Polyarticular juvenile idiopathic arthritis has a distinct co-inhibitor receptor profile.

OBJECTIVES: Juvenile Idiopathic Arthritis (JIA) is the most common rheumatic disease of childhood; the pathogenesis is associated with T cell activation. T cell activation can be counter-balanced by signals generated by inhibitory receptors (IRs) such as CTLA-4, PD-1, LAG-3, and TIM-3. Here, we identify the role of IRs in the pathogenesis of different JIA subtypes. METHODS: In total, we included 67 oligoarticular JIA, 12 IgM-RF negative polyarticular JIA, 17 enthesitis related arthritis, 11 systemic JIA patients and 10 healthy controls. We collected plasma (and synovial fluid) samples from the patients either at the onset or during a flare of their disease. We measured the soluble levels of co-IRs (IL-2Rα, 4-1BB, CD86, TGF-ß1, CTLA-4, PD-L1, PD-1, TIM-3, LAG- 3, Galectin-9) by cytometric bead array kits and their cellular expression (PD-1, CTLA-4, TIM-3, LAG-3) by flow cytometry. We compared the plasma levels and cellular expressions of different co-IRs within different JIA subgroups. RESULTS: The polyarticular-JIA group was different from the three other examined JIA subgroups, having higher levels of plasma sCTLA-4(p< 0.001), sPD-1(p< 0.05), and s4-1BB(p< 0.05) when compared with the other JIA subgroups and healthy controls. We analyzed the cellular surface expression of different co-IRs on the PBMCs of different JIA subtypes. Similar to plasma levels, both the percentage(p< 0.05) and the MFI (mean fluorescence intensity) (p< 0.01) of CTLA4 expression were higher in the poly-JIA subgroup. CONCLUSION: This is the first report studying the expression profile of different co-IRs in different subtypes of JIA. Polyarticular JIA patients had a different co-IR profile, having more CTLA-4, PD-1 and 4-1BB in their plasma than the other subtypes of JIA.

Organohalogen chalcones: design, synthesis, ADMET prediction, molecular dynamics study and inhibition effect on acetylcholinesterase and carbonic anhydrase.

In an effort to discover potential acetylcholinesterase (AChE) and carbonic anhydrase (CA) inhibitors, a novel series of organohalogen chalcone derivatives (12-20, 23-30) was synthesized, and their chemical structures were characterized by spectral analysis. They showed a highly potent inhibition effect on AChE and hCAs (Ki values range from 5.07 ± 0.062 to 65.53 ± 4.36 nM for AChE, 13.54 ± 2.55 to 94.11 ± 10.39 nM for hCA I, and 5.21 ± 0.54 to 57.44 ± 3.12 nM for hCA II). In addition, the chalcone derivatives with the highest inhibitor score docked into the active site of the indicated metabolic enzyme receptors, and their absorption, metabolism, and toxic properties were evaluated according to ADMET's estimation.Compounds 16 and 19 exhibited the highest inhibition score, emerged as lead compounds, and inspired the development of more potent compounds.

Lipid production and cellular changes in Fremyella diplosiphon exposed to nanoscale zerovalent iron nanoparticles and ampicillin.

With the dramatic decrease in fossil fuel stocks and their detrimental effects on the environment, renewable energy sources have gained imminent importance in the mitigation of emissions. As lipid-enriched energy stocks, cyanobacteria are the leading group of microorganisms contributing to the advent of a new energy era. In the present study, the impact of Nanofer 25 s nanoscale zero-valent iron nanoparticles (nZVIs) and ampicillin on lipid production and cellular structural changes in Fremyella diplosiphon strain B481-SD were investigated. Total lipid abundance, fatty acid methyl ester (FAME) compositions, and alkene production as detected by high-resolution two-dimensional gas chromatography with time-of-flight mass spectrometry (GC × GC/TOF-MS) was significantly higher (p < 0.05) in the individual application of 0.8 mg/L ampicillin, 3.2 mg/L nZVIs, and a combined regimen of 0.8 mg/L ampicillin and 3.2 mg/L nZVIs compared to the untreated control. In addition, we identified significant increases (p < 0.05) in monounsaturated fatty acids (MUFAs) in F. diplosiphon treated with the combination regimen compared to the untreated control, 0.8 mg/L of ampicillin, and 3.2 mg/L of nZVIs. Furthermore, individual treatment with 0.8 mg/L ampicillin and the combination regimen (0.8 mg/L ampicillin + 3.2 mg/L nZVIs) significantly increased (p < 0.05) Nile red fluorescence compared to the untreated control, indicating neutral membrane lipids to be the main target of ampicillin added treatments. Transmission electron microscopy studies revealed the presence of single-layered thylakoid membranes in the untreated control, while complex stacked membranes of 5-8 layers were visualized in ampicillin and nZVI-treated F. diplosiphon. Our results indicate that nZVIs in combination with ampicillin significantly enhanced total lipids, essential FAMEs, and alkenes in F. diplosiphon. These findings offer a promising approach to augment the potential of using the strain as a large-scale biofuel agent.

Phenotypic and molecular genetics study of Geotrichum candidumLink (1809) and Geotrichum silvicola Pimenta (2005) cultivated on mitis salivarius agar.

BACKGROUND: Geotrichum is a genus of fungi found in different habitats throughout the world. Although Geotrichum and its related species have been extensively reclassified and taxonomically revised, it is still the target for many researches. METHODS AND RESULTS: In this study, phenotypic and molecular genetics comparisons were performed between Geotrichum candidum and Geotrichum silvicola. Mitis Salivarius Agar was used as the growing medium for the phenotypic comparison study, which was carried out at two temperatures (20-25 and 37 °C). For genotypic comparison, we compared the 18 S, ITS, and 28 S sequences of universal DNA barcode regions of both species. Important findings on the new culture media for fungal isolation were revealed by the results. The phenotypic variation between the two species' colonies, including their shapes, sizes, textures and growth rates, were strikingly different. DNA sequences of both species showed that pairwise identities of the species were 99.9% for 18 S, 100% for ITS and 99.6% for 28 S regions. CONCLUSIONS: Contrary to what is commonly seen, the results showed that 18 S, ITS and 28 S failed to discriminate the species. The first investigation into the performance of Mitis Salivarius Agar as a fungus culture medium is reported in this work, and proved its efficiency. Additionally, this is the first study to compare G. candidum with G. silvicola by means of both phenotypic and genotypic analysis.

MicroRNA-Mediated Drug Repurposing Unveiled Potential Candidate Drugs for Prolactinoma Treatment.

INTRODUCTION: Prolactinomas, also called lactotroph adenomas, are the most encountered type of hormone-secreting pituitary neuroendocrine tumors in the clinic. The preferred first-line therapy is a medical treatment with dopamine agonists (DAs), mainly cabergoline, to reduce serum prolactin levels, tumor volume, and mass effect. However, in some cases, patients have displayed DA resistance with aggressive tumor behavior or are faced with recurrence after drug withdrawal. Also, currently used therapeutics have notorious side effects and impair the life quality of the patients. METHODS: Since the amalgamation of clinical and laboratory data besides tumor histopathogenesis and transcriptional regulatory features of the tumor emerges to exhibit essential roles in the behavior and progression of prolactinomas; in this work, we integrated mRNA- and microRNA (miRNA)-level transcriptome data that exploit disease-specific signatures in addition to biological and pharmacological data to elucidate a rational prioritization of pathways and drugs in prolactinoma. RESULTS: We identified 8 drug candidates through drug repurposing based on mRNA-miRNA-level data integration and evaluated their potential through in vitro assays in the MMQ cell line. Seven repurposed drugs including 5-fluorocytosine, nortriptyline, neratinib, puromycin, taxifolin, vorinostat, and zileuton were proposed as potential drug candidates for the treatment of prolactinoma. We further hypothesized possible mechanisms of drug action on MMQ cell viability through analyzing the PI3K/Akt signaling pathway and cell cycle arrest via flow cytometry and Western blotting. DISCUSSION: We presented the transcriptomic landscape of prolactinoma through miRNA and mRNA-level data integration and proposed repurposed drug candidates based on this integration. We validated our findings through testing cell viability, cell cycle phases, and PI3K/Akt protein expressions. Effects of the drugs on cell cycle phases and inhibition of the PI3K/Akt pathway by all drugs gave us promising output for further studies using these drugs in the treatment of prolactinoma. This is the first study that reports miRNA-mediated repurposed drugs for prolactinoma treatment via in vitro experiments.

Human splenic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are strategically located immune regulatory cells in cancer.

In contrast to the mouse, functional assets of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in the human spleen remain to be better elucidated. Here, we report that the spleen in gastric and pancreatic cancer adopts an immune regulatory character, harbors excessive amount of PMN-MDSC, and anatomically enables their interaction with T cells. Compared to the peripheral blood, the spleen from cancer patients contained significantly higher levels of low-density PMN-MDSC, but not early-stage MDSC (e-MDSC) and monocytic-MDSC (M-MDSC). Low-density fraction of polymorphonuclear (PMN) cells was enriched in immature myeloid cells and displayed higher levels of CD10, CD16, and ROS than their blood-derived counterparts. They were also positive for PD-L1, LOX-1, and pSTAT3. The white pulp and periarteriolar lymphoid sheath (PALS) were strategically surrounded by PMN cells that were in contact with T cells. Unlike those from the blood, both low-density and normal-density PMN cells from the human spleen suppressed T cell proliferation and IFN-γ production. Independent of clinical grade, high PMN-MDSC percentages were associated with decreased survival in gastric cancer. In summary, our results outline the immune regulatory role of the spleen in cancer where neutrophils acquire MDSC functions and feasibly interact with T cells.

Design, synthesis and biological evaluation of novel bischalcone derivatives as potential anticancer agents.

Building on our previous work that discovered chalcone as a promising pharmacophore for anticancer activity, we have various other chalcone derivatives and have synthesized a series of novel bischalcone to explore their anticancer activity. Among all tested compounds, compounds 6a, 6b, and 6c showed the highest antiproliferative activity against A-549 cancer cell lines with the average IC50 values of 4.18, 4.52, and 5.05 µM, respectively. Moreover, compound 6c showed high antiproliferative activity against the Caco-2 cell line; thus, it was 2- and 4-fold more active than the reference compounds, i.e., methotrexate and capecitabine. Compound 6a also induced cell-cycle arrest in the S phase, whereas compounds 6b and 6c were observed to stop at the G0/G1 phase. Thereafter, we evaluated that compound 6c also had the highest apoptosis/necrosis ratio than other compounds and the standard compound. The anticancer property of the 6c was also supported by molecular docking studies carried out on the EGFR and HER2 receptors. Overall, we expect that these compounds can be further developed for the potential treatment of lung cancer.

Synthesis of N-alkylated pyrazolo[3,4-d]pyrimidine analogs and evaluation of acetylcholinesterase and carbonic anhydrase inhibition properties.

Fused pyrimidines, especially pyrazolo[3,4-d]pyrimidines, are among the most preferred building blocks for pharmacology studies, as they exhibit a broad spectrum of biological activity. In this study, new derivatives of pyrazolo[3,4-d]pyrimidine were synthesized by alkylation of the N1 nitrogen atom. We synthesized 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2 from commercially available aminopyrazolopyrimidine 1 using N-iodosuccinimide as an iodinating agent. The synthesis of compound 2 started with nucleophilic substitution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine with R-X (X: -OMs, -Br, -Cl), affording N-alkylated pyrazolo[3,4-d]pyrimidine. We performed this synthesis using a weak inorganic base and the mild temperature was also used for a two-step procedure to generate N-alkylated pyrazolo[3,4-d]pyrimidine derivatives. Also, all compounds were tested for their ability to inhibit acetylcholinesterase (AChE) and the human carbonic anhydrase (hCA) isoforms I and II, with Ki values in the range of 15.41 ± 1.39-63.03 ± 10.68 nM for AChE, 17.68 ± 1.92-66.27 ± 5.43 nM for hCA I, and 8.41 ± 2.03-28.60 ± 7.32 nM for hCA II. Notably, compound 10 was the most selective and potent CA I inhibitor with a significant selectivity ratio of 26.90.

Novel insights into diabetes mellitus due to DNAJC3-defect: Evolution of neurological and endocrine phenotype in the pediatric age group.

BACKGROUND: A number of inborn errors of metabolism caused by abnormal protein trafficking that lead to endoplasmic reticulum storage diseases (ERSD) have been defined in the last two decades. One such disorder involves biallelic mutations in the gene encoding endoplasmic reticulum resident co-chaperone DNAJC3 (P58IPK ) that leads to diabetes in the second decade of life, in addition to multiple endocrine dysfunction and nervous system involvement. OBJECTIVE: The aim of this study was to define the natural history of this new form of diabetes, especially the course of abnormalities related to glucose metabolism. METHODS: Whole-exome and Sanger sequencing was used to detect DNAJC3 defect in two patients. Detailed analysis of their clinical history as well as biochemical, neurological and radiological studies were carried out to deduce natural history of neurological and endocrine phenotype. RESULTS: DNAJC3 defect led to beta-cell dysfunction causing hyperinsulinemichypoglycemia around 2 years of age in both patients, which evolved into diabetes with insulin deficiency in the second decade of life, probably due to beta cell loss. Endocrine phenotype involved severe early-onset growth failure due to growth hormone deficiency, and hypothyroidism of central origin. Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life. CONCLUSION: Biallelic loss-of-function in the ER co-chaperone DNAJC3 leads to a new form of diabetes with early onset hyperinsulinemic hypoglycemia evolving into insulin deficiency as well as severe growth failure, hypothyroidism and diffuse neurodegeneration.

Impact of Zero-Valent Iron Nanoparticles and Ampicillin on Adenosine Triphosphate and Lactate Metabolism in the Cyanobacterium Fremyella diplosiphon.

In cyanobacteria, the interplay of ATP and lactate dynamics underpins cellular energetics; their pronounced shifts in response to zero-valent iron (nZVI) nanoparticles and ampicillin highlight the nuanced metabolic adaptations to environmental challenges. In this study, we investigated the impact of nZVIs and ampicillin on Fremyella diplosiphon cellular energetics as determined by adenosine triphosphate (ATP) content, intracellular and extracellular lactate levels, and their impact on cell morphology as visualized by transmission electron microscopy. While a significant increase in ATP concentration was observed in 0.8 mg/L ampicillin-treated cells compared to the untreated control, a significant decline was noted in cells treated with 3.2 mg/L nZVIs. ATP levels in the combination regimen of 0.8 mg/L ampicillin and 3.2 mg/L nZVIs were significantly elevated (p < 0.05) compared to the 3.2 mg/L nZVI treatment. Intracellular and extracellular lactate levels were significantly higher in 0.8 mg/L ampicillin, 3.2 mg/L nZVIs, and the combination regimen compared to the untreated control; however, extracellular lactate levels were the highest in cells treated with 3.2 mg/L nZVIs. Visualization of morphological changes indicated increased thylakoid membrane stacks and inter-thylakoidal distances in 3.2 mg/L nZVI-treated cells. Our findings demonstrate a complex interplay of nanoparticle and antibiotic-induced responses, highlighting the differential impact of these stressors on F. diplosiphon metabolism and cellular integrity.

Chronic non-bacterial osteomyelitis and immune checkpoint molecules.

OBJECTIVE: We aimed to investigate the plasma levels and cell surface expression of two checkpoint molecules, TIM-3 (T cell immunoglobulin and mucin domain-containing protein 3) and PD-1 (programmed cell death protein 1), in pediatric patients with chronic non-bacterial osteomyelitis (CNO). METHODS: Plasma samples of CNO patients were collected at diagnosis or during biologic agent treatment. Plasma levels of TIM-3 and PD-1 were measured using the sandwich enzyme-linked immunosorbent assay method, and the expression of the two immune checkpoint molecules on the cell surface was analyzed by isolating peripheral blood mononuclear cells by density gradient centrifugation technique. RESULTS: Twenty-seven patients with CNO (14 boys, 51.9%) and six healthy controls (3 boys, 50%) were enrolled in the study. There were no age differences between CNO patients and healthy controls (median age 14.5 vs. 13.5 years, respectively, p=0.762). Of the CNO patients, 18 were included at the time of diagnosis while 9 were receiving biologic treatment at enrollment. The median plasma PD-1 levels were significantly lower in the CNO group than in the healthy controls (p=0.011). However, no significant difference was found in the cellular expression of PD-1 and TIM-3 on CD3+CD4+ T cells in patients and healthy controls (p=0.083 and p=0.245, respectively). There was also no statistically significant difference in plasma TIM-3 levels of the patient and control groups (p=0.981). CONCLUSION: CNO is an autoinflammatory disease, and overall, our results suggest that T cell exhaustion may not be significant in CNO. Further research is needed to find out whether the immune checkpoints are mainly associated with autoimmunity but not autoinflammation. Key Points • The median plasma PD-1 levels were significantly lower in the CNO group than in the healthy controls. • No significant difference was found in the cellular expression of PD-1 and TIM-3 on CD3+CD4+ T cells in patients and healthy controls. • Our results suggest that T cell exhaustion may not be significant in CNO pathogenesis.

Restless legs syndrome in patients with psoriasis: association with inflammation and sleep quality.

BACKGROUND: We aimed to evaluate if psoriasis associated with restless legs syndrome (RLS) due to its close relationship with metabolic disorders. METHODS: This was a cross-sectional study in which the relationship between RLS and psoriasis was evaluated. Seventy consecutive psoriasis patients and 70 controls without any skin disorder were included in this study. Data including age, gender, body weight, height, and Psoriasis Area Severity Index (PASI) scores were recorded. Diagnosis of RLS was established using International RLS Study Group (IRLSSG) diagnostic criteria. International RLS Rating Scale (IRLSRS) was used to evaluate the severity of symptoms. Each participant completed forms of the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), and the Dermatology Life Quality Index (DLQI). RESULTS: The RLS frequency in patients with psoriasis was 18.6% vs. 5.7% in the control group (P = 0.018). In psoriasis patients, BMI, DLQI, IRLSRS, hemoglobin, ferritin, CRP, and uric acid levels were significantly higher than those of the controls. In psoriasis patients with RLS, PASI, DLQI, PSQI, IRLSRS scores, CRP level, and BMI were significantly higher, and hemoglobin level was significantly lower relative to the psoriasis patients without RLS. PASI score was the sole independent associate of RLS presence in psoriasis patients. CONCLUSION: Restless legs syndrome was significantly more common in psoriasis patients, and the presence of RLS was associated with significantly more severe psoriasis, more severe systemic inflammation, lower serum hemoglobin values, worse quality of life, and sleep quality.

A Transcriptomic and Reverse-Engineering Strategy Reveals Molecular Signatures of Arachidonic Acid Metabolism in 12 Cancers.

Cancer and arachidonic acid (AA) have important linkages. For example, AA metabolites regulate several critical biological functions associated with carcinogenesis: angiogenesis, apoptosis, and cancer invasion. However, little is known about the comparative changes in metabolite expression of the arachidonic acid pathway (AAP) in carcinogenesis. In this study, we examined transcriptome data from 12 cancers, such as breast invasive carcinoma, colon adenocarcinoma, lung adenocarcinoma, and prostate adenocarcinoma. We also report here a reverse-engineering strategy wherein we estimated metabolic signatures associated with AAP by (1) making deductive inferences through transcriptome-level data extraction, (2) remodeling AA metabolism, and (3) performing a comparative analysis of cancer types to determine the similarities and differences between different cancer types with respect to AA metabolic alterations. We identified 77 AAP gene signatures differentially expressed in cancers and 37 AAP metabolites associated with them. Importantly, the metabolite 15(S)-HETE was identified in almost all cancers, while arachidonate, 5-HETE, PGF2α, 14,15-EET, 8,9-EET, 5,6-EET, and 20-HETE were discovered as other most regulated metabolites. This study shows that the 12 cancers studied herein, although in different branches of the AAP, have altered expression of AAP gene signatures. Going forward, AA related-cancer research generally, and the molecular signatures and their estimated metabolites reported herein specifically, hold broad promise for precision/personalized medicine in oncology as potential therapeutic and diagnostic targets.

Antibiotic-Induced Changes in Pigment Accumulation, Photosystem II, and Membrane Permeability in a Model Cyanobacterium.

Fremyella diplosiphon is a well-studied a model cyanobacterium for photosynthesis due to its efficient light absorption potential and pigment accumulation. In the present study, the impact of ampicillin, tetracycline, kanamycin, and cefotaxime on pigment fluorescence and photosynthetic capacity in Fremyella diplosiphon strains B481-WT and B481-SD was investigated. Our results indicated that both strains exposed to kanamycin from 0.2 to 3.2 mg/L and tetracycline from 0.8 to 12.8 mg/L enhanced growth and pigment accumulation. Additionally, B481-SD treated with 0.2-51.2 mg/L ampicillin resulted in a significant enhancement of pigment fluorescence. A detrimental effect on growth and pigmentation in both the strains exposed to 6.4-102.5 mg/L kanamycin and 0.8-102.5 mg/L cefotaxime was observed. Detection of reactive oxygen species revealed highest levels of oxidative stress at 51.2 and 102.5 mg/L kanamycin for B481-SD and 102.5 mg/L for B481-WT. Membrane permeability detected by lactate dehydrogenase assay indicated maximal activity at 0.8 mg/L ampicillin, kanamycin, and tetracycline treatments on day 6. Abundant vacuolation, pyrophosphate, and cyanophycin granule formation were observed in treated cells as a response to antibiotic stress. These findings on the hormetic effect of antibiotics on F. diplosiphon indicate that optimal antibiotic concentrations induce cellular growth while high concentrations severely impact cellular functionality. Future studies will be aimed to enhance cellular lipid productivity at optimal antibiotic concentrations to disintegrate the cell wall, thus paving the way for clean bioenergy applications.

Integrative Analysis of Motor Neuron and Microglial Transcriptomes from SOD1G93A Mice Models Uncover Potential Drug Treatments for ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neurons that mainly affects the motor cortex, brainstem, and spinal cord. Under disease conditions, microglia could possess two distinct profiles, M1 (toxic) and M2 (protective), with the M2 profile observed at disease onset. SOD1 (superoxide dismutase 1) gene mutations account for up to 20% of familial ALS cases. Comparative gene expression differences in M2-protective (early) stage SOD1G93A microglia and age-matched SOD1G93A motor neurons are poorly understood. We evaluated the differential gene expression profiles in SOD1G93A microglia and SOD1G93A motor neurons utilizing publicly available transcriptomics data and bioinformatics analyses, constructed biomolecular networks around them, and identified gene clusters as potential drug targets. Following a drug repositioning strategy, 5 small compounds (belinostat, auranofin, BRD-K78930611, AZD-8055, and COT-10b) were repositioned as potential ALS therapeutic candidates that mimic the protective state of microglia and reverse the toxic state of motor neurons. We anticipate that this study will provide new insights into the ALS pathophysiology linking the M2 state of microglia and drug repositioning.

Investigation of intestinal microbiome in chronic spontaneous urticaria patients.

BACKGROUND: Chronic urticaria is a disorder characterized by itchy erythematous plaques with edema lasting 6 weeks or more. The prevalence is 1%, and two thirds of these cases are "chronic spontaneous urticaria (CSU)." Drugs, food, infections, and systemic diseases may be etiologic factors for CSU, although it may be idiopathic. OBJECTIVES: The aim of this study was to compare the diversity and distribution of the intestinal microbiome in CSU patients with that of healthy individuals. The hypothesis was to determine the probable association of intestinal microbiome with CSU. METHODS: This study was conducted in Sakarya University Training and Research Hospital, Department of Dermatology. In this study, 20 CSU patients and 10 healthy volunteers were included. Stool samples were collected from all participants. 16S RNA sequencing and bioinformatic analysis were performed after isolation of DNA isolation from all samples. RESULTS: Diversity in microorganisms, stool pH averages, Bristol scores, and the ratio of Firmicutes/Bacteroidetes were the significant changes between the two groups. LIMITATIONS: Due to high cost involved in microbiota studies, only a limited number of patients and volunteers participated. CONCLUSION: The alteration in the intestinal microbiota (dysbiosis) may be an essential factor for CSU development and may explain idiopathic cases.

Specific FSTL1 polymorphism may determine the risk of cardiomyopathy in patients with acromegaly.

BACKGROUND: We have investigated the role of a cardiomyokine, follistatin-like 1 (FSTL1), and its single nucleotide polymorphism on acromegalic cardiomyopathy. METHODS: The study was performed as a cross-sectional case research in a Tertiary Referral Centre. Forty-six patients with acromegaly (29 F-17 M, mean age: 50.3 ± 12.1 years) were included. FSTL1 levels were measured and the rs1259293 region of the FSTL1 gene was subjected to polymorphism analysis. 1.5 Tesla MRI was used to obtain cardiac images. RESULTS: There were 15 active (6 F-9M) and 31 (22 F-9M) controlled patients. Active patients had a higher left ventricular mass (LVM) and left ventricular mass index (LVMi). GH levels were positively correlated with left ventricular end-diastolic volume index (LVEDVi), stroke volume index (SVi), cardiac index (Ci), LVM and LVMi; r = 0.35, 0.38, 0.34, 0.39 and 0.39, respectively. IGF-1 index was positively correlated with LVEDVi, left ventricular end-systolic volume index (LVESVi), SVi, Ci, LVM and LVMi; r = 0.36, 0.34, 0.32, 0.31, 0.42 and 0.42, respectively. Twenty out of 46 patients with acromegaly (43.5%) had myocardial fibrosis. FSTL1 levels were neither correlated with disease activity nor with any functional and structural cardiac parameter. Multivariate linear regression analysis revealed no association between FSTL1 and any study parameters. The rs1259293 variant genotype CC was significantly associated with low left ventricular mass. CONCLUSIONS: Serum FSTL1 levels are not associated with functional and structural measures of myocardium in patients with acromegaly. However, the risk of left ventricular hypertrophy is reduced in CC genotyped individuals of FSTL1.

Past, Present, and Future of Therapies for Pituitary Neuroendocrine Tumors: Need for Omics and Drug Repositioning Guidance.

Innovation roadmaps are important, because they encourage the actors in an innovation ecosystem to creatively imagine multiple possible science future(s), while anticipating the prospects and challenges on the innovation trajectory. In this overarching context, this expert review highlights the present unmet need for therapeutic innovations for pituitary neuroendocrine tumors (PitNETs), also known as pituitary adenomas. Although there are many drugs used in practice to treat PitNETs, many of these drugs can have negative side effects and show highly variable outcomes in terms of overall recovery. Building innovation roadmaps for PitNETs' treatments can allow incorporation of systems biology approaches to bring about insights at multiple levels of cell biology, from genes to proteins to metabolites. Using the systems biology techniques, it will then be possible to offer potential therapeutic strategies for the convergence of preventive approaches and patient-centered disease treatment. Here, we first provide a comprehensive overview of the molecular subtypes of PitNETs and therapeutics for these tumors from the past to the present. We then discuss examples of clinical trials and drug repositioning studies and how multi-omics studies can help in discovery and rational development of new therapeutics for PitNETs. Finally, this expert review offers new public health and personalized medicine approaches on cases that are refractory to conventional treatment or recur despite currently used surgical and/or drug therapy.

Reduced irisin levels in patients with acromegaly.

OBJECTIVES: Several metabolic disturbances are seen in acromegaly however, data regarding the contribution of irisin to these disturbances is currently insufficient. In a cohort of patients with acromegaly, we measured serum irisin levels in active and controlled cases and determined independent factors that effect serum irisin including fibronectin type III domain-containing protein 5 (FNDC5) genotyping. METHODS: A cross-sectional case-control study including 46 patients with acromegaly (28 F/18 M, age: 50.3 ± 12.1 year, BMI: 30.7 ± 5.1 kg/m2) and 81 age-, gender-, body mass index- and body composition-matched healthy controls was conducted. 15 acromegalic patients (33%) had active disease. Irisin levels were measured by enzyme-linked immunosorbent assay. Three different regions (rs3480, rs1746661, and rs16835198) of FNDC5 were subjected to polymorphism analyses. RESULTS: Both groups were overweight and had similar body composition. Irisin levels were lower in patients with acromegaly than controls (median [IQR]: 44.8 [41.7-46.7] ng/mL vs. 51.7 [45.5-60.1] ng/mL, p≤0.001, respectively). Active and controlled patients had similar irisin levels. Irisin was not correlated with growth hormone (GH), insulin-like growth factor 1 (IGF-1), and IGF-1 index. In multiple linear regression model, somatostatin receptor ligand use (ß=-20.30, 95% CI [-34]-[-6], p=0.006) was determined as the only independent factor that affect serum irisin. CONCLUSIONS: Serum irisin levels are low in patients with acromegaly who are on somatostatin receptor ligand therapy. Single nucleotide polymorphisms (SNPs) of FNDC5 have no independent effects on circulating irisin levels under somatostatin ligand action. Endocrine muscle functions also seem to be regulated by somatostatin action, which requires further studies.