In the central nervous system, zinc is released along with glutamate during neurotransmission and, in excess, can promote neuronal death. Experimental studies have shown that metallothioneins I/II ...(MT-I/II), which chelate free zinc, can affect seizures and reduce neuronal death after status epilepticus. Our aim was to evaluate the expression of MT-I/II in the hippocampus of patients with temporal lobe epilepsy (TLE). Hippocampi from patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) were evaluated for expression of MT-I/II and for neuronal, astroglial, and microglial populations. Compared to control cases, MTLE group displayed widespread increase in MT-I/II expression, astrogliosis and reduced neuronal population. MT-I/II levels did not correlate with any clinical variables, but patients with secondary generalized seizures (SGS) had less MT-I/II than patients without SGS. In conclusion, MT-I/II expression was increased in hippocampi from MTLE patients and our data suggest that it may be associated with different seizure spread patterns.
Muscle-invasive bladder cancer (MIBC) remains a pressing health concern due to conventional treatment failure and significant molecular heterogeneity, hampering the development of novel targeted ...therapeutics. In our quest for novel targetable markers, recent glycoproteomics and bioinformatics data have pinpointed (glucose transporter 1) GLUT1 as a potential biomarker due to its increased expression in tumours compared to healthy tissues. This study explores this hypothesis in more detail, with emphasis on GLUT1 glycosylation patterns and cancer specificity. Immunohistochemistry analysis across a diverse set of human bladder tumours representing all disease stages revealed increasing GLUT1 expression with lesion severity, extending to metastasis, while remaining undetectable in healthy urothelium. In line with this, GLUT1 emerged as a marker of reduced overall survival. Revisiting nanoLC-EThcD-MS/MS data targeting immature
-glycosylation on muscle-invasive tumours identified GLUT1 as a carrier of short glycosylation associated with invasive disease. Precise glycosite mapping uncovered significant heterogeneity between patient samples, but also common glycopatterns that could provide the molecular basis for targeted solutions. Immature
-glycosylation conferred cancer specificity to GLUT1, laying the molecular groundwork for enhanced targeted therapeutics in bladder cancer. Future studies should focus on a comprehensive mapping of GLUT1 glycosites for highly specific cancer-targeted therapy development for bladder cancer.
Cancer remains a leading cause of death worldwide due to the lack of safer and more effective therapies. Cancer vaccines developed from neoantigens are an emerging strategy to promote protective and ...therapeutic anti-cancer immune responses. Advances in glycomics and glycoproteomics have unveiled several cancer-specific glycosignatures, holding tremendous potential to foster effective cancer glycovaccines. However, the immunosuppressive nature of tumours poses a major obstacle to vaccine-based immunotherapy. Chemical modification of tumour associated glycans, conjugation with immunogenic carriers and administration in combination with potent immune adjuvants constitute emerging strategies to address this bottleneck. Moreover, novel vaccine vehicles have been optimized to enhance immune responses against otherwise poorly immunogenic cancer epitopes. Nanovehicles have shown increased affinity for antigen presenting cells (APCs) in lymph nodes and tumours, while reducing treatment toxicity. Designs exploiting glycans recognized by APCs have further enhanced the delivery of antigenic payloads, improving glycovaccine's capacity to elicit innate and acquired immune responses. These solutions show potential to reduce tumour burden, while generating immunological memory. Building on this rationale, we provide a comprehensive overview on emerging cancer glycovaccines, emphasizing the potential of nanotechnology in this context. A roadmap towards clinical implementation is also delivered foreseeing advances in glycan-based immunomodulatory cancer medicine.
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•Glycans can be explored in anti-cancer vaccines and/or to target APCs.•Glycans conjugation to immunogens is required for effective immune responses.•Glycovaccine co-administration with immune adjuvants is required for anti-cancer efficacy.•Glycoengineering set foregrounds for glycovaccines but clinical translation is still needed.•A roadmap towards glycovaccines' clinical implementation is provided.
Advanced-stage solid primary tumors and metastases often express mucin 16 (MUC16), carrying immature glycans such as the Tn antigen, resulting in specific glycoproteoforms not found in healthy human ...tissues. This presents a valuable approach for designing targeted therapeutics, including cancer glycovaccines, which could potentially promote antigen recognition and foster the immune response to control disease spread and prevent relapse. In this study, we describe an adjuvant-free poly(lactic-co-glycolic acid) (PLGA)-based nanoglycoantigen delivery approach that outperforms conventional methods by eliminating the need for protein carriers while exhibiting targeted and adjuvant properties. To achieve this, we synthesized a library of MUC16-Tn glycoepitopes through single-pot enzymatic glycosylation, which were then stably engrafted onto the surface of PLGA nanoparticles, generating multivalent constructs that better represent cancer molecular heterogeneity. These glycoconstructs demonstrated affinity for Macrophage Galactose-type Lectin (MGL) receptor, known to be highly expressed by immature antigen-presenting cells, enabling precise targeting of immune cells. Moreover, the glycopeptide-grafted nanovaccine candidate displayed minimal cytotoxicity and induced the activation of dendritic cells in vitro, even in the absence of an adjuvant. In vivo, the formulated nanovaccine candidate was also nontoxic and elicited the production of IgG specifically targeting MUC16 and MUC16-Tn glycoproteoforms in cancer cells and tumors, offering potential for precise cancer targeting, including targeted immunotherapies.
Background
Type-2 diabetes (T2D) patients with body mass index (BMI) below 35 kg/m
2
carry lower remission rates than severely obese T2D individuals submitted to “standard limb lengths” Roux-en-Y ...gastric bypass (RYGB). Mild-obese patients appear to have more severe forms of T2D, where the mechanisms of glycemic control after a standard-RYGB may be insufficient. The elongation of the biliopancreatic limb may lead to greater stimulation of the distal intestine, alterations in bile acids and intestinal microbiota, among other mechanisms, leading to better metabolic outcomes. The aim of this study is to evaluate the safety and efficacy of the RYGB with a biliopancreatic limb of 200 cm in the control of T2D in patients with BMI 30–35 kg/m
2
.
Methods
From January 2011 to May 2015, 102 T2D patients with BMI from 30 to 34.9 kg/m
2
underwent laparoscopic RYGB with the biliopancreatic-limb of 200 cm and the alimentary-limb of 50 cm.
Results
There were no deaths or reoperations. The mean follow-up was 28.1 months. The mean BMI dropped from 32.5 to 25.1 kg/m
2
, while the mean fasting glucose decreased from 182.9 to 89.8 mg/dl and the mean glycated hemoglobin (HbA1c) went from 8.7 to 5.2%. During follow-up, 92.2% had their T2D under complete control (HbA1c < 6%, no anti-diabetic medications), while 7.8% were under partial control. Control of hypertension and dyslipidemia were 89.4 and 85.5%, respectively. No patient developed hypoalbuminemia, and there were mild micronutrient deficiencies.
Conclusions
RYGB with long-biliopancreatic and short-alimentary limbs is safe and seems effective in achieving complete control of T2D in patients with BMIs between 30 and 35 kg/m
2
.
Cancer presents a high mortality rate due to ineffective treatments and tumour relapse with progression. Cancer vaccines hold tremendous potential due to their capability to eradicate tumour and ...prevent relapse. In this study, we present a novel glycovaccine for precise targeting and immunotherapy of aggressive solid tumours that overexpress CD44 standard isoform (CD44s) carrying immature Tn and sialyl-Tn (sTn) O-glycans. We describe an enzymatic method and an enrichment strategy to generate libraries of well-characterized cancer-specific CD44s-Tn and/or sTn glycoproteoforms, which mimic the heterogeneity found in tumours. We conjugated CD44-Tn-derived glycopeptides with carrier proteins making them more immunogenic, with further demonstration of the importance of this conjugation to overcome the glycopeptides' intrinsic toxicity. We have optimized the glycopeptide-protein maleimide-thiol conjugation chemistry to avoid undesirable cross-linking between carrier proteins and CD44s glycopeptides. The resulting glycovaccines candidates were well-tolerated in vivo, inducing both humoral and cellular immunity, including immunological memory. The generated antibodies exhibited specific reactivity against synthetic CD44s-Tn glycopeptides, CD44s-Tn glycoengineered cells, and human tumours. In summary, we present a promising prototype of a cancer glycovaccine for future therapeutical pre-clinical efficacy validation.
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Resting sympathetic hyperactivity and impaired parasympathetic reactivation after exercise have been described in patients with heart failure (HF). However, the association of these autonomic changes ...in patients with HF and sarcopenia is unknown.
The aim of this study was to evaluate the impact of autonomic modulation on sarcopenia in male patients with HF.
We enrolled 116 male patients with HF and left ventricular ejection fraction < 40%. All patients underwent a maximal cardiopulmonary exercise testing. Maximal heart rate was recorded and delta heart rate recovery (∆HRR) was assessed at 1st and 2nd minutes after exercise. Muscle sympathetic nerve activity (MSNA) was recorded by microneurography. Dual-energy X-ray absorptiometry was used to measure body composition and sarcopenia was defined by the sum of appendicular lean muscle mass (ALM) divided by height in meters squared and handgrip strength.
Sarcopenia was identified in 33 patients (28%). Patients with sarcopenia had higher MSNA than those without (47 41-52 vs. 40 34-48 bursts/min, p = 0.028). Sarcopenic patients showed lower ∆HRR at 1st (15 10-21 vs. 22 16-30 beats/min, p < 0.001) and 2nd min (25 19-39 vs. 35 24-48 beats/min, p = 0.017) than non-sarcopenic. There was a positive correlation between ALM and ∆HRR at 1st (r = 0.26, p = 0.008) and 2nd min (r = 0.25, p = 0.012). We observed a negative correlation between ALM and MSNA (r = -0.29, p = 0.003).
Sympatho-vagal imbalance seems to be associated with sarcopenia in male patients with HF. These results highlight the importance of a therapeutic approach in patients with muscle wasting and increased peripheral sympathetic outflow.
Deregulation of the IGF system observed in human tumors indicates a role in malignant cell transformation and in tumor cell proliferation. Although overexpression of the IGF2 and IGF1R genes was ...described in adrenocortical tumors (ACTs), few studies reported their profiles in pediatric ACTs. In this study, the IGF2 and IGF1R expression was evaluated by RT-qPCR according to the patient's clinical/pathological features in 60 pediatric ACT samples, and IGF1R protein was investigated in 45 samples by immunohistochemistry (IHC). Whole transcriptome and functional assays were conducted after IGF1R inhibition with OSI-906 in NCI-H295A cell line. Significant IGF2 overexpression was found in tumor samples when compared with non-neoplastic samples (P<0.001), significantly higher levels of IGF1R in patients with relapse/metastasis (P=0.031) and moderate/strong IGF1R immunostaining in 62.2% of ACTs, but no other relationship with patient survival and clinical/pathological features was observed. OSI-906 treatment downregulated genes associated with MAPK activity, induced limited reduction of cell viability and increased the apoptosis rate. After 24h, the treatment also decreased the expression of genes related to the steroid biosynthetic process, the protein levels of the steroidogenic acute regulatory protein (STAR), and androgen secretion in cell medium, supporting the role of IGF1R in steroidogenesis of adrenocortical carcinoma cells. Our data showed that the IGF1R overexpression could be indicative of aggressive ACTs in children. However, in vitro treatments with high concentrations of OSI-906 (>1μM) showed limited reduction of cell viability, suggesting that OSI-906 alone could not be a suitable therapy to abolish carcinoma cell growth.
Trans women are specifically vulnerable to interpersonal violence. Being perceived as the gender that a transgender person identifies with, defined in some contexts as passing, may influence violence ...ratings. The EVAS (Violence and Health Self-Evaluation) study was a cross-sectional study that enrolled 121 trans women between 2019 and 2020 in Rio de Janeiro, Brazil, aiming to investigate the association between self-reported passing and different types of interpersonal violence. We enrolled 121 participants who had a median age of 36.3 (interquartile range IQR 13.7). Most of them were Black/mixed (78.5%) and had at least a high school education (63%). Most participants considered themselves as trans women (71.9%). Their median monthly income was $252.50 (IQR $302.50). Only 40 (33.1%) trans women had a main partner. Trans women with high passing had a higher prevalence of family violence and lower prevalence of observed police violence, violence in open and closed public spaces. Participants that reported a high passing had higher prevalence of family violence (p = .016); moreover, they reported observing less frequently police violence in the neighborhood they lived in for the last 12 months (p = .012) as well as having lower rates of suffering violence. Trans women who reported high passing had 81% (56%-92%) lower chance of suffering violence in open public places more than once, while prior racism experience had a positive association with violence in an open public place (aOR = 3.93, 95% CI .48, 15.40). Passing seems to protect from violence in public spaces, whilst it increases family violence. Data also suggest that observing police violence and violence in close public spaces. There is an urgent need to better understand the complex relationships around violence and foster its prevention.
Reaction norms fitted through random regression models (RRM) have been widely used in animal and plant breeding for analyses of genotype × environment (G × E) interaction. However, in annual crops, ...they remain unexplored. Thus, this study aimed to evaluate the applicability and efficiency of RRM fitted through Legendre polynomials as a tool to recommend cotton (Gossypium hirsutum L.) genotypes. To this end, a data set with 12 genotypes of cotton evaluated in 10 environments for fiber length (FL) and fiber fineness was used. The restricted maximum likelihood/best linear unbiased prediction (REML/BLUP) procedure was used to estimate the variance components and to predict the genetic values. Results showed that there was genetic variability among cotton genotypes and that the reaction norms over the environmental gradient illustrated the G × E interaction. Very high selective accuracies (rĝg>0.90) were found for both traits in all environments, which indicates high reliability in the genotype's recommendation. The areas under the reaction norms were calculated for the recommendation of genotypes for unfavorable, favorable, and overall environments. Regarding genotypes recommendation, areas under reaction norms allow recommending genotypes for unfavorable and favorable environments, as well as for overall recommendation, for both traits. This study is the first considering reaction norms fitted through RRM for the recommendation of cotton genotypes and demonstrated the potential of this technique in cotton breeding, besides its great potential to deal with G × E interactions.
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