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1.
Gels ; 10(4)2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38667671

RESUMO

Neural Invasion (NI) is a key pathological feature of cancer in the colonization of distant tissues, and its underlying biological mechanisms are still scarcely known. The complex interactions between nerve and tumor cells, along with the stroma, make it difficult to reproduce this pathology in effective study models, which in turn has limited the understanding of NI pathogenesis. In this study, we have designed a three-dimensional model of NI squamous cell carcinoma combining human epidermoid carcinoma cells (hECCs) with a complete peripheral nerve segment encapsulated in a fibrine-agarose hydrogel. We recreated two vital processes of NI: a pre-invasive NI model in which hECCs were seeded on the top of the nerve-enriched stroma, and an invasive NI model in which cancer cells were immersed with the nerve in the hydrogel. Histological, histochemical and immunohistochemical analyses were performed to validate the model. Results showed that the integration of fibrin-agarose advanced hydrogel with a complete nerve structure and hECCs successfully generated an environment in which tumor cells and nerve components coexisted. Moreover, this model correctly preserved components of the neural extracellular matrix as well as allowing the proliferation and migration of cells embedded in hydrogel. All these results suggest the suitability of the model for the study of the mechanisms underlaying NI.

2.
Exp Hematol Oncol ; 13(1): 38, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38581035

RESUMO

Rhabdomyosarcoma (RMS), such as other childhood tumors, has witnessed treatment advancements in recent years. However, high-risk patients continue to face poor survival rates, often attributed to the presence of the PAX3/7-FOXO1 fusion proteins, which has been associated with metastasis and treatment resistance. Despite efforts to directly target these chimeric proteins, clinical success remains elusive. In this study, the main aim was to address this challenge by investigating regulators of FOXO1. Specifically, we focused on TRIB3, a potential regulator of the fusion protein in RMS. Our findings revealed a prominent TRIB3 expression in RMS tumors, highlighting its correlation with the presence of fusion protein. By conducting TRIB3 genetic inhibition experiments, we observed an impairment on cell proliferation. Notably, the knockdown of TRIB3 led to a decrease in PAX3-FOXO1 and its target genes at protein level, accompanied by a reduction in the activity of the Akt signaling pathway. Additionally, inducible silencing of TRIB3 significantly delayed tumor growth and improved overall survival in vivo. Based on our analysis, we propose that TRIB3 holds therapeutic potential for treating the most aggressive subtype of RMS. The findings herein reported contribute to our understanding of the underlying molecular mechanisms driving RMS progression and provide novel insights into the potential use of TRIB3 as a therapeutic intervention for high-risk RMS patients.

3.
Lancet Reg Health Am ; 31: 100705, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38445021

RESUMO

Background: Reducing maternal mortality ratio (MMR) remains a paramount goal for low- and middle-income countries (LMICs), especially after COVID-19's devastating impact on maternal health indicators. We describe our experience implementing the Hospital Padrino Strategy (HPS), a collaborative model between a high-complexity hospital (Fundación Valle del Lili) and 43 medium- and low-complexity hospitals in one Colombian department (an administrative and territorial division) from 2021 to 2022, to sustain the trend towards reducing MMR. The study aimed to assess the effects of implementing HPS on both hospital performance and maternal health indicators in Valle del Cauca department (VCD). Methods: A mixed-methods study was conducted, comprising two phases. In the first phase, we investigated a cohort of hospitals through prospective follow-up to assess the outcomes of HPS implementation on hospital performance and maternal health indicators in VCD. In the second phase, qualitative data were collected through focus groups with 131 health workers from 33 hospitals to explore the implications of the HPS implementation on healthcare personnel. All data were obtained from records within the HPS implementation and from the Health Secretary of VCD. Findings: Evidence shows that in the context of HPS, 51 workshops involved 980 healthcare workers, covering the entire territory. Substantial improvements were observed in hospital conditions and healthcare personnel's technical competencies when providing obstetric care. Seven hundred eighty-five pregnant women with obstetric or perinatal emergencies received care through telehealth systems, with a progressive increase in technology adoption. Nine percent required Intensive Care Unit (ICU) admission, and none died. The MMR decreased from 78.8 in 2021 to 12.0 cases per 100,000 live births by 2022. Improvements in indicators and conducted training sessions instilled confidence and empowerment among the healthcare teams in the sponsored hospitals, as evidenced in focus groups derived from a sample of 131 healthcare workers from 33 hospitals. Interpretation: Implementing the Hospital Padrino Strategy led to a significant MMR reduction, and consolidated a model of social healthcare innovation replicable in LMICs. Funding: The Hospital Padrino Strategy was funded by the Fundación Valle del Lili and the Health Secretary of Valle del Cauca. Furthermore, this study received funding from a general grant for research from Tecnoquimicas S.A.

4.
Glob Chang Biol ; 30(3): e17186, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38450925

RESUMO

The Arctic is a global warming 'hot-spot' that is experiencing rapid increases in air and ocean temperatures and concomitant decreases in sea ice cover. These environmental changes are having major consequences on Arctic ecosystems. All Arctic endemic marine mammals are highly dependent on ice-associated ecosystems for at least part of their life cycle and thus are sensitive to the changes occurring in their habitats. Understanding the biological consequences of changes in these environments is essential for ecosystem management and conservation. However, our ability to study climate change impacts on Arctic marine mammals is generally limited by the lack of sufficiently long data time series. In this study, we took advantage of a unique dataset on hooded seal (Cystophora cristata) movements (and serum samples) that spans more than 30 years in the Northwest Atlantic to (i) investigate foraging (distribution and habitat use) and dietary (trophic level of prey and location) habits over the last three decades and (ii) predict future locations of suitable habitat given a projected global warming scenario. We found that, despite a change in isotopic signatures that might suggest prey changes over the 30-year period, hooded seals from the Northwest Atlantic appeared to target similar oceanographic characteristics throughout the study period. However, over decades, they have moved northward to find food. Somewhat surprisingly, foraging habits differed between seals breeding in the Gulf of St Lawrence vs those breeding at the "Front" (off Newfoundland). Seals from the Gulf favoured colder waters while Front seals favoured warmer waters. We predict that foraging habitats for hooded seals will continue to shift northwards and that Front seals are likely to have the greatest resilience. This study shows how hooded seals are responding to rapid environmental change and provides an indication of future trends for the species-information essential for effective ecosystem management and conservation.


Assuntos
Caniformia , Focas Verdadeiras , Animais , Ecossistema , Aquecimento Global , Hábitos
5.
Biomed Pharmacother ; 174: 116449, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38518607

RESUMO

Traumatic nerve injuries are nowadays a significant clinical challenge and new substitutes with adequate biological and mechanical properties are in need. In this context, fibrin-agarose hydrogels (FA) have shown the possibility to generate tubular scaffolds with promising results for nerve repair. However, to be clinically viable, these scaffolds need to possess enhanced mechanical properties. In this line, genipin (GP) crosslinking has demonstrated to improve biomechanical properties with good biological properties compared to other crosslinkers. In this study, we evaluated the impact of different GP concentrations (0.05, 0.1 and 0.2% (m/v)) and reaction times (6, 12, 24, 72 h) on bioartificial nerve substitutes (BNS) consisting of nanostructured FA scaffolds. First, crosslinked BNS were studied histologically, ultrastructurally and biomechanically and then, its biocompatibility and immunomodulatory effects were ex vivo assessed with a macrophage cell line. Results showed that GP was able to improve the biomechanical resistance of BNS, which were dependent on both the GP treatment time and concentration without altering the structure. Moreover, biocompatibility analyses on macrophages confirmed high cell viability and a minimal reduction of their metabolic activity by WST-1. In addition, GP-crosslinked BNS effectively directed macrophage polarization from a pro-inflammatory (M1) towards a pro-regenerative (M2) phenotype, which was in line with the cytokines release profile. In conclusion, this study considers time and dose-dependent effects of GP in FA substitutes which exhibited increased biomechanical properties while reducing immunogenicity and promoting pro-regenerative macrophage shift. These tubular substitutes could be useful for nerve application or even other tissue engineering applications such as urethra.

6.
Dev Psychol ; 60(3): 491-504, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38421799

RESUMO

This study investigated how adults over the lifespan flexibly adapt their use of prosocial speech acts when conveying bad news to communicative partners. Experiment 1a (N = 100 Scottish adults aged 18-72 years) assessed whether participants' use of prosocial speech acts varied according to audience design considerations (i.e., whether or not the recipient of the news was directly affected). Experiment 1b (N = 100 Scottish adults aged 19-70 years) assessed whether participants adjusted for whether the bad news was more or less severe (an index of general knowledge). Younger adults displayed more flexible adaptation to the recipient manipulation, while no age differences were found for severity. These findings are consistent with prior work showing age-related decline in audience design but not in the use of general knowledge during language production. Experiment 2 further probed younger adults (N = 40, Scottish, aged 18-37 years) and older adults' (N = 40, Scottish, aged 70-89 years) prosocial linguistic behavior by investigating whether health (vs. nonhealth-related) matters would affect responses. While older adults used prosocial speech acts to a greater extent than younger adults, they did not distinguish between conditions. Our results suggest that prosocial linguistic behavior is likely influenced by a combination of differences in audience design and communicative styles at different ages. Collectively, these findings highlight the importance of situating prosocial speech acts within the pragmatics and aging literature, allowing us to uncover the factors modulating prosocial linguistic behavior at different developmental stages. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Assuntos
Envelhecimento , Fala , Idoso , Humanos , Comunicação , Idioma , Longevidade , Fala/fisiologia , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais
7.
Head Neck ; 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38362701

RESUMO

BACKGROUND: Recurrent intestinal-type sinonasal adenocarcinoma (ITAC) can occur several years after primary treatment and with different histology. We aimed to clarify if such recurrences could be second primary tumors and to identify actionable mutations as targets for personalized treatment of recurrent ITAC. METHODS: Twelve pairs of primary and recurrent ITAC were histologically examined and analyzed by next-generation sequencing. RESULTS: Histological differences between primary and recurrent tumor pairs were observed in five cases. Frequent mutations included TP53, APC, TSC2, ATM, EPHA2, BRCA2, LRP1B, KRAS, and KMT2B. There was 86% concordance of somatic mutations between the tumor pairs, while four cases carried additional mutations in the recurrence. CONCLUSIONS: We found all cases to be clonal recurrences and not second primary tumors. Moreover, tumor pairs showed a remarkable genomic stability, suggesting that personalized treatment of a recurrence may be based on actionable molecular genetic targets observed in the primary tumor.

8.
Artigo em Inglês | MEDLINE | ID: mdl-38342426

RESUMO

INTRODUCTION: The enlarged vestibular aqueduct (EVA) is the most frequent malformation of the inner ear associated with sensorineural hearing loss (5-15%). It exists when the diameter in imaging tests is greater than 1.5 mm at its midpoint. The association between hearing loss and EVA has been described in a syndromic and non-syndromic manner. It can appear as a familial or isolated form and the audiological profile is highly variable. The gene responsible for sensorineural hearing loss associated with EVA is located in the same region described for Pendred syndrome, where the SCL26A4 gene is located. OBJECTIVE: To describe a series of children diagnosed with EVA in order to study their clinical and audiological characteristics, as well as the associated genetic and vestibular alterations. METHOD: Retrospective study of data collection of children diagnosed with EVA, from April 2014 to February 2023. RESULTS: Of the 17 cases, 12 were male and 5 were female. 5 of them were unilateral and 12 bilateral. In 5 cases, a cranial traumatism triggered the hearing loss. Genetic alterations were detected in 3 cases: 2 mutations in the SCL26A4 gene and 1 mutation in the MCT1 gene. 13 patients (76.5%) were rehabilitated with hearing aids and 9 of them required cochlear implantation. DISCUSSION: The clinical importance of AVD lies in the fact that it is a frequent finding in the context of postneonatal hearing loss. It is convenient to have a high suspicion to diagnose it with imaging tests, to monitor its evolution, and to rehabilitate early.

9.
Int J Pharm ; 651: 123754, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38163526

RESUMO

Osteoarthritis is the most common chronic joint disease and a major health care concern due to the lack of efficient treatments. This is mainly related to the local and degenerative nature of this disease. Kartogenin was recently reported as a disease-modifying osteoarthritis drug that promotes cartilage repair, but its therapeutic effect is impeded by its very low solubility. Therefore, we designed a unique nanocrystal-chitosan particle intra-articular delivery system for osteoarthritis treatment that merges the following formulation techniques: nanosize reduction of a drug by wet milling and spray drying. The intermediate formulation (kartogenin nanocrystals) increased the solubility and dissolution rates of kartogenin. The final drug delivery system consisted of an easily resuspendable and ready-to-use microsphere powder for intra-articular injection. Positively charged chitosan microspheres with a median size of approximately 10 µm acted as a mothership drug delivery system for kartogenin nanocrystals in a simulated intra-articular injection. The microspheres showed suitable stability and a controlled release profile in synovial fluid and were nontoxic in human synoviocytes. The cartilage retention skills of the microspheres were also explored ex vivo using cartilage. This drug delivery system shows promise for advancement to preclinical stages in osteoarthritis therapy and scale-up production.


Assuntos
Anilidas , Quitosana , Nanopartículas , Osteoartrite , Ácidos Ftálicos , Humanos , Quitosana/química , Preparações Farmacêuticas , Osteoartrite/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Injeções Intra-Articulares , Microesferas
10.
Haematologica ; 109(2): 521-532, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37534527

RESUMO

Diagnostic criteria for juvenile myelomonocytic leukemia (JMML) are currently well defined, however in some patients diagnosis still remains a challenge. Flow cytometry is a well established tool for diagnosis and follow-up of hematological malignancies, nevertheless it is not routinely used for JMML diagnosis. Herewith, we characterized the CD34+ hematopoietic precursor cells collected from 31 children with JMML using a combination of standardized EuroFlow antibody panels to assess the ability to discriminate JMML cells from normal/reactive bone marrow cell as controls (n=29) or from cells of children with other hematological diseases mimicking JMML (n=9). CD34+ precursors in JMML showed markedly reduced B-cell and erythroid-committed precursors compared to controls, whereas monocytic and CD7+ lymphoid precursors were significantly expanded. Moreover, aberrant immunophenotypes were consistently present in CD34+ precursors in JMML, while they were virtually absent in controls. Multivariate logistic regression analysis showed that combined assessment of the number of CD34+CD7+ lymphoid precursors and CD34+ aberrant precursors or erythroid precursors had a great potential in discriminating JMMLs versus controls. Importantly our scoring model allowed highly efficient discrimination of truly JMML versus patients with JMML-like diseases. In conclusion, we show for the first time that CD34+ precursors from JMML patients display a unique immunophenotypic profile which might contribute to a fast and accurate diagnosis of JMML worldwide by applying an easy to standardize single eight-color antibody combination.


Assuntos
Leucemia Mielomonocítica Juvenil , Criança , Humanos , Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/genética , Citometria de Fluxo , Antígenos CD34/genética , Monócitos/patologia
11.
Psychol Rev ; 131(1): 18-35, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36862451

RESUMO

Language and social cognition come together in communication, but their relation has been intensely contested. Here, I argue that these two distinctively human abilities are connected in a positive feedback loop, whereby the development of one cognitive skill boosts the development of the other. More specifically, I hypothesize that language and social cognition codevelop in ontogeny and coevolve in diachrony through the acquisition, mature use, and cultural evolution of reference systems (e.g., demonstratives: "this" vs. "that"; articles: "a" vs. "the"; pronouns: "I" vs. "you"). I propose to study the connection between reference systems and communicative social cognition across three parallel timescales-language acquisition, language use, and language change, as a new research program for cultural evolutionary pragmatics. Within that framework, I discuss the coevolution of language and communicative social cognition as cognitive gadgets, and introduce a new methodological approach to study how universals and cross-linguistic differences in reference systems may result in different developmental pathways to human social cognition. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Assuntos
Evolução Cultural , Humanos , Cognição Social , Idioma , Comunicação , Linguística , Cognição
12.
Nucleic Acids Res ; 52(3): 1156-1172, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38055836

RESUMO

The Rad5/HLTF protein has a central role in the tolerance to DNA damage by mediating an error-free mode of bypassing unrepaired DNA lesions, and is therefore critical for the maintenance of genome stability. We show in this work that, following cellular stress, Rad5 is regulated by relocalization into two types of nuclear foci that coexist within the same cell, which we termed 'S' and 'I'. Rad5 S-foci form in response to genotoxic stress and are associated with Rad5's function in maintaining genome stability, whereas I-foci form in the presence of proteotoxic stress and are related to Rad5's own proteostasis. Rad5 accumulates into S-foci at DNA damage tolerance sites by liquid-liquid phase separation, while I-foci constitute sites of chaperone-mediated sequestration of Rad5 at the intranuclear quality control compartment (INQ). Relocalization of Rad5 into each type of foci involves different pathways and recruitment mechanisms, but in both cases is driven by the evolutionarily conserved E2 ubiquitin-conjugating enzyme Rad6. This coordinated differential relocalization of Rad5 interconnects DNA damage response and proteostasis networks, highlighting the importance of studying these homeostasis mechanisms in tandem. Spatial regulation of Rad5 under cellular stress conditions thus provides a useful biological model to study cellular homeostasis as a whole.


Assuntos
DNA Helicases , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Humanos , Dano ao DNA , DNA Helicases/genética , Reparo do DNA , Replicação do DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Instabilidade Genômica , Proteostase/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo
13.
J Exp Psychol Learn Mem Cogn ; 50(1): 109-136, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37561512

RESUMO

This study aims to advance our understanding of the nature and source(s) of individual differences in pragmatic language behavior over the adult lifespan. Across four story continuation experiments, we probed adults' (N = 496 participants, ages 18-82) choice of referential forms (i.e., names vs. pronouns to refer to the main character). Our manipulations were based on Fossard et al.'s (2018) scale of referential complexity which varies according to the visual properties of the scene: low complexity (one character), intermediate complexity (two characters of different genders), and high complexity (two characters of the same gender). Since pronouns signal topic continuity (i.e., that the discourse will continue to be about the same referent), the use of pronouns is expected to decrease as referential complexity increases. The choice of names versus pronouns, therefore, provides insight into participants' perception of the topicality of a referent, and whether that varies by age and cognitive capacity. In Experiment 1, we used the scale to test the association between referential choice, aging, and cognition, identifying a link between older adults' switching skills and optimal referential choice. In Experiments 2-4, we tested novel manipulations that could impact the scale and found both the TIMING of a competitor referent's presence and EMPHASIS placed on competitors modulated referential choice, leading us to refine the scale for future use. Collectively, Experiments 1-4 highlight what type of contextual information is prioritized at different ages, revealing older adults' preserved sensitivity to (visual) scene complexity but reduced sensitivity to linguistic prominence cues, compared to younger adults. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Assuntos
Idioma , Linguística , Humanos , Masculino , Feminino , Idoso , Cognição , Envelhecimento/psicologia , Longevidade
14.
Polymers (Basel) ; 15(21)2023 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-37959942

RESUMO

Edible films based on fruit and vegetable purees combined with different food-grade biopolymeric binding agents (e.g., pectin, gelatin, starch, sodium alginate) are recognized as interesting packaging materials that benefit from the physical, mechanical, and barrier properties of biopolymers as well as the sensory and nutritional properties of purees. In the current contribution, edible antioxidant films based on pear juice and pregelatinized cassava starch were developed. In particular, the suitability of using pregelatinized cassava starch for the non-thermal production of these novel edible films was evaluated. In addition, the effects on the films' properties derived from the use of pear juice instead of the complete puree, from the content of juice used, and from the carbohydrate composition associated with the ripening of pears were all studied. The produced films were characterized in terms of their total polyphenol content, water sensitivity, and water barrier, optical, mechanical and antioxidant properties. Results showed that the use of pear juice leads to films with enhanced transparency compared with puree-based films, and that juice concentration and carbohydrate composition associated with the degree of fruit ripeness strongly govern the films' properties. Furthermore, the addition of pregelatinized cassava starch at room temperature discloses a significant and favorable impact on the cohesiveness, lightness, water resistance, and adhesiveness of the pear-juice-based films, which is mainly attributed to the effective interactions established between the starch macromolecules and the juice components.

15.
Int J Mol Sci ; 24(22)2023 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-38003405

RESUMO

Flow cytometry is a single-cell based technology aimed to quantify the scattering of light and the emission of multiple fluorescence signals by individual cells, biological vesicles, or synthetic microscopical particles when examined one by one at high speed using lasers or other suitable illumination sources [...].


Assuntos
Biologia Molecular , Citometria de Fluxo
16.
Front Psychol ; 14: 1221679, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38023032

RESUMO

Introduction: Eating disorders (EDs) are serious psychological problems that affect not only the individual, but also their entire environment. The prevalence rates of EDs are higher among the adolescent population. A better understanding of ED risk factors is essential to design effective prevention and intervention programs that focus beyond the areas of weight and appearance. Methods: The main objective of this systematic review was to identify the risk factors of EDs and provide a comprehensive approach, analyzing the interplay between individuals, their inner circle, and the society characteristics. The Web of Science, Scopus, CENTRAL and PsycInfo databases were searched. Results: The initial search produced 8,178 references. After removing duplicates and performing the selection process by three independent reviewers, 42 articles were included in the systematic review according to the pre-specified inclusion criteria. The results suggest the relevance of society and the inner circle on the development of EDs. Discussion: The internalization of the thin ideal, promoted by the current society, and living in an unsupportive, unaffectionate, non-cohesive environment were associated with the onset of EDs symptomatology. Other associated variables with this ED indicator were poor-quality relationships and feeling judged about appearance. These aspects seem to be essential for the development of individual characteristics like self-esteem or adaptative coping during adolescence. This systematic review has shown the complex etiology of EDs and the relevance of the interplay between the different areas involved. Furthermore, this information could be relevant to improve the design of innovative and more effective prevention and intervention programs. Systematic review registration: PROSPERO, identifier CRD42022320881.

17.
Int J Mol Sci ; 24(20)2023 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-37894790

RESUMO

Despite advances in surgery and radiotherapy, the overall prognosis of sinonasal intestinal-type adenocarcinoma (ITAC) is poor, and new treatment options are needed. Recent studies have indicated alterations in cellular signaling pathways that may serve as targets for modern inhibitors. Our aim was to evaluate the frequency of mTOR and ERK pathway upregulation in a retrospective series of 139 ITAC and to test the efficacy and mechanism of action of candidate targeted inhibitors in cell line ITAC-3. An immunohistochemical analysis on p-AKT, p-mTOR, p-S6, p-4E-BP1, and p-ERK indicated, respectively, a 68% and 57% mTOR and ERK pathway activation. In vitro studies using low doses of mTOR inhibitor everolimus and ERK inhibitor selumetinib showed significant growth inhibition as monotherapy and especially as combined therapy. This effect was accompanied by the downregulation of mTOR and ERK protein expression. Our data open a new and promising possibility for personalized treatment of ITAC patients.


Assuntos
Adenocarcinoma , Transdução de Sinais , Humanos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Everolimo/farmacologia , Everolimo/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estudos Retrospectivos , Serina-Treonina Quinases TOR/metabolismo
18.
Front Med (Lausanne) ; 10: 1215246, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37809329

RESUMO

Introduction: SARS-CoV-2 viral load has been related to COVID-19 severity. The main aim of this study was to evaluate the relationship between SARS-CoV-2 viremia and SNPs in genes previously studied by our group as predictors of COVID-19 severity. Materials and methods: Retrospective observational study including 340 patients hospitalized for COVID-19 in the University Hospital La Princesa between March 2020 and December 2021, with at least one viremia determination. Positive viremia was considered when viral load was above the quantifiable threshold (20 copies/ml). A total of 38 SNPs were genotyped. To study their association with viremia a multivariate logistic regression was performed. Results: The mean age of the studied population was 64.5 years (SD 16.6), 60.9% patients were male and 79.4% white non-Hispanic. Only 126 patients (37.1%) had at least one positive viremia. After adjustment by confounders, the presence of the minor alleles of rs2071746 (HMOX1; T/T genotype OR 9.9 p < 0.0001), rs78958998 (probably associated with SERPING1 expression; A/T genotype OR 2.3, p = 0.04 and T/T genotype OR 12.9, p < 0.0001), and rs713400 (eQTL for TMPRSS2; C/T + T/T genotype OR 1.86, p = 0.10) were associated with higher risk of viremia, whereas the minor alleles of rs11052877 (CD69; A/G genotype OR 0.5, p = 0.04 and G/G genotype OR 0.3, p = 0.01), rs2660 (OAS1; A/G genotype OR 0.6, p = 0.08), rs896 (VIPR1; T/T genotype OR 0.4, p = 0.02) and rs33980500 (TRAF3IP2; C/T + T/T genotype OR 0.3, p = 0.01) were associated with lower risk of viremia. Conclusion: Genetic variants in HMOX1 (rs2071746), SERPING1 (rs78958998), TMPRSS2 (rs713400), CD69 (rs11052877), TRAF3IP2 (rs33980500), OAS1 (rs2660) and VIPR1 (rs896) could explain heterogeneity in SARS-CoV-2 viremia in our population.

20.
Mar Drugs ; 21(9)2023 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-37755112

RESUMO

Marine sponges usually host a wide array of secondary metabolites that play crucial roles in their biological interactions. The factors that influence the intraspecific variability in the metabolic profile of organisms, their production or ecological function remain generally unknown. Understanding this may help predict changes in biological relationships due to environmental variations as a consequence of climate change. The sponge Dendrilla antarctica is common in shallow rocky bottoms of the Antarctic Peninsula and is known to produce diterpenes that are supposed to have defensive roles. Here we used GC-MS to determine the major diterpenes in two populations of D. antarctica from two islands, Livingston and Deception Island (South Shetland Islands). To assess the potential effect of heat stress, we exposed the sponge in aquaria to a control temperature (similar to local), heat stress (five degrees higher) and extreme heat stress (ten degrees higher). To test for defence induction by predation pressure, we exposed the sponges to the sea star Odontaster validus and the amphipod Cheirimedon femoratus. Seven major diterpenes were isolated and identified from the samples. While six of them were already reported in the literature, we identified one new aplysulphurane derivative that was more abundant in the samples from Deception Island, so we named it deceptionin (7). The samples were separated in the PCA space according to the island of collection, with 9,11-dihydrogracilin A (1) being more abundant in the samples from Livingston, and deceptionin (7) in the samples from Deception. We found a slight effect of heat stress on the diterpene profiles of D. antarctica, with tetrahydroaplysulphurin-1 (6) and the gracilane norditerpene 2 being more abundant in the group exposed to heat stress. Predation pressure did not seem to influence the metabolite production. Further research on the bioactivity of D. antarctica secondary metabolites, and their responses to environmental changes will help better understand the functioning and fate of the Antarctic benthos.


Assuntos
Anfípodes , Poríferos , Animais , Terpenos , Regiões Antárticas , Comportamento Predatório , Bandagens , Estrelas-do-Mar
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