Ulipristal acetate decreases transforming growth factor β3 serum and tumor tissue concentrations in patients with uterine fibroids.

Fertil Steril. 2018 Mar 07;:

Authors: Ciebiera M, Włodarczyk M, Wrzosek M, Słabuszewska-Jóźwiak A, Nowicka G, Jakiel G

Abstract
OBJECTIVE: To evaluate and compare transforming growth factor β3 (TGF-β3) serum concentration in patients with uterine fibroids (UFs) without hormone treatment, treated with ulipristal acetate (UPA), and controls; to evaluate TGF-β3 concentrations in UF tissue in patients without hormone treatment and those treated with UPA; and to evaluate the correlations of age and body mass index (BMI) with TGF-β3 serum and UF tissue levels between the groups.
DESIGN: Retrospective cohort study.
SETTING: University teaching hospital.
PATIENT(S): A total of 141 patients divided into three groups: UFs non-UPA, UFs, and UPA, controls.
INTERVENTION(S): Medical history and examination, genital ultrasound scan, blood and tissue sampling, and measurement of TGF-β3 serum and tissue concentrations.
MAIN OUTCOME MEASURE(S): Evaluation of the impact of UPA (3 months treatment), age and BMI on TGF-β3 serum and UF tissue levels.
RESULT(S): The values of TGF-β3 serum and tissue concentrations statistically significantly differed between the non-UPA and UPA groups. The mean TGF-β3 serum concentrations were non-UPA group 32.24 ± 34.55 pg/mL, UPA group 10.88 ± 7.15 pg/mL, and controls 11.97 ± 10.30 pg/mL. The mean TGF-β3 tissue concentrations were non-UPA group 171.29 ± 91.81 pg/mg and UPA group 99.99 ± 60.63 pg/mg. Statistically significantly lower mean TGF-β3 serum and tissue concentrations were observed in patients treated with UPA. No statistically significant correlations between TGF-β3 concentrations and age or BMI were found.
CONCLUSION(S): Reduction of serum and tissue TGF-β3 concentrations in UFs may be an important component of the effect of UPA on UF biology. Further research in this area is necessary.

PMID: 29525690 [PubMed - as supplied by publisher]

The Genomic Landscape and Pharmacogenomic Interactions of Clock Genes in Cancer Chronotherapy.

Cell Syst. 2018 Mar 01;:

Authors: Ye Y, Xiang Y, Ozguc FM, Kim Y, Liu CJ, Park PK, Hu Q, Diao L, Lou Y, Lin C, Guo AY, Zhou B, Wang L, Chen Z, Takahashi JS, Mills GB, Yoo SH, Han L

Abstract
Cancer chronotherapy, treatment at specific times during circadian rhythms, endeavors to optimize anti-tumor effects and to lower toxicity. However, comprehensive characterization of clock genes and their clinical relevance in cancer is lacking. We systematically characterized the alterations of clock genes across 32 cancer types by analyzing data from The Cancer Genome Atlas, Cancer Therapeutics Response Portal, and The Genomics of Drug Sensitivity in Cancer databases. Expression alterations of clock genes are associated with key oncogenic pathways, patient survival, tumor stage, and subtype in multiple cancer types. Correlations between expression of clock genes and of other genes in the genome were altered in cancerous versus normal tissues. We identified interactions between clock genes and clinically actionable genes by analyzing co-expression, protein-protein interaction, and chromatin immunoprecipitation sequencing data and also found that clock gene expression is correlated to anti-cancer drug sensitivity in cancer cell lines. Our study provides a comprehensive analysis of the circadian clock across different cancer types and highlights potential clinical utility of cancer chronotherapy.

PMID: 29525205 [PubMed - as supplied by publisher]

Early detection using qPCR of Pseudomonas aeruginosa infection in children with cystic fibrosis undergoing eradication treatment.

J Cyst Fibros. 2018 Mar 07;:

Authors: Blanchard AC, Rooney AM, Yau Y, Zhang Y, Stapleton PJ, Horton E, Klingel M, Stanojevic S, Ratjen F, Coburn B, Waters V

Abstract
BACKGROUND: Infection with Pseudomonas aeruginosa (Pa) with a chronic phenotype is associated with antibiotic eradication therapy (AET) failure. Our objective was to determine whether higher levels of Pa (detected using qPCR) prior to culture positivity were associated with AET failure in pediatric CF patients.
METHODS: Pa-specific qPCR was performed on stored sputa prior to culture positivity in pediatric CF patients with new-onset culture-positive Pa infections undergoing AET with a 28-day course of tobramycin-inhaled solution (TIS). DNA concentrations were compared in patients in whom AET was successful (Eradicated) to those with persistently positive sputum cultures (Persistent).
RESULTS: Forty-seven patients were included. AET was successful in 32 cases (68%), but failed in 15 cases (32%). Median sputum Pa-specific DNA concentration preceding the positive sputum culture was 2.2 × 10-6 μg/mL in Eradicated cases compared to 3 × 10-5 μg/mL in Persistent cases (p = 0.14). There was no significant difference in DNA concentration in the last sputum sample prior to culture positivity, nor in maximal DNA values. There was also no difference in sputum Pa DNA concentrations in patients who had a mucoid (compared to non-mucoid) Pa infection.
CONCLUSIONS: Pediatric CF patients with new-onset Pa infections have detectable Pa-specific DNA in the year preceding a positive culture, however, there is no significant difference in Pa DNA concentrations between patients in whom AET is successful compared to those in whom it fails. Therefore, early molecular detection of Pa may not lead to improved eradication success rates.

PMID: 29525410 [PubMed - as supplied by publisher]

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/03/12

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.

FoxO3a mediates the inhibitory effects of the antiepileptic drug Lamotrigine on breast cancer growth.

Mol Cancer Res. 2018 Mar 09;:

Authors: Pellegrino M, Rizza P, Nigro A, Ceraldi R, Ricci E, Perrotta I, Aquila S, Lanzino M, Andò S, Morelli C, Sisci D

Abstract
Breast cancer (BC) is a complex and heterogeneous disease, with distinct histological features dictating the therapy. Although the clinical outcome of BC patients has been considerably improved, the occurrence of resistance to common endocrine and chemotherapy treatments remains the major cause of relapse and mortality. Thus, efforts in identifying new molecules to be employed in BC therapy are needed. As a "faster" alternative to reach this aim, we evaluated if Lamotrigine (LTG), a broadly used anticonvulsivant, could be "repurposed" as an antitumoral drug in BC. Our data show that LTG inhibits the proliferation, the anchorage-dependent and independent cell growth in BC cells (BCCs), including hormone-resistant cell models. These effects were associated with cell cycle arrest and modulation of related proteins (cyclin D1, cyclin E, p27Kip1 and p21Waf1/Cip1), all target genes of FoxO3a, an ubiquitous transcription factor negatively regulated by AKT. LTG also increases the expression of another FoxO3a target, PTEN, which, in turn, downregulates the PI3K/Akt signaling pathway, with consequent dephosphorylation, thus activation, of FoxO3a. Moreover, LTG induces FoxO3a expression by increasing its transcription through FoxO3a recruitment on specific FHRE located on its own promoter, in an autoregulatory fashion. Finally, LTG significantly reduced tumor growth in vivo, increasing FoxO3a expression.
IMPLICATIONS: The anticonvulsivant drug LTG shows strong antiproliferative activity on BC, both in vitro and in vivo, thus drug repurposing could represent a valuable option for a molecularly targeted therapy in BC patients.

PMID: 29523760 [PubMed - as supplied by publisher]

Comparative assessment of strategies to identify similar ligand-binding pockets in proteins.

BMC Bioinformatics. 2018 Mar 09;19(1):91

Authors: Govindaraj RG, Brylinski M

Abstract
BACKGROUND: Detecting similar ligand-binding sites in globally unrelated proteins has a wide range of applications in modern drug discovery, including drug repurposing, the prediction of side effects, and drug-target interactions. Although a number of techniques to compare binding pockets have been developed, this problem still poses significant challenges.
RESULTS: We evaluate the performance of three algorithms to calculate similarities between ligand-binding sites, APoc, SiteEngine, and G-LoSA. Our assessment considers not only the capabilities to identify similar pockets and to construct accurate local alignments, but also the dependence of these alignments on the sequence order. We point out certain drawbacks of previously compiled datasets, such as the inclusion of structurally similar proteins, leading to an overestimated performance. To address these issues, a rigorous procedure to prepare unbiased, high-quality benchmarking sets is proposed. Further, we conduct a comparative assessment of techniques directly aligning binding pockets to indirect strategies employing structure-based virtual screening with AutoDock Vina and rDock.
CONCLUSIONS: Thorough benchmarks reveal that G-LoSA offers a fairly robust overall performance, whereas the accuracy of APoc and SiteEngine is satisfactory only against easy datasets. Moreover, combining various algorithms into a meta-predictor improves the performance of existing methods to detect similar binding sites in unrelated proteins by 5-10%. All data reported in this paper are freely available at https://osf.io/6ngbs/ .

PMID: 29523085 [PubMed - in process]

Eating less or more - Mindset induced changes in neural correlates of pre-meal planning.

Appetite. 2018 Mar 07;:

Authors: Hege MA, Veit R, Krumsiek J, Kullmann S, Heni M, Rogers PJ, Brunstrom JM, Fritsche A, Preissl H

Abstract
Obesity develops due to an imbalance between energy intake and expenditure. Besides the decision about what to eat, daily energy intake might be even more dependent on the decision about the portion size to be consumed. For decisions between different foods, attentional focus is considered to play a key role in the choice selection. In the current study, we investigated the attentional modulation of portion size selection during pre-meal planning. We designed a functional magnetic resonance task in which healthy participants were directed to adopt different mindsets while selecting their portion size for lunch. Compared with a free choice condition, participants reduced their portion sizes when considering eating for health or pleasure, which was accompanied by increased activity in left prefrontal cortex and left orbitofrontal cortex, respectively. When planning to be full until dinner, participants selected larger portion sizes and showed a trend for increased activity in left insula. These results provide first evidence that also the cognitive process of pre-meal planning is influenced by the attentional focus at the time of choice, which could provide an opportunity for influencing the control of meal size selection by mindset manipulation.

PMID: 29524474 [PubMed - as supplied by publisher]

Genome Wide Association Study Identifies the HMGCS2 Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients.

J Am Heart Assoc. 2018 Mar 09;7(6):

Authors: Singh S, McDonough CW, Gong Y, Alghamdi WA, Arwood MJ, Bargal SA, Dumeny L, Li WY, Mehanna M, Stockard B, Yang G, de Oliveira FA, Fredette NC, Shahin MH, Bailey KR, Beitelshees AL, Boerwinkle E, Chapman AB, Gums JG, Turner ST, Cooper-DeHoff RM, Johnson JA

Abstract
BACKGROUND: Thiazide and thiazide-like diuretics are first-line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide-like diuretic/chlorthalidone-induced glucose change.
METHODS AND RESULTS: Genome-wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR-2 (Pharmacogenomic Evaluation of Antihypertensive Responses-2). Single-nucleotide polymorphisms with P<5×10-8 were further prioritized using in silico analysis based on their expression quantitative trait loci function. Among blacks, an intronic single-nucleotide polymorphism (rs9943291) in the HMGCS2 was associated with increase in glucose levels following chlorthalidone treatment (ß=12.5; P=4.17×10-8). G-allele carriers of HMGCS2 had higher glucose levels (glucose change=+16.29 mg/dL) post chlorthalidone treatment compared with noncarriers of G allele (glucose change=+2.80 mg/dL). This association was successfully replicated in an independent replication cohort of hydrochlorothiazide-treated participants from the PEAR study (ß=5.54; P=0.023). A meta-analysis of the 2 studies was performed by race in Meta-Analysis Helper, where this single-nucleotide polymorphism, rs9943291, was genome-wide significant with a meta-analysis P value of 3.71×10-8. HMGCS2, a part of the HMG-CoA synthase family, is important for ketogenesis and cholesterol synthesis pathways that are essential in glucose homeostasis.
CONCLUSIONS: These results suggest that HMGCS2 is a promising candidate gene involved in chlorthalidone and Hydrochlorothiazide (HCTZ)-induced glucose change. This may provide insights into the mechanisms involved in thiazide-induced hyperglycemia that may ultimately facilitate personalized approaches to antihypertensive selection for hypertension treatment.
CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.

PMID: 29523524 [PubMed - in process]

Azoramide, a novel regulator, favors adipogenesis against osteogenesis through inhibiting the GLP-1 receptor-PKA-β-catenin pathway.

Stem Cell Res Ther. 2018 Mar 09;9(1):57

Authors: Ruan B, Zhu Z, Yan Z, Yang W, Zhai D, Wang L, Ye Z, Lu H, Xiang A, Liang J, Jiang Y, Xu C, Wang Z, Wei M, Lei X, Cao X, Lu Z

Abstract
BACKGROUND: The reciprocal fate decision of mesenchymal stem cells (MSCs) to either bone or adipocytes is determined by Wnt-related signaling and the glucagon-like peptide-1 receptor (GLP-1R). Azoramide, an ER stress alleviator, was reported to have an antidiabetic effect. In this study, we investigated the function of azoramide in regulating the lineage determination of MSCs for either adipogenic or osteogenic differentiation.
METHODS: In this study, microcomputed tomography and histological analysis on bone morphogenetic protein (BMP)2-induced parietal periosteum bone formation assays, C3H10T1/2 and mouse bone marrow MSC-derived bone formation and adipogenesis assays, and specific staining for bone tissue and lipid droplets were used to evaluate the role of azoramide on the lineage determination of MSC differentiation. Cells were harvested for Western blot and quantitative real-time polymerase chain reaction (PCR), and immunofluorescence staining was used to explore the potential mechanism of azoramide for regulating MSC differentiation.
RESULTS: Based on MSC-derived bone formation assays both in vivo and in vitro, azoramide treatment displayed a cell fate determining ability in favor of adipogenesis over osteogenesis. Further mechanistic characterizations disclosed that both the GLP-1R agonist peptide exendin-4 (Ex-4) and GLP-1R small interfering (si)RNA abrogated azoramide dual effects. Moreover, cAMP-protein kinase A (PKA)-mediated nuclear β-catenin activity was responsible for the negative function of azoramide on bone formation in favor of adipogenesis.
CONCLUSIONS: These data provide the first evidence to show that azoramide may serve as an antagonist against GLP-1R in MSC lineage determination.

PMID: 29523188 [PubMed - in process]

Correction to: Immunosuppression Drug Therapy in Lung Transplantation for Cystic Fibrosis.

Paediatr Drugs. 2018 Mar 09;:

Authors: Burcham P, Sarzynski L, Khalfoun S, Novak KJ, Miller JC, Tumin D, Hayes D

Abstract
In the print publication the name of the seventh author was incorrectly published.

PMID: 29524176 [PubMed - as supplied by publisher]

Aberrant GSH reductase and NOX activities concur with defective CFTR to pro-oxidative imbalance in cystic fibrosis airways.

J Bioenerg Biomembr. 2018 Mar 09;:

Authors: de Bari L, Favia M, Bobba A, Lassandro R, Guerra L, Atlante A

Abstract
Cystic fibrosis (CF) is associated to impaired Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel also causing decreased glutathione (GSH) secretion, defective airway bacterial clearance and inflammation. Here we checked the main ROS-producing and ROS-scavenging enzymes as potential additional factors involved in CF pathogenesis. We found that CFBE41o-cells, expressing F508del CFTR, have increased NADPH oxidase (NOX) activity and expression level, mainly responsible of the increased ROS production, and decreased glutathione reductase (GR) activity, not dependent on GR protein level decrease. Furthermore, defective CFTR proved to cause both extracellular and intracellular GSH level decrease, probably by reducing the amount of extracellular GSH-derived cysteine required for cytosolic GSH synthesis. Importantly, we provide evidence that defective CFTR and NOX/GR activity imbalance both contribute to NADPH and GSH level decrease and ROS overproduction in CF cells.

PMID: 29524019 [PubMed - as supplied by publisher]

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]