Immunotherapy for cancer treatment has gained increased attention in recent years. Recently, our group reported the case of a patient with glioblastoma who underwent vaccination based on dendritic ...cells and experienced a strong Th1 immune response together with near-complete tumor remission. Here we report the results of a phase I/II prospective, non-controlled clinical trial with 37 patients harboring glioblastoma or grade 4 astrocytomas. At the time of first recurrence after surgery, patients began receiving monthly intradermal injections of allogenic DC-autologous tumor cell hybridomas. Overall survival, quality of life, and immunological profiles were assessed prospectively. Compared with patients in the Genomic Data Commons data bank, overall survival for vaccinated patients with glioblastoma was 27.6 ± 2.4 months (vs. 16.3 ± 0.7, log-rank
< 0.001, hazard ratio 0.53, 95%CI 0.36-0.78,
< 0.01), and it was 59.5 ± 15.9 for vaccinated astrocytoma grade 4 patients (vs. 19.8 ± 2.5, log-rank
< 0.05, hazard ratio 0.18, 95%CI 0.05-0.62,
< 0.01). Furthermore, seven vaccinated patients (two IDH-1-mutated and five wild type) remain alive at the time of this report (overall survival 47.9 months, SD 21.1, range: 25.4-78.6 months since diagnosis; and 34.2 months since recurrence, range: 17.8 to 40.7, SD 21.3). We believe that the data reported here can foster the improvement of treatment protocols for high-grade gliomas based on cellular immunotherapy.
The toxicological knowledge of mancozeb (MZ)-containing commercial formulations on non-target species is scarce and limited. Therefore, the objective of this work was to represent a realistic ...application scenario by evaluating the toxicity of environmental relevant and higher concentrations of a commercial formulation of MZ using zebrafish embryos. Following determination of the 96-h LC
50
value, the embryos at the blastula stage (~ 2 h post-fertilisation, hpf) were exposed to 0.5, 5, and 50 μg L
−1
of the active ingredient (~ 40× lower than the 96-h LC
50
). During the exposure period (96 h), lethal, sublethal, and teratogenic parameters, as well as behaviour analysis, at 120 hpf, were assayed. Biochemical parameters such as oxidative stress–linked enzymes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR)), reactive oxygen species (ROS) levels, and glutathione levels (GSH and GSSG), as well as the activity of degradation (glutathione
S
-transferase (GST) and carboxylesterase (CarE)), neurotransmission (acetylcholinesterase (AChE)), and anaerobic respiration (lactate dehydrogenase (LDH))–related enzymes, were analysed at the end of the exposure period. Exposed embryos showed a marked decrease in the hatching rate and many malformations (cardiac and yolk sac oedema and spinal torsions), with a higher prevalence at the highest concentration. A dose-dependent decreased locomotor activity and a response to an aversive stimulus, as well as a light-dark transition decline, were observed at environmental relevant concentrations. Furthermore, the activities of SOD and GR increased while the activity of GST, AChE, and MDA contents decreased. Taken together, the involvement of mancozeb metabolites and the generation of ROS are suggested as responsible for the developmental phenotypes. While further studies are needed to fully support the hypothesis presented, the potential cumulative effects of mancozeb-containing formulations and its metabolites could represent an environmental risk which should not be disregarded.
•The OphtalMimic device offers a precise simulation of human ocular conditions for improved ophthalmic drug product evaluation.•A novel hydrogel-based hybrid membrane closely replicates the human ...cornea’s water content and morphology.•The device successfully differentiated between the drainage profiles of various ophthalmic formulations.•The system demonstrated its potential as a reliable platform for the high-throughput screening of ophthalmic drugs.•This advancement aligns with ethical mandates to reduce animal testing and accelerate the development of safer and more effective ophthalmic drugs.
Envisaging to improve the evaluation of ophthalmic drug products while minimizing the need for animal testing, our group developed the OphthalMimic device, a 3D-printed device that incorporates an artificial lacrimal flow, a cul-de-sac area, a moving eyelid, and a surface that interacts effectively with ophthalmic formulations, thereby providing a close representation of human ocular conditions. An important application of such a device would be its use as a platform for dissolution/release tests that closely mimic in vivo conditions. However, the surface that artificially simulates the cornea should have a higher resistance (10 min) than the previously described polymeric films (5 min). For this key assay upgrade, we describe the process of obtaining and thoroughly characterizing a hydrogel-based hybrid membrane to be used as a platform base to simulate the cornea artificially. Also, the OphthalMimic device suffered design improvements to fit the new membrane and incorporate the moving eyelid. The results confirmed the successful synthesis of the hydrogel components. The membrane’s water content (86.25 ± 0.35 %) closely mirrored the human cornea (72 to 85 %). Furthermore, morphological analysis supported the membrane’s comparability to the natural cornea. Finally, the performance of different formulations was analysed, demonstrating that the device could differentiate their drainage profile through the viscosity of PLX 14 (79 ± 5 %), PLX 16 (72 ± 4 %), and PLX 20 (57 ± 14 %), and mucoadhesion of PLXCS0.5 (69 ± 1 %), PLX16CS1.0 (65 ± 3 %), PLX16CS1.25 (67 ± 3 %), and the solution (97 ± 8 %). In conclusion, using the hydrogel-based hybrid membrane in the OphthalMimic device represents a significant advancement in the field of ophthalmic drug evaluation, providing a valuable platform for dissolution/release tests. Such a platform aligns with the ethical mandate to reduce animal testing and promises to accelerate the development of safer and more effective ophthalmic drugs.
The behavior of lyotropic biomimetic systems in drug delivery was reviewed. These behaviors are influenced by drug properties, the initial water content, type of lyotropic liquid crystals (LLC), ...swell ability, drug loading rate, the presence of ions with higher or less kosmotropic or chaotropic force, and the electrostatic interaction between the drug and the lipid bilayers. The in vivo interaction between LCC-drugs, and the impact on the bioavailability of drugs, was reviewed. The LLC with a different architecture can be formed by the self-assembly of lipids in aqueous medium, and can be tuned by the structures and physical properties of the emulsion. These LLC lamellar phase, cubic phase, and hexagonal phase, possess fascinating viscoelastic properties, which make them useful as a dispersion technology, and a highly ordered, thermodynamically stable internal nanostructure, thereby offering the potential as a sustained drug release matrix for drug delivery. In addition, the biodegradable and biocompatible nature of lipids demonstrates a minimum toxicity and thus, they are used for various routes of administration. This review is not intended to provide a comprehensive overview, but focuses on the advantages over non modified conventional materials and LLC biomimetic properties.
AIM: To assess the immunoexpression of hypoxiarelated markers in samples from cirrhosis and primary and metastatic hepatocellular carcinoma(HCC).METHODS: From a total of 5836 autopsies performed at ...the Pathology Department- University of Sao Paulo School of Medicine Hospital- from 2003 to 2009, 188 presented primary liver tumors. Immunohistochemical reactivity for monocarboxylate transporters(MCTs)-1, 2 and 4, CD147 and glucose transporter-1(GLUT1)was assessed in necropsies from 80 cases of HCC. Data were stored and analyzed using the IBM SPSS statistical software(version 19, IBM Company, Armonk, NY). All comparisons were examined for statistical significance using Pearson’s χ2 test and Fisher’s exact test(when n < 5). The threshold for significant P values was established as P < 0.05.RESULTS: Plasma membrane expression of MCT4 and overall expression of GLUT1 showed progressively higher expression from non-neoplastic to primary HCC and to metastases. In contrast, overall expression of MCT2 was progressively decreased from non-neoplastic to primary HCC and to metastases. MCT1(overall and plasma membrane expression), MCT2 and CD147 plasma membrane expression were associated with absence of cirrhosis, while plasma membrane expression of CD147 was also associated with absence of HBV infection. MCT2 overall expression was associated with lower liver weight, absence of metastasis and absence of abdominal dissemination. Additionally, MCT4 plasma membrane positivity was strongly associated with Ki-67 expression. CONCLUSION: MCT4 and GLUT1 appear to play a role in HCC progression, while MCT2 is lost during progression and associated with better prognosis.
Background
Phase angle (PhA), proposed as an indicator of the number, integrity, and function of cells and evaluated in some clinical situations, decreases after bariatric surgery (BS). In contrast, ...higher values are found in physically active or exercising individuals. We therefore evaluated the influence of physical activity on PhA after BS.
Methods
The PhA and body composition (obtained by bioelectrical impedance analysis), physical activity level (obtained by International Physical Activity Questionnaire), and metabolic equivalents (METs) were evaluated in adult women submitted to BS. The PhA and body composition were evaluated at three time points: before and 6 and 12 months after surgery. Physical activity level and METs were measured at the two postoperative time points.
Results
A reduction in PhA was observed 6 (
p
< 0.01) and 12 months (
p
< 0.01) after BS, with no significant difference between time points. A moderate or high physical activity level was found in 81% of the volunteers after 6 months and in 65% after 12 months. METs were reduced after 12 months compared to 6 months. A positive correlation (
p
< 0.05) was observed between PhA and body cell mass after surgery. There was a significant positive correlation (
p
< 0.01) between PhA and METs after 12 months.
Conclusions
Physical activity may attenuate the PhA reduction that occurs after BS, with this parameter reflecting the engagement of these patients in this type of activity.
Graphical abstract
PNPLA3 (rs738409) and TM6SF2 (rs58542926) variants, interindividual and ethnic differences may be risk factors for non-alcoholic fatty liver disease (NAFLD). The PNPLA3 G allele is associated with ...worse NAFLD evolution in Hispanics and Caucasians. TM6SF2 is associated with hypertriglyceridemia, NAFLD, and cardiovascular disease. We aimed to evaluate the association between genetic ancestry by Ancestry Informative Markers (AIM), PNPLA3 and TM6SF2 polymorphisms in patients with biopsy-proven NAFLD in an admixed population.
We included adults with biopsy-proven NAFLD and excluded patients with the presence of other chronic liver disease, alcohol intake >100g/week, HIV, drug-induced fatty liver disease, or liver transplantation. We classified NAFLD using the Non-Alcoholic Steatohepatitis Clinical Research Network (NASH-CRN) histological scoring system. The PNPLA3 (rs738409 c.444C>G) and TM6SF2 (rs58542926 c.449C>T) genotyping were performed by RT-PCR. Genetic ancestry was determined using 46 insertion-deletion AIM; α<0.05 was considered significant.
A total of 248 patients with NAFLD were enrolled 34 with simple steatosis (NAFL); 214 with NASH. Overall, we detected a greater European ancestry contribution (0.645), followed by African (0.173), Amerindian (0.095), and East Asian (0.087) ancestry contribution, without differences between NAFL and NASH patients. However, we found a higher African genetic ancestry contribution among patients with NAFL who had the PNPLA3 C/C genotype than those with the G allele (0.216 ± 0.205 versus 0.105 ± 0.101, respectively; p=0.047). Ancestry contributions did not differ among TM6SF2 genotypes.
Among NAFL patients, greater African genetic ancestry was associated to a lower frequency of the PNPLA3 G allele, demonstrating a possible NASH ancestry-related protective factor.
The aim of this work was to develop a dense lamellar scaffold, as a biomimetic material with potential applications in the regeneration of tracheal tissue after surgical tumor resection. The ...scaffolds were produced by plastic compression technique, exploiting the use of total phenolic compounds (TPC) from
Psidium guajava
Linn as a potential cross-linking agent in a polymeric mixture based on collagen (COL), silk fibroin (SF), and polyethylene glycol 400 (PEG 400). Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) confirmed the chemical interactions between the polymers and the cross-linking of TPC between COL and SF. Morphological analyses showed scaffolds with porosity, interconnectivity, and a porous surface structure with a gyroid-like geometry. The analysis of the anisotropic degree resulted in anisotropic structures (0.1% TFC and 0.3% TFC) and an isotropic structure (0.5% TFC). In the mechanical properties, it was evidenced greater resistance for the 0.3% TFC formulation. The addition of TPC percentages did not result in a significant difference (
p
> 0.05) in swelling capacity and disintegration rate. The results confirmed that TPC were able to modulate the morphological, morphometric, and mechanical properties of scaffolds. Thus, this study describes a potential new material to improve the regeneration of major tracheal structures after surgical tumor removal.
Graphical Abstract
The chronic inflammatory microenvironment and immune cell dysfunction have been described as critical components for gastric tumor initiation and progression. The diffuse subtype is related to poor ...clinical outcomes, pronounced inflammation, and the worst prognosis. We investigated the association of polymorphisms in inflammatory response-related genes (
,
,
,
,
,
,
,
,
,
, and
) with gastric cancer susceptibility, progression and prognosis in a Brazilian sample, focusing on the diffuse subtype. We also performed the analysis regarding the total sample of cases (not stratified for tumor subtypes), allowing the comparison between the findings. We further investigated the polymorphisms in linkage disequilibrium and performed haplotype association analyses. In the case-control study, rs1042522 (
) was associated with a stronger risk for developing gastric cancer in the sample stratified for diffuse subtype patients when compared to the risk observed for the total cases; CTC haplotype (rs699947/rs833061/rs2010963
) was associated with risk while rs699947 was associated with protection for gastric malignancy in the total sample. Regarding the associations with the clinicopathological features of gastric cancer, for the diffuse subtype we found that rs699947 and rs833061 (
) were associated with outcomes related to a worse progression while rs5275 (
), rs909253 (
), and rs2227956 (
) were associated to a better progression of the disease. In the total sample, rs699947 and rs833061 (
), rs4644 (
), and rs1042522 (
) were able to predict a worse progression while rs5275 (
), rs2227956 (
), and rs3025039 (
) a better progression. Besides, rs909253 (
) predicted protection for the overall and disease-free survivals for gastric cancer. In conclusion, these results helped us to clarify the potential role of these polymorphisms in genes involved in the modulation of the inflammatory response in the pathogenesis of gastric cancer.
Abstract New wound dressings based on polymeric membranes have been widely exploited for clinical applications to assist in the healing process and prevent additional complications (e.g., bacterial ...infections). Here we propose the development of a new production method of polymeric membranes based on chitosan, incorporating glycolic extract of Aloe vera with joint synthesis of silver nanoparticles for use as a new bioactive dressing. The membranes were obtained by casting technique, and their morphological, physicochemical characteristics, degree of swelling, degradation profile and antimicrobial activity evaluated. Morphological analyzes confirmed the synthesis and presence of silver nanoparticles in the polymeric membrane. The chemical compatibility between the materials was demonstrated through thermal analysis (TGA and DSC) combined with ATR-FTIR tests, showing the complexation of the membranes (Mb-Ch-Ex.Av-NPs). All membranes were characterized as hydrophilic material (with a contact angle (ө) < 90°); however, the highest degree of swelling was obtained for the chitosan. (Mb-Ch) membrane (69.91 ± 5.75%) and the lowest for Mb-Ch-Ex.Av-NPs (26.62 ± 8.93%). On the other hand, the degradation profile was higher for Mb-Ch-Ex.Av-NPs (77.85 ± 7.51%) and lower for Mb-Ch (57.60 ± 2.29%). The manufactured bioactive dressings showed activity against Escherichia coli and Staphylococcus aureus . Our work confirmed the development of translucent and flexible chitosan-based membranes, incorporating Aloe vera glycolic extract with joint synthesis of silver nanoparticles for use as a new bioactive dressing, with proven antimicrobial activity. Graphical Abstract
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