Phagocytosis depends on TRPV2-mediated calcium influx and requires TRPV2 in lipids rafts: alteration in macrophages from patients with cystic fibrosis.

Sci Rep. 2018 Mar 09;8(1):4310

Authors: Lévêque M, Penna A, Le Trionnaire S, Belleguic C, Desrues B, Brinchault G, Jouneau S, Lagadic-Gossmann D, Martin-Chouly C

Abstract
Whereas many phagocytosis steps involve ionic fluxes, the underlying ion channels remain poorly defined. As reported in mice, the calcium conducting TRPV2 channel impacts the phagocytic process. Macrophage phagocytosis is critical for defense against pathogens. In cystic fibrosis (CF), macrophages have lost their capacity to act as suppressor cells and thus play a significant role in the initiating stages leading to chronic inflammation/infection. In a previous study, we demonstrated that impaired function of CF macrophages is due to a deficient phagocytosis. The aim of the present study was to investigate TRPV2 role in the phagocytosis capacity of healthy primary human macrophage by studying its activity, its membrane localization and its recruitment in lipid rafts. In primary human macrophages, we showed that P. aeruginosa recruits TRPV2 channels at the cell surface and induced a calcium influx required for bacterial phagocytosis. We presently demonstrate that to be functional and play a role in phagocytosis, TRPV2 might require a preferential localization in lipid rafts. Furthermore, CF macrophage displays a perturbed calcium homeostasis due to a defect in TRPV2. In this context, deregulated TRPV2-signaling in CF macrophages could explain their defective phagocytosis capacity that contribute to the maintenance of chronic infection.

PMID: 29523858 [PubMed - in process]

Considering exercise-associated hyponatraemia as a continuum.

BMJ Case Rep. 2018 Mar 09;2018:

Authors: Lewis D, Blow A, Tye J, Hew-Butler T

Abstract
Exercise-associated hyponatraemia (EAH) always involves a component of overhydration relative to available exchangeable sodium stores. In the majority of cases, this is purely due to excessive consumption of fluids during exercise. In a lesser number of cases, it is apparent that excessive sodium loss through sweat may play a role by decreasing the amount of acutely available exchangeable sodium. Two cases demonstrating the latter, one in an individual with cystic fibrosis (CF) and another in an endurance athlete without CF, demonstrate how elevated dermal sweat losses may contribute to a relative dilutional EAH along a pathophysiological continuum.

PMID: 29523608 [PubMed - in process]

Mini-guts in a dish: Perspectives of adult Cystic Fibrosis (CF) patients and parents of young CF patients on organoid technology.

J Cyst Fibros. 2018 Mar 06;:

Authors: Boers SN, de Winter-de Groot KM, Noordhoek J, Gulmans V, van der Ent CK, van Delden JJM, Bredenoord AL

Abstract
BACKGROUND: Organoid technology enables the cultivation of human tissues in a dish. Its precision medicine potential could revolutionize the Cystic Fibrosis (CF) field. We provide a first thematic exploration of the patient perspective on organoid technology to set the further research agenda, which is necessary for responsible development of this ethically challenging technology.
METHODS: 23 semi-structured qualitative interviews with 14 Dutch adult CF patients and 12 parents of young CF patients to examine their experiences, opinions, and attitudes regarding organoid technology.
RESULTS: Four themes emerged: (1) Respondents express a close as well as a distant relationship to organoids; (2) the open-endedness of organoid technology sparks hopes and concerns, (3) commercial use evokes cautiousness. (4) Respondents mention the importance of sound consent procedures, long-term patient engagement, responsible stewardship, and stringent conditions for commercial use.
CONCLUSIONS: The precision medicine potential of organoid technology can only be realized if the patient perspective is taken adequately into account.

PMID: 29523474 [PubMed - as supplied by publisher]

Whole-exome sequencing identifies rare compound heterozygous mutations in the MYBPC3 gene associated with severe familial hypertrophic cardiomyopathy.

Eur J Med Genet. 2018 Mar 07;:

Authors: Zhou N, Qin S, Liu Y, Tang L, Zhao W, Pan C, Qiu Z, Wang X, Shu X

Abstract
Most patients with hypertrophic cardiomyopathy have single-gene autosomal dominant mutations in loci that encode for sarcomeric proteins. The aim of this study was to determine whether pathogenic mutations were present by whole-exome sequencing (WES) in two families with hypertrophic cardiomyopathy (HCM) that presented during adolescence. Blood samples and clinical data were collected from individuals in two families with HCM. DNA was extracted. Mutations were identified using whole-exome sequencing (WES), and the genotypes of family members were identified using Sanger sequencing. Compound heterozygous mutations in the MYBPC3 gene (c.659A > G, p.Tyr220Cys; c.772G > A, p.Glu258Lys,NM_000256, Family 1), (c.873delG, p. Ile292PhefsTer8; c.3G > A, p.Met1?, NM_000256, Family 2) were identified by WES. Patient 1 carried the maternally inherited c.659A > G mutation and the paternally inherited c.772G > A mutation. Patient 2 carried the maternally inherited frameshift mutation c.873delG and the paternally inherited mutation c.3G > A. Two families with HCM presenting during adolescence (age of onset is about 11 years old) demonstrated compound heterozygous mutations in the MYBPC3 gene. These findings suggested an association of MYBPC3 mutations with the early onset of symptoms and worsened prognoses. Our study highlights the importance of genetic screening of all family members in cases of HCM.

PMID: 29524613 [PubMed - as supplied by publisher]

Mutations in the fourth β-propeller domain of LRP4 are associated with isolated syndactyly with fusion of the third and fourth fingers.

Hum Mutat. 2018 Mar 10;:

Authors: Sukenik Halevy R, Chien HC, Heinz B, Bamshad MJ, Nickerson DA, Kircher M, Ahituv N

Abstract
Isolated hand syndactyly is a common limb malformation with limited known genetic etiology. We used exome sequencing to discover two novel variants, chr11 g.46896373C>G; p.D1403H and chr11 g.46893078G>T; p.Q1564K, in LRP4 in a child with isolated bilateral syndactyly of the third and fourth fingers. Each variant was inherited from a different parent and neither parent was affected. Variants in LRP4 have been previously associated with syndactyly in Cenani-Lenz syndactyly syndrome and Sclerosteosis 2, but have not been reported in individuals with isolated syndactyly. LRP4 inhibits LRP6/LRP5-mediated activation of canonical Wnt signaling and mediates sclerostin-dependent inhibition of bone formation. p.D1403H and p.Q1564K are located within the fourth β-propeller of the extracellular protein domain that has yet to be associated with human disease. Functional analyses of p.D1403H and p.Q1564K show that they significantly decrease LRP4's inhibition of Wnt signaling. These results suggest that variants in the fourth β-propeller of the extracellular protein domain may cause a phenotype distinct from previously characterized LRP4 variants. This article is protected by copyright. All rights reserved.

PMID: 29524275 [PubMed - as supplied by publisher]

Novel heterozygous pathogenic variants in CHUK in a patient with AEC-like phenotype, immune deficiencies and 1q21.1 microdeletion syndrome: a case report.

BMC Med Genet. 2018 Mar 09;19(1):41

Authors: Cadieux-Dion M, Safina NP, Engleman K, Saunders C, Repnikova E, Raje N, Canty K, Farrow E, Miller N, Zellmer L, Thiffault I

Abstract
BACKGROUND: Ectodermal dysplasias (ED) are a group of diseases that affects the development or function of the teeth, hair, nails and exocrine and sebaceous glands. One type of ED, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC or Hay-Wells syndrome), is an autosomal dominant disease characterized by the presence of skin erosions affecting the palms, soles and scalp. Other clinical manifestations include ankyloblepharon filiforme adnatum, cleft lip, cleft palate, craniofacial abnormalities and ectodermal defects such as sparse wiry hair, nail changes, dental changes, and subjective hypohydrosis.
CASE PRESENTATION: We describe a patient presenting clinical features reminiscent of AEC syndrome in addition to recurrent infections suggestive of immune deficiency. Genetic testing for TP63, IRF6 and RIPK4 was negative. Microarray analysis revealed a 2 MB deletion on chromosome 1 (1q21.1q21.2). Clinical exome sequencing uncovered compound heterozygous variants in CHUK; a maternally-inherited frameshift variant (c.1365del, p.Arg457Aspfs*6) and a de novo missense variant (c.1388C > A, p.Thr463Lys) on the paternal allele.
CONCLUSIONS: To our knowledge, this is the fourth family reported with CHUK-deficiency and the second patient with immune abnormalities. This is the first case of CHUK-deficiency with compound heterozygous pathogenic variants, including one variant that arose de novo. In comparison to cases found in the literature, this patient demonstrates a less severe phenotype than previously described.

PMID: 29523099 [PubMed - in process]

Advances in the Approach to the Patient with Food Allergy.

J Allergy Clin Immunol. 2018 Mar 07;:

Authors: Scurlock AM, Jones SM

Abstract
Advances in food allergy diagnosis, management, prevention and therapeutic interventions have been significant over the past two decades. Evidence based national and international guidelines have streamlined food allergy diagnosis and management, while paradigm shifting work in primary prevention of peanut allergy has resulted in significant modifications in the approach to early food introduction in infants and toddlers. Innovative investigation of food allergy epidemiology, systems biology, impact, and management has provided important insights. While active therapeutic approaches to food allergy presently remain experimental, progress toward licensed therapies has been substantial. Mechanistic understanding of the immunologic processes underlying food allergy and immunotherapy will inform the future design of therapeutic approaches targeting the food allergic response. Global strategies to mitigate the substantial medical, economic, and psychosocial burden of food allergy in affected individuals and families will require engagement of stakeholders across multiple sectors in research, healthcare, public health, government, educational institutions and industry. However, the relationship between the well-informed allergy care provider and the patient and family remains fundamental for optimizing the care of the patient with food allergy.

PMID: 29524535 [PubMed - as supplied by publisher]

From Feedback Loop Transitions to Biomarkers in the Psycho-Immune-Neuroendocrine Network: Detecting the Critical Transition from Health to Major Depression.

Neurosci Biobehav Rev. 2018 Mar 07;:

Authors: Stapelberg NJC, Pratt R, Neumann DL, Shum DHK, Brandis S, Muthukkumarasamy V, Stantic B, Blumenstein M, Headrick JP

Abstract
BACKGROUND: Biological pathways underlying major depressive disorder (MDD) can be viewed as systems biology networks. The psycho-immune-neuroendocrine (PINE) network comprises central nervous, immune, endocrine and autonomic systems, integrating biological mechanisms of MDD. Such networks exhibit recurrent motifs with specific functions, including positive and negative feedback loops, and are subject to critical transitions, influenced by feedback loop transitions (FLTs).
AIMS: We aim to identify critical feedback loops and their FLTs, as well sentinel network nodes (SNNs), key network nodes that drive FLTs, within the PINE network. Examples of biomarkers are provided which may reflect early warning signs of impending critical transition to MDD.
RESULTS: Disruption of homeostatic feedback loops reflects the physiological transition to MDD. Putative FLTs are identified within hypothalamic-pituitary-adrenal (HPA) and sympathetic-parasympathetic axes, the kynurenine pathway, gut function and dysbiosis.
CONCLUSIONS: Progression from health to disease is driven by FLTs in the PINE network, which is likely to undergo changes characteristic of system instability. Biomarkers of system instability may effectively predict the critical transition to MDD.

PMID: 29524456 [PubMed - as supplied by publisher]

Differentiation by nerve growth factor (NGF) involves mechanisms of crosstalk between energy homeostasis and mitochondrial remodeling.

Cell Death Dis. 2018 Mar 09;9(3):391

Authors: Martorana F, Gaglio D, Bianco MR, Aprea F, Virtuoso A, Bonanomi M, Alberghina L, Papa M, Colangelo AM

Abstract
Neuronal differentiation involves extensive modification of biochemical and morphological properties to meet novel functional requirements. Reorganization of the mitochondrial network to match the higher energy demand plays a pivotal role in this process. Mechanisms of neuronal differentiation in response to nerve growth factor (NGF) have been largely characterized in terms of signaling, however, little is known about its impact on mitochondrial remodeling and metabolic function. In this work, we show that NGF-induced differentiation requires the activation of autophagy mediated by Atg9b and Ambra1, as it is disrupted by their genetic knockdown and by autophagy blockers. NGF differentiation involves the induction of P-AMPK and P-CaMK, and is prevented by their pharmacological inhibition. These molecular events correlate with modifications of energy and redox homeostasis, as determined by ATP and NADPH changes, higher oxygen consumption (OCR) and ROS production. Our data indicate that autophagy aims to clear out exhausted mitochondria, as determined by enhanced localization of p62 and Lysotracker-red to mitochondria. In addition, we newly demonstrate that NGF differentiation is accompanied by increased mitochondrial remodeling involving higher levels of fission (P-Drp1) and fusion proteins (Opa1 and Mfn2), as well as induction of Sirt3 and the transcription factors mtTFA and PPARγ, which regulate mitochondria biogenesis and metabolism to sustain increased mitochondrial mass, potential, and bioenergetics. Overall, our data indicate a new NGF-dependent mechanism involving mitophagy and extensive mitochondrial remodeling, which plays a key role in both neurogenesis and nerve regeneration.

PMID: 29523844 [PubMed - in process]

Polygonumins A, a newly isolated compound from the stem of Polygonum minus Huds with potential medicinal activities.

Sci Rep. 2018 Mar 09;8(1):4202

Authors: Ahmad R, Sahidin I, Taher M, Low C, Noor NM, Sillapachaiyaporn C, Chuchawankul S, Sarachana T, Tencomnao T, Iskandar F, Rajab NF, Baharum SN

Abstract
Polygonumins A, a new compound, was isolated from the stem of Polygonum minus. Based on NMR results, the compound's structure is identical to that of vanicoside A, comprising four phenylpropanoid ester units and a sucrose unit. The structure differences were located at C-3″″'. The cytotoxic activity of polygonumins A was evaluated on several cancer cell lines by a cell viability assay using tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The compound showed the highest antiproliferative (p < 0.05) activities against K562 (Human Leukaemia Cell Line), MCF7 (Human breast adenocarcinoma cell line), and HCT116 (Colorectal cancer cells) cells. Cytotoxic studies against V79-4 cells were carried out and showed that polygonumins A was toxic at 50 µg/ml, suggesting that this compound may be used as an anticancer drug without affecting normal cells. Polygonumins A also showed promising activity as an HIV-1 protease inhibitor with 56% relative inhibition. Molecular docking results indicated that the compound possesses high binding affinity towards the HIV protease over the low binding free energy range of -10.5 to -11.3 kcal/mol. P. minus is used in Malaysian traditional medicine for the treatment of tumour cells. This is the first report on the use of P. minus as an HIV-1 protease inhibitor.

PMID: 29523802 [PubMed - in process]

Ion mobility-derived collision cross section database: Application to mycotoxin analysis.

Anal Chim Acta. 2018 Jul 19;1014:50-57

Authors: Righetti L, Bergmann A, Galaverna G, Rolfsson O, Paglia G, Dall'Asta C

Abstract
The recent hyphenation of ion mobility spectrometry (IMS) with high resolution mass spectrometry (HRMS) has risen as a powerful technique for both targeted and non-targeted screening, reducing background noise and allowing separation of isomeric and isobaric compounds. Nevertheless, such an approach remains largely unexplored in food safety applications, such as mycotoxin analysis. To implement ion mobility in routinely MS-based mycotoxin workflows, searchable databases with collusion cross section (CCS) values and accurate mass-values are required. This paper provides for the first time a traveling-wave IMS (TWIMS)-derived CCS database for mycotoxins, including more than 100 CCS values. The measurements showed high reproducibility (RSD < 2%) across different instrumental conditions as well as several complex cereal matrices, showing a mean inter-matrix precision of RSD <0.9%. As a proof of concept, the database was applied to the analysis of several spiked as well as naturally incurred cereal-based samples. In addition, the effect of adducts on the drift time was studied in a series of mycotoxins in order to understand potential deviations from expected drift time behaviors. Overall, our study confirmed that CCS values represent a physicochemical property that can be used alongside the traditional molecular identifiers of precursor ion accurate mass, fragment ions, isotopic pattern, and retention time.

PMID: 29523251 [PubMed - in process]

Adverse Drug Events Associated with Low-Dose (10 mg) Versus High-Dose (25 mg) Empagliflozin in Patients Treated for Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Diabetes Ther. 2018 Mar 09;:

Authors: Dai X, Luo ZC, Zhai L, Zhao WP, Huang F

Abstract
INTRODUCTION: Empagliflozin is a new, emerging oral hypoglycemic agent (OHA) which has shown significant benefits in type 2 diabetes mellitus (T2DM) patients with cardiovascular disease. In this analysis, our aim was to systematically compare the adverse drug events (ADEs) associated with a low (10 mg) versus a high (25 mg) dose of empagliflozin as (1) monotherapy, (2) as an add-on to other OHAs, and (3) as an add-on specifically to metformin, in patients who were treated for T2DM.
METHODS: This was a systematic review and meta-analysis of randomized controlled trials that compared empagliflozin 10 mg versus 25 mg in patients who were treated for T2DM and which reported adverse drug reactions as their clinical endpoints. Statistical analysis was carried out using the latest version of the RevMan software (ver. 5.3) whereby odds ratios (OR) and 95% confidence intervals (CI) were generated.
RESULTS: Eight trials with a total number of 8514 patients treated for T2DM were included in this meta-analysis and systematic review, of whom 4261 patients received 10 mg empagliflozin and 4253 patients received 25 mg empagliflozin. Our results showed that there were no significant differences between the patients with T2DM receiving 10 empagliflozin and those receiving 25 mg empagliflozin in terms of drug-related adverse effects (OR 1.06, 95% CI 0.93-1.21; P = 0.40, I2 = 0%), adverse events leading to drug discontinuation (OR 0.99, 95% CI 0.86-1.14; P = 0.87, I2 = 0%), and serious adverse events (OR 1.06, 95% CI 0.95-1.18; P = 0.31, I2 = 0%) when empagliflozin was provided as monotherapy or as an add-on to other anti-diabetic medications. The same results were obtained when empagliflozin was used as an add-on to metformin or as monotherapy. The duration of the follow-up periods did not affect the results. However, the incidence of genital and urinary tract infections (UTIs) was significantly higher in female patients than in male patients with 10 or 25 mg empagliflozin.
CONCLUSIONS: The incidence of ADEs was not significantly different in T2DM patients receiving 10 versus 25 mg empagliflozin as monotherapy or as add-on to metformin or other anti-diabetic drugs during a shorter or longer follow-up period. However, genital and UTIs were more common in female patients with T2DM irrespective of empagliflozin dosage.

PMID: 29524188 [PubMed - as supplied by publisher]

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pharmacogenomics

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"systems biology"

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PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

In Silico Chemogenomics Drug Repositioning Strategies for Neglected Tropical Diseases.

Curr Med Chem. 2018 Mar 08;:

Authors: Andrade CH, Neves BJ, Melo-Filho CC, Rodrigues J, Silva DC, Braga RC, Cravo PVL

Abstract
Only ~1% of all drug candidates against Neglected Tropical Diseases (NTDs) have reached clinical trials in the last decades, underscoring the need for new, safe and effective treatments. In such context, drug repositioning, which allows finding novel indications for approved drugs whose pharmacokinetic and safety profiles are already known, is emerging as a promising strategy for tackling NTDs. Chemogenomics is a direct descendent of the typical drug discovery process that involves the systematic screening of chemical compounds against drug targets in high-throughput screening (HTS) efforts, for the identification of lead compounds. However, different to the one-drug-one-target paradigm, chemogenomics attempts to identify all potential ligands for all possible targets and diseases. In this review, we summarize current methodological development efforts in drug repositioning that use state-of-the-art computational ligand- and structure-based chemogenomics approaches. Furthermore, we highlighted the recent progress in computational drug repositioning for some NTDs, based on curation and modeling of genomic, biological, and chemical data. Additionally, we also present in-house and other successful examples and suggest possible solutions to existing pitfalls.

PMID: 29521204 [PubMed - as supplied by publisher]

The Rare Extragonadal Omental Teratoma: A Case Report.

J Minim Invasive Gynecol. 2017 Sep - Oct;24(6):1046-1048

Authors: Rampinelli F, Donarini P, Visenzi C, Ficarelli S, Gambino A, Ciravolo G

Abstract
Teratomas of extragonadal origin are extremely rare, and the most common extragonadal site to find teratomas is the omentum. Teratomas are typically found in women of reproductive age, but they are also seen in young girls and postmenopausal women. Generally, teratomas arise from germ cells that may induce different cells to originate from the 3 primitive embryonic layers. Three main theories have been proposed to explain their location. The present report summarizes these theories as well as describes a case of a mature cystic teratoma of the omentum that was managed by laparoscopic resection.

PMID: 28662988 [PubMed - indexed for MEDLINE]

Rare cancers: Challenges & issues.

Indian J Med Res. 2017 Jan;145(1):17-27

Authors: Pillai RK, Jayasree K

Abstract
Rare cancers account for about 22 per cent of all cancers diagnosed worldwide, disproportionately affecting some demographic groups, with an occurrence of less than 6 per 100,000 individuals annually. Many rare cancers in adults, adolescents and children are not curable, and patients and care providers have little option to take therapeutic decisions. The epidemiology of rare cancers is a challenging area of study but is inadequately addressed. Despite efforts mainly in some European nations, a few improvements have been observed in the management of rare cancers. Reasons for this obvious stagnation are multifactorial and are mainly inherent to logistical difficulties in carrying out clinical trials in very small patient populations, hesitation of the pharmaceutical industry to spend in small markets and complexity in creating adequate information for the development of cost-effective drugs. Rare cancers also face specific challenges that include late and incorrect diagnosis, lack of clinical expertise and lack of research interest and development of new therapies. The utilization of nationally representative study findings for the patients' evaluation may possibly offer chances to find out pathogenesis and prevalence, and this will eventually lead to control and prevention. Currently, advancing targeted therapies offer a great opportunity for the better management of rare cancers. Conducting clinical trials with small patient population, innovative clinical trial approach, prevailing controlling obstacles for international cooperation and financial support for research are the present challenges for rare cancers. The International Rare Cancers Initiative functions as a main platform for achieving new international clinical trials in rare tumours. This review delineates the current challenges and issues in the interpretation, management and research scenarios of rare cancers.

PMID: 28574010 [PubMed - indexed for MEDLINE]

Twenty-First Century Diseases: Commonly Rare and Rarely Common?

Antioxid Redox Signal. 2017 Sep 20;27(9):511-516

Authors: Daunert S, Sittampalam GS, Goldschmidt-Clermont PJ

Abstract
Alzheimer's drugs are failing at a rate of 99.6%, and success rate for drugs designed to help patients with this form of dementia is 47 times less than for drugs designed to help patients with cancers ( www.scientificamerican.com/article/why-alzheimer-s-drugs-keep-failing/2014 ). How can it be so difficult to produce a valuable drug for Alzheimer's disease? Each human has a unique genetic and epigenetic makeup, thus endowing individuals with a highly unique complement of genes, polymorphisms, mutations, RNAs, proteins, lipids, and complex sugars, resulting in distinct genome, proteome, metabolome, and also microbiome identity. This editorial is taking into account the uniqueness of each individual and surrounding environment, and stresses the point that a more accurate definition of a "common" disorder could be simply the amalgamation of a myriad of "rare" diseases. These rare diseases are being grouped together because they share a rather constant complement of common features and, indeed, generally respond to empirically developed treatments, leading to a positive outcome consistently. We make the case that it is highly unlikely that such treatments, despite their statistical success measured with large cohorts using standardized clinical research, will be effective on all patients until we increase the depth and fidelity of our understanding of the individual "rare" diseases that are grouped together in the "buckets" of common illnesses. Antioxid. Redox Signal. 27, 511-516.

PMID: 28482684 [PubMed - indexed for MEDLINE]

A clinical study of 21 patients with hemophagocytic syndrome in 295 cases diagnosed with nasal type, extranodal nature killer/T cell lymphoma.

Cancer Biol Ther. 2017 Apr 03;18(4):252-256

Authors: Li N, Zhang L, Liu J, Zhang J, Weng HW, Zhuo HY, Zou LQ

Abstract
Nasal type, extranodal nature killer (NK)/T cell lymphoma-associated hemophagocytic syndrome (NK/T-LAHS) is a rare and fatal disorder with extremely poor prognosis. To investigate its clinical characteristics and risk factors, we retrospectively analyzed 295 patients with nasal type, extranodal nature killer/T cell lymphoma, of which 21 were diagnosed with hemophagocytic syndrome, with a cumulative incidence of 7.1%. The most frequently clinical characteristics were fever, lymphadenopathy, hepatosplenomegaly, pancytopenia, hyperferritinemia, liver dysfunction, hypertriglyceridemia, hypofibrinogenemia and evaluated lactate dehydrogenase (LDH) level. After a median follow-up of 27 months, the 2-year survival for the 295 patients was 74.6%. Significant difference for 2-year survival was found between patients with and without hemophagocytic syndrome (4.8% vs. 80.0%, P<0.001). After developing hemophagocytic syndrome, all patients survived no more than 3 months, with a median survival of 35 days. Risk factors for NK/T-LAHS were bone marrow (BM) involvement (P = 0.019; relative risk, 13.649; 95% confidence interval (CI): 1.538-121.103), hepatosplenomegaly (P = 0.003; relative risk, 9.616; 95%CI: 2.154-42.918), and elevated LDH level (>314U/L) (P = 0.038; relative risk, 6.293; 95%CI: 1.108-35.735). We conducted a risk model for all 295 patients based on the 3 adverse factors as follows: low risk (233 cases, 79.0%), no factor; intermediate risk (43 cases, 14.6%), one factor; high risk (19 cases, 6.4%), 2 or 3 factors. The probabilities for developing LAHS were 0.9% for low-, 14.0% for intermediate-, and 68.4% for high-risk group. Significant differences in the 3 risk groups were observed (P<0.001).

PMID: 28278074 [PubMed - indexed for MEDLINE]

High-dose vitamin D in Addison's disease regulates T-cells and monocytes: A pilot trial.

Nutrition. 2017 Dec 02;49:66-73

Authors: Penna-Martinez M, Filmann N, Bogdanou D, Shoghi F, Huenecke S, Schubert R, Herrmann E, Koehl U, Husebye ES, Badenhoop K

Abstract
OBJECTIVES: On the basis of the immunomodulatory actions of vitamin D (VD), we investigated the effects of high-dose VD therapy over a 3 mo period on the immune response in patients with Addison's disease (AD).
METHODS: This randomized, controlled, crossover trial included 13 patients with AD who received either cholecalciferol (4000 IU/d) for 3 mo followed by 3 mo placebo oil or the sequential alternative placebo followed by verum. Glucocorticoid replacement doses remained stable. The primary outcome measures were changes in 25-hydroxyvitamin D3 (25(OH)D3) levels and immune cells including T helper cells (Th; CD3+CD4+), late-activated Th cells (CD3+CD4+HLA-DR+), regulatory T cells (CD3+CD4+CD25brightCD127dim/neg), cytotoxic T cells (Tc; CD3+CD8+), late-activated Tc cells (CD3+CD8+HLA-DR+), and monocytes. The explorative analysis included the correlation of changes with VD-related gene polymorphisms and 21-hydroxylase antibody titers.
RESULTS: Ten of 13 patients (77%) were VD deficient. Median 25(OH)D3 concentrations increased significantly to 41.5 ng/ml (median changes: 19.95 ng/ml; P = 0.0005) after 3 mo of cholecalciferol treatment. Within the T-cells, only the late-activated Th (median changes: 1.6%; P = 0.02) and late-activated Tc cells (median changes: 4.05%; P = 0.03) decreased, whereas monocytes (median changes: 1.05%; P = 0.008) increased after VD therapy. T-cell changes were associated with two polymorphisms (CYP27B1-rs108770012 and VDR-rs10735810), but no changes in the 21-hydroxylase antibody titers were observed.
CONCLUSIONS: Three months of treatment with cholecalciferol achieved sufficient 25(OH)D3 levels and can regulate late-activated T-cells and monocytes in patients with AD. Explorative analysis revealed potential genetic contributions. This pilot trial provides novel insights about immunomodulation in AD.

PMID: 29522979 [PubMed - as supplied by publisher]