleotide in the DNA, usually found in the non-coding segments. Although the majority of SNPs are harmless, some located in the proximity of candidate genes may result in altered expression or function of these genes and cause diseases or affect how different pathologies react to treatment. The roles miRNAs and certain SNPs play in the development and growth of AVMs are currently uncertain, yet progress in deciphering the minutiae of this pathology is already visible.

Methods and results: We performed an electronic Medline (PubMed, PubMed Central) and Google Academic exploration using permutations of the terms: "arteriovenous malformations," "single nucleotide polymorphisms," "microRNA," "non-coding RNA," and "genetic mutations." The findings were then divided into two categories, namely the miRNAs and the candidate gene SNPs associated with AVMs respectively. 6 miRNAs and 12 candidate gene SNPs were identified and discussed.

Conclusions: The following literature review focuses on the discoveries made in ascertaining the different implications of miRNAs and candidate gene SNPs in the formation and evolution of brain AVMs, as well as highlighting the possible directions of future research and biological treatment.

Abbreviations: ACVRL1/ALK1: activin receptor-like kinase 1; Akt: protein kinase B; ANGPTL4: angiopoietin-like 4; ANRIL: antisense noncoding RNA in the INK4 locus; AVM: arteriovenous malformation; AVM-BEC: arteriovenous malformation brain endothelial cell; BRCA1: breast cancer type 1 susceptibility protein; CCS: case-control study; CDKN2A/B: cyclin-dependent kinase inhibitor 2A/B; CLTC: clathrin heavy chain; DNA: deoxyribonucleic acid; ERK: extracellular signal-regulated kinase; GPR124: probable G-protein coupled receptor 124; GWAS: genome-wide association study; HHT: hereditary hemorrhagic telangiectasia; HIF1A: hypoxia-inducible factor 1A; IA: intracranial aneurysm; ICH: intracranial hemorrhage; Id-1: inhibitor of DNA-binding protein A; IL-17: interleukin 17; MAP4K3: mitogen-activated protein kinase kinase kinase kinase 3; miRNA: microRNA; MMP: matrix metalloproteinase; NFkB: nuclear factor kappa-light-chain of activated B cells; NOTCH: neurogenic locus notch homolog; p38MAPK: p38 mitogen-activated protein kinase; PI3K: phosphoinositide 3-kinase; RBBP8: retinoblastoma-binding protein 8; RNA: ribonucleic acid; SNAI1: Snail Family Transcriptional Repressor 1; SNP: single nucleotide polymorphism; SOX-17: SRY-related HMG-box; TGF-β: transformation growth factor β; TGFR: transformation growth factor receptor; TIMP-4, tissue inhibitor of metalloproteinase 4; TSP-1: thrombospondin-1; UTR: untranslated region; VEGF: Vascular Endothelial Growth Factor; VSMC: vascular smooth muscle cell; Wnt1: Wnt family member 1.

Keywords: Arteriovenous malformation (AVM); biological therapy; hemorrhagic stroke; microRNA (miRNA); non-coding RNA; single nucleotide polymorphisms (SNP).

OBJECTIVE

To compare the changes of gene expression profiles of multiple myeloma cell line RPMI 8226 before and after 24-hour intervention of arsenic trioxide.

METHODS

The responses of the RPMI 8226 cells to arsenic trioxide were determined with cDNA microarray which included 4,096 different human genes.

RESULTS

Of these 4,096 genes, the expressions of 273 genes were altered significantly at mRNA level. The expressions of 121 genes were up-regulated while the expressions of 152 genes were down-regulated.

CONCLUSIONS

The effect of arsenic trioxide on RPMI 8226 cells is related to changing the expression levels of a number of genes. ZFYVE16, ALK1 and TXNIP genes may play important roles in apoptosis and differentiation of RPMI 8226 cells.