Mass spectrometry-based plasma proteomics: state of the art and future outlook

Mass spectrometry-based plasma proteomics is a field where intense research has been performed during the last decade. Being closely linked to biomarker discovery, the field has received a fair amount of criticism, mostly due to the low number of novel biomarkers reaching the clinic. However, plasma proteomics is under gradual development with improvements on fractionation methods, mass spectrometry instrumentation and analytical approaches. These recent developments have contributed to the revival of plasma proteomics. The goal of this review is to summarize these advances, focusing in particular on fractionation methods, both for targeted and global mass spectrometry-based plasma analysis.     

AdoMet analog synthesis and utilization: current state of the art

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Bilateral internal thoracic artery grafting: current state of the art

The purpose of this article is to review the key literature and assess the current status of bilateral internal thoracic artery grafting. Numerous retrospective studies have demonstrated a benefit of bilateral internal thoracic artery grafting over single internal thoracic artery grafting in terms of the long-term risk of all-cause death, cardiac-related death, and cardiac events. The survival benefit of bilateral internal thoracic artery grafting manifests relatively early after operation for high-risk patients. The skeletonization technique reduces the risk of sternal wound complications in all patients and particularly in those with diabetes. Both the left and right internal thoracic arteries have better patency when grated to the left coronary territory than saphenous vein. However, the right internal thoracic artery does not always have good patency when grafted to the right coronary artery. Bilateral internal thoracic artery grafting using the skeletonization technique is recommended for revascularization of the left coronary territory.     

The current state of the art of quantitative phosphoproteomics and its applications to diabetes research

Protein phosphorylation is a fundamental regulatory mechanism in many cellular processes and aberrant perturbation of phosphorylation has been implicated in various human diseases. Kinases and their cognate inhibitors have been considered as hotspots for drug development. Therefore, the emerging tools, which enable a system-wide quantitative profiling of phosphoproteome, would offer a powerful impetus in unveiling novel signaling pathways, drug targets and/or biomarkers for diseases of interest. This review highlights recent advances in phosphoproteomics, the current state of the art of the technologies and the challenges and future perspectives of this research area. Finally, some exemplary applications of phosphoproteomics in diabetes research are underscored.     

Adenohypophysial cell types in the lamprey pituitary: current state of the art

Adenohypophysial cell types in the pituitary of adult sea lampreys, Petromyzon marinus, was localized by means of immunocytochemical and lectin cytochemical techniques. At least four types of adenohypophysial hormone cells are present in the pituitary of adult sea lampreys. The first type of cell is ACTH-like and occupies most parts of the rostral pars distalis (RPD), but a few scattered ACTH-like cells are also present in the proximal pars distalis (PPD). The second type of cell is MSH-like and occupies the whole pars intermedia. The third type of cell is GH/PRL-like and occupies the dorsal half of the PPD. These GH/PRL-like cells were initially detected by heterologous immunocytochemistry using antibodies to salmon GH, salmon PRL and blue shark GH, after hydrated autoclave pretreatment of sections. Later, by use of an antiserum raised against a synthetic peptide corresponding to the partial sequence of lamprey GH/PRL, the same cells as those containing GH/PRL-like immunoreactivity were stained positively. Similarity of the topographic distributions between lamprey GH/PRL-like cells and gnathostome fish GH cells in the pituitary suggests that GH/PRL-like cells in the lamprey may be GH cells. The last type of cell is GTH-like and occupies the ventral half of the PPD. Although GTH has not yet been isolated from the lamprey pituitary, our immunocytochemical data suggest that GTH-like material in the sea lamprey pituitary is more closely related to mammalian-like LH, rather than to FSH or TSH. These four types of adenohypophysial cells occupy most parts of the lamprey adenohypophysis and indeed there is little room for TSH or PRL cells. Thus, the present study further suggests that GH and LH-like GTH are ancestral forms of GH/PRL/SL family and glycoprotein hormones, respectively.     

Digital cytology: current state of the art and prospects for the future

The growth of digital methods in pathology is accelerating. Digital images can be used for a variety of applications in cytology, including rapid interpretations, primary diagnosis and second opinions, continuing education and proficiency testing. All of these functions can be performed using small static digital images, real-time dynamic digital microscopy, or whole-slide images. This review will discuss the general principles of digital pathology, its methods and applications to cytologic specimens. As cytologic specimens have unique features compared to histopathology specimens, the key differences will be discussed. Technical and administrative issues in digital pathology applications and the outlook for the future of the field will be presented.     

Bt maize and mycotoxins: the current state of research

The commercialisation of Bt (Bacillus thuringensis) maize expressing the Cry endotoxin specific for some types of Lepidopteran and Coleopteran pests has lead researchers to study the reduction in mycotoxin concentrations in Bt hybrids compared to the correspondent isogenic plants. Indeed, insect damage is one of the main inoculation pathways of mycotoxinogenic moulds. The present study aims to evaluate, according to the scientific literature published to date, the real efficiency of Bt maize hybrids in reducing the mycotoxin problem. The results obtained from the analysis of the literature do not show significant variations in the content of aflatoxins, zearalenone and trichothecenes, between Bt hybrids and corresponding isogenic control plants. The only mycotoxins where Bt hybrids have any effect are the fumonisin group, but even in this case studies in commercially planted fields have shown that their effect is mitigated by many biotic and abiotic factors.     

The state of the art of paleoparasitological research in the Old World

Paleoparasitology in the Old World has mainly concerned the study of latrine sediments and coprolites collected from mummified bodies or archaeological strata, mostly preserved by natural conditions. Human parasites recovered include cestodes, trematodes, and nematodes. The well preserved conditions of helminth eggs allowed paleoepidemiological approaches taking into account the number of eggs found by archaeological stratum. Tentatively, sanitation conditions were assessed for each archaeological period.     

Carbonic anhydrases: current state of the art, therapeutic applications and future prospects

Carbonic anhydrases (CAs, EC 4.2.1.1) are wide-spread enzymes, present in mammals in at least 14 different isoforms. Some of these isozymes are cytosolic (CA I, CA II, CA III, CA VII, CA XIII), others are membrane-bound (CA IV, CA IX, CA XII and CA XIV), CA V is mitochondrial and CA VI is secreted in the saliva and milk. Three cytosolic acatalytic forms are also known (CARP VIII, CARP X and CARP XI). The catalytically active isoforms, which play important physiological and patho-physiological functions, are strongly inhibited by aromatic and heterocyclic sulfonamides. The catalytic and inhibition mechanisms of these enzymes are understood in great detail, and this greatly helped the design of potent inhibitors, some of which possess important clinical applications. The use of such CA inhibitors (CAIs) as antiglaucoma drugs are discussed in detail, together with the recent developments that led to isozyme-specific and organ-selective inhibitors. A recent discovery is connected with the involvement of CAs and their sulfonamide inhibitors in cancer: many potent CAIs were shown to inhibit the growth of several tumor cell lines in vitro and in vivo, thus constituting interesting leads for developing novel antitumor therapies. Future prospects for drug design of inhibitors of these ubiquitous enzymes are dealt with. Although activation of CAs has been a controversial issue for some time, recent kinetic, spectroscopic and X-ray crystallographic experiments offered an explanation of this phenomenon, based on the catalytic mechanism. It has been demonstrated recently, that molecules that act as carbonic anhydrase activators (CAAs) bind at the entrance of the enzyme active site participating in facilitated proton transfer processes between the active site and the reaction medium. In addition to CA II-activator adducts, X-ray crystallographic studies have been also reported for ternary complexes of this isozyme with activators and anion (azide) inhibitors. Structure-activity correlations for diverse classes of activators is discussed for the isozymes for which the phenomenon has been studied, i.e., CA I, II, III and IV. The possible physiological relevance of CA activation/inhibition is also addressed, together with recent pharmacological/ biomedical applications of such compounds in different fields of life sciences.     

The audacity of proteomics: a chance to overcome current challenges in schizophrenia research

The evidence on the mechanisms underlying schizophrenia seems to support a series of divergent possibilities that may play a contributory role in the disease pathogenesis. Hypotheses regarding disease mechanisms range from structural and neurodevelopmental abnormalities to neurotransmitter deficits and genetic predisposition. Nevertheless, little progress has been made in the field of schizophrenia with respect to the key pathophysiological processes, and this is a fundamental barrier to identifying or predicting the therapeutic value of novel drug targets. All multi-omics approaches, including proteomics, would be perfectly suited to such a complex disease as a means of tackling the widening chasm between the aforementioned hypotheses. Proteomic studies have been performed in a variety of tissues and biological fluids, from post-mortem CNS tissue to cerebrospinal fluid and blood, and in recently generated mutant animal models with schizophrenia-like phenotypes. In this review, we present an overview of several proteomic studies in the field of schizophrenia research and discuss how proteomics could assist with identifying schizophrenia markers more efficiently, covering both clinical and basic research.     

Thematic review series: patient-oriented research. Imaging atherosclerosis: state of the art

The ability to image obstructive arterial disease brought about a revolution in clinical cardiovascular care; the development of newer technologies that image arterial wall thicknesses, areas, volumes, and composition allows valid imaging of atherosclerosis for the first time. Development of noninvasive imaging of atherosclerosis has further led to a quantum shift in research in the field by enabling the study of asymptomatic populations and thus allowing investigators to focus on preclinical disease without the many biases associated with the study of symptomatic patients. These noninvasive investigations have broad implications for clinical care as well. Coronary angiography, computed tomographic (CT) imaging of coronary calcium, intravascular ultrasound, multidetector CT angiography, B mode ultrasound of the carotid arteries, and MRI of the carotid arteries all have unique strengths and weaknesses for imaging atherosclerosis. Certain of these techniques are extremely useful as outcome variables for clinical trials, and others are uniquely useful as predictors of the risk of cardiovascular disease. All are informative in one way or another with regard to the role of plaque remodeling and composition in disease causation. CT and MRI technology are advancing very rapidly, and research and clinical uses of these imaging modalities promise to further advance our understanding of atherosclerosis and its prevention.     

European rabbit research in the Iberian Peninsula: state of the art and future perspectives

The European rabbit (Oryctolagus cuniculus) is a high-profile prey, native from the Iberian Peninsula, the only region in the world where the two rabbit subspecies (O. cuniculus algirus and O. cuniculus cuniculus) currently co-exist in natural conditions. In this area, this important prey represents a keystone species and ecosystem engineer of Mediterranean landscapes, being also the most harvested and one of the most managed small-game species. Additionally, the species can create damage to crops in some parts of the Iberian Peninsula where it is regarded as an agricultural pest. The scientific interest towards the species is becoming increasingly apparent most likely as a repercussion of declining population trends over the last decades. The latter has been the result of the impact of habitat deterioration, viral diseases, unsustainable hunting, and predation. In this paper, I present a review of the scientific literature currently available on the European rabbit in the Iberian Peninsula. I discuss knowledge gaps and highlight priority research guidelines to suppress them, in an attempt to provide a general perspective to target research efforts more effectively. This analysis is particularly relevant due to the current vulnerability of rabbit populations in Iberia and to the recent news of cuts in scientific funding in most Mediterranean countries.     

Pidotimod: the state of art

Despite the use of antibiotics and vaccines, the frequency of respiratory tract infections is still high and these infections interest a wide range of patients, from children to aged people, including in particular these extreme categories because of the deficiency of their immune system, due to immaturity in the former case and to “immunosenescence” in the latter. For that reason immunostimulant drugs are getting more important to prevent and to attenuate infections. Pidotimod (3-L-pyroglutamyl-L-thiazolidine-4carboxylic acid) is a synthetic dipeptide with immunomodulatory properties. We reviewed studies conducted on different categories of patients, with particular attention on children and senile patients suffering from recurrent respiratory tract infections, associated, or not, with asthma or COPD. The outcomes considered are both clinical and laboratory parameters. The common end-point of these studies is that Pidotimod has an immunomodulatory activity which is able both to improve the clinical conditions of patients and to enhance and stimulate their immunity cells (lymphocytes but not only) functions acting on adaptive and innate immunity. Pidotimod is also able to increase the concentration of salivary IgA directed against bacteria; furthermore, it can modulate airway epithelial cells functions up-regulating the expression of toll-like receptors and acting on adhesion molecules. According to studies conducted on patients with atopic asthma, it seems that Pidotimod could affect T-lymphocytes balance with a possible addictional anti-allergic activity. Furthermore, it has been demonstrated an improvement of FEV1 and PEF in asthmatic patients treated with Pidotimod. Main clinical outcomes are the reduction of the number of infectious episodes, lesser severity of signs and symptoms and, consequently, a reduction in use of antibiotics and symptomatic drugs, less working and school days lost, less mortality and morbidity. The studies considered give positive results, confirming Pidotimod’s efficacy. Furthermore, many studies show a good safety profile of the drug, without recording serious adverse events and mutagenic potential, and a very low incidence of side effects. Pidotimod is also a more safe solution in patients subjected to vaccination, if compared to lyophilized polibacterial, which can’t be administered for thirty days before vaccination.     

Stem cell transplantation in pediatric leukemia and myelodysplasia: state of the art and current challenges

The role of stem cell transplantation in the treatment of leukemia and myelodysplasia (MDS) in children has changed over the past decade. In pediatric acute lymphoblastic leukemia (ALL), the overall cure-rate is high with conventional chemotherapy. However, selected patients with a high-risk of relapse are often treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first remission (CR1). Patients with a bone-marrow relapse who attain a second remission frequently receive HSCT. High minimal residual disease (MRD) levels directly prior to HSCT determines the relapse risk. Therefore, MRD positive patients are eligible for more experimental approaches such as intensified or experimental chemotherapy pre-HSCT, as well as immune modulation post-HSCT. In pediatric acute myeloid leukemia (AML) the role of allo-HSCT in CR1 is declining, due to better outcome with modern multi-agent chemotherapy. In relapsed AML patients, allo-HSCT still seems indispensable. Targeted therapy may change the role of HSCT, in particular in chronic myeloid leukemia, where the role of allografting is changing in the imatinib era. In MDS, patients are usually transplanted immediately without prior cytoreduction. New developments in HSCT, such as the role of alternative conditioning regimens, and innovative stem cell sources such as peripheral blood and cord blood, will also be addressed.     

Dark Agouti rat model of chemotherapy-induced mucositis: Establishment and current state of the art

Mucositis is a major oncological problem. The entire gastrointestinal and genitourinary tract and also other mucosal surfaces can be affected in recipients of radiotherapy, and/or chemotherapy. Major progress has been made in recent years in understanding the mechanisms of oral and small intestinal mucositis, which appears to be more prominent than colonic damage. This progress is largely due to the development of representative laboratory animal models of mucositis. This review focuses on the development and establishment of the Dark Agouti rat mammary adenocarcinoma model by the Mucositis Research Group of the University of Adelaide over the past 20 years to characterize the mechanisms underlying methotrexate-, 5-fluorouracil-, and irinotecan-induced mucositis. It also aims to summarize the results from studies using different animal model systems to identify new molecular and cellular markers of mucositis.