Transdermal Opioids and the Quality of Life of the Cancer Patient: A Systematic Literature Review.

OBJECTIVE: This systematic literature review aims to evaluate the effectiveness of transdermal opioids in managing cancer pain and their impact on the quality of life (QoL) of patients. DATA SOURCES: A systematic literature review conducted following the PRISMA protocol, focusing on randomized clinical trials found in the Lilacs, Embase, PubMed, and SciELO databases over the last 20 years. STUDY SELECTION AND DATA EXTRACTION: We included randomized clinical trials, published in English, Portuguese, or Spanish, which assessed the impact of transdermal opioids on the QoL. Data extraction was facilitated using the Rayyan app. DATA SYNTHESIS: Six articles meeting the inclusion and exclusion criteria were analyzed. These studies covered a population ranging from 24 to 422 cancer patients experiencing moderate to severe pain. The risk of bias was assessed in each study, generally being categorized as uncertain or high. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The findings indicate that the analgesic effectiveness and side effects of transdermal formulations (specifically buprenorphine and fentanyl) for managing moderate to severe cancer pain are comparable to, or in some cases superior to, those of oral opioids traditionally employed. CONCLUSIONS: Transdermal therapy was suggested to have several advantages over oral opioid therapy in enhancing cancer patients' QoL. These benefits span various dimensions, including pain management, physical functioning, mental health, vitality, overall patient improvement, anger/aversion, strength/activity, general QoL, cognitive and emotional functions, fatigue, and insomnia.

Comprehensive Analysis of Lung Adenocarcinoma and Brain Metastasis through Integrated Single-Cell Transcriptomics.

Lung adenocarcinoma (LUAD) is a highly prevalent and lethal form of lung cancer, comprising approximately half of all cases. It is often diagnosed at advanced stages with brain metastasis (BM), resulting in high mortality rates. Current BM management involves complex interventions and conventional therapies that offer limited survival benefits with neurotoxic side effects. The tumor microenvironment (TME) is a complex system where cancer cells interact with various elements, significantly influencing tumor behavior. Immunotherapies, particularly immune checkpoint inhibitors, target the TME for cancer treatment. Despite their effectiveness, it is crucial to understand metastatic lung cancer and the specific characteristics of the TME, including cell-cell communication mechanisms, to refine treatments. Herein, we investigated the tumor microenvironment of brain metastasis from lung adenocarcinoma (LUAD-BM) and primary tumors across various stages (I, II, III, and IV) using single-cell RNA sequencing (scRNA-seq) from publicly available datasets. Our analysis included exploring the immune and non-immune cell composition and the expression profiles and functions of cell type-specific genes, and investigating the interactions between different cells within the TME. Our results showed that T cells constitute the majority of immune cells present in primary tumors, whereas microglia represent the most dominant immune cell type in BM. Interestingly, microglia exhibit a significant increase in the COX pathway. Moreover, we have shown that microglia primarily interact with oligodendrocytes and endothelial cells. One significant interaction was identified between DLL4 and NOTCH4, which demonstrated a relevant association between endothelial cells and microglia and between microglia and oligodendrocytes. Finally, we observed that several genes within the HLA complex are suppressed in BM tissue. Our study reveals the complex molecular and cellular dynamics of BM-LUAD, providing a path for improved patient outcomes with personalized treatments and immunotherapies.

Deciphering Key microRNA Regulated Pathways in Tissue-Engineered Blood Vessels: Implications for Vascular Scaffold Production.

MicroRNAs (miRNAs) are non-coding RNAs involved in the regulation of gene expression associated with cell differentiation, proliferation, adhesion, and important biological functions such as inflammation. miRNAs play roles associated with the pathogenesis of chronic degenerative disorders including cardiovascular diseases. Understanding the influence of miRNAs and their target genes can effectively streamline the identification of key biologically active pathways that are important in the development of vascular grafts through the tissue engineering of blood vessels. To determine miRNA expression levels and identify miRNA target genes and pathways with biological roles in scaffolds that have been repopulated with adipose-derived stem cells (ASCs) generated through tissue engineering for the construction of blood vessels. miRNA quantification assays were performed in triplicate to determine miRNA expression in a total of 20 samples: five controls (natural inferior vena cava), five scaffolds recellularized with ASCs and differentiated into the endothelium (luminal layer), five samples of complete scaffolds seeded with ASCs differentiated into the endothelium (luminal layer) and smooth muscle (extraluminal layer), and five samples of ASC without cell differentiation. Several differentially expressed miRNAs were identified and predicted to modulate target genes with roles in key pathways associated with angiogenesis, vascular system control, and endothelial and smooth muscle regulation, including migration, proliferation, and growth. These findings underscore the involvement of these pathways in the regulatory mechanisms that are essential for vascular scaffold production through tissue engineering. Our research contributes to the knowledge of miRNA-regulated mechanisms, which may impact the design of vascular substitutes, and provide valuable insights for enhancing clinical practice. The molecular pathways regulated by miRNAs in tissue engineering of blood vessels (TEBV) allowed us to elucidate the main phenomena involved in cellular differentiation to constitute a blood vessel, with the main pathways being essential for angiogenesis, cellular differentiation, and differentiation into vascular smooth muscle.

Metabolic reprogramming and lipid droplets are involved in Zika virus replication in neural cells.

Zika virus (ZIKV) infection is a global public health concern linked to adult neurological disorders and congenital diseases in newborns. Host lipid metabolism, including lipid droplet (LD) biogenesis, has been associated with viral replication and pathogenesis of different viruses. However, the mechanisms of LD formation and their roles in ZIKV infection in neural cells are still unclear. Here, we demonstrate that ZIKV regulates the expression of pathways associated with lipid metabolism, including the upregulation and activation of lipogenesis-associated transcription factors and decreased expression of lipolysis-associated proteins, leading to significant LD accumulation in human neuroblastoma SH-SY5Y cells and in neural stem cells (NSCs). Pharmacological inhibition of DGAT-1 decreased LD accumulation and ZIKV replication in vitro in human cells and in an in vivo mouse model of infection. In accordance with the role of LDs in the regulation of inflammation and innate immunity, we show that blocking LD formation has major roles in inflammatory cytokine production in the brain. Moreover, we observed that inhibition of DGAT-1 inhibited the weight loss and mortality induced by ZIKV infection in vivo. Our results reveal that LD biogenesis triggered by ZIKV infection is a crucial step for ZIKV replication and pathogenesis in neural cells. Therefore, targeting lipid metabolism and LD biogenesis may represent potential strategies for anti-ZIKV treatment development.

Low muscle mass in lung cancer is associated with an inflammatory and immunosuppressive tumor microenvironment.

BACKGROUND: Computed tomographies (CT) are useful for identifying muscle loss in non-small lung cancer (NSCLC) cachectic patients. However, we lack consensus on the best cutoff point for pectoralis muscle loss. We aimed to characterize NSCLC patients based on muscularity, clinical data, and the transcriptional profile from the tumor microenvironment to build a cachexia classification model. METHODS: We used machine learning to generate a muscle loss prediction model, and the tumor's cellular and transcriptional profile was characterized in patients with low muscularity. First, we measured the pectoralis muscle area (PMA) of 211 treatment-naive NSCLC patients using CT available in The Cancer Imaging Archive. The cutoffs were established using machine learning algorithms (CART and Cutoff Finder) on PMA, clinical, and survival data. We evaluated the prediction model in a validation set (36 NSCLC). Tumor RNA-Seq (GSE103584) was used to profile the transcriptome and cellular composition based on digital cytometry. RESULTS: CART demonstrated that a lower PMA was associated with a high risk of death (HR = 1.99). Cutoff Finder selected PMA cutoffs separating low-muscularity (LM) patients based on the risk of death (P-value = 0.003; discovery set). The cutoff presented 84% of success in classifying low muscle mass. The high risk of LM patients was also found in the validation set. Tumor RNA-Seq revealed 90 upregulated secretory genes in LM that potentially interact with muscle cell receptors. The LM upregulated genes enriched inflammatory biological processes. Digital cytometry revealed that LM patients presented high proportions of cytotoxic and exhausted CD8+ T cells. CONCLUSIONS: Our prediction model identified cutoffs that distinguished patients with lower PMA and survival with an inflammatory and immunosuppressive TME enriched with inflammatory factors and CD8+ T cells.

Bioprospecting for new exopolysaccharide-producing microalgae of marine origin.

Microalgae are photosynthetic organisms that can produce biomolecules with industrial interest, including exopolysaccharides (EPS). Due to their structural and compositional diversity, microalgae EPS present interesting properties that can be considered in cosmetic and/or therapeutic areas. Seven microalgae strains from three different lineages, namely Dinophyceae (phylum Miozoa), Haptophyta, and Chlorophyta, were investigated as EPS producers. All strains were found to be EPS producers, though the highest EPS yield was obtained for Tisochrysis lutea, followed by Heterocapsa sp. (126.8 and 75.8 mg L-1, respectively). Upon assessment of the polymers' chemical composition, significant contents of unusual sugars, including fucose, rhamnose, and ribose, were found. Heterocapsa sp. EPS stood out due to its high content of fucose (40.9 mol%), a sugar known to confer biological properties to polysaccharides. The presence of sulfate groups (10.6-33.5 wt%) was also noticed in the EPS produced by all microalgae strains, thus contributing to the possibility that these EPS might have biological activities worth exploring.

Survival in patients undergoing surgical resection for brain metastasis from lung cancer and utility of different prognostic scales.

Brain metastases (BM) from lung cancer are among the most common intracranial tumors. Several studies have published scales to estimate the survival of patients with BM. Routine access to molecular diagnostics and modern oncologic treatments, including targeted therapy and immunotherapy, is limited in low- and middle-income countries (LMICs); therefore, incorporating them into recent prognostic scales may diminish the reliability of the scales in LMICs. This retrospective study aimed to determine the survival of 55 patients who were surgically treated for BM from lung cancer at a Brazilian public tertiary teaching hospital between 2012 and 2022. We determined clinical factors associated with survival, and compared observed survival rates with the estimated survival on prognostic scales. The mean overall survival (OS) was 9.3 months (range:0.2-76.5). At univariate analysis, female sex and improved postoperative Karnofsky performance status (KPS) score were associated with longer survival. The median survival did not differ between groups when classified using the Graded Prognostic Assessment (GPA)-2008, Lung-molecular GPA-2017, and Lung-GPA-2021 scales. According to the Diagnosis-Specific (DS)-GPA-2012 scale, there was a significant difference between the groups. In the multivariate Cox regression survival analysis, a higher DS-GPA-2012 and improved postoperative KPS score remained significantly associated with longer survival. In conclusion, this cohort showed a mean OS of < 1 year. Improved KPS score after surgery was associated with increased survival. This cohort DS-GPA scale demonstrated the highest concordance with observed survival, indicating its potential as a valuable tool for patient stratification in surgical treatment decision-making in LMICs.

Circulating Extracellular Vesicles microRNAs Are Altered in Women Undergoing Preterm Birth.

Preterm labor (PTL) and preterm premature rupture of membranes (PPROM) lead to high perinatal morbidity/mortality rates worldwide. Small extracellular vesicles (sEV) act in cell communication and contain microRNAs that may contribute to the pathogenesis of these complications. We aimed to compare the expression, in sEV from peripheral blood, of miRNAs between term and preterm pregnancies. This cross-sectional study included women who underwent PTL, PPROM, and term pregnancies, examined at the Botucatu Medical School Hospital, SP, Brazil. sEV were isolated from plasma. Western blot used to detect exosomal protein CD63 and nanoparticle tracking analysis were performed. The expression of 800 miRNAs was assessed by the nCounter Humanv3 miRNA Assay (NanoString). The miRNA expression and relative risk were determined. Samples from 31 women-15 preterm and 16 term-were included. miR-612 expression was increased in the preterm groups. miR-612 has been shown to increase apoptosis in tumor cells and to regulate the nuclear factor κB inflammatory pathway, processes involved in PTL/PPROM pathogenesis. miR-1253, miR-1283, miR378e, and miR-579-3p, all associated with cellular senescence, were downregulated in PPROM compared with term pregnancies. We conclude that miRNAs from circulating sEV are differentially expressed between term and preterm pregnancies and modulate genes in pathways that are relevant to PTL/PPROM pathogenesis.

Mechanisms Contributing to the Comorbidity of COPD and Lung Cancer.

Lung cancer and chronic obstructive pulmonary disease (COPD) often co-occur, and individuals with COPD are at a higher risk of developing lung cancer. While the underlying mechanism for this risk is not well understood, its major contributing factors have been proposed to include genomic, immune, and microenvironment dysregulation. Here, we review the evidence and significant studies that explore the mechanisms underlying the heightened lung cancer risk in people with COPD. Genetic and epigenetic changes, as well as the aberrant expression of non-coding RNAs, predispose the lung epithelium to carcinogenesis by altering the expression of cancer- and immune-related genes. Oxidative stress generated by tobacco smoking plays a role in reducing genomic integrity, promoting epithelial-mesenchymal-transition, and generating a chronic inflammatory environment. This leads to abnormal immune responses that promote cancer development, though not all smokers develop lung cancer. Sex differences in the metabolism of tobacco smoke predispose females to developing COPD and accumulating damage from oxidative stress that poses a risk for the development of lung cancer. Dysregulation of the lung microenvironment and microbiome contributes to chronic inflammation, which is observed in COPD and known to facilitate cancer initiation in various tumor types. Further, there is a need to better characterize and identify the proportion of individuals with COPD who are at a high risk for developing lung cancer. We evaluate possible novel and individualized screening strategies, including biomarkers identified in genetic studies and exhaled breath condensate analysis. We also discuss the use of corticosteroids and statins as chemopreventive agents to prevent lung cancer. It is crucial that we optimize the current methods for the early detection and management of lung cancer and COPD in order to improve the health outcomes for a large affected population.

Liquid Biopsy in Lung Cancer: Biomarkers for the Management of Recurrence and Metastasis.

Liquid biopsies have emerged as a promising tool for the detection of metastases as well as local and regional recurrence in lung cancer. Liquid biopsy tests involve analyzing a patient's blood, urine, or other body fluids for the detection of biomarkers, including circulating tumor cells or tumor-derived DNA/RNA that have been shed into the bloodstream. Studies have shown that liquid biopsies can detect lung cancer metastases with high accuracy and sensitivity, even before they are visible on imaging scans. Such tests are valuable for early intervention and personalized treatment, aiming to improve patient outcomes. Liquid biopsies are also minimally invasive compared to traditional tissue biopsies, which require the removal of a sample of the tumor for further analysis. This makes liquid biopsies a more convenient and less risky option for patients, particularly those who are not good candidates for invasive procedures due to other medical conditions. While liquid biopsies for lung cancer metastases and relapse are still being developed and validated, they hold great promise for improving the detection and treatment of this deadly disease. Herein, we summarize available and novel approaches to liquid biopsy tests for lung cancer metastases and recurrence detection and describe their applications in clinical practice.

Evaluating the Probiotic Potential of Lactic Acid Bacteria Implicated in Natural Fermentation of Table Olives, cv. Cobrançosa.

The probiotic features of Lactiplantibacillus (L.) pentosus and L. paraplantarum strains, endogenous in Cobrançosa table olives from northeast Portugal, were assessed in terms of functional properties and health benefits. Fourteen lactic acid bacteria strains were compared with Lacticaseibacillus casei from a commercial brand of probiotic yoghurt and L. pentosus B281 from Greek probiotic table olives, in attempts to select strains with higher probiotic performances than those references. For functional properties, the i53 and i106 strains, respectively, exhibited: 22.2 ± 2.2% and 23.0 ± 2.2% for Caco-2 cell adhesion capacity; 21.6 ± 7.8% and 21.5 ± 1.4% for hydrophobicity; 93.0 ± 3.0% and 88.5 ± 4.5% for autoaggregation ability by 24 h of incubation; and ability to co-aggregate with selected pathogens-from 29 to 40% to Gram+ (e.g., Staphylococcus aureus ATCC 25923 and Enterococcus faecalis ATCC 29212); and from 16 to 44% for Gram- (e.g., Escherichia coli ATCC 25922 and Salmonella enteritidis ATCC 25928). The strains proved to be resistant (i.e., halo zone ≤14 mm) to some antibiotics (e.g., vancomycin, ofloxacin, and streptomycin), but susceptible (i.e., halo zone ≥ 20 mm) to others (e.g., ampicillin and cephalothin). The strains exhibited health-beneficial enzymatic activity (such as acid phosphatase and naphthol-AS-BI-phosphohydrolase), but not health-harmful enzymatic activity (such as ß-glucuronidase and N-acetyl-ß-glucosaminidase). Additionally, the antioxidant activity and cholesterol assimilation features, respectively, of the strains were 19.6 ± 2.8% and 77.5 ± 0.5% for i53, and 19.6 ± 1.8% and 72.2 ± 0.9% for i106. This study indicated that the addition of L. pentosus strains i53 and/or i106 to Cobrançosa table olives is likely to enhance the added value of the final product, in view of the associated potential benefits upon human health.

Neurological impairment caused by Schistosoma mansoni systemic infection exhibits early features of idiopathic neurodegenerative disease.

Schistosomiasis, a neglected tropical disease caused by trematodes of the Schistosoma genus, affects over 250 million people around the world. This disease has been associated with learning and memory deficits in children, whereas reduced attention levels, impaired work capacity, and cognitive deficits have been observed in adults. Strongly correlated with poverty and lack of basic sanitary conditions, this chronic endemic infection is common in Africa, South America, and parts of Asia and contributes to inhibition of social development and low quality of life in affected areas. Nonetheless, studies on the mechanisms involved in the neurological impairment caused by schistosomiasis are scarce. Here, we used a murine model of infection with Schistosoma mansoni in which parasites do not invade the central nervous system to evaluate the consequences of systemic infection on neurologic function. We observed that systemic infection with S. mansoni led to astrocyte and microglia activation, expression of oxidative stress-induced transcription factor Nrf2, oxidative damage, Tau phosphorylation, and amyloid-ß peptide accumulation in the prefrontal cortex of infected animals. We also found impairment in spatial learning and memory as evaluated by the Morris water maze task. Administration of anthelmintic (praziquantel) and antioxidant (N-acetylcysteine plus deferoxamine) treatments was effective in inhibiting most of these phenotypes, and the combination of both treatments had a synergistic effect to prevent such changes. These data demonstrate new perspectives toward the understanding of the pathology and possible therapeutic approaches to counteract long-term effects of systemic schistosomiasis on brain function.

6-Shogaol Exerts a Neuroprotective Factor in Offspring after Maternal Immune Activation in Rats.

6-Shogaol is one of the main active phenolic components of ginger and has neuroprotective effects by protecting brain against the oxidative stress and regulate the levels of neurotrophic factors. The objective of the present study was to verify the effect of 6-shogaol on neurochemical parameters in offspring after maternal immune activation by lipopolysaccharide (LPS) in rats. Twelve pregnant Wistar rats received 100 µg/kg of LPS or saline solution on the gestational day 9.5. Male offspring participated in the study and from the postnatal days (PND) 30 and 55, respectively, they were supplemented with 6-shogaol or saline solution, by gavage at a dose of 10 mg/kg/day, orally for 5 days. In PND 37 and 62, analysis of kinase signaling regulated by extracellular signal 1/2 (ERK 1/2), levels of neurotrophic factor derived from the brain (BDNF), and neuron-specific enolase (NSE), lipid and protein oxidative damage was evaluated by 4-hydroxy-2-nonenal (HNE) and 3-nitrotyrosine (3-NT), respectively, and myeloperoxidase (MPO) activity was performed in the hippocampus. Prenatal exposure to LPS significantly decreased ERK and BDNF levels in PND 37 and 62, increased NSE levels and lipid damage in rats in PND 37, and increased 3-NT level in rats in PND 62. With treatment using 6-shogaol, an increase in ERK and BDNF levels was identified in PND 37 and 62 and a reduction in HNE and MPO activity in rats in PND 37 and 62, respectively. 6-Shogaol positively increased markers of neuronal growth, plasticity and synaptic activity and reduced oxidative damage in the hippocampus in an animal model of autism by maternal immune activation.

A symbiotic bacterium of shipworms produces a compound with broad spectrum anti-apicomplexan activity.

Apicomplexan parasites cause severe disease in both humans and their domesticated animals. Since these parasites readily develop drug resistance, development of new, effective drugs to treat infection caused by these parasites is an ongoing challenge for the medical and veterinary communities. We hypothesized that invertebrate-bacterial symbioses might be a rich source of anti-apicomplexan compounds because invertebrates are susceptible to infections with gregarines, parasites that are ancestral to all apicomplexans. We chose to explore the therapeutic potential of shipworm symbiotic bacteria as they are bona fide symbionts, are easily grown in axenic culture and have genomes rich in secondary metabolite loci [1,2]. Two strains of the shipworm symbiotic bacterium, Teredinibacter turnerae, were screened for activity against Toxoplasma gondii and one strain, T7901, exhibited activity against intracellular stages of the parasite. Bioassay-guided fractionation identified tartrolon E (trtE) as the source of the activity. TrtE has an EC50 of 3 nM against T. gondii, acts directly on the parasite itself and kills the parasites after two hours of treatment. TrtE exhibits nanomolar to picomolar level activity against Cryptosporidium, Plasmodium, Babesia, Theileria, and Sarcocystis; parasites representing all branches of the apicomplexan phylogenetic tree. The compound also proved effective against Cryptosporidium parvum infection in neonatal mice, indicating that trtE may be a potential lead compound for preclinical development. Identification of a promising new compound after such limited screening strongly encourages further mining of invertebrate symbionts for new anti-parasitic therapeutics.

Impact of Nutritional Status on Survival in Head and Neck Cancer Patients After Total Laryngectomy.

Malnutrition is an important prognostic indicator of laryngeal squamous cell carcinoma. Retrospective study with head and neck cancer patients who underwent total laryngectomy. 243 patients of both sex were evaluated. The univariate analyses demonstrated an increased risk of death for the patients with greater weight loss, hypoalbuminemia, radiotherapy as an initial treatment, salvage surgery, and radical neck dissection. In a Multivariate Cox regression, older age (p = 0.03, 95% confidence interval [CI] 1.003-1.06, hazard ratio [HR] 1.029), Nutritional Risk Index ≤100 (p = 0.008, 95% CI 1.18-3.12, HR 1.921) and adjuvant radiotherapy (p = 0.029, 95% CI 0.31-3.12, HR 0.544) demonstrated prognostic significance in survival. Nutritional status is a modifiable variable and these findings highlight the need to adoption of simple nutritional assessment methods routinely during the treatment of head and neck cancer patients, in order to help improve prognosis after surgery.

Deacetylation and Desuccinylation of the Fucose-Rich Polysaccharide Fucopol: Impact on Biopolymer Physical and Chemical Properties.

FucoPol is an acylated polysaccharide with demonstrated valuable functional properties that include a shear thinning fluid behaviour, a film-forming capacity, and an emulsion forming and stabilizing capacity. In this study, the different conditions (concentration, temperature, and time) for alkaline treatment were investigated to deacylate FucoPol. Complete deacetylation and desuccinylation was achieved with 0.02 M NaOH, at 60 °C for 15 min, with no significant impact on the biopolymer's sugar composition, pyruvate content, and molecular mass distribution. FucoPol depyruvylation by acid hydrolysis was attempted, but it resulted in a very low polymer recovery. The effect of the ionic strength, pH, and temperature on the deacetylated/desuccinylated polysaccharide, d-FucoPol, was evaluated, as well as its emulsion and film-forming capacity. d-FucoPol aqueous solutions maintained the shear thinning behaviour characteristic of FucoPol, but the apparent viscosity decreased significantly. Moreover, contrary to FucoPol, whose solutions were not affected by the media's ionic strength, the d-FucoPol solutions had a significantly higher apparent viscosity for a higher ionic strength. On the other hand, the d-FucoPol solutions were not affected by the pH in the range of 3.6-11.5, while FucoPol had a decreased viscosity for acidic pH values and for a pH above 10.5. Although d-FucoPol displayed an emulsification activity for olive oil similar to that of FucoPol (98 ± 0%) for an oil-to-water ratio of 2:3, the emulsions were less viscous. The d-FucoPol films were flexible, with a higher Young's modulus (798 ± 152 MPa), a stress at the break (22.5 ± 2.5 MPa), and an elongation at the break (9.3 ± 0.7%) than FucoPol (458 ± 32 MPa, 15.5 ± 0.3 MPa and 8.1 ± 1.0%, respectively). Given these findings, d-FucoPol arises as a promising novel biopolymer, with distinctive properties that may render it useful for utilization as a suspending or emulsifier agent, and as a barrier in coatings and packaging films.

Typical Lung Carcinoids with Metastasis: Potential Role of MicroRNAs in the Regulation of Adaptive Immunity Associated with Disease: a Case Study.

BACKGROUND/AIMS: Lung carcinoids are uncommon neuroendocrine tumours. Molecular features of lung carcinoids have been poorly defined. microRNAs (miRNAs) are potent gene expression regulators with important roles in cancer development and progression. However, little is known on the role of miRNAs in the pathogenesis of lung carcinoids. Our goals were to identify commonly deregulated miRNAs in a rare case of lung carcinoid of typical histology with metastasis, as well as map miRNA target genes in pathways potentially associated with disease development and progression. METHODS: miRNA expression profiles were assessed using the TaqMan Low Density Arrays, which is a platform including 384 miRNAs. miRNA profiles were generated in the tumor and its corresponding lymph node metastasis, compared to reference normal lung tissues. Furthermore, miRNA expression was validated in a separate, publicly available external dataset (n=19 typical lung carcinoids; 2/19 were metastatic tumors, compared to six normal lung tissues, GSE77380). Following this analysis, computational tools were applied for data interpretation. miRTarBase was used to determine miRNA-target genes, followed by ToppGene Suite analysis to identify pathways and biological functions. In addition, the expression of genes targeted by miRNAs was validated in a second, separate external dataset (n=13 tumour samples, GSE35679). GEO2R data analysis tool was used in both validation analyses (miRNAs and genes). RESULTS: We identified 15 commonly significantly downregulated miRNAs (fold change, FC≥2 and p<0.05) in the tumour and its paired metastasis, with further decreasing levels in the metastatic lesion. Downregulation of miR-126-3p and miR-146b-5p was validated in the external dataset GSE77380. In addition, SOX2 and TCF4 genes, targeted by miR-126-3p, were consistently overexpressed in a subset of six typical lung carcinoids from the external dataset GSE35679. Pathways analysis showed that miRNAs miR-126-3p and miR-146b-5p target genes with a role in the regulation of adaptive immune response. CONCLUSION: Our results contribute to the identification of miRNA expression changes in a typical lung carcinoid and its corresponding lymph node metastasis. Down-regulated levels of miR-126-3p and miR-146b-5p and target gene over-expression could play a role in the progression of this case of primary typical lung carcinoid to regional metastasis. Identified miRNAs and target genes are potential candidates for validation in a larger number of cases.

Sinus node disfunction in an adolescent with systemic lupus erythematosus.

Cardiac involvement in systemic lupus erythematosus (SLE) is well documented. The pericardium, myocardium and endocardium, as well as the coronary arteries, the valves and the conduction system can all be affected. While pericarditis is common, arrythmias are less frequently described.We present a 13-year-old male, who had fatigue, anorexia, weight loss, myalgias and arthralgias for four months. On physical examination, we identified bradycardia (heart rate 31-50 bpm), oral and nasal ulcers and polyarthritis. The laboratory results showed hemolytic anemia, hypocomplementemia, antinuclear and anti-dsDNA antibodies, hematuria and non-nephrotic proteinuria. Renal function was normal. Lupus nephritis class II was diagnosed by kidney biopsy. On the transthoracic echocardiogram we identified a minimal pericardial effusion, suggesting pericarditis, and, on the electrocardiogram, we detected sinus arrest with junctional rhythm, denoting sinus node dysfunction. The patient was diagnosed with juvenile SLE with cardiac, renal, musculoskeletal and hematologic involvement. Disease remission and cardiac rhythm control were obtained with steroids and mycophenolate mofetil. Currently, the patient is asymptomatic, with normal sinus rhythm.We described an adolescent with SLE who had sinus node dysfunction upon diagnosis. Other cases have been reported in adults but none in juvenile SLE. All SLE patients should have a thorough cardiac examination to promptly diagnose and treat the innumerous cardiac manifestations of this disease.

Influence of nutritional status and frailty phenotype on health-related quality of life of patients with bladder or kidney cancer.

PURPOSE: This research aimed to assess the impact of nutritional status and frailty in the health-related quality of life (HRQoL) of patients with bladder or kidney cancer. METHODS: This was a cross-sectional study with individuals aged 20 years or older. Frailty phenotype was defined using the criteria of Fried et al. (2001). Patient-Generated Subjective Global Assessment (PG-SGA) classified nutritional status. The European Organization for Research and Treatment of Cancer Quality of life questionnaire Core-30 third version (EORTC QLQ-C30) assessed HRQoL. RESULTS: Forty-four patients with bladder and 44 with kidney cancer, mostly male, with a mean age of 65.9 and 58.6 years, respectively, were evaluated. Presence of frailty was not different between young and older adults. More than 80% of the robust subjects were well-nourished, while there was a predominance of frail with some degree of malnutrition (p < 0.05). The summary score of HRQoL was worse among the frails than pre-frails and robusts, both in bladder (68.5 vs 86.8 vs 89.5; p = 0.002) and in kidney cancer (54.9 vs 82.9 vs 91.4; p < 0.001), as well as in malnourished compared to well-nourished with bladder (72.9 vs 90.3; p = 0.003) and kidney cancer (69.4 vs 88.3; p = 0.001). After adjusted, frailty and malnutrition continued associated with poor summary score (p < 0.05). CONCLUSION: These findings indicate that frailty and malnutrition negatively affect HRQoL of patients with bladder or kidney cancer in several aspects.

Characterization and Biotechnological Potential of Extracellular Polysaccharides Synthesized by Alteromonas Strains Isolated from French Polynesia Marine Environments.

Marine environments comprise almost three quarters of Earth's surface, representing the largest ecosystem of our planet. The vast ecological and metabolic diversity found in marine microorganisms suggest that these marine resources have a huge potential as sources of novel commercially appealing biomolecules, such as exopolysaccharides (EPS). Six Alteromonas strains from different marine environments in French Polynesia atolls were selected for EPS extraction. All the EPS were heteropolysaccharides composed of different monomers, including neutral monosaccharides (glucose, galactose, and mannose, rhamnose and fucose), and uronic acids (glucuronic acid and galacturonic acid), which accounted for up to 45.5 mol% of the EPS compositions. Non-carbohydrate substituents, such as acetyl (0.5-2.1 wt%), pyruvyl (0.2-4.9 wt%), succinyl (1-1.8 wt%), and sulfate (1.98-3.43 wt%); and few peptides (1.72-6.77 wt%) were also detected. Thermal analysis demonstrated that the EPS had a degradation temperature above 260 °C, and high char yields (32-53%). Studies on EPS functional properties revealed that they produce viscous aqueous solutions with a shear thinning behavior and could form strong gels in two distinct ways: by the addition of Fe2+, or in the presence of Mg2+, Cu2+, or Ca2+ under alkaline conditions. Thus, these EPS could be versatile materials for different applications.