Integrated bioinformatics approaches and expression assays identified new markers in pituitary adenomas.

Pituitary adenomas (PA) include about one third of primary central nervous tumors in adolescent and young adult. Despite extensive research, the underlying mechanism of PA tumorigenesis is still unknown. In the present study, through bioinformatics analysis of a PA-related dataset downloaded from GEO database, we attempted to identify pair(s) of lncRNA/target mRNA whose expression changes may be involved in the tumorigenesis of PAs. For this end, we evaluated expression of a set of bioinformatically obtained genes in 46 PA tissues against adjacent non-tumor pituitary tissues. The bioinformatics step led to selection of four genes for validation through expression assays. Expression levels of HIF1A and MAPK1 were increased in NFPA tissues (P < 0.0001 and =0.0042, respectively). Expression level of BANCR was significantly decreased in tumor tissues (P < 0.0001). However, expression of STAT3 was not meaningfully different between the two tissue types (P = 0.56). Since there was no significant correlation between MAPK1 and BANCR expressions in either tumor or adjacent normal tissues, the regulatory effect of BANCR on MAPK1 was not confirmed. In conclusion, this study offers information about deregulation of bioinformatically identified genes in PA tumors and indicates that further studies in this field is needed to understand the involved molecular mechanisms.

Evaluation of Clinical and Immunological Alterations Associated with ICF Syndrome.

PURPOSE: Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive combined immunodeficiency. The detailed immune responses are not explored widely. We investigated known and novel immune alterations in lymphocyte subpopulations and their association with clinical symptoms in a well-defined ICF cohort. METHODS: We recruited the clinical findings from twelve ICF1 and ICF2 patients. We performed detailed immunological evaluation, including lymphocyte subset analyses, upregulation, and proliferation of T cells. We also determined the frequency of circulating T follicular helper (cTFH) and regulatory T (Treg) cells and their subtypes by flow cytometry. RESULTS: There were ten ICF1 and two ICF2 patients. We identified two novel homozygous missense mutations in the ZBTB24 gene. Respiratory tract infections were the most common recurrent infections among the patients. Gastrointestinal system (GIS) involvements were observed in seven patients. All patients received intravenous immunoglobulin replacement therapy and antibacterial prophylaxis; two died during the follow-up period. Immunologically, CD4+ T-cell counts, percentages of recent thymic emigrant T cells, and naive CD4+ T decreased in two, five, and four patients, respectively. Impaired T-cell proliferation and reduced CD25 upregulation were detected in all patients. These changes were more prominent in CD8+ T cells. GIS involvements negatively correlated with CD3+ T-, CD3+CD4+ T-, CD16+CD56+ NK-cell counts, and CD4+/CD8+ T-cell ratios. Further, we observed expanded cTFH cells and reduced Treg and follicular regulatory T cells with a skewing to a TH2-like phenotype in all tested subpopulations. CONCLUSION: The ICF syndrome encompasses various manifestations affecting multiple end organs. Perturbed T-cell responses with increased cTFH and decreased Treg cells may provide further insight into the immune aberrations observed in ICF syndrome.

Angiotensin-Converting Enzyme (ACE) level, but not ACE gene polymorphism, is associated with prognosis of COVID-19 infection: Implications for diabetes and hypertension.

BACKGROUND: The renin-angiotensin-aldosterone system was shown to be activated in severe COVID-19 infection. We aimed to investigate the relationship between angiotensin converting enzyme (ACE) levels, ACE gene polymorphism, type 2 diabetes (T2DM), and hypertension (HT) and the prognosis of COVID-19 infection. METHODS: This cross-sectional study analyzed the clinical features of adult patients with SARS-CoV-2 infection. ACE gene analysis and ACE level measurements were performed. The patients were grouped according to ACE gene polymorphism (DD, ID or II), disease severity (mild, moderate, or severe), and the use of dipeptidyl peptidase-4 enzyme inhibitor (DPP4i), ACE-inhibitor (ACEi) or angiotensin receptor blocker (ARB). Intensive care unit (ICU) admissions and mortality were also recorded. RESULTS: A total of 266 patients were enrolled. Gene analysis detected DD polymorphism in the ACE 1 gene in 32.7% (n = 87), ID in 51.5% (n = 137), and II in 15.8% (n = 42) of the patients. ACE gene polymorphisms were not associated with disease severity, ICU admission, or mortality. ACE levels were higher in patients who died (p = 0.004) or were admitted to the ICU (p<0.001) and in those with severe disease compared to cases with mild (p = 0.023) or moderate (p<0.001) disease. HT, T2DM, and ACEi/ARB or DPP4i use were not associated with mortality or ICU admission. ACE levels were similar in patients with or without HT (p = 0.374) and with HT using or not using ACEi/ARB (p = 0.999). They were also similar in patients with and without T2DM (p = 0.062) and in those with and without DPP4i treatment (p = 0.427). ACE level was a weak predictor of mortality but an important predictor of ICU admission. It predicted ICU admission in total (cutoff value >37.092 ng/mL, AUC: 0.775, p<0.001). CONCLUSION: Our findings suggest that higher ACE levels, but not ACE gene polymorphism, ACEi/ARB or DPP4i use, were associated with the prognosis of COVID-19 infection. The presence of HT and T2DM and ACEi/ARB or DPP4i use were not associated with mortality or ICU admission.

KRAS-Mutant Lung Cancer: Targeting Molecular and Immunologic Pathways, Therapeutic Advantages and Restrictions.

RAS mutations are among the most common oncogenic mutations in human cancers. Among RAS mutations, KRAS has the highest frequency and is present in almost 30% of non-small-cell lung cancer (NSCLC) patients. Lung cancer is the number one cause of mortality among cancers as a consequence of outrageous aggressiveness and late diagnosis. High mortality rates have been the reason behind numerous investigations and clinical trials to discover proper therapeutic agents targeting KRAS. These approaches include the following: direct KRAS targeting; synthetic lethality partner inhibitors; targeting of KRAS membrane association and associated metabolic rewiring; autophagy inhibitors; downstream inhibitors; and immunotherapies and other immune-modalities such as modulating inflammatory signaling transcription factors (e.g., STAT3). The majority of these have unfortunately encountered limited therapeutic outcomes due to multiple restrictive mechanisms including the presence of co-mutations. In this review we plan to summarize the past and most recent therapies under investigation, along with their therapeutic success rate and potential restrictions. This will provide useful information to improve the design of novel agents for treatment of this deadly disease.

Circulating long non-coding RNAs as novel diagnostic biomarkers for Alzheimer's disease (AD): A systematic review and meta-analysis.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been reported to be involved in the pathogenesis of neurodegenerative diseases. It has also been hypothesized that plasma exosomal lncRNAs may be used as Alzheimer's disease (AD) biomarkers. In this systematic review, we compiled all studies on the subject to evaluate the accuracy of lncRNAs in identifying AD cases through meta-analysis. METHODS: A PRISMA-compliant systematic search was conducted in PubMed/MEDLINE, EMBASE, and Web of Science databases for English publications till September 2022. We included all observational studies published which investigated the sensitivity and specificity of various lncRNAs in plasma samples of AD diagnosis. Our search strategy included lncRNA and all the related spelling and abbreviation variations combined with the keyword Alzheimer's disease. Methodological quality was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines and the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-II) tool. The meta-analysis was carried out using the area under the Receiver Operator Characteristic (ROC) curves (AUC) and sensitivity and specificity values to assess the accuracy of the identified lncRNAs in AD diagnosis. To account for the predicted heterogeneity of the study, a random-effects model was used. All the statistical analyses and visualizations were conducted using Stata 17.0 software. RESULTS: A total of seven studies (AD patients = 553, healthy controls = 513) were included in the meta-analysis. Three lncRNAs were upregulated (RNA BACE-AS1, RNA NEAT1, RNA GAS5), and one lncRNA (MALAT1) was downregulated in plasma samples of AD patients. RNA 51A and RNA BC200 were reported to have variable expression patterns. A lncRNA (RNA 17A) was not significantly different between AD and control groups. The pooled sensitivity, specificity, and AUC values of lncRNAs in identifying AD were (0.74; 95% CI [0.63, 0.82], I2 = 79.2%), (0.88; 95% CI [0.75, 0.94], I2 = 88.9%), and 0.86; 95% CI [0.82, 0.88], respectively. In addition, the pooled diagnostic odds ratio (DOR) of the five individual lncRNAs in AD diagnosis was 20. CONCLUSION: lncRNAs had high accuracy in identifying AD and must be seen as a promising diagnostic biomarker of the disease.

Tau immunotherapy in Alzheimer's disease and progressive supranuclear palsy.

Tubulin-associated unit (tau) has been associated with more than 25 neurological disorders-the so-called tauopathies. Hence, finding a novel therapeutic agent targeting tau to halt the progression of diseases has been of interest. Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) are the most studied tauopathies. AD is characterized by two cardinal pathological mechanisms: amyloid ß (Aß) plaques and neurofibrillary tangles (NFTs), leading to atrophy of the brain. Over the last few years, attention has been on NFTs composed of the hyperphosphorylated microtubule-associated protein tau. Tau contributes to the synaptic plasticity of axons; hyperphosphorylated and aggregated tau have been shown to increase the likelihood of cognitive impairments. PSP is also associated with tau accumulation in NFTs and neuropil threads, making this condition a candidate for tau-targeted therapies. Many tau-targeting therapies have been developed, and clinical trials are being conducted. Tau-targeting drugs are classified into four subgroups based on the pathological target: tau phosphorylation inhibitors, stabilizers of microtubules, enhancing tau clearance, and tau aggregation inhibitors. On the other hand, the desired specificity and sensitivity of tau immunotherapy agents without interrupting normal proteome are the fundamental point of tremendous attention. Starting with animal studies of these therapies to clinical trials, both are divided into passive and active immunotherapies, while passive immunotherapies are the method of desire. Targeting aggregation and phosphorylation sites of tau is the chief target of therapies. This article reviews the latest animal and clinical studies of tau-based immunotherapies and tau-targeted drugs for AD and PSP.

IL-6 and TNF-α responses to acute and regular exercise in adult individuals with multiple sclerosis (MS): a systematic review and meta-analysis.

BACKGROUND: In both the general population and people with multiple sclerosis (PwMS), physical exercise is associated with improved mental well-being. Moreover, there is evidence of the possible protection of physical activity against disease progression in multiple sclerosis (MS). However, the question arises if acute or regular exercise has any impact on the immune system in PwMS. To answer this question, we performed a systematic review and meta-analysis on both plasma and serum cytokine levels (IL-6 and TNF-α) before and after acute and regular exercise among PwMS and compared to healthy controls. METHOD: We performed an online search via PubMed, EMBASE, SCOPUS, Web of Science, and Cochrane Library till September 2021 to identify original studies on IL-6 and TNF-α changes after acute and regular exercise in PwMS and controls. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), 11 original studies were included in the meta-analysis. Sensitivity analyses were used to identify the origins of heterogeneity. R 4.0.4 was used to perform the meta-analysis of IL-6 and TNF-α levels before and after acute and regular exercise in PwMS, compared to controls. This study does not qualify for a clinical trial number. RESULTS: IL-6 levels did neither increase nor decrease after acute and regular exercise in PwMS, and compared to controls (pre- vs. post-intervention: Standardized Mean Difference (SMD) -0.09, 95% CI [-0.29; 0.11], p-value = 0.37, PwMS vs. Control: SMD -0.08, 95% CI [-0.33; 0.16], p-value = 0.47). In PwMS, TNF-α levels decreased after regular exercise and when TNF-α levels of both acute and regular exercise were pooled (pre- vs. post-intervention: SMD -0.51, 95% CI [-0.91; 0.11], p-value = 0.01, PwMS vs. Control: SMD -0.23, 95% CI [-0.66; 0.18], p-value = 0.26). TNF-α levels did neither increase nor decrease after acute and regular exercise in PwMS, when compared to controls. CONCLUSION: This systematic review and meta-analysis show that exercise does not lead to significant changes in peripheral levels of IL-6 in PwMS in contrast to the observed response in healthy subjects and other medical contexts. However, regular exercise had a specific anti-inflammatory effect on blood TNF-α levels in PwMS. It remains to be investigated why PwMS display this different exercise-induced pattern of cytokines.

Blood levels of brain-derived neurotrophic factor (BDNF) in people with multiple sclerosis (MS): A systematic review and meta-analysis.

BACKGROUND: Multiple sclerosis is an autoimmune demyelinating disease marked by the involvement of multiple pathophysiological pathways, including BDNF. BDNF (brain-derived neurotrophic factor) is one of the main neurotrophic factors in the adult brain. The amount of BDNF in the blood can be utilized as a surrogate for the central expression of this marker. Given contradicting reports, we set out to answer the question, "How do blood levels of BDNF differ in people with multiple sclerosis (PwMS) compared to controls?" METHODS: We performed a thorough search in MEDLINE, EMBASE, Web of Science, and the Cochrane Library databases, resulting in 13 eligible investigations. Eleven studies compared BDNF in serum of PwMS versus healthy controls (HC), and two studies provided BDNF levels in the plasma of PwMs. R version 4.0.4 was used for meta-analysis and visualizations. Mean difference (MD) was used for the measurement of effect size. RESULTS: The final analysis included thirteen studies with 689 patients with MS and 583 controls. The preliminary results indicated that MS patients had statistically significant lower levels of BDNF than controls: SMD -5.1992 (95% CI [-8.4488; -1.9496], p-value < 0.0001. Additionally, subgroup analysis revealed a statistically significant difference in serum and plasma levels (p-value=0.01). Performing univariate meta-regression, disease duration and the proportion of males had, respectively, a significant negative and positive correlation with BDNF levels. CONCLUSION: Circulating levels of BDNF are decreased in MS. Future studies should investigate the role of BDNF as a biomarker of disease severity and/or progression for a personalized approach to MS.

Novel approaches for the synthesis of a library of fluorescent chromenopyrimidine derivatives.

A library of some new fluorescent chromenopyrimidine derivatives has been synthesized by new approaches. Water-promoted and one-pot reaction can produce new dialkylylamino)-5H-chromeno[2,3-d]pyrimidin-2-yl) phenols. These compounds can also be produced using domino reaction. Two parallel methods are compared. Novel N-alkyl-N-phenyl-5H-chromeno[2,3-d]-pyrimidin-4-amines and 4-alkoxy-5H-chromeno[2, 3-d]pyrimidines are synthesized by Lewis-acid catalyzed reactions. The fluorescence emission intensity of the four compounds from each of libraries after excitation in 290 nm is measured. Compound 2-(4,5-bis(N-methyl-N-phenylamino)-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol was isolated as a byproduct. The details of an interesting exchangeable intramolecular H- bonding of two of the new compounds are reported by X-ray analysis data.