Pancreatic Neuroendocrine Neoplasms in Multiple Endocrine Neoplasia Type 1

Pancreatic neuroendocrine tumors (pNETs) are a rare group of cancers accounting for about 1–2% of all pancreatic neoplasms. About 10% of pNETs arise within endocrine tumor syndromes, such as Multiple Endocrine Neoplasia type 1 (MEN1). pNETs affect 30–80% of MEN1 patients, manifesting prevalently as multiple microadenomas. pNETs in patients with MEN1 are particularly difficult to treat due to differences in their growth potential, their multiplicity, the frequent requirement of extensive surgery, the high rate of post-operative recurrences, and the concomitant development of other tumors. MEN1 syndrome is caused by germinal heterozygote inactivating mutation of the MEN1 gene, encoding the menin tumor suppressor protein. MEN1-related pNETs develop following the complete loss of function of wild-type menin. Menin is a key regulator of endocrine cell plasticity and its loss in these cells is sufficient for tumor initiation. Somatic biallelic loss of wild-type menin in the neuroendocrine pancreas presumably alters the epigenetic control of gene expression, mediated by histone modifications and DNA hypermethylation, as a driver of MEN1-associated pNET tumorigenesis. In this light, epigenetic-based therapies aimed to correct the altered DNA methylation, and/or histone modifications might be a possible therapeutic strategy for MEN1 pNETs, for whom standard treatments fail.     

EMT Molecular Signatures of Pancreatic Neuroendocrine Neoplasms

Neuroendocrine neoplasms (NENs) are relatively rare neoplasms occurring predominantly in the gastrointestinal tract and pancreas. Their heterogeneity poses challenges for diagnosis and treatment. There is a paucity of markers for characterisation of NEN tumours. For routine diagnosis, immunohistochemistry of the NEN-specific markers CgA and synaptophysin and the proliferation marker Ki-67 are used. These parameters, however, are qualitative and lack the capacity to fully define the tumour phenotype. Molecules of epithelial–mesenchymal transition (EMT) are potential candidates for improved tumour characterisation. Using qRT-PCR, we measured mRNA levels of 27 tumour markers, including 25 EMT-associated markers, in tumour tissue and matched non-tumour tissues for 13 patients with pancreatic NENs. Tissue from patients with three different grades of tumour had distinctly different mRNA profiles. Of the 25 EMT-associated markers analysed, 17 were higher in G3 tissue relative to matched non-tumour tissue, including CD14, CD24, CD31, CD44, CD45, CD56, CK6, CK7, CK13, CK20, NSE, CDX2, CgA, DAXX, PCNA, laminin and Ki-67. The differences in levels of seven EMT-associated markers, Ki-67, DAXX, CD24, CD44, vimentin, laminin and PDX1 plus CgA and NSE (neuroendocrine markers) enabled a distinct molecular signature for each tumour grade to be generated. EMT molecules differentially expressed in three tumour grades have potential for use in tumour stratification and prognostication and as therapeutic targets for treatment of neuroendocrine cancers, following validation with additional samples.     

Duodenal Ampulla Neuroendocrine Tumor with GISTs of the Proximal Jejunum: A Case Report

Neuroendocrine tumors (NEN) are a type of heterogenous, slow-growing tumors, that only in about half of the cases can be found in the gastrointestinal tract. Half of these is in the small intestine. The ampullary NENs are rare, accounting for less than 1% of gastroenteropancreatic NENs. Gastrointestinal stromal tumors (GIST) are a more common type of tumors of the gastrointestinal tract that consist of pacemaker cells. The occurrence of both tumors simultaneously is rare, but in patients with neurofibromatosis type 1, the co-existence of NEN and GIST is more often. Here we report a case of simultaneous occurrence of a well-differentiated NEN and a GIST in a patient without neurofibromatosis. Also, we provide a short review of the current knowledge and treatment strategies regarding these tumors.     

Insights into the Potential Mechanisms of JAK2V617F Somatic Mutation Contributing Distinct Phenotypes in Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPN) are a group of blood cancers in which the bone marrow (BM) produces an overabundance of erythrocyte, white blood cells, or platelets. Philadelphia chromosome-negative MPN has three subtypes, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The over proliferation of blood cells is often associated with somatic mutations, such as JAK2, CALR, and MPL. JAK2V617F is present in 95% of PV and 50–60% of ET and PMF. Based on current molecular dynamics simulations of full JAK2 and the crystal structure of individual domains, it suggests that JAK2 maintains basal activity through self-inhibition, whereas other domains and linkers directly/indirectly enhance this self-inhibited state. Nevertheless, the JAK2V617F mutation is not the only determinant of MPN phenotype, as many normal individuals carry the JAK2V617F mutation without a disease phenotype. Here we review the major MPN phenotypes, JAK-STAT pathways, and mechanisms of development based on structural biology, while also describing the impact of other contributing factors such as gene mutation allele burden, JAK-STAT-related signaling pathways, epigenetic modifications, immune responses, and lifestyle on different MPN phenotypes. The cross-linking of these elements constitutes a complex network of interactions and generates differences in individual and cellular contexts that determine the phenotypic development of MPN.     

Current and New Challenges in the Management of Pancreatic Neuroendocrine Tumors: The Role of miRNA-Based Approaches as New Reliable Biomarkers

Pancreatic neuroendocrine tumors (PanNETs) are rare tumors; however, their incidence greatly increases with age, and they occur more frequently among the elderly. They represent 5% of all pancreatic tumors, and despite the fact that low-grade tumors often have an indolent evolution, they portend a poor prognosis in an advanced stages and undifferentiated tumors. Additionally, functional pancreatic neuroendocrine tumors greatly impact quality of life due to the various clinical syndromes that result from abnormal hormonal secretion. With limited therapeutic and diagnostic options, patient stratification and selection of optimal therapeutic strategies should be the main focus. Modest improvements in the management of pancreatic neuroendocrine tumors have been achieved in the last years. Therefore, it is imperative to find new biomarkers and therapeutic strategies to improve patient survival and quality of life, limiting the disease burden. MicroRNAs (miRNAs) are small endogenous molecules that modulate the expression of thousands of genes and control numerous critical processes involved in tumor development and progression. New data also suggest the implication of miRNAs in treatment resistance and their potential as prognostic or diagnostic biomarkers and therapeutic targets. In this review, we discusses the current and new challenges in the management of PanNETs, including genetic and epigenetic approaches. Furthermore, we summarize the available data on miRNAs as potential prognostic, predictive, or diagnostic biomarkers and discuss their function as future therapeutic targets.     

The Yin-Yang of DNA Damage Response: Roles in Tumorigenesis and Cellular Senescence

Senescent cells are relatively stable, lacking proliferation capacity yet retaining metabolic activity. In contrast, cancer cells are rather invasive and devastating, with uncontrolled proliferative capacity and resistance to cell death signals. Although tumorigenesis and cellular senescence are seemingly opposite pathological events, they are actually driven by a unified mechanism: DNA damage. Integrity of the DNA damage response (DDR) network can impose a tumorigenesis barrier by navigating abnormal cells to cellular senescence. Compromise of DDR, possibly due to the inactivation of DDR components, may prevent cellular senescence but at the expense of tumor formation. Here we provide an overview of the fundamental role of DDR in tumorigenesis and cellular senescence, under the light of the Yin-Yang concept of Chinese philosophy. Emphasis is placed on discussing DDR outcome in the light of in vivo models. This information is critical as it can help make better decisions for clinical treatments of cancer patients.     

New Insights into Immune-Mediated Mechanisms in Parkinson’s Disease

The immune system has been increasingly recognized as a major contributor in the pathogenesis of Parkinson’s disease (PD). The double-edged nature of the immune system poses a problem in harnessing immunomodulatory therapies to prevent and slow the progression of this debilitating disease. To tackle this conundrum, understanding the mechanisms underlying immune-mediated neuronal death will aid in the identification of neuroprotective strategies to preserve dopaminergic neurons. Specific innate and adaptive immune mediators may directly or indirectly induce dopaminergic neuronal death. Genetic factors, the gut-brain axis and the recent identification of PD-specific T cells may provide novel mechanistic insights on PD pathogenesis. Future studies to address the gaps in the identification of autoantibodies, variability in immunophenotyping studies and the contribution of gut dysbiosis to PD may eventually provide new therapeutic targets for PD.     

Insights into the Mechanisms of Heat Priming and Thermotolerance in Tobacco Pollen

Global warming leads to a progressive rise in environmental temperature. Plants, as sessile organisms, are threatened by these changes; the male gametophyte is extremely sensitive to high temperature and its ability to preserve its physiological status under heat stress is known as acquired thermotolerance. This latter can be achieved by exposing plant to a sub-lethal temperature (priming) or to a progressive increase in temperature. The present research aims to investigate the effects of heat priming on the functioning of tobacco pollen grains. In addition to evaluating basic physiological parameters (e.g., pollen viability, germination and pollen tube length), several aspects related to a correct pollen functioning were considered. Calcium (Ca²⁺) level, reactive oxygen species (ROS) and related antioxidant systems were investigated, also to the organization of actin filaments and cytoskeletal protein such as tubulin (including tyrosinated and acetylated isoforms) and actin. We also focused on sucrose synthase (Sus), a key metabolic enzyme and on the content of main soluble sugars, including UDP-glucose. Results here obtained showed that a pre-exposure to sub-lethal temperatures can positively enhance pollen performance by altering its metabolism. This can have a considerable impact, especially from the point of view of breeding strategies aimed at improving crop species.     

Mechanistic Insights of Aberrant Splicing with Splicing Factor Mutations Found in Myelodysplastic Syndromes

Pre-mRNA splicing is an essential process for gene expression in higher eukaryotes, which requires a high order of accuracy. Mutations in splicing factors or regulatory elements in pre-mRNAs often result in many human diseases. Myelodysplastic syndrome (MDS) is a heterogeneous group of chronic myeloid neoplasms characterized by many symptoms and a high risk of progression to acute myeloid leukemia. Recent findings indicate that mutations in splicing factors represent a novel class of driver mutations in human cancers and affect about 50% of Myelodysplastic syndrome (MDS) patients. Somatic mutations in MDS patients are frequently found in genes SF3B1, SRSF2, U2AF1, and ZRSR2. Interestingly, they are involved in the recognition of 3′ splice sites and exons. It has been reported that mutations in these splicing regulators result in aberrant splicing of many genes. In this review article, we first describe molecular mechanism of pre-mRNA splicing as an introduction and mainly focus on those four splicing factors to describe their mutations and their associated aberrant splicing patterns.     

The Role of Connexin 43 in Renal Disease: Insights from In Vivo Models of Experimental Nephropathy

Renal disease is a major public health challenge since its prevalence has continuously increased over the last decades. At the end stage, extrarenal replacement therapy and transplantation remain the only treatments currently available. To understand how the disease progresses, further knowledge of its pathophysiology is needed. For this purpose, experimental models, using mainly rodents, have been developed to unravel the mechanisms involved in the initiation and progression of renal disease, as well as to identify potential targets for therapy. The gap junction protein connexin 43 has recently been identified as a novel player in the development of kidney disease. Its expression has been found to be altered in many types of human renal pathologies, as well as in different animal models, contributing to the activation of inflammatory and fibrotic processes that lead to renal damage. Furthermore, Cx43 genetic, pharmacogenetic, or pharmacological inhibition preserved renal function and structure. This review summarizes the existing advances on the role of this protein in renal diseases, based mainly on different in vivo animal models of acute and chronic renal diseases.     

Role of Somatostatin Signalling in Neuroendocrine Tumours

Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. Due to the fact that somatostatin regulates cell growth and hormone secretion, somatostatin receptors (SSTRs) have become valuable targets for the treatment of different types of neuroendocrine tumours (NETs). NETs are a heterogeneous group of tumours that can develop in various parts of the body, including the digestive system, lungs, and pituitary. NETs are usually slow growing, but they are often diagnosed in advanced stages and can display aggressive behaviour. The mortality rate of NETs is not outstandingly increased compared to other malignant tumours, even in the metastatic setting. One of the intrinsic properties of NETs is the expression of SSTRs that serve as drug targets for SST analogues (SSAs), which can delay tumour progression and downregulate hormone overproduction. Additionally, in many NETs, it has been demonstrated that the SSTR expression level provides a prognostic value in predicting a therapeutic response. Furthermore, higher a SSTR expression correlates with a better survival rate in NET patients. In recent studies, other epigenetic regulators affecting SST signalling or SSA–mTOR inhibitor combination therapy in NETs have been considered as novel strategies for tumour control. In conclusion, SST signalling is a relevant regulator of NET functionality. Alongside classical SSA treatment regimens, future advanced therapies and treatment modalities are expected to improve the disease outcomes and overall health of NET patients.     

The Effect of Chronic Iloperidone Treatment on Cytochrome P450 Expression and Activity in the Rat Liver: Involvement of Neuroendocrine Mechanisms

In order to achieve a desired therapeutic effect in schizophrenia patients and to maintain their mental wellbeing, pharmacological therapy needs to be continued for a long time, usually from the onset of symptoms and for the rest of the patients’ lives. The aim of our present research is to find out the in vivo effect of chronic treatment with atypical neuroleptic iloperidone on the expression and activity of cytochrome P450 (CYP) in rat liver. Male Wistar rats received a once-daily intraperitoneal injection of iloperidone (1 mg/kg) for a period of two weeks. Twenty-four hours after the last dose, livers were excised to study cytochrome P450 expression (mRNA and protein) and activity, pituitaries were isolated to determine growth hormone-releasing hormone (GHRH), and blood was collected for measuring serum concentrations of hormones and interleukin. The results showed a broad spectrum of changes in the expression and activity of liver CYP enzymes, which are important for drug metabolism (CYP1A, CYP2B, CYP2C, and CYP3A) and xenobiotic toxicity (CYP2E1). Iloperidone decreased the expression and activity of CYP1A2, CP2B1/2, CYP2C11, and CYP3A1/2 enzymes but increased that of CYP2E1. The CYP2C6 enzyme remained unchanged. At the same time, the level of GHRH, GH, and corticosterone decreased while that of T₃ increased, with no changes in IL-2 and IL-6. The presented results indicate neuroendocrine regulation of the investigated CYP enzymes during chronic iloperidone treatment and suggest a possibility of pharmacokinetic/metabolic interactions produced by the neuroleptic during prolonged combined treatment with drugs that are substrates of iloperidone-affected CYP enzymes.     

Insights into the Genomic Regions and Candidate Genes of Senescence-Related Traits in Upland Cotton via GWAS

Senescence is the last stage of plant development and is controlled by both internal and external factors. Premature senescence significantly affects the yield and quality of cotton. However, the genetic architecture underlying cotton senescence remains unclear. In this study, genome-wide association studies (GWAS) were performed based on 3,015,002 high-quality SNP markers from the resequencing data of 355 upland cotton accessions to detect genomic regions for cotton senescence. A total of 977 candidate genes within 55 senescence-related genomic regions (SGRs), SGR1–SGR55, were predicted. Gene ontology (GO) analysis of candidate genes revealed that a set of biological processes was enriched, such as salt stress, ethylene processes, and leaf senescence. Furthermore, in the leaf senescence GO term, one candidate gene was focused on: Gohir.A12G270900 (GhMKK9), located in SGR36, which encodes a protein of the MAP kinase kinase family. Quantitative real-time PCR (qRT-PCR) analysis showed that GhMKK9 was up-regulated in old cotton leaves. Overexpression of GhMKK9 in Arabidopsis accelerated natural leaf senescence. Virus-induced gene silencing (VIGS) of GhMKK9 in cotton increased drought tolerance. These results suggest that GhMKK9 is a positive regulator and might be involved in drought-induced senescence in cotton. The results provide new insights into the genetic basis of cotton senescence and will be useful for improving cotton breeding in the future.     

Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies

The Wnt signalling pathway is a central communication cascade between cells to orchestrate polarity and fate during development and adult tissue homeostasis in various organisms. This pathway can be regulated by different signalling molecules in several steps. One of the coordinators in this pathway is Nemo-like kinase (NLK), which is an atypical proline-directed serine/threonine mitogen-activated protein (MAP) kinase. Very recently, NLK was established as an essential regulator in different cellular processes and abnormal NLK expression was highlighted to affect the development and progression of various diseases. In this review, we focused on the recent discoveries by using NLK-deficient mice, which show a phenotype in the development and function of organs such as the lung, heart and skeleton. Furthermore, NLK could conduct the function and differentiation of cells from the immune system, in addition to regulating neurodegenerative diseases, such as Huntington’s disease and spinocerebellar ataxias. Overall, generations of NLK-deficient mice have taught us valuable lessons about the role of this kinase in certain diseases and development.     

Structural Insights into the Substrate Transport Mechanisms in GTR Transporters through Ensemble Docking

Glucosinolate transporters (GTRs) are part of the nitrate/peptide transporter (NPF) family, members of which also transport specialized secondary metabolites as substrates. Glucosinolates are defense compounds derived from amino acids. We selected 4-methylthiobutyl (4MTB) and indol-3-ylmethyl (I3M) glucosinolates to study how GTR1 from Arabidopsis thaliana transports these substrates in computational simulation approaches. The designed pipeline reported here includes massive docking of 4MTB and I3M in an ensemble of GTR1 conformations (in both inward and outward conformations) extracted from molecular dynamics simulations, followed by clustered and substrate–protein interactions profiling. The identified key residues were mutated, and their role in substrate transport was tested. We were able to identify key residues that integrate a major binding site of these substrates, which is critical for transport activity. In silico approaches employed here represent a breakthrough in the plant transportomics field, as the identification of key residues usually takes a long time if performed from a purely wet-lab experimental perspective. The inclusion of structural bioinformatics in the analyses of plant transporters significantly speeds up the knowledge-gaining process and optimizes valuable time and resources.