Manish Butte

Aberrant methylation of HTATIP2 and UCHL1 as a predictive biomarker for cholangiocarcinoma.

Mol Med Rep. 2017 Dec 19;:

Authors: Nanok C, Jearanaikoon P, Proungvitaya S, Limpaiboon T

Abstract
Cholangiocarcinoma (CCA) is the most common primary liver cancer in Northeastern Thailand where liver fluke infection is highly endemic. Although aberrant DNA methylation in CCA has been reported by several investigators, little is known regarding the associations between them. In the present study, the results obtained from our previously published methylation array were analyzed and 10 candidate genes involved in DNA repair [protein phosphatase 4 catalytic subunit (PPP4C)], apoptosis [runt related transcription factor 3 (RUNX3), interferon regulatory factor 4 (IRF4), ubiquitin C‑terminal hydrolase L1 (UCHL1) and tumor protein p53 inducible protein 3 (TP53I3)], cell proliferation [cyclin D2 (CCND2) and Ras association domain family member 1 (RASSF1)], drug metabolism [aldehyde dehydrogenase 1 family member A3 (ALDH1A3) and solute carrier family 29 member 1 (SLC29A1)] and angiogenesis [human immunodeficiency virus‑1 tat interactive protein 2 (HTATIP2)] were selected for quantification of their methylation levels in 54 CCA and 19 adjacent normal tissues using methylation‑sensitive high‑resolution melting. The associations between the methylation status of the individual genes and clinical parameters were statistically analyzed. High methylation levels were observed in UCHL1, IRF4, CCND2, HTATIP2 and TP53I3. The median methylation level of UCHL1 was 57.3% (range, 3.15 to 88.7%) and HTATIP2 was 13.6% (range, 7.5 to 36.7%). By contrast, low methylation of HTATIP2 and UCHL1 was identified in adjacent normal tissues. The methylation status of HTATIP2 and UCHL1 was associated with patients’ overall survival. CCA patients with high methylation of HTATIP2 and low methylation of UCHL1 exhibited longer overall survival. In addition, multivariate Cox regression analysis demonstrated that UCHL1 methylation was an independent factor for CCA with hazard ratio of 1.81 (95% confidence interval, 1.01‑3.25) in high methylation group. The combination of HTATIP2 and UCHL1 methylation status strongly supported their potential predictive biomarker in which patients with CCA who had high methylation of HTATIP2 and low methylation of UCHL1 showed longer overall survival than those with low HTATIP2 methylation and high UCHL1 methylation. In conclusion, the present study revealed the value of aberrant DNA methylation of HTATIP2 and UCHL1, which may serve as a potential predictive biomarker for CCA.

PMID: 29359783 [PubMed – as supplied by publisher]

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Childhood-onset inflammatory bowel diseases associated with mutation of Wiskott-Aldrich syndrome protein gene.

World J Gastroenterol. 2017 Dec 28;23(48):8544-8552

Authors: Ohya T, Yanagimachi M, Iwasawa K, Umetsu S, Sogo T, Inui A, Fujisawa T, Ito S

Abstract
AIM: To screen primary immunodeficiency, Wiskott-Aldrich syndrome (WAS), and chronic granulomatous disease (CGD) among children with inflammatory bowel disease (IBD).
METHODS: This was a single-center retrospective study. Eighteen children with IBD were investigated. We analyzed their expression of Wiskott-Aldrich syndrome protein (WASP) in lymphocytes and superoxide generation in phagocytes using flow cytometry. When the expression of WASP or superoxide generation was low or absent, we performed genetic analysis to determine the cause of this.
RESULTS: Eighteen patients were classified as having ulcerative colitis (n = 10), Crohn’s disease (n = 5), or IBD-unclassified (n = 3). In total, three patients revealed low expression of WASP associated with a WAS gene c.1378 C>T p.Pro460Ser mutation, which has previously been reported as a pathogenic mutation in WAS and X-linked thrombocytopenia. However, with respect to the major symptoms of WAS, none of these three patients showed either thrombocytopenia or increased susceptibility to infection, but one patient showed generalized eczema. No CGD patients were discovered in this study.
CONCLUSION: Despite the lack of typical clinical manifestations of WAS, low expression of WASP could be associated with the pathogenesis of a subtype of IBD patients.

PMID: 29358862 [PubMed – in process]

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Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors.

Ann Rheum Dis. 2018 Jan 22;:

Authors: Giannelou A, Wang H, Zhou Q, Park YH, Abu-Asab MS, Ylaya K, Stone DL, Sediva A, Sleiman R, Sramkova L, Bhatla D, Serti E, Tsai WL, Yang D, Bishop K, Carrington B, Pei W, Deuitch N, Brooks S, Edwan JH, Joshi S, Prader S, Kaiser D, Owen WC, Sonbul AA, Zhang Y, Niemela JE, Burgess SM, Boehm M, Rehermann B, Chae J, Quezado MM, Ombrello AK, Buckley RH, Grom AA, Remmers EF, Pachlopnik JM, Su HC, Gutierrez-Cruz G, Hewitt SM, Sood R, Risma K, Calvo KR, Rosenzweig SD, Gadina M, Hafner M, Sun HW, Kastner DL, Aksentijevich I

Abstract
OBJECTIVES: To characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1, a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype.
METHODS: We studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients’ primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM).
RESULTS: We identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1β were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients’ fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth.
CONCLUSIONS: Mutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.

PMID: 29358286 [PubMed – as supplied by publisher]

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Prevalence and disease associations in feline thrombocytopenia: a retrospective study of 194 cases.

J Small Anim Pract. 2018 Jan 22;:

Authors: Ellis J, Bell R, Barnes DC, Miller R

Abstract
OBJECTIVES: To assess the prevalence of thrombocytopenia in a referral population of cats in the UK, to identify disease processes associated with thrombocytopenia and to assess the proportion of thrombocytopenic cats that tested positive for feline leukaemia virus or feline immunodeficiency virus.
MATERIALS AND METHODS: Retrospective analysis of medical records at a UK referral hospital. Cats were grouped by mechanism of thrombocytopenia and disease process (where known).
RESULTS: Prevalence of thrombocytopenia was 5·9%. The most common disease processes associated with thrombocytopenia were haematological or infectious disease and neoplasia; 11% of thrombocytopenic cats tested were positive for feline leukaemia virus, which is lower than reported previously. Cats presenting with unexplained haemorrhage had significantly lower platelet counts than other thrombocytopenic cats. Primary immune-mediated thrombocytopenia was less commonly diagnosed than in dogs and associated with the most severe platelet depletion in this study.
CLINICAL SIGNIFICANCE: Thrombocytopenia in cats may be more prevalent than previously reported and severe thrombocytopenia may be associated with spontaneous haemorrhage. Severe thrombocytopenia in cats appears less commonly immune-mediated than in dogs. Thrombocytopenia did not appear to be associated with retroviral infections.

PMID: 29355998 [PubMed – as supplied by publisher]

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The circulating T helper subsets and regulatory T cells in patients with common variable immunodeficiency with no known monogenic disease.

J Investig Allergol Clin Immunol. 2018 Jan 18;:0

Authors: Azizi G, Mirshafiey A, Abolhassani H, Yazdani R, Ansariha FJ, Shaghaghi M, Mortazavi-Jahromi SS, Noorbakhsh F, Rezaei N, Aghamohammadi A

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency (PID), characterized by heterogeneous clinical manifestations and defects in B- and T- cells. In the present study, we investigated the T helper (Th) cell subsets and regulatory T (Treg) cells, and their related cytokines and transcription factors in the CVID patients with no definite genetic diagnosis.
METHODS: The study population comprised 13 CVID patients and 13 healthy controls (HC). Mutation analysis was done by whole exome sequencing in CVID patients to rule out monogenic PIDs. Th subsets and Treg were examined by flow cytometry. The expression of determinant cytokines (IFN-γ, IL-17, IL-22, and IL-10), and cell subset specific transcription factors were evaluated before and after stimulation.
RESULTS: The main clinical presentations of these patients were infections only and lymphoproliferations phenotypes, but no autoimmune and allergy phenotype were recorded. The frequencies of CD4+ T cells, Th17, and Treg cells were significantly reduced in CVID patients, however the subsets of Th1, Th1-like Th17 and Th22 cells were normal. After stimulation, retinoic-acid-orphan-receptor-C (RORC), and runt-related transcription factor 1 (RUNX1), IL17, and IL10 genes’ expression in CVID patients were significantly lower, in comparison to the HC. Moreover, there was a lower concentration of IL-17 and IL-10 in cell culture supernatants of stimulated CD4+ T cells of CVID patients than HC.
CONCLUSIONS: Our findings demonstrate that the imbalance of Th17 and Tregs could be an associated with infections only and lymphoproliferations phenotype in CVID patients without monogenic disorders.

PMID: 29345621 [PubMed – as supplied by publisher]

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Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients.

J Leukoc Biol. 2017 Dec 27;:

Authors: Ben-Mustapha I, Agrebi N, Barbouche MR

Abstract
Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency disease due to impaired Fas-Fas ligand apoptotic pathway. It is characterized by chronic nonmalignant, noninfectious lymphadenopathy and/or splenomegaly associated with autoimmune manifestations primarily directed against blood cells. Herein, we review the heterogeneous ALPS molecular bases and discuss recent findings revealed by the study of consanguineous patients. Indeed, this peculiar genetic background favored the identification of a novel form of AR ALPS-FAS associated with normal or residual protein expression, expanding the spectrum of ALPS types. In addition, rare mutational mechanisms underlying the splicing defects of FAS exon 6 have been identified in AR ALPS-FAS with lack of protein expression. These findings will help decipher critical regions required for the tight regulation of FAS exon 6 splicing. We also discuss the genotype-phenotype correlation and disease severity in AR ALPS-FAS. Altogether, the study of ALPS molecular bases in endogamous populations helps to better classify the disease subgroups and to unravel the Fas pathway functioning.

PMID: 29345341 [PubMed – as supplied by publisher]

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Prevalence and Outcomes of Primary Immunodeficiency in Hospitalized Children in the United States.

J Allergy Clin Immunol Pract. 2018 Jan 12;:

Authors: Rubin Z, Pappalardo A, Schwartz A, Antoon JW

Abstract
BACKGROUND: Primary immunodeficiency diseases (PIDDs) are rare yet life-threatening chronic conditions in children. The prevalence and outcomes of PIDDs in the pediatric population in the United States are not well understood.
OBJECTIVE: The objectives of this study were to (1) determine the epidemiology of children hospitalized with PIDD in the United States and (2) characterize the clinical outcomes of hospitalized children with PIDDs.
METHODS: Retrospective cohort analysis of the 2003-2012 Kids’ Inpatient Database of children aged 2-18 years admitted with a primary or secondary diagnosis code of PIDD was performed. Secondary immunodeficiency diseases were excluded.
RESULTS: There were 26,794 pediatric patients hospitalized with a diagnosis of a PIDD from 2003 to 2012. The national prevalence of all PIDDs per 100,000 was 66.6, 82.2, 97.4, and 126.8 in 2003, 2006, 2009, and 2012, respectively. The highest prevalence was in children 0-5 years of age (15,105 hospitalizations; 56%). There was no difference in prevalence between B-cell defects and T-cell defects. PIDDs affected all ethnic populations equally. Respiratory-related diagnoses were the most common comorbidity by an organ system. Overall mortality was 1.99%. Age was inversely correlated with clinical outcome. Children 0-5 years had higher mortality (424 deaths, 79.85%), mean hospital charges ($35,480), and length of stay (LOS) (5.6 days) compared with older age cohorts.
CONCLUSIONS: The prevalence of PIDDs in the hospitalized pediatric population in the United States may have increased over time. Younger age is associated with higher mortality, hospital costs, and LOS. Further study is needed to determine cost-effective management strategies to improve outcomes in infants and young children with PIDD.

PMID: 29339125 [PubMed – as supplied by publisher]

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Carcinogenic potential of antitumor therapies – is the risk predictable?

J BUON. 2017 Nov-Dec;22(6):1378-1384

Authors: Nenova I, Grudeva-Popova J

Abstract
The growing number of successfully cured cancer patients has created a new field in oncogenesis. The life expectancy of such patients has increased, however this favorable event may create enough time for epigenetic events to occur which can cause a new carcinognic event, i.e. a secondary malignancy. The terms in use are second primary malignancies as well as therapy-related neoplasms in case the treatment of the first neoplasm is a direct cause. Second primary malignancies can be hematological neoplasms or solid tumors, with solid tumors having higher frequency. Hematological malignancies, especially t MDS (therapy-related myelodysplastic syndrome) and t AML (therapy-related acute myeloid leukemia), are causally associated with cytotoxic chemotherapy, while secondary solid tumors are related to radiotherapy. The pathogenic mechanisms of clonal selection in second malignancies are in connection with induction of fusion oncogenes, induction of genetic instability, selection of resistant cell clones and hereditary predisposition. The most common oncogenic agents are external (antineoplastic systemic treatments including radiation therapy), patient-specific factors (genetic, demographic, hormonal) and tumorspecific factors (tissue radiosensitivity, immunodeficiency). There are special features in the clinical picture, biological characteristics and evolution of the second neoplasm – different latency period, aggressive course and treatment resistance. Risks, types and characteristics of secondary malignancies are analyzed in specific groups of patients. For example, the peak of t-AML is several years after a primary malignancy and for solid tumors, the risk increases progressively during the observation period. In this review, the authors outline that the risk of second malignancies is predictable and can be controllable by adequate monitoring of patients as well as by personalized treatment of the first neoplasm.

PMID: 29332326 [PubMed – in process]

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Value of the Overall Pneumococcal Polysaccharide Response in the Diagnosis of Primary Humoral Immunodeficiencies.

Front Immunol. 2017;8:1862

Authors: Lopez B, Bahuaud M, Fieschi C, Mehlal S, Jeljeli M, Rogeau S, Brabant S, Deleplancque AS, Dubucquoi S, Poizot S, Terriou L, Launay D, Batteux F, Labalette M, Lefèvre G

Abstract
Background: An overall response assay [OVA, based on a 23-valent pneumococcal polysaccharide vaccine (PPV23)] is widely used to screen for anti-pneumococcal antibodies. Given the heterogeneity of response from one polysaccharide (PS) to another, a World Health Organization-standardized serotype-specific enzyme-linked immunosorbent assay (SSA) is considered to be the only reliable method for testing anti-PS antibody responses in individuals with suspected primary immunodeficiencies (PIDs).
Objective: To evaluate the OVA relative to the reference SSA.
Methods: Serum samples of adult patients referred for a suspected PID were collected before and then 4-8 weeks after immunization with PPV23. The anti-pneumococcal response was systematically assessed with an SSA (7-16 serotypes) and interpreted according to the American Academy of Asthma, Allergy and Immunology’s current guidelines. We used receiver operating characteristic curves and agreement indices to assess the OVA’s diagnostic value in a first cohort. In order to validate these findings, a second (validation) cohort was then prospectively included.
Results: Sixty-two adult patients were included, and 42 (67.7%) were defined as poor responders according to the SSA. Only the post-immunization titer in the OVA was able to correctly identify poor responders; a titer below 110 mg/L gave a positive predictive value of 100% [identifying 24 (57.1%) of the 42 poor responders], and similar levels of diagnostic performance were observed in the validation cohort. The pre-vaccination antibody titer, the post/pre-vaccination antibody titer ratio and a post-vaccination titer above 110 mg/L in the OVA were not predictive of the response in the SSA.
Conclusion: A post-vaccination antibody titer below 110 mg/L in the OVA was constantly associated with a poor PPV23 response using the SSA. In all other cases, SSA is the only reliable method for assessing diagnostic vaccination with PPV23.

PMID: 29326723 [PubMed]

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