Utilizing neurodegenerative markers for the diagnostic evaluation of amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive deterioration of upper and lower motor neurons. A definitive diagnostic test or biomarker for ALS is currently unavailable, leading to a diagnostic delay following the onset of initial symptoms. Our study focused on cerebrospinal fluid (CSF) concentrations of clusterin, tau protein, phosphorylated tau protein, and beta-amyloid1-42 in ALS patients and a control group. METHODS: Our study involved 54 ALS patients and 58 control subjects. Among the ALS patients, 14 presented with bulbar-onset ALS, and 40 with limb-onset ALS. We quantified biomarker levels using enzyme-linked immunosorbent assay (ELISA) and compared the results using the Mann-Whitney U-test. RESULTS: Significant elevations in neurodegenerative markers, including tau protein (p < 0.0001), phosphorylated tau protein (p < 0.0001), and clusterin (p = 0.038), were observed in ALS patients compared to controls. Elevated levels of tau protein and phosphorylated tau protein were also noted in both bulbar and limb-onset ALS patients. However, no significant difference was observed for beta-amyloid1-42. ROC analysis identified tau protein (AUC = 0.767) and p-tau protein (AUC = 0.719) as statistically significant predictors for ALS. CONCLUSION: Our study demonstrates that neurodegenerative marker levels indicate an ongoing neurodegenerative process in ALS. Nonetheless, the progression of ALS cannot be predicted solely based on these markers. The discovery of a specific biomarker could potentially complement existing diagnostic criteria for ALS.

Endoluminal radiofrequency ablation in patients with malignant biliary obstruction: a randomised trial.

BACKGROUND: Endoluminal radiofrequency ablation (RFA) has been promoted as palliative treatment for patients with cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC) in order to improve biliary drainage and eventually prolong survival. No high level evidence is, however, available on this technique. DESIGN: In this randomised controlled study, we compared endoluminal RFA plus stenting with stenting alone (control group) in patients with malignant biliary obstruction; metal stents were primarily placed. Primary outcome was overall survival; secondary outcomes were stent patency, quality of life and adverse events. In a superiority design, survival was assumed to be doubled by RFA as compared with 6.4 months in the control group (n=280). RESULTS: A total of 161 patients (male:female 90:71, mean age 71±9 years) were randomised before recruitment was terminated for futility after an interim analysis. Eighty-five patients had CCA (73 hilar, 12 distal) and 76 had pancreatic cancer. There was no difference in survival in both subgroups: for patients with CCA, median survival was 10.5 months (95% CI 6.7 to 18.3) in the RFA group vs 10.6 months (95% CI 9.0 to 24.8), p=0.58)) in the control group. In the subgroup with pancreatic cancer, median survival was 6.4 months (95% CI 4.3 to 9.7) for the RFA vs 7.7 months (95% CI 5.6 to 11.3), p=0.73) for the control group. No benefit was seen in the RFA group with regard to stent patency (at 12 months 40% vs 36% in CCA and 66% vs 65% in PDAC), and quality of life was unchanged by either treatment and comparable between the groups. Adverse events occurred in seven patients in each groups. CONCLUSION: A combination of endoluminal RFA and stenting was not superior to stenting alone in prolonging survival or improving stent patency in patients with malignant biliary obstruction. TRIAL REGISTRATION NUMBER: NCT03166436.

Pesticides and Parabens Contaminating Aquatic Environment: Acute and Sub-Chronic Toxicity towards Early-Life Stages of Freshwater Fish and Amphibians.

Pesticides and personal care products are two very important groups of contaminants posing a threat to the aquatic environment and the organisms living in it.. Therefore, this study aimed to describe the effects of widely used pesticides and parabens on aquatic non-target biota such as fish (using model organisms Danio rerio and Cyprinus carpio) and amphibians (using model organism Xenopus laevis) using a wide range of endpoints. The first part of the experiment was focused on the embryonal toxicity of three widely used pesticides (metazachlor, prochloraz, and 4-chloro-2-methyl phenoxy acetic acid) and three parabens (methylparaben, propylparaben, and butylparaben) with D. rerio, C. carpio, and X. laevis embryos. An emphasis was placed on using mostly sub-lethal concentrations that are partially relevant to the environmental concentrations of the substances studied. In the second part of the study, an embryo-larval toxicity test with C. carpio was carried out with prochloraz using concentrations 0.1, 1, 10, 100, and 1000 µg/L. The results of both parts of the study show that even the low, environmentally relevant concentrations of the chemicals tested are often able to affect the expression of genes that play either a prominent role in detoxification and sex hormone production or indicate cell stress or, in case of prochloraz, to induce genotoxicity.

Alcobiosis, an algal-fungal association on the threshold of lichenisation.

Alcobiosis, the symbiosis of algae and corticioid fungi, frequently occurs on bark and wood. Algae form a layer in or below fungal basidiomata reminiscent of the photobiont layer in lichens. Identities of algal and fungal partners were confirmed by DNA barcoding. Algal activity was examined using gas exchange and chlorophyll fluorescence techniques. Carbon transfer from algae to fungi was detected as 13C, assimilated by algae, transferred to the fungal polyol. Nine fungal partners scattered across Agaricomycetes are associated with three algae from Trebouxiophycae: Coccomyxa sp. with seven fungal species on damp wood, Desmococcus olivaceus and Tritostichococcus coniocybes, both with a single species on bark and rain-sheltered wood, respectively. The fungal partner does not cause any obvious harm to the algae. Algae enclosed in fungal tissue exhibited a substantial CO2 uptake, but carbon transfer to fungal tissues was only detected in the Lyomyces-Desmococcus alcobiosis where some algal cells are tightly enclosed by hyphae in goniocyst-like structures. Unlike lichen mycobionts, fungi in alcobioses are not nutritionally dependent on the algal partner as all of them can live without algae. We consider alcobioses to be symbioses in various stages of co-evolution, but still quite different from true lichens.

An updated classification of cyanobacterial orders and families based on phylogenomic and polyphasic analysis.

Cyanobacterial taxonomy is facing a period of rapid changes thanks to the ease of 16S rRNA gene sequencing and established workflows for description of new taxa. Since the last comprehensive review of the cyanobacterial system in 2014 until 2021, at least 273 species in 140 genera were newly described. These taxa were mainly placed into previously defined orders and families although several new families were proposed. However, the classification of most taxa still relied on hierarchical relationships inherited from the classical morphological taxonomy. Similarly, the obviously polyphyletic orders such as Synechococcales and Oscillatoriales were left unchanged. In this study, the rising number of genomic sequences of cyanobacteria and well-described reference strains allowed us to reconstruct a robust phylogenomic tree for taxonomic purposes. A less robust but better sampled 16S rRNA gene phylogeny was mapped to the phylogenomic backbone. Based on both these phylogenies, a polyphasic classification throughout the whole phylum of Cyanobacteria was created, with ten new orders and fifteen new families. The proposed system of cyanobacterial orders and families relied on a phylogenomic tree but still employed phenotypic apomorphies where possible to make it useful for professionals in the field. It was, however, confirmed that morphological convergence of phylogenetically distant taxa was a frequent phenomenon in cyanobacteria. Moreover, the limited phylogenetic informativeness of the 16S rRNA gene, resulting in ambiguous phylogenies above the genus level, emphasized the integration of genomic data as a prerequisite for the conclusive taxonomic placement of a vast number of cyanobacterial genera in the future.

Periprocedural safety profile of peroral endoscopic myotomy (POEM)-a retrospective analysis of adverse events according to two different classifications.

BACKGROUND: Peroral endoscopic myotomy (POEM) is nowadays a standard method for treatment of achalasia; nevertheless, it remains an invasive intervention with corresponding risk of adverse events (AEs). The classification and grading of AEs are still a matter of discussion. The aim of our retrospective study was to assess the occurrence of all "undesirable" events and "true" adverse events in patients undergoing POEM and to compare the outcomes when either Clavien-Dindo classification (CDC) or American Society of Gastrointestinal Endoscopy (ASGE) lexicon classification applied. METHODS: This was a retrospective analysis of prospectively managed database of all patients who had undergone POEM between December 2012 and August 2018. We assessed the pre-, peri-, and early-postoperative (up to patient's discharge) undesirable events (including those not fulfilling criteria for AEs) and "true" AEs according the definition in either of the classifications. RESULTS: A total of 231 patients have successfully undergone 244 POEM procedures (13 × re-POEM). Twenty-nine procedures (11.9%) passed uneventfully, while in 215 procedures (88.1%), a total of 440 undesirable events occurred. The CDC identified 27 AEs (17 minor, 10 major) occurring in 23/244 (9.4%) procedures. The ASGE lexicon identified identical 27 AEs (21 mild or moderate, 6 severe or fatal) resulting in the severity distribution of AEs being the only difference between the two classifications. Only the absence of previous treatment was found to be a risk factor [p = 0.047, OR with 95% CI: 4.55 (1.02; 20.25)] in the combined logistic regression model. CONCLUSION: Undesirable events are common in patients undergoing POEM but the incidence of true AEs is low according to both classifications. Severe adverse events are infrequent irrespective of the classification applied. CDC may be more appropriate than ASGE lexicon for classifying POEM-related AEs given a surgical nature of this procedure.

Use of all-male triploid population of zebrafish (Danio rerio) for evaluation of 17α-ethinylestradiol effects.

OBJECTIVES: We tested the toxicity of ethinylestradiol, a semisynthetic estrogen used in oral contraceptives, on all-male triploid zebrafish using commercial feeds and three different doses concentrations. We aimed to determine whether ethinylestradiol peroral administration resulted in vitellogenin production and whether all-male triploid zebrafish could serve as a model species for xenoestrogen testing. METHODS: The actual concentrations of 17α-ethinylestradiol were 0.0035 (low); 0.0315 (medium) and 0.365 (high) µg/g. Positive control represented commercial feeds containing 0.0465 µg/g of ß-estradiol. The experiment lasted 8 weeks. RESULTS: Our results indicate that 17α-ethinylestradiol consumption does induce vitellogenin production in triploid zebrafish. CONCLUSIONS: The simple presence of vitellogenin is a definite symptom indicative of the potential for such changes due to the action of estrogenic substances. As such, this experiment has shown that the use of all-male triploid zebrafish populations, rather than the mixed-sex populations of other species previously used, could serve as a suitable alternative model population for controlled testing of the effects of xenoestrogens on fish.

Impact of Endoluminal Radiofrequency Ablation on Immunity in Pancreatic Cancer and Cholangiocarcinoma.

Radiofrequency ablation (RFA) is a mini-invasive loco-regional ablation technique that is increasingly being used as a palliative treatment for pancreatic cancer and cholangiocarcinoma. Ablation-triggered immune system stimulation has been proposed as a mechanism behind the systemic effects of RFA. The aim of our study was to investigate the immune response to endoluminal biliary RFA. Peripheral blood samples were collected from patients with pancreatic cancer and cholangiocarcinoma randomised to receive endoluminal biliary radiofrequency ablation + stent (19 patients) or stent only (21 patients). We observed an early increase in IL-6 levels and a delayed increase in CXCL1, CXCL5, and CXCL11 levels as well as an increase in CD8+ and NK cells. However, these changes were not specific to RFA treatment. Explicitly in response to RFA, we observed a delayed increase in serum CXCL1 levels and an early decrease in the number of anti-inflammatory CD206+ blood monocytes. Our study provides the first evidence of endoluminal biliary RFA-based regulation of the systemic immune response in patients with pancreatic cancer and cholangiocarcinoma. These changes were characterised by a general inflammatory response. RFA-specific activation of the adaptive immune system was not confirmed.

Endoscopic pyloromyotomy for the treatment of severe and refractory gastroparesis: a pilot, randomised, sham-controlled trial.

OBJECTIVE: Endoscopic pyloromyotomy (G-POEM) is a minimally invasive treatment option with promising uncontrolled outcome results in patients with gastroparesis. DESIGN: In this prospective randomised trial, we compared G-POEM with a sham procedure in patients with severe gastroparesis. The primary outcome was the proportion of patients with treatment success (defined as a decrease in the Gastroparesis Cardinal Symptom Index (GCSI) by at least 50%) at 6 months. Patients randomised to the sham group with persistent symptoms were offered cross-over G-POEM. RESULTS: The enrolment was stopped after the interim analysis by the Data and Safety Monitoring Board prior to reaching the planned sample of 86 patients. A total of 41 patients (17 diabetic, 13 postsurgical, 11 idiopathic; 46% male) were randomised (21 G-POEM, 20-sham). Treatment success rate was 71% (95% CI 50 to 86) after G-POEM versus 22% (8-47) after sham (p=0.005). Treatment success in patients with diabetic, postsurgical and idiopathic gastroparesis was 89% (95% CI 56 to 98), 50% (18-82) and 67% (30-90) after G-POEM; the corresponding rates in the sham group were 17% (3-57), 29% (7-67) and 20% (3-67).Median gastric retention at 4 hours decreased from 22% (95% CI 17 to 31) to 12% (5-22) after G-POEM and did not change after sham: 26% (18-39) versus 24% (11-35). Twelve patients crossed over to G-POEM with 9 of them (75%) achieving treatment success. CONCLUSION: In severe gastroparesis, G-POEM is superior to a sham procedure for improving both symptoms and gastric emptying 6 months after the procedure. These results are not entirely conclusive in patients with idiopathic and postsurgical aetiologies. TRIAL REGISTRATION NUMBER: NCT03356067; ClinicalTrials.gov.

Monoclonal Antibodies in the Treatment of Relapsing Multiple Sclerosis: an Overview with Emphasis on Pregnancy, Vaccination, and Risk Management.

Monoclonal antibodies have become a mainstay in the treatment of patients with relapsing multiple sclerosis (RMS) and provide some benefit to patients with primary progressive MS. They are highly precise by specifically targeting molecules displayed on cells involved in distinct immune mechanisms of MS pathophysiology. They not only differ in the target antigen they recognize but also by the mode of action that generates their therapeutic effect. Natalizumab, an [Formula: see text]4[Formula: see text]1 integrin antagonist, works via binding to cell surface receptors, blocking the interaction with their ligands and, in that way, preventing the migration of leukocytes across the blood-brain barrier. On the other hand, the anti-CD52 monoclonal antibody alemtuzumab and the anti-CD20 monoclonal antibodies rituximab, ocrelizumab, ofatumumab, and ublituximab work via eliminating selected pathogenic cell populations. However, potential adverse effects may be serious and can necessitate treatment discontinuation. Most importantly, those are the risk for (opportunistic) infections, but also secondary autoimmune diseases or malignancies. Monoclonal antibodies also carry the risk of infusion/injection-related reactions, primarily in early phases of treatment. By careful patient selection and monitoring during therapy, the occurrence of these potentially serious adverse effects can be minimized. Monoclonal antibodies are characterized by a relatively long pharmacologic half-life and pharmacodynamic effects, which provides advantages such as permitting infrequent dosing, but also creates disadvantages regarding vaccination and family planning. This review presents an overview of currently available monoclonal antibodies for the treatment of RMS, including their mechanism of action, efficacy and safety profile. Furthermore, we provide practical recommendations for risk management, vaccination, and family planning.

Cyanobacteria Microcystis aeruginosa Contributes to the Severity of Fish Diseases: A Study on Spring Viraemia of Carp.

Fish are exposed to numerous stressors in the environment including pollution, bacterial and viral agents, and toxic substances. Our study with common carps leveraged an integrated approach (i.e., histology, biochemical and hematological measurements, and analytical chemistry) to understand how cyanobacteria interfere with the impact of a model viral agent, Carp sprivivirus (SVCV), on fish. In addition to the specific effects of a single stressor (SVCV or cyanobacteria), the combination of both stressors worsens markers related to the immune system and liver health. Solely combined exposure resulted in the rise in the production of immunoglobulins, changes in glucose and cholesterol levels, and an elevated marker of impaired liver, alanine aminotransferase (ALT). Analytical determination of the cyanobacterial toxin microcystin-LR (MC-LR) and its structurally similar congener MC-RR and their conjugates showed that SVCV affects neither the levels of MC in the liver nor the detoxification capacity of the liver. MC-LR and MC-RR were depurated from liver mostly in the form of cysteine conjugates (MC-LR-Cys, MC-RR-Cys) in comparison to glutathione conjugates (LR-GSH, RR-GSH). Our study brought new evidence that cyanobacteria worsen the effect of viral agents. Such inclusion of multiple stressor concept helps us to understand how and to what extent the relevant environmental stressors co-influence the health of the fish population.

Tenebriella gen. nov. - The dark twin of Oscillatoria.

Oscillatoria has long been known to be polyphyletic. After recent resequencing of the reference strain for this genus, many Oscillatoria-like groups phylogenetically distant from the type species O. princeps remained unresolved. Here we describe one of these groups as a new genus Tenebriella. Most of the studied strains originate from Central Europe, where they are able to form prominent microbial mats. Despite the overall Oscillatoria-like morphology, Tenebriella can be distinguished by darker trichomes and forms a separate monophyletic clade in phylogenies inferred from the 16S rRNA gene and two additional loci (rpoC1, rbcLX). Within Tenebriella we recognize two new species differing from each other by morphological and ecological characteristics. First species does not fit any known taxon description, and thus is described as a new species T. amphibia. The latter one corresponds with the information available for Oscillatoria curviceps Agardh ex Gomont, and thus new combination T. curviceps is proposed. The phylogenetic analyses of the 16S-23S ITS region together with the comparison of the hypothetical secondary structures confirmed recognition of these two species and additionally revealed presence of a morphologically cryptic species Tenebriella sp. The results corroborate frequent recurrence of convergent morphotypes in the evolution of cyanobacteria and justify further exploration even of the intensively studied European freshwaters using molecular phylogenetics to discover new and ecologically relevant taxa.

Swarming Aqua Sperm Micromotors for Active Bacterial Biofilms Removal in Confined Spaces.

Microscale self-propelled robots show great promise in the biomedical field and are the focus of many researchers. These tiny devices, which move and navigate by themselves, are typically based on inorganic microstructures that are not biodegradable and potentially toxic, often using toxic fuels or elaborate external energy sources, which limits their real-world applications. One potential solution to these issues is to go back to nature. Here, the authors use high-speed Aqua Sperm micromotors obtained from North African catfish (Clarias gariepinus, B. 1822) to destroy bacterial biofilm. These Aqua Sperm micromotors use water-induced dynein ATPase catalyzed adenosine triphosphate (ATP) degradation as biocompatible fuel to trigger their fast speed and snake-like undulatory locomotion that facilitate biofilm destruction in less than one minute. This efficient biofilm destruction is due to the ultra-fast velocity as well as the head size of Aqua Sperm micromotors being similar to bacteria, which facilitates their entry to and navigation within the biofilm matrix. In addition, the authors demonstrate the real-world application of Aqua Sperm micromotors by destroying biofilms that had colonized medical and laboratory tubing. The implemented system extends the biomedical application of Aqua Sperm micromotors to include hybrid robots for fertilization or cargo tasks.

Multiple sclerosis and COVID-19.

This paper reviews currently available data on the novel coronavirus and clinical features of COVID-19, followed by a detailed section on possible modifications of immunomodulatory therapy in multiple sclerosis patients with COVID-19, based on what we know so far. There are discussed: (i) The COVID-19 disease (Epidemiological background SARS-CoV-1 coronavirus; Autoimmune response to COVID-19; Asymptomatic course; SARS-CoV-2 test; COVID-19 symptoms), (ii) Treatment of COVID-19 (Experimental plasma treatment; Antiviral therapy; Antimalarial treatment scheme; Biological treatment; Corticosteroid treatment; Symptomatic treatment; Vaccine preparation) and (iii) Multiple sclerosis and SARS-CoV-2 infection (Epidemiological recommendation).

Current therapeutic landscape in multiple sclerosis: an evolving treatment paradigm.

PURPOSE OF REVIEW: To critically assess the current landscape of disease-modifying agents for multiple sclerosis (MS). Treatment algorithms will be discussed and studies for new agents in late development or recently approved are analyzed in terms of their impact on current treatment strategies. RECENT FINDINGS: A real-world study from Wales suggests that early initiation of highly effective therapy may provide more benefit that an escalation approach in relapsing MS. A study from the MSBase dataset found evidence that early treatment with highly effective therapies decreased the risk of developing secondary progressive MS. Ocrelizumab is highly efficacious in relapsing MS and in a group of patients with primary progressive MS. Another CD20 directed mAb, ofatumumab, is in phase 3. A large study examining extended interval dosing of natalizumab in an attempt to decrease the risk of developing progressive multifocal leukoencephalopathy is underway. Cladribine and alemtuzumab may work by immune reconstitution. Siponimod was recently approved by United States Federal Drug Administration for relapsing MS and active secondary progressive MS. Other S1P receptor modulators are being studied in phase 3 trials for relapsing MS. Cladribine received FDA approval as treatment for relapsing and active secondary progressive MS. Autologous hematopoetic stem-cell transplantation may be an option for treatment-refractory MS. SUMMARY: Development of disease-modifying agents in MS continues to be successful. Treatment algorithms need to take new developments into account.

Taxonomic resolution of the genus Cyanothece (Chroococcales, Cyanobacteria), with a treatment on Gloeothece and three new genera, Crocosphaera, Rippkaea, and Zehria.

The systematics of single-celled cyanobacteria represents a major challenge due to morphological convergence and application of various taxonomic concepts. The genus Cyanothece is one of the most problematic cases, as the name has been applied to oval-shaped coccoid cyanobacteria lacking sheaths with little regard to their phylogenetic position and details of morphology and ultrastructure. Hereby we analyze an extensive set of complementary genetic and phenotypic evidence to disentangle the relationships among these cyanobacteria. We provide diagnostic characters to separate the known genera Cyanothece, Gloeothece, and Aphanothece, and provide a valid description for Crocosphaera gen. nov. We describe two new genera, Rippkaea and Zehria, to characterize two distinct phylogenetic lineages outside the previously known genera. We further describe 13 new species in total including Cyanothece svehlovae, Gloeothece aequatorialis, G. aurea, G. bryophila, G. citriformis, G. reniformis, Gloeothece tonkinensis, G. verrucosa, Crocosphaera watsonii, C. subtropica, C. chwakensis, Rippkaea orientalis, and Zehria floridana to recognize the intrageneric diversity as rendered by polyphasic analysis. We discuss the close relationship of free-living cyanobacteria from the Crocosphaera lineage to nitrogen-fixing endosymbionts of marine algae. The current study includes several experimental strains (Crocosphaera and "Cyanothece") important for the study of diazotrophy and the global oceanic nitrogen cycle, and provides evidence suggesting ancestral N2 -fixing capability in the chroococcalean lineage.

Discovery of a Pederin Family Compound in a Nonsymbiotic Bloom-Forming Cyanobacterium.

The pederin family includes a number of bioactive compounds isolated from symbiotic organisms of diverse evolutionary origin. Pederin is linked to beetle-induced dermatitis in humans, and pederin family members possess potent antitumor activity caused by selective inhibition of the eukaryotic ribosome. Their biosynthesis is accomplished by a polyketide/nonribosomal peptide synthetase machinery employing an unusual trans-acyltransferase mechanism. Here, we report a novel pederin type compound, cusperin, from the free-living cyanobacterium Cuspidothrix issatschenkoi (earlier Aphanizomenon). The chemical structure of cusperin is similar to that of nosperin recently isolated from the lichen cyanobiont Nostoc sharing the tehrahydropyran moiety and major part of the linear backbone. However, the cusperin molecule is extended by a glycine residue and lacks one hydroxyl substituent. Pederins were previously thought to be exclusive to symbiotic relationships. However, C. issatschenkoi is a nonsymbiotic planktonic organism and a frequent component of toxic water blooms. Cusperin is devoid of the cytotoxic activity reported for other pederin family members. Hence, our findings raise questions about the role of pederin analogues in cyanobacteria and broaden the knowledge of ecological distribution of this group of polyketides.

The cyanobacterial metabolite nocuolin a is a natural oxadiazine that triggers apoptosis in human cancer cells.

Oxadiazines are heterocyclic compounds containing N-N-O or N-N-C-O system within a six membered ring. These structures have been up to now exclusively prepared via organic synthesis. Here, we report the discovery of a natural oxadiazine nocuolin A (NoA) that has a unique structure based on 1,2,3-oxadiazine. We have identified this compound in three independent cyanobacterial strains of genera Nostoc, Nodularia, and Anabaena and recognized the putative gene clusters for NoA biosynthesis in their genomes. Its structure was characterized using a combination of NMR, HRMS and FTIR methods. The compound was first isolated as a positive hit during screening for apoptotic inducers in crude cyanobacterial extracts. We demonstrated that NoA-induced cell death has attributes of caspase-dependent apoptosis. Moreover, NoA exhibits a potent anti-proliferative activity (0.7-4.5 µM) against several human cancer lines, with p53-mutated cell lines being even more sensitive. Since cancers bearing p53 mutations are resistant to several conventional anti-cancer drugs, NoA may offer a new scaffold for the development of drugs that have the potential to target tumor cells independent of their p53 status. As no analogous type of compound was previously described in the nature, NoA establishes a novel class of bioactive secondary metabolites.

Renal Proteomic Responses to Severe Sepsis and Surgical Trauma: Dynamic Analysis of Porcine Tissue Biopsies.

Although the burden of septic acute kidney injury continues to increase, the molecular pathogenesis remains largely obscure. The aim of this exploratory study was a discovery-driven analysis of dynamic kidney tissue protein expression changes applied for the first time in a classic large mammal model of sepsis. To achieve this goal, analyses of protein expression alterations were performed in serial samples of kidney cortical biopsies (before, 12 and 22 h of sepsis) in mechanically ventilated pigs challenged with continuous infusion of pseudomonas aeruginosa and compared with sham-operated control data. Global protein expression was analyzed using two-dimensional gel electrophoresis and mass spectrometry-based proteomics. Normodynamic sepsis was associated with 43% reduction in glomerular filtration. The exposure to surgical stress per se altered the renal protein expression profile, while sepsis induced distinct and highly dynamic proteome evolution shifting the balance toward cellular distress phenotype. We identified 20 proteins whose expression changes discriminated effects of sepsis from those induced by surgery. The data implicate endoplasmic reticulum stress, oxidative stress, mitochondrial energy metabolism, immune/inflammatory signaling, and tubular transport as major activated pathways. Thus, by coupling the power of sequential tissue proteomics with whole-animal physiological studies, our study helped to establish a first global overview of critical renal proteomic events occurring during surgical trauma and early sepsis in a porcine model. The study supports the notion that multiple potentially subtle and even transient changes in several proteins which are members of key functional interrelated systems appear to play a role in septic acute kidney injury.