Transcriptional, epigenetic and pharmacological control of JAK/STAT pathway in NK cells

Differentiation of Natural Killer (NK) cells is a stepwise process having its origin in the bone marrow and proceeding in the periphery, where these cells follow organ specific trajectories. Several soluble factors and cytokines regulate the distinct stages of NK cell differentiation, and ultimately, their functional properties. Cytokines activating the Janus kinases (JAKs) and members of the signal transducer and activator of transcription (STAT) pathway control distinct aspects of NK cell biology, ranging from development, terminal differentiation, activation, and generation of cells with adaptive properties. Here, we discuss how the recent advances of next generation sequencing (NGS) technology have led to unravel novel molecular aspects of gene regulation, with the aim to provide genomic views of how STATs regulate transcriptional and epigenetic features of NK cells during the different functional stages

An Energy Blockchain, a Use Case on Tendermint

The recent advances in distributed energy systems require new models for exchanging energy among prosumers in microgrids. The blockchain technology promises to solve the digital issues related to distributed systems without a trusted authority and to allow quick and secure energy transactions, which are verified and cryptographically protected. Transactions are approved and subsequently recorded on all the machines participating in the blockchain. This work demonstrates how users, which are nodes of the energy and digital networks, exchange energy supported by a customized blockchain based on Tendermint. We focus on the procedures for generating blocks and defining data structures for storing energy transactions

High Proportions of People With Nonceliac Wheat Sensitivity Have Autoimmune Disease or Antinuclear Antibodies.

BACKGROUND & AIMS: There is much interest in wheat sensitivity among people without celiac disease (CD), but little is known about any risks associated with the condition. We evaluated the prevalence of autoimmune diseases (ADs) among patients with nonceliac wheat sensitivity (NCWS), and investigated whether they carry antinuclear antibodies (ANA). METHODS: We performed a retrospective study of 131 patients diagnosed with NCWS (121 female; mean age, 29.1 years) at 2 hospitals in Italy from January 2001 through June 2011. Data were also collected from 151 patients with CD or irritable bowel syndrome (IBS) (controls). Patient medical records were reviewed to identify those with ADs. We also performed a prospective study of 42 patients (38 female; mean age, 34 years) diagnosed with NCWS from July 2011 through March 2014 at 3 hospitals in Italy. One hundred age- and sex-matched subjects with CD or IBS served as controls. Serum samples were collected from all subjects and ANA levels were measured by immunofluorescence analysis. Participants completed a questionnaire and their medical records were reviewed to identify those with ADs. RESULTS: In the retrospective analysis, similar portions of subjects with NCWS (29%) and CD (29%) developed ADs (mainly Hashimoto's thyroiditis, 29 cases), compared with a smaller proportion of subjects with IBS (4%) (P < .001). In the prospective study, 24% of subjects with NCWS, 20% of subjects with CD, and 2% of subjects with IBS developed ADs (P < .001). In the retrospective study, serum samples tested positive for ANA in 46% of subjects with NCWS (median titer, 1:80), 24% of subjects with CD (P < .001), and 2% of subjects IBS (P < .001); in the prospective study, serum samples were positive for ANA in 28% of subjects with NCWS, 7.5% of subjects with CD (P = .02), and 6% of subjects with IBS (P = .005 vs patients with NCWS). ANA positivity was associated with the presence of the HLA DQ2/DQ8 haplotypes (P < .001). CONCLUSIONS: Higher proportions of patients with NCWS or CD develop autoimmune disorders, are ANA positive, and showed DQ2/DQ8 haplotypes compared with patients with IBS

Anti-Transglutaminase Antibody Assay of the Culture Medium of Intestinal Biopsy Specimen Can Improve the Accuracy of Celiac Disease Diagnosis.

BACKGROUND: We measured anti-transglutaminase (anti-tTG) antibody in the culture medium of intestinal biopsy specimens from patients with suspected celiac disease (CD) and evaluated the relationship between antibody production and severity of intestinal mucosal damage. METHODS: We performed diagnostic testing for CD on 273 consecutive patients. In addition to routine histologic evaluation of duodenal biopsy specimens, we assayed anti-tTG antibodies in serum and in the culture medium of duodenal biopsy specimens. RESULTS: CD was diagnosed in 191 of the 273 patients. Sensitivity and specificity of the serum anti-endomysium (EmA) and anti-tTG assays were 83% and 85% and 99% and 95%, respectively, and both had 88% diagnostic accuracy. EmA and anti-tTG assayed in the culture medium had 98% sensitivity, 100% specificity, and 98% diagnostic accuracy (vs serum assays; P <0.0001). Twenty-nine CD patient specimens (16%) were negative for serum anti-tTG and EmA; for 24 of these patients, anti-tTG assay of the culture medium was positive. The CD patients whose biopsy specimens were positive for serum antibodies showed the following intestinal histologies: total villous atrophy, 35%; severe villous atrophy, 25%; mild atrophy, 25%; villi with no atrophy but with increased intraepithelial lymphocytes, 15%. None of the CD patients whose specimens were negative for serum antibodies showed total or severe villous atrophy; 77% had mild villous atrophy, and 23% had no villous atrophy but had increased intraepithelial lymphocyte counts. Mild villous atrophy was also seen in specimens from approximately 15% of patients without CD. CONCLUSION: Anti-tTG assay of the culture medium of biopsy specimens can improve the accuracy of CD diagnosis in patients negative for serum antibodies

Misinterpreting Diarrhea-Predominant Irritable Bowel Syndrome and Functional Diarrhea: Pathophysiological Highlights

Irritable bowel syndrome with predominant diarrhea (IBS-D) and functional diarrhea (FD) are disorders of gut–brain interaction characterized by recurring symptoms which have a serious impact on the patient’s quality of life. Their pathophysiology is far from being completely understood. In IBS-D growing evidence suggests that bile acid malabsorption (BAM) could be present in up to 30% of patients. Microscopic colitis (MC) is a well-known cause of watery diarrhea and some patients, at first, can be diagnosed as IBS-D or FD. Both BAM and MC are often responsible for the lack of response to conventional treatments in patients labelled as “refractory”. Moreover, because BAM and MC are not mutually exclusive, and can be found in the same patient, they should always be considered in the diagnostic workout when a specific treatment for BAM or MC is unsatisfactory. In the present review the possible shared pathogenetic mechanisms between BAM and MC are discussed highlighting how MC can induce a secondary BAM. Moreover, a brief overview of the current literature regarding the prevalence of their association is provided

JAK inhibition differentially affects NK cell and ILC1 homeostasis

Janus kinase (JAK) inhibitors are widely used in the treatment of multiple autoimmune and inflammatory diseases. Immunologic and transcriptomic profiling have revealed major alterations on natural killer (NK) cell homeostasis associated with JAK inhibitions, while information on other innate lymphoid cells (ILCs) is still lacking. Herein, we observed that, in mice, the homeostatic pool of liver ILC1 was less affected by JAK inhibitors compared to the pool of NK cells present in the liver, spleen and bone marrow. JAK inhibition had overlapping effects on the transcriptome of both subsets, mainly affecting genes regulating cell cycle and apoptosis. However, the differential impact of JAK inhibition was linked to the high levels of the antiapoptotic gene Bcl2 expressed by ILC1. Our findings provide mechanistic explanations for the effects of JAK inhibitors on NK cells and ILC1 which could be of major clinically relevance

CCRL2 Expression by Specialized Lung Capillary Endothelial Cells Controls NK-cell Homing in Lung Cancer

Patterns of receptors for chemotactic factors regulate the homing of leukocytes to tissues. Here we report that the CCRL2/chemerin/CMKLR1 axis represents a selective pathway for the homing of natural killer (NK) cells to the lung. C-C motif chemokine receptor-like 2 (CCRL2) is a nonsignaling seven-transmembrane domain receptor able to control lung tumor growth. CCRL2 constitutive or conditional endothelial cell targeted ablation, or deletion of its ligand chemerin, were found to promote tumor progression in a Kras/p53Flox lung cancer cell model. This phenotype was dependent on the reduced recruitment of CD27- CD11b+ mature NK cells. Other chemotactic receptors identified in lung-infiltrating NK cells by single-cell RNA sequencing (scRNA-seq), such as Cxcr3, Cx3cr1, and S1pr5, were found to be dispensable in the regulation of NK-cell infiltration of the lung and lung tumor growth. scRNA-seq identified CCRL2 as the hallmark of general alveolar lung capillary endothelial cells. CCRL2 expression was epigenetically regulated in lung endothelium and it was upregulated by the demethylating agent 5-aza-2'-deoxycytidine (5-Aza). In vivo administration of low doses of 5-Aza induced CCRL2 upregulation, increased recruitment of NK cells, and reduced lung tumor growth. These results identify CCRL2 as an NK-cell lung homing molecule that has the potential to be exploited to promote NK cell-mediated lung immune surveillance

High Incidence of Invasive Fungal Diseases in Patients with FLT3-Mutated AML Treated with Midostaurin: Results of a Multicenter Observational SEIFEM Study

The potential drug-drug interactions of midostaurin may impact the choice of antifungal (AF) prophylaxis in FLT3-positive acute myeloid leukemia (AML) patients. To evaluate the incidence of invasive fungal diseases (IFD) during the treatment of FLT3-mutated AML patients and to correlate it to the different AF prophylaxis strategies, we planned a multicenter observational study involving 15 SEIFEM centers. One hundred fourteen patients treated with chemotherapy + midostaurin as induction/reinduction, consolidation or both were enrolled. During induction, the incidence of probable/proven and possible IFD was 10.5% and 9.7%, respectively; no statistically significant difference was observed according to the different AF strategy adopted. The median duration of neutropenia was similar in patients with or without IFD. Proven/probable and possible IFD incidence was 2.4% and 1.8%, respectively, during consolidation. Age was the only risk factor for IFD (OR, 95% CI, 1.10 [1.03–1.19]) and complete remission achievement after first induction the only one for survival (OR, 95% CI, 5.12 [1.93–13.60]). The rate of midostaurin discontinuation was similar across different AF strategies. The IFD attributable mortality during induction was 8.3%. In conclusion, the 20.2% overall incidence of IFD occurring in FLT3-mutated AML during induction with chemotherapy + midostaurin, regardless of AF strategy type, was noteworthy, and merits further study, particularly in elderly patients