What's new about the tumor microenvironment of urothelial carcinoma?

Urothelial carcinoma is a significant global health concern that accounts for a substantial part of cancer diagnoses and deaths worldwide. The tumor microenvironment is a complex ecosystem composed of stromal cells, soluble factors, and altered extracellular matrix, that mutually interact in a highly immunomodulated environment, with a prominent role in tumor development, progression, and treatment resistance. This article reviews the current state of knowledge of the different cell populations that compose the tumor microenvironment of urothelial carcinoma, its main functions, and distinct interactions with other cellular and non-cellular components, molecular alterations and aberrant signaling pathways already identified. It also focuses on the clinical implications of these findings, and its potential to translate into improved quality of life and overall survival. Determining new targets or defining prognostic signatures for urothelial carcinoma is an ongoing challenge that could be accelerated through a deeper understanding of the tumor microenvironment.

Whole genome analysis and antimicrobial resistance of Neisseria gonorrhoeae isolates from Ghana.

Introduction: Gonorrhoea is a major public health concern. With the global emergence and spread of resistance to last-line antibiotic treatment options, gonorrhoea threatens to be untreatable in the future. Therefore, this study performed whole genome characterization of Neisseria gonorrhoeae collected in Ghana to identify lineages of circulating strains as well as their phenotypic and genotypic antimicrobial resistance (AMR) profiles. Methods: Whole genome sequencing (WGS) was performed on 56 isolates using both the Oxford Nanopore MinION and Illumina MiSeq sequencing platforms. The Comprehensive Antimicrobial Resistance Database (CARD) and PUBMLST.org/neisseria databases were used to catalogue chromosomal and plasmid genes implicated in AMR. The core genome multi-locus sequence typing (cgMLST) approach was used for comparative genomics analysis. Results and Discussion: In vitro resistance measured by the E-test method revealed 100%, 91.0% and 85.7% resistance to tetracycline, penicillin and ciprofloxacin, respectively. A total of 22 sequence types (STs) were identified by multilocus sequence typing (MLST), with ST-14422 (n = 10), ST-1927 (n = 8) and ST-11210 (n = 7) being the most prevalent. Six novel STs were also identified (ST-15634, 15636-15639 and 15641). All isolates harboured chromosomal AMR determinants that confer resistance to beta-lactam antimicrobials and tetracycline. A single cefixime-resistant strain, that belongs to N. gonorrhoeae multiantigen sequence type (NG-MAST) ST1407, a type associated with widespread cephalosporin resistance was identified. Neisseria gonorrhoeae Sequence Typing for Antimicrobial Resistance (NG-STAR), identified 29 unique sequence types, with ST-464 (n = 8) and the novel ST-3366 (n = 8) being the most prevalent. Notably, 20 of the 29 STs were novel, indicative of the unique nature of molecular AMR determinants in the Ghanaian strains. Plasmids were highly prevalent: pTetM and pblaTEM were found in 96% and 92% of isolates, respectively. The TEM-135 allele, which is an amino acid change away from producing a stable extended-spectrum ß-lactamase that could result in complete cephalosporin resistance, was identified in 28.5% of the isolates. Using WGS, we characterized N. gonorrhoeae strains from Ghana, giving a snapshot of the current state of gonococcal AMR in the country and highlighting the need for constant genomic surveillance.

Curettage or Resection? A Review on the Surgical Treatment of Low-Grade Chondrosarcomas.

Introduction Low-grade chondrosarcomas (LG-CS), including atypical cartilaginous tumors (ACT), are locally aggressive lesions. The focus of the discussion sits on the differential diagnosis between benign lesions or aggressive cartilaginous tumors and on their treatment: intralesional curettage or wide resection. This study presents the results obtained in the surgical treatment of 21 cases of LG-CS. Methods This retrospective study includes 21 consecutive patients from a single center with LG-CS who underwent surgery from 2013 to 2021. Fourteen were located in the appendicular skeleton, and seven in the axial (shoulder blade, spine, or pelvis). Mortality rate, recurrence, metastatic disease, overall survival, recurrence-free survival, and metastatic disease-free survival were analyzed for each type of procedure and each disease location. Operative complications and residual tumors were also recorded in cases where resection was performed. Survival was calculated using the Kaplan-Meier method. Results Thirteen patients underwent intralesional curettage (11 appendicular and 2 axial lesions), and eight underwent wide resection (5 axial and 3 appendicular). There were six recurrences during the follow-up, 43% of the axial lesions recurred, rising to 100% in axial curetted ones. Appendicular LG-CS recurred in 21% of cases, and only 18% of curetted appendicular lesions were not eradicated. The overall survival for the entire follow-up is 90.5%, and the 5-year survival rate is 83% (12 patients have adequate follow-up). Recurrence-free and metastasis-free survival were higher in resection cases, with 75% and 87.5%, vs. curettage 69.2% and 76.9%, respectively. In 9% of cases, the preoperative biopsy was inconsistent with the pathology of the surgical specimen. Discussion LG-CS and ACT are described as having high survival and low potential for metastatic disease. For this reason, these lesions are subject to a change in treatment philosophy to reflect these characteristics. Intra-lesional curettage is advocated as a less invasive technique for eradicating atypical cartilage tumors and has fewer and less severe complications, which was in accordance with our findings. Diagnosis, however, is challenging; misgrading is frequent and should be considered. Because of this risk of under-treating higher-grade lesions, some authors still defend wide-resection as the treatment of choice. We observed a trend towards longer survival, less recurrence, and metastatic disease with wide resection. Metastatic disease was higher than expected, present in 19% of cases, and always associated with local recurrence. Conclusion LG-CS is still a diagnostic and treatment challenge; patient selection is fundamental. Overall survival is high, independent of treatment choice or lesion location. We found a higher rate of metastatic disease than described in the literature; this, coupled with a misgrading rate of 9%, reflects the difficulty of preoperative diagnosis and the risk of treating high-grade chondrosarcomas as a low-grade lesion. More studies should be carried out with larger samples to obtain statistically robust results.

Carotid Body Resection Prevents Short-Term Spatial Memory Decline in Prediabetic Rats Without Changing Insulin Signaling in the Hippocampus and Prefrontal Cortex.

Individuals who develop type 2 diabetes (T2D) at an early age are at higher risk of developing neurodegenerative disorders such as Alzheimer's and Parkinson's disease. A shared dysfunctional characteristic between T2D and these neurodegenerative disorders is insulin resistance. Recently, it was shown that prediabetes animals and patients exhibited increased carotid body (CB) activity. Moreover, these organs are deeply involved in the development of metabolic diseases, since upon abolishment of their activity via carotid sinus nerve (CSN) resection, several dysmetabolic features of T2D were reverted. Herein, we investigated if CSN resection may also prevent cognitive impairment associated with brain insulin resistance. We explored a diet-induced prediabetes animal model where Wistar rats are kept in a high fat-high sucrose (HFHSu) diet for 20 weeks. We evaluated CSN resection effects on behavioral parameters and on insulin signaling-related proteins levels, in the prefrontal cortex and the hippocampus. HFHSu animals exhibited impaired short-term memory evaluated by the y-maze test. Remarkably, CSN resection prevented the development of this phenotype. HFHSu diet or CSN resection did not promote significant alterations in insulin signaling-associated proteins levels. Our findings suggest that CBs modulation might have a role in preventing short-term spatial memory deficits associated with peripheral dysmetabolic states.

Unveiling new secrets in Parkinson's disease: The glycatome.

We are witnessing a considerable increase in the incidence of Parkinson's disease (PD), which may be due to the general ageing of the population. While there is a plethora of therapeutic strategies for this disease, they still fail to arrest disease progression as they do not target and prevent the neurodegenerative process. The identification of disease-causing mutations allowed researchers to better dissect the underlying causes of this disease, highlighting, for example, the pathogenic role of alpha-synuclein. However, most PD cases are sporadic, which is making it hard to unveil the major causative mechanisms of this disease. In the recent years, epidemiological evidence suggest that type-2 diabetes mellitus (T2DM) individuals have higher risk and worst outcomes of PD, allowing to raise the hypothesis that some dysregulated processes in T2DM may contribute or even trigger the neurodegenerative process in PD. One major consequence of T2DM is the unprogrammed reaction between sugars, increased in T2DM, and proteins, a reaction named glycation. Pre-clinical reports show that alpha-synuclein is a target of glycation, and glycation potentiates its pathogenicity which contributes for the neurodegenerative process. Moreover, it triggers, anticipates, or aggravates several PD-like motor and non-motor complications. A given profile of proteins are differently glycated in diseased conditions, altering the brain proteome and leading to brain dysfunction and neurodegeneration. Herein we coin the term Glycatome as the profile of glycated proteins. In this review we report on the mechanisms underlying the association between T2DM and PD, with particular focus on the impact of protein glycation.

Acute coronary syndrome and stress: Is there a relationship?

INTRODUCTION: Acute coronary syndrome (ACS) is the result of a complex pathophysiological process with various dynamic factors. The 10-item Perceived Stress Scale (PSS-10) is a validated instrument for estimating stress levels in clinical practice and may be useful in the assessment of ACS. METHODS: We carried out a single-center prospective study engaging patients hospitalized with ACS between March 20, 2019 and March 3, 2020. The PSS-10 was completed during the hospitalization period. The ACS group was compared to a control group (the general Portuguese population), and a subanalysis in the stress group were then performed. RESULTS: A total of 171 patients with ACS were included, of whom 36.5% presented ST-elevation myocardial infarction (STEMI), 38.1% were female and the mean PSS score was 19.5±7.1. Females in the control group scored 16.6±6.3 on the PSS-10 and control males scored 13.4±6.5. The female population with ACS scored 22.8±9.8 on the PSS-10 (p<0.001). Similarly, ACS males scored a mean of 17.4±6.4 (p<0.001). Pathological stress levels were not a predictor of major adverse cardiovascular events or severity at admission. CONCLUSIONS: ACS patients had higher perceived stress levels compared to the control group. Perceived stress level was not associated with worse prognosis in ACS patients.

Revascularization strategies in STEMI and multivessel disease.

INTRODUCTION: The main treatment for ST-elevation myocardial infarction (STEMI) is the re-establishment of the coronary flow of infarct-related arteries. However, 50% of cases present multivessel disease (MVD), negatively affecting mortality. Complete revascularization (CR) is currently advocated since it reduces major adverse cardiovascular events (MACE). OBJECTIVE: Evaluation of the adopted revascularization strategy and its prognostic value in a Portuguese cohort of STEMI patients with MVD. MATERIAL AND METHODS: Retrospective analysis of patients admitted with STEMI included in the Portuguese Registry of Acute Coronary Syndromes between 2010 and 2019. Patients were divided in two groups regarding revascularization strategy (complete versus incomplete) and compared. Independent predictors of a composite of all-cause mortality and rehospitalization for cardiovascular causes were assessed by multivariate logistic regression. RESULTS: A total of 3500 patients were included. A CR strategy was performed in 21.8% of patients, who were younger and healthier. They also presented more hemodynamically stable and had less kidney dysfunction and anaemia. Their coronary anatomy was less complex, with a higher prevalence of 2-vessel and a lower proportion of chronic occlusions. In-hospital and 1-year adverse events were less frequent between patients with CR. CONCLUSION: In hemodynamically stable STEMI patients, CR substantially reduced in-hospital and 1-year all-cause mortality and MACE.

Prognostic value of brain natriuretic peptide in ST-elevation myocardial infarction patients: A Portuguese registry.

INTRODUCTION: Brain natriuretic peptide (BNP) is a highly sensitive and specific biomarker for the extent of myocardial infarction that is strongly related to short- and long-term prognosis in patients with acute coronary syndromes. OBJECTIVE: To assess the prognostic value of BNP levels in a Portuguese cohort of ST-elevation myocardial infarction (STEMI) patients. METHODS: We performed a retrospective analysis of patients admitted with STEMI included in the Portuguese Registry of Acute Coronary Syndromes (ProACS) between 2010 and 2019. Patients were divided into three groups according to BNP level (<100 pg/ml, 100-399 pg/ml and ≥400 pg/ml) and compared. Independent predictors of a composite of all-cause mortality and rehospitalization for cardiovascular causes were assessed by multivariate logistic regression. For sample homogenization, propensity score matching and pairwise matching with a tolerance level of 0.005 were performed. RESULTS: A total of 1650 patients were included, of whom 21.5% presented high BNP levels (≥400 pg/ml). These were older and had more comorbidities, lower admission systolic blood pressure and hemoglobin, higher heart rate, Killip class and creatinine, worse left ventricular systolic function and severe coronary anatomy. Higher BNP was associated with more in-hospital complications, in-hospital mortality and adverse outcomes at one year. CONCLUSION: BNP levels during the index hospitalization were a powerful prognostic biomarker for all-cause mortality and major adverse cardiac events in patients admitted with STEMI to Portuguese hospitals.

Antimicrobial Blue Light for Prevention and Treatment of Highly Invasive Vibrio vulnificus Burn Infection in Mice.

Vibrio vulnificus is an invasive marine bacterium that causes a variety of serious infectious diseases. With the increasing multidrug-resistant variants, treatment of V. vulnificus infections is becoming more difficult. In this study, we explored antimicrobial blue light (aBL; 405 nm wavelength) for the treatment of V. vulnificus infections. We first assessed the efficacy of aBL against five strains of V. vulnificus in vitro. Next, we identified and quantified intracellular porphyrins in V. vulnificus to provide mechanistic insights. Additionally, we measured intracellular reactive oxygen species (ROS) production and bacterial membrane permeabilization following aBL exposures. Lastly, we conducted a preclinical study to investigate the efficacy and safety of aBL for the prevention and treatment of burn infections caused by V. vulnificus in mice. We found that aBL effectively killed V. vulnificus in vitro in both planktonic and biofilm states, with up to a 5.17- and 4.57-log10 CFU reduction being achieved, respectively, following an aBL exposure of 216 J/cm2. Protoporphyrin IX and coproporphyrins were predominant in all the strains. Additionally, intracellular ROS was significantly increased following aBL exposures (P < 0.01), and there was evidence of aBL-induced permeabilization of the bacterial membrane (P < 0.0001). In the preclinical studies, we found that female mice treated with aBL 30 min after bacterial inoculation showed a survival rate of 81% following 7 days of observation, while only 28% survival was observed in untreated female mice (P < 0.001). At 6 h post-inoculation, an 86% survival was achieved in aBL-treated female mice (P = 0.0002). For male mice, 86 and 63% survival rates were achieved when aBL treatment was given 30 min and 6 h after bacterial inoculation, respectively, compared to 32% survival in the untreated mice (P = 0.0004 and P = 0.04). aBL did not reduce cellular proliferation or induce apoptosis. We found five cytokines were significantly upregulated in the males after aBL treatment, including MCSF (P < 0.001), MCP-5 (P < 0.01), TNF RII (P < 0.01), CXCL1 (P < 0.01), and TIMP-1 (P < 0.05), and one in the females (TIMP-1; P < 0.05), suggesting that aBL may induce certain inflammatory processes. In conclusion, aBL may potentially be applied to prevent and treat V. vulnificus infections.

Efecto de las Técnicas Instrumentales KineticXer® en la Modificación de Parámetros Séricos y Mecánicos en Usuarios Sedentarios con Dolor Lumbar Inespecífico / Effect of KineticXer® Instrumental Techniques in the Modification of Serum and Mechanical Parameters in Sedentary Users with Nonspecific Low Back Pain

Introducción. El dolor lumbar es una de las causas mas comunes de discapacidad en el mundo, existen diferentes tratamientos conservadores dentro de la kinesiología para el manejo de este. La presente investigación describe los efectos de la aplicación de técnicas de liberación miofascial instrumental y, cómo éstas modifican parámetros mecánicos y la expresión de parámetros séricos, tales como: Leucocitos, Bilirrubina y Fierro en estudiantes sedentarios que presenten dolor lumbar inespecífico de la Universidad de las Américas. Objetivo. Describir el efecto de la técnica de liberación miofascial instrumental en la modificación de parámetros mecánicos y séricos en usuarios sedentarios con dolor lumbar inespecífico. Métodos. Analítico experimental. Resultado. Fueron intervenidos 14 participantes sedentarios con dolor lumbar inespecífico, los resultados no fueron significativos en los cambios serios, por el contrario, fueron significativo en los cambios mecánicos. Conclusión. Las técnicas de liberación miofascial instrumental pueden ser una herramienta eficaz para el manejo del dolor lumbar inespecífico, pero faltan mas estudios para demostrar sus efectos a nivel sérico.

Introduction. Low back pain is one of the most common causes of disability in the world, there are different conservative treatments within kinesiology for its management. The present research describes the effects of the application of instrumental myofascial release techniques and how they modify mechanical parameters and the expression of serum parameters, such as: Leukocytes, Biliverdin and Iron in sedentary students with non-specific lumbar pain from the University of Las Américas. Objective. To describe the effect of the instrumental myofascial release technique in the modification of mechanical and serum parameters in sedentary users with nonspecific low back pain. Methods. Case series Results. 14 sedentary participants with non-specific lumbar pain were operated on, the results were not significant in the serious changes, on the contrary, they were significant in the mechanical changes. Conclusion. Instrumental myofascial release techniques can be an effective tool for the management of nonspecific low back pain, but more studies are needed to demonstrate their effects at the serum level.

Glycation modulates glutamatergic signaling and exacerbates Parkinson's disease-like phenotypes.

Alpha-synuclein (aSyn) is a central player in the pathogenesis of synucleinopathies due to its accumulation in typical protein aggregates in the brain. However, it is still unclear how it contributes to neurodegeneration. Type-2 diabetes mellitus is a risk factor for Parkinson's disease (PD). Interestingly, a common molecular alteration among these disorders is the age-associated increase in protein glycation. We hypothesized that glycation-induced neuronal dysfunction is a contributing factor in synucleinopathies. Here, we dissected the impact of methylglyoxal (MGO, a glycating agent) in mice overexpressing aSyn in the brain. We found that MGO-glycation potentiates motor, cognitive, olfactory, and colonic dysfunction in aSyn transgenic (Thy1-aSyn) mice that received a single dose of MGO via intracerebroventricular injection. aSyn accumulates in the midbrain, striatum, and prefrontal cortex, and protein glycation is increased in the cerebellum and midbrain. SWATH mass spectrometry analysis, used to quantify changes in the brain proteome, revealed that MGO mainly increase glutamatergic-associated proteins in the midbrain (NMDA, AMPA, glutaminase, VGLUT and EAAT1), but not in the prefrontal cortex, where it mainly affects the electron transport chain. The glycated proteins in the midbrain of MGO-injected Thy1-aSyn mice strongly correlate with PD and dopaminergic pathways. Overall, we demonstrated that MGO-induced glycation accelerates PD-like sensorimotor and cognitive alterations and suggest that the increase of glutamatergic signaling may underly these events. Our study sheds new light into the enhanced vulnerability of the midbrain in PD-related synaptic dysfunction and suggests that glycation suppressors and anti-glutamatergic drugs may hold promise as disease-modifying therapies for synucleinopathies.

Dysmetabolism and Neurodegeneration: Trick or Treat?

Accumulating evidence suggests the existence of a strong link between metabolic syndrome and neurodegeneration. Indeed, epidemiologic studies have described solid associations between metabolic syndrome and neurodegeneration, whereas animal models contributed for the clarification of the mechanistic underlying the complex relationships between these conditions, having the development of an insulin resistance state a pivotal role in this relationship. Herein, we review in a concise manner the association between metabolic syndrome and neurodegeneration. We start by providing concepts regarding the role of insulin and insulin signaling pathways as well as the pathophysiological mechanisms that are in the genesis of metabolic diseases. Then, we focus on the role of insulin in the brain, with special attention to its function in the regulation of brain glucose metabolism, feeding, and cognition. Moreover, we extensively report on the association between neurodegeneration and metabolic diseases, with a particular emphasis on the evidence observed in animal models of dysmetabolism induced by hypercaloric diets. We also debate on strategies to prevent and/or delay neurodegeneration through the normalization of whole-body glucose homeostasis, particularly via the modulation of the carotid bodies, organs known to be key in connecting the periphery with the brain.

Risperidone in analgesia induced by paracetamol and meloxicam in experimental pain.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the best therapeutic options to treat pain. Their use in combination with other drugs may broaden their applicability in analgesia if their ceiling and adverse effects are reduced. The aim of this study was to evaluate the pharmacological interaction of two NSAIDs, paracetamol and meloxicam, with the antipsychotic drug risperidone in mice, in several experimental tests of nociceptive and inflammatory pain. Antinociception was assessed by dose-response curves to paracetamol and meloxicam before and after the i.p. administration of 0.5 mg/kg of risperidone. Results are presented as means ± SEM and differences were calculated by one-way ANOVA followed by Tukey's post-test. Paracetamol and meloxicam produced a dose-related antinociceptive effect with diverse potencies. Risperidone increased the analgesia mediated by paracetamol and meloxicam only in the tonic tests that detected inflammatory pain. This suggests that COX inhibition is only a partial explanation of the increased analgesic potency of paracetamol and meloxicam since the effects of NSAIDs in the CNS are mediated by multiple mechanisms. These results indicate that the combination of risperidone with paracetamol or meloxicam could be a new and effective alternative for the management of inflammatory pain.

Insulin-degrading enzyme: an ally against metabolic and neurodegenerative diseases.

Insulin-degrading enzyme (IDE) function goes far beyond its known proteolytic role as a regulator of insulin levels. IDE has a wide substrate promiscuity, degrading several proteins such as amyloid-ß peptide, glucagon, islet amyloid polypeptide (IAPP), and insulin-like growth factors, which have diverse physiological and pathophysiological functions. Importantly, IDE plays other non-proteolytic functions such as: a chaperone/dead-end chaperone, an E1-ubiquitin activating enzyme, and a proteasome modulator. It also responds as a heat shock protein, regulating cellular proteostasis. Notably, amyloidogenic proteins such as IAPP, amyloid-ß, and α-synuclein have been reported as substrates for IDE chaperone activity. This is of utmost importance as failure of IDE may result in increased protein aggregation, a key hallmark in the pathogenesis of beta cells in type 2 diabetes mellitus and of neurons in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In this review, we focus on the biochemical and biophysical properties of IDE and the regulation of its physiological functions. We further raise the hypothesis that IDE plays a central role in the pathological context of dysmetabolic and neurodegenerative diseases and discuss its potential as a therapeutic target. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Cocaine-associated myocardial infarction: Features of diagnosis and treatment.

Temporal relation of myocardial infarction with cocaine use was first reported in 1982, coronary spasm being the presumed aetiology since most patients presented with normal coronary arteries. However, severe and diffused coronary atherosclerosis is also common in cocaine users with myocardial infarction. The management of these patients presenting with chest pain includes therapy directed to antagonize sympathetic activation and mechanical reperfusion or thrombolytic therapy if ischaemia continues.

What is the real impact of on-site percutaneous coronary intervention? A propensity score analysis of patients admitted with acute coronary syndrome. / Qual o verdadeiro impacto da intervenção coronária percutânea on­site? Análise de score de propensão de doentes admitidos por síndrome coronária aguda.

INTRODUCTION: In an era in which coronary heart disease is one of the leading causes of death worldwide, several studies report the persistence of obstacles to accessing revascularization, and percutaneous coronary intervention in particular, which may be associated with worse outcomes. OBJECTIVES: To compare cardiovascular outcomes in patients admitted to hospitals with and without on-site percutaneous coronary intervention (PCI) capabilities. MATERIAL AND METHODS: A retrospective study based on the National Registry of Acute Coronary Syndromes (ACS) - with data collection from 2010 to 2018. Division of the patients into two groups: with and without ST-elevation. Two subgroups were subsequently created according to the presence/absence of on-site PCI. A propensity score was performed to standardize the results. Patients without information about hospital admission (with/without PCI) were excluded. RESULTS: 6008 patients were included after exclusion criteria and propensity score were applied. We found that patients admitted for ACS with ST-elevation (STE-ACS) had more episodes of sustained ventricular tachycardia (OR 2.14; CI (1.26-3.61); p=0.004) in hospitals without on-site PCI. Regarding ACS without ST elevation (NSTE-ACS), there were more cases of congestive heart failure (OR 0.79; CI (0.65-0.98)) in hospitals with on-site PCI. CONCLUSION: The incidence of a greater number of major adverse events in hospitalizations without on-site PCI, particularly in the case of STE-ACS, is a consequence of the delay before revascularization. National and local strategies must be established to reduce the negative impact of the absence of on-site PCI and the resulting time before revascularization.