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1.
Bioconjug Chem ; 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38958375

RESUMO

Conventional serum markers often fail to accurately detect cholestasis accompanying many liver diseases. Although elevation in serum bile acid (BA) levels sensitively reflects impaired hepatobiliary function, other factors altering BA pool size and enterohepatic circulation can affect these levels. To develop fluorescent probes for extracorporeal noninvasive hepatobiliary function assessment by real-time monitoring methods, 1,3-dipolar cycloaddition reactions were used to conjugate near-infrared (NIR) fluorochromes with azide-functionalized BA derivatives (BAD). The resulting compounds (NIRBADs) were chromatographically (FC and PTLC) purified (>95%) and characterized by fluorimetry, 1H NMR, and HRMS using ESI ionization coupled to quadrupole TOF mass analysis. Transport studies using CHO cells stably expressing the BA carrier NTCP were performed by flow cytometry. Extracorporeal fluorescence was detected in anesthetized rats by high-resolution imaging analysis. Three NIRBADs were synthesized by conjugating alkynocyanine 718 with cholic acid (CA) at the COOH group via an ester (NIRBAD-1) or amide (NIRBAD-3) spacer, or at the 3α-position by a triazole link (NIRBAD-2). NIRBADs were efficiently taken up by cells expressing NTCP, which was inhibited by taurocholic acid (TCA). Following i.v. administration of NIRBAD-3 to rats, liver uptake and consequent release of NIR fluorescence could be extracorporeally monitored. This transient organ-specific handling contrasted with the absence of release to the intestine of alkynocyanine 718 and the lack of hepatotropism observed with other probes, such as indocyanine green. NIRBAD-3 administration did not alter serum biomarkers of hepatic and renal toxicity. NIRBADs can serve as probes to evaluate hepatobiliary function by noninvasive extracorporeal methods.

2.
Clin Pharmacol Ther ; 116(2): 328-345, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38803056

RESUMO

Although the treatment landscape has rapidly evolved over the last years, hepatocellular carcinoma (HCC) is one of the most lethal cancers. With recent advances, both immunotherapy and tyrosine kinase inhibitors (TKIs)-based chemotherapy constitute the standard treatment for advanced HCC. A systematic search of randomized clinical trials employing TKIs was performed in 17 databases, obtaining 25 studies evaluating the prognosis, tumor response, and presence of adverse events (AEs) related to TKIs in HCC. Overall effect sizes were estimated for the hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI), either extracted or calculated with the Parmar method, employing STATA 16. Heterogeneity was assessed by Chi-square-based Q-test and inconsistency (I2) statistic; source of heterogeneity by meta-regression and subgroup analysis; and publication bias by funnel plot asymmetry and Egger's test. The research protocol was registered in PROSPERO (CRD42023397263). Meta-analysis revealed a correlation between survival and tumor response parameters and TKI treatment vs. placebo, despite detecting high heterogeneity. Combined TKI treatment showed a significantly better objective response rate (ORR) with no heterogeneity, whereas publication bias was only detected with time to progression (TTP). Few gastrointestinal and neurological disorders were associated with TKI treatment vs. placebo or with combined treatment. However, a higher number of serious AEs were related to TKI treatment vs. sorafenib alone. Results show positive clinical benefits from TKI treatment, supporting the approval and maintenance of TKI-based therapy for advanced HCC, while establishing appropriate strategies to maximize efficacy and minimize toxicity.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Inibidores de Proteínas Quinases , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Medição de Risco , Resultado do Tratamento , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico
3.
Arch Bronconeumol ; 60(7): 417-422, 2024 Jul.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-38729884

RESUMO

INTRODUCTION: Treatment with LABA/LAMA is recommended in GOLD B patients. We hypothesized that triple therapy (LABA/LAMA/ICS) will be superior to LABA/LAMA in achieving and maintaining clinical control (CC), a composite outcome that considers both impact and disease stability in a subgroup of GOLD B patients (here termed GOLD B+ patients) characterized by: (1) remaining symptomatic (CAT≥10) despite regular LABA/LAMA therapy; (2) having suffered one moderate exacerbation in the previous year; and (3) having blood eosinophil counts (BEC) ≥150cells/µL. METHODS: The ANTES B+ study is a prospective, multicenter, open label, randomized, pragmatic, controlled trial designed to test this hypothesis. It will randomize 1028 B+ patients to continue with their usual LABA/LAMA combination prescribed by their attending physician or to begin fluticasone furoate (FF) 92µg/umeclidinium (UMEC) 55µg/vilanterol (VI) 22µg in a single inhaler q.d. for 12 months. The primary efficacy outcome will be the level of CC achieved. Secondary outcomes include the clinical important deterioration index (CID), annual rate of exacerbations, and FEV1. Exploratory objectives include the interaction of BEC and smoking status, all-cause mortality and proportion of patients on LABA/LAMA arm that switch therapy arms. Safety analysis include adverse events and incidence of pneumonia. RESULTS: The first patient was recruited on February 29, 2024; results are expected in the first quarter of 2026. CONCLUSIONS: The ANTES B+ study is the first to: (1) explore the efficacy and safety of triple therapy in a population of B+ COPD patients and (2) use a composite index (CC) as the primary result of a COPD trial.


Assuntos
Álcoois Benzílicos , Combinação de Medicamentos , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Estudos Prospectivos , Álcoois Benzílicos/uso terapêutico , Álcoois Benzílicos/administração & dosagem , Clorobenzenos/uso terapêutico , Clorobenzenos/administração & dosagem , Quinuclidinas/uso terapêutico , Quinuclidinas/administração & dosagem , Quimioterapia Combinada , Antagonistas Muscarínicos/uso terapêutico , Antagonistas Muscarínicos/administração & dosagem , Androstadienos/uso terapêutico , Androstadienos/administração & dosagem , Resultado do Tratamento , Corticosteroides/uso terapêutico , Broncodilatadores/uso terapêutico , Broncodilatadores/administração & dosagem , Administração por Inalação , Masculino , Feminino , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Eosinófilos , Pessoa de Meia-Idade
4.
Trop Anim Health Prod ; 56(5): 170, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38769239

RESUMO

There are no studies regarding the estimation of genetic parameters and genetic trends for reproductive traits and somatic cells in goats. Their knowledge allows optimization of selection schemes. The objective of this study was to estimate genetic parameters and genetic and phenotypic trends for age at first kidding (AFK), kidding interval (KIN) and somatic cell score (SCS). Analyses were conducted within and across seven US goat breeds, namely, Nubian (NU), Alpine (AL), LaMancha (LM), Toggenburg (TO), Saanen (SA), Nigerian Dwarf (ND) and Oberhasli (OB), and a set of all of these breeds (AB). The restricted maximum likelihood methodology and trivariate animal models were used. Genetic and phenotypic trends were estimated using regression models. The average and standard deviation of AFK, KIN and SCS for AB were 573.6 ± 178.5 days, 418.8 ± 125.5 days and 4.67 ± 2.23 Log2, respectively. The heritabilities (h2) and standard errors of AFK, KIN and SCS for AB were 0.28 ± 0.02, 0.04 ± 0.02 and 0.22 ± 0.01, respectively. The h2 ranged from 0.15 (SA) to 0.37 (NU) for AFK, from 0.04 (AB) to 0.10 (AL) for KIN, and from 0.11 (TO) to 0.26 (LM and ND) for SCS. Genetic correlations between AFK and KIN and between AFK and SCS for AB were positive and weak (0.07 and 0.12, respectively) but significant (P < 0.01). Genetic correlations between SCS and KIN were significant (P < 0.01) for all the breeds and ranged from -0.15 (NU) to 0.44 (AL). Genetic correlations between AFK and SCS in the NU and AL breeds were similar (approximately 0.21). A positive genetic trend was found for KIN in the SA breed, which caused an increase in the number of days between consecutive kiddings. The genetic trend of SCS for the NU, AL and ND breeds was negative and decreased annually, which is beneficial for producers. These first results show the intensity and direction of some favorable/unfavorable relationships between AFK or KIN and SCS Log2 in some U.S. goat genetic groups.


Assuntos
Cabras , Reprodução , Animais , Cabras/genética , Feminino , Cruzamento , Fenótipo , Estados Unidos , Masculino , Indústria de Laticínios
5.
Am J Physiol Cell Physiol ; 327(1): C11-C33, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38708523

RESUMO

In contrast to other types of cancers, there is no available efficient pharmacological treatment to improve the outcomes of patients suffering from major primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma. This dismal situation is partly due to the existence in these tumors of many different and synergistic mechanisms of resistance, accounting for the lack of response of these patients, not only to classical chemotherapy but also to more modern pharmacological agents based on the inhibition of tyrosine kinase receptors (TKIs) and the stimulation of the immune response against the tumor using immune checkpoint inhibitors (ICIs). This review summarizes the efforts to develop strategies to overcome this severe limitation, including searching for novel drugs derived from synthetic, semisynthetic, or natural products with vectorial properties against therapeutic targets to increase drug uptake or reduce drug export from cancer cells. Besides, immunotherapy is a promising line of research that is already starting to be implemented in clinical practice. Although less successful than in other cancers, the foreseen future for this strategy in treating liver cancers is considerable. Similarly, the pharmacological inhibition of epigenetic targets is highly promising. Many novel "epidrugs," able to act on "writer," "reader," and "eraser" epigenetic players, are currently being evaluated in preclinical and clinical studies. Finally, gene therapy is a broad field of research in the fight against liver cancer chemoresistance, based on the impressive advances recently achieved in gene manipulation. In sum, although the present is still dismal, there is reason for hope in the non-too-distant future.


Assuntos
Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Animais , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Imunoterapia/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/imunologia , Colangiocarcinoma/patologia , Epigênese Genética/efeitos dos fármacos
7.
Sleep Med Clin ; 19(2): 275-282, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38692752

RESUMO

In patients with chronic obstructive pulmonary disease (COPD) and asthma, exacerbations determine the natural history of both diseases. Patients with both respiratory diseases who suffer from obstructive sleep apnea (OSA) as a comorbidity (overlap syndromes) have a higher risk of exacerbations and hospitalization. In cases of OSA/COPD and OSA/asthma, continuous positive airway pressure treatment is indicated. Adequate adherence to therapy appears to reduce exacerbations and their severity, especially in OSA/COPD overlap. However, there is a lack of randomized trials that definitively demonstrate this evidence.


Assuntos
Asma , Doença Pulmonar Obstrutiva Crônica , Apneia Obstrutiva do Sono , Humanos , Doença Pulmonar Obstrutiva Crônica/terapia , Doença Pulmonar Obstrutiva Crônica/complicações , Apneia Obstrutiva do Sono/terapia , Apneia Obstrutiva do Sono/complicações , Asma/terapia , Asma/complicações , Pressão Positiva Contínua nas Vias Aéreas/métodos , Progressão da Doença , Comorbidade
8.
J Bodyw Mov Ther ; 38: 180-190, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38763561

RESUMO

Low back pain is a painful disorder that prevents normal mobilization, increases muscle tension and whose first-line treatment is usually non-steroidal anti-inflammatory drugs, together with non-invasive manual therapies, such as deep oscillation therapy. This systematic review aims to investigate and examine the scientific evidence of the effectiveness of deep oscillation therapy in reducing pain and clinical symptomatology in patients with low back pain, through the use of motion capture technology. To carry out this systematic review, the guidelines of the PRISMA guide were followed. A literature search was performed from 2013 to March 2022 in the PubMed, Elsevier, Science Director, Cochrane Library, and Springer Link databases to collect information on low back pain, deep oscillation, and motion capture. The risk of bias of the articles was assessed using the Cochrane risk of bias tool. Finally, they were included 16 articles and 5 clinical trials which met the eligibility criteria. These articles discussed the effectiveness of deep oscillation therapy in reducing pain, eliminating inflammation, and increasing lumbar range of motion, as well as analyzing the use of motion capture systems in the analysis, diagnosis, and evaluation of a patient with low back pain before, during and after medical treatment. There is no strong scientific evidence that demonstrates the high effectiveness of deep oscillation therapy in patients with low back pain, using motion capture systems. This review outlines the background for future research directed at the use of deep oscillation therapy as a treatment for other types of musculoskeletal injuries.


Assuntos
Dor Lombar , Amplitude de Movimento Articular , Humanos , Dor Lombar/terapia , Amplitude de Movimento Articular/fisiologia , Modalidades de Fisioterapia , Captura de Movimento
9.
Heliyon ; 10(8): e29177, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38644877

RESUMO

The development of programming skills and computational thinking in the formal educational context is one of the most recent horizons set by many educational systems worldwide. Although the first computational thinking initiatives are being applied from the earliest school ages, this research focuses on the secondary education level. Specifically, the objective is the following: to analyse the implementation of Arduino, as well as the benefits and opportunities it brings to secondary school students. For this purpose, documentary research has been undertaken applying a systematic review according to the PRISMA 2020 framework following the PiCoS strategy. Atlas.ti 9 was used to analyse the information. Out of 316 papers identified, 37 were included in the research. In relation to the results, Arduino is primarily used in technology and physics subjects, although it is also used to develop interdisciplinary STEAM projects. As a rule, it is used to learn programming languages, but likewise as a resource to develop science experiments. LED lights, servomotors and breadboards are among the most commonly used resources together with the Arduino board. and Scratch was the most widely used software. The initiatives implemented have yielded both positive and negative results, for example, one drawback is that some projects are very difficult, and some achievements such as: increased motivation towards the contents addressed or also the development of some soft skills, such as problem solving.

10.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167166, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38642480

RESUMO

BACKGROUND AND AIMS: Liver regeneration is essential for the preservation of homeostasis and survival. Bile acids (BAs)-mediated signaling is necessary for liver regeneration, but BAs levels need to be carefully controlled to avoid hepatotoxicity. We studied the early response of the BAs-fibroblast growth factor 19 (FGF19) axis in healthy individuals undergoing hepatectomy for living donor liver transplant. We also evaluated BAs synthesis in mice upon partial hepatectomy (PH) and acute inflammation, focusing on the regulation of cytochrome-7A1 (CYP7A1), a key enzyme in BAs synthesis from cholesterol. METHODS: Serum was obtained from twelve human liver donors. Mice underwent 2/3-PH or sham-operation. Acute inflammation was induced with bacterial lipopolysaccharide (LPS) in mice fed control or antoxidant-supplemented diets. BAs and 7α-hydroxy-4-cholesten-3-one (C4) levels were measured by HPLC-MS/MS; serum FGF19 by ELISA. Gene expression and protein levels were analyzed by RT-qPCR and western-blot. RESULTS: Serum BAs levels increased after PH. In patients with more pronounced hypercholanemia, FGF19 concentrations transiently rose, while C4 levels (a readout of CYP7A1 activity) dropped 2 h post-resection in all cases. Serum BAs and C4 followed the same pattern in mice 1 h after PH, but C4 levels also dropped in sham-operated and LPS-treated animals, without marked changes in CYP7A1 protein levels. LPS-induced serum C4 decline was attenuated in mice fed an antioxidant-supplemented diet. CONCLUSIONS: In human liver regeneration FGF19 upregulation may constitute a protective response from BAs excess during liver regeneration. Our findings suggest the existence of post-translational mechanisms regulating CYP7A1 activity, and therefore BAs synthesis, independent from CYP7A1/Cyp7a1 gene transcription.


Assuntos
Ácidos e Sais Biliares , Colesterol 7-alfa-Hidroxilase , Fatores de Crescimento de Fibroblastos , Hepatectomia , Regeneração Hepática , Humanos , Animais , Ácidos e Sais Biliares/metabolismo , Ácidos e Sais Biliares/biossíntese , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/genética , Regeneração Hepática/efeitos dos fármacos , Colesterol 7-alfa-Hidroxilase/metabolismo , Colesterol 7-alfa-Hidroxilase/genética , Camundongos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Transplante de Fígado , Lipopolissacarídeos/farmacologia
11.
Humanidad. med ; 24(1)abr. 2024.
Artigo em Espanhol | LILACS-Express | LILACS | ID: biblio-1557975

RESUMO

Introducción: Es importante la relación entre el desarrollo de las categorías originalidad, flexibilidad, autonomía y motivación del modo de actuación creativo. El objetivo del artículo consistió en elaborar un sistema de indicaciones para el desarrollo de categorías del modo de actuación creativo en estudiantes universitarios. Métodos: Se realizó una investigación mixta, donde el universo lo constituyeron estudiantes de la carrera de Pedagogía-Sicología de la Universidad de Sancti Spíritus "José Martí Pérez" en el curso 2021-2022 y se tomó una muestra aleatoria intencional de 24 educandos del tercer año. Resultados: El procesamiento estadístico de los instrumentos aplicados permitió ubicar al 75 % de la muestra entre un nivel medio y bajo en el desarrollo de categorías del modo de actuación creativo, por carencias en su expresión. Discusión: Desde fundamentos teóricos referenciados se analizó una propuesta de indicaciones que permiten la sistematización de contenidos de aprendizaje y facilitan el desarrollo de acciones autónomas y motivadoras para solucionar problemáticas en el contexto laboral. Conclusiones: La elaboración de indicaciones, desde la disciplina principal integradora y en estrecha relación con las categorías declaradas del modo de actuación creativo, facilitaron su desarrollo y demostraron pertinencia y factibilidad en el contexto de la práctica laboral.


Introduction: The relationship between the development of the categories of originality, flexibility, autonomy and motivation of the creative mode of action is important. The objective of the article was to develop a system of indications for the development of categories of the creative mode of action in university students. Methods: A mixed investigation was carried out, where the universe was made up of students of the Pedagogy-Psychology degree at the University of Sancti Spíritus "José Martí Pérez" in the 2021-2022 academic year and an intentional random sample of 24 students from the third year was taken. In the research, actions were designed to solve problems in work practice and a self-assessment scale about the development of the categories of the creative mode of action. Results: The statistical processing of the applied instruments allowed 75 % of the sample to be placed between a medium and low level in the development of categories of the creative mode of action, due to deficiencies in its expression. Discussion: From referenced theoretical foundations, a proposal of indications was analyzed that allow the systematization of learning content and facilitate the development of autonomous and motivating actions to solve problems in the work context. Conclusions: The development of indications, from the main integrative discipline and in close relationship with the declared categories of the creative mode of action, facilitated its development and demonstrated relevance and feasibility in the context of work practice.

12.
Biochem Pharmacol ; : 116166, 2024 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-38527556

RESUMO

The liver plays a pivotal role in drug disposition owing to the expression of transporters accounting for the uptake at the sinusoidal membrane and the efflux across the basolateral and canalicular membranes of hepatocytes of many different compounds. Moreover, intracellular mechanisms of phases I and II biotransformation generate, in general, inactive compounds that are more polar and easier to eliminate into bile or refluxed back toward the blood for their elimination by the kidneys, which becomes crucial when the biliary route is hampered. The set of transporters expressed at a given time, i.e., the so-called transportome, is encoded by genes belonging to two gene superfamilies named Solute Carriers (SLC) and ATP-Binding Cassette (ABC), which account mainly, but not exclusively, for the uptake and efflux of endogenous substances and xenobiotics, which include many different drugs. Besides the existence of genetic variants, which determines a marked interindividual heterogeneity regarding liver drug disposition among patients, prevalent diseases, such as cirrhosis, non-alcoholic steatohepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, viral hepatitis, hepatocellular carcinoma, cholangiocarcinoma, and several cholestatic liver diseases, can alter the transportome and hence affect the pharmacokinetics of drugs used to treat these patients. Moreover, hepatic drug transporters are involved in many drug-drug interactions (DDI) that challenge the safety of using a combination of agents handled by these proteins. Updated information on these questions has been organized in this article by superfamilies and families of members of the transportome involved in hepatic drug disposition.

13.
Cell Rep ; 43(3): 113924, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38507413

RESUMO

The posttranslational modification of proteins critically influences many biological processes and is a key mechanism that regulates the function of the RNA-binding protein Hu antigen R (HuR), a hub in liver cancer. Here, we show that HuR is SUMOylated in the tumor sections of patients with hepatocellular carcinoma in contrast to the surrounding tissue, as well as in human cell line and mouse models of the disease. SUMOylation of HuR promotes major cancer hallmarks, namely proliferation and invasion, whereas the absence of HuR SUMOylation results in a senescent phenotype with dysfunctional mitochondria and endoplasmic reticulum. Mechanistically, SUMOylation induces a structural rearrangement of the RNA recognition motifs that modulates HuR binding affinity to its target RNAs, further modifying the transcriptomic profile toward hepatic tumor progression. Overall, SUMOylation constitutes a mechanism of HuR regulation that could be potentially exploited as a therapeutic strategy for liver cancer.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/metabolismo , Modelos Animais de Doenças , Proteína Semelhante a ELAV 1/metabolismo , Neoplasias Hepáticas/patologia , RNA/metabolismo , Sumoilação
14.
Biomed Pharmacother ; 174: 116439, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38518601

RESUMO

Triple-negative breast cancer (TNBC) is characterised by its aggressiveness and resistance to chemotherapy, demanding the development of effective strategies against its unique characteristics. Derived from lapacho tree bark, ß-lapachone (ß-LP) selectively targets cancer cells with elevated levels of the detoxifying enzyme NQO1. Hydroxytyrosol (HT) is a phenolic compound derived from olive trees with important anticancer properties that include the inhibition of cancer stem cells (CSCs) and metastatic features in TNBC, as well as relevant antioxidant activities by mechanisms such as the induction of NQO1. We aimed to study whether these compounds could have synergistic anticancer activity in TNBC cells and the possible role of NQO1. For this pourpose, we assessed the impact of ß-LP (0.5 or 1.5 µM) and HT (50 and 100 µM) on five TNBC cell lines. We demonstrated that the combination of ß-LP and HT exhibits anti-proliferative, pro-apoptotic, and cell cycle arrest effects in several TNBC cells, including docetaxel-resistant TNBC cells. Additionally, it effectively inhibits the self-renewal and clonogenicity of CSCs, modifying their aggressive phenotype. However, the notable impact of the ß-LP-HT combination does not appear to be solely associated with the levels of the NQO1 protein and ROS. RNA-Seq analysis revealed that the combination's anticancer activity is linked to a strong induction of endoplasmic reticulum stress and apoptosis through the unfolded protein response. In conclusion, in this study, we demonstrated how the combination of ß-LP and HT could offer an affordable, safe, and effective approach against TNBC.


Assuntos
Apoptose , Proliferação de Células , NAD(P)H Desidrogenase (Quinona) , Naftoquinonas , Álcool Feniletílico , Álcool Feniletílico/análogos & derivados , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Naftoquinonas/farmacologia , Linhagem Celular Tumoral , Álcool Feniletílico/farmacologia , Apoptose/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/metabolismo , NAD(P)H Desidrogenase (Quinona)/genética , Proliferação de Células/efeitos dos fármacos , Feminino , Sinergismo Farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
15.
Pediatr Dermatol ; 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38444084

RESUMO

PIK3CA-related overgrowth spectrum (PROS) encompasses different clinical entities caused by somatic activating mutations in PIK3CA. Among PROS, CLOVES syndrome represents a severe phenotype with poor survival rate. We present the case of a 4-month-old girl with CLOVES syndrome successfully treated with alpelisib, a PIKC3A inhibitor.

16.
Inorg Chem ; 63(21): 9648-9658, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38506446

RESUMO

The addition of 2 equiv of the phosphaylide H2C═PPh3 to the dimethyl uranium metallocene Cp*2UMe2 (Cp* = η5-C5Me5) in toluene with gentle heating at 40 °C generates the phosphorano-stabilized bis(carbene) Cp*2U[C(H)PPh3]2 (1) in good yield. Characterization of 1 by X-ray crystallographic analysis reveals two short uranium-carbon bonds, ranging from 2.301(5) to 2.322(5) Å, consistent with the presence of U═C carbene-type bonds. Monitoring the reaction by NMR spectroscopy suggests that it proceeds through the intermediate formation of the methyl carbene complex Cp*2U[C(H)PPh3](Me) (1Int); however, prolonged heating of these solutions leads to the ortho-cyclometalated carbene species Cp*2U{κ2-[C(H)PPh2(C6H4)]} (2) via intramolecular C-H activation. Rapid conversion from 1 to 2 occurs within hours upon heating its toluene solutions to 100 °C. Preliminary reactivity studies of 1 show that it readily reacts with alcohols, such as HODipp (Dipp = 2,6-diisopropylphenyl) and HOC(CF3)3, to give the mixed carbene alkoxide compounds Cp*2U[C(H)PPh3](OR) (R = Dipp (4Dipp), C(CF3)3 (5CF3)). In one case, the reaction of 1 with HODipp in the presence of adventitious water led to the formation of a few crystals of the terminal U(IV) oxo complex, [Ph3PCH3][Cp*2U(O)(ODipp)] (3oxo). The isolation of 1 marks the first instance of an unchelated, heteroatom-stabilized bis(carbene) complex of uranium that also provides an entryway to the synthesis of its monocarbene derivatives through protonolysis.

17.
Sci Total Environ ; 918: 170492, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38307270

RESUMO

The widespread use of anticoagulant rodenticides (ARs) poses a worldwide threat to farmland wildlife. These compounds accumulate in tissues of both target and non-target species, potentially endangering both direct consumers and their predators. However, investigations on ARs in blood of free-ranging predatory birds are rare. Here, the long-eared owl (Asio otus) has been used as a model predator to assess AR exposure in different agricultural landscapes from a Mediterranean semiarid region. A total of 69 owlets from 38 nests were blood-sampled over 2021 and 2022, aiming to detect AR residues and explore factors that determine their exposure, such as land uses. In addition, prothrombin time (PT) test was conducted to assess potential effects of AR contamination. Overall, nearly all the samples (98.6 %) tested positive for at least one compound and multiple ARs were found in most of the individuals (82.6 %). Among the ARs detected, flocoumafen was the most common compound (88.4 % of the samples). AR total concentration (ΣARs) in blood ranged from 0.06 to 34.18 ng mL-1, detecting the highest levels in the most intensively cultivated area. The analysis of owl pellets from 19 breeding territories showed relevant among-site differences in the contribution of rodents and birds into the diet of long-eared owls, supporting its high dietary plasticity and indicating AR presence at multiple trophic levels. Moreover, a positive and significant correlation was found between ΣARs and PT (Rho = 0.547, p < 0.001), which demonstrates the direct effect of ARs on free-living nestlings. Our results provide a preliminary overview of AR exposure in a little-studied owl species inhabiting agricultural and rural landscapes. Despite the low detected levels, these findings indicate widespread exposure -often to multiple compounds- from early life stages, which raises concern and draws attention to an ongoing and unresolved contamination issue.


Assuntos
Rodenticidas , Estrigiformes , Animais , Anticoagulantes/análise , Rodenticidas/análise , Tempo de Protrombina , Animais Selvagens
18.
Sensors (Basel) ; 24(3)2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38339548

RESUMO

Low back pain (LBP) is a highly common musculoskeletal condition and the leading cause of work absenteeism. This project aims to develop a medical test to help healthcare professionals decide on and assign physical treatment for patients with nonspecific LBP. The design uses machine learning (ML) models based on the classification of motion capture (MoCap) data obtained from the range of motion (ROM) exercises among healthy and clinically diagnosed patients with LBP from Imbabura-Ecuador. The following seven ML algorithms were tested for evaluation and comparison: logistic regression, decision tree, random forest, support vector machine (SVM), k-nearest neighbor (KNN), multilayer perceptron (MLP), and gradient boosting algorithms. All ML techniques obtained an accuracy above 80%, and three models (SVM, random forest, and MLP) obtained an accuracy of >90%. SVM was found to be the best-performing algorithm. This article aims to improve the applicability of inertial MoCap in healthcare by making use of precise spatiotemporal measurements with a data-driven treatment approach to improve the quality of life of people with chronic LBP.


Assuntos
Dor Lombar , Organotiofosfatos , Dispositivos Eletrônicos Vestíveis , Humanos , Dor Lombar/diagnóstico , Qualidade de Vida , Aprendizado de Máquina , Algoritmos , Amplitude de Movimento Articular , Máquina de Vetores de Suporte
19.
Sensors (Basel) ; 24(3)2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38339630

RESUMO

Low back pain (LBP) is a common issue that negatively affects a person's quality of life and imposes substantial healthcare expenses. In this study, we introduce the (Back-pain Movement) BackMov test, using inertial motion capture (MoCap) to assess lumbar movement changes in LBP patients. The test includes flexion-extension, rotation, and lateralization movements focused on the lumbar spine. To validate its reproducibility, we conducted a test-retest involving 37 healthy volunteers, yielding results to build a minimal detectable change (MDC) graph map that would allow us to see if changes in certain variables of LBP patients are significant in relation to their recovery. Subsequently, we evaluated its applicability by having 30 LBP patients perform the movement's test before and after treatment (15 received deep oscillation therapy; 15 underwent conventional therapy) and compared the outcomes with a specialist's evaluations. The test-retest results demonstrated high reproducibility, especially in variables such as range of motion, flexion and extension ranges, as well as velocities of lumbar movements, which stand as the more important variables that are correlated with LBP disability, thus changes in them may be important for patient recovery. Among the 30 patients, the specialist's evaluations were confirmed using a low-back-specific Short Form (SF)-36 Physical Functioning scale, and agreement was observed, in which all patients improved their well-being after both treatments. The results from the specialist analysis coincided with changes exceeding MDC values in the expected variables. In conclusion, the BackMov test offers sensitive variables for tracking mobility recovery from LBP, enabling objective assessments of improvement. This test has the potential to enhance decision-making and personalized patient monitoring in LBP management.


Assuntos
Dor Lombar , Humanos , Dor Lombar/diagnóstico , Dor Lombar/terapia , Captura de Movimento , Reprodutibilidade dos Testes , Qualidade de Vida , Fenômenos Biomecânicos , Amplitude de Movimento Articular
20.
Arch. bronconeumol. (Ed. impr.) ; 60(1): 10-15, enero 2024. tab, graf
Artigo em Inglês | IBECS | ID: ibc-229516

RESUMO

Introduction: The Global Lung Function Initiative (GLI) has proposed new criteria for airflow limitation (AL) and recommends using these to interpret spirometry. The objective of this study was to explore the impact of the application of the AL GLI criteria in two well characterized GOLD-defined COPD cohorts.MethodsCOPD patients from the BODE (n=360) and the COPD History Assessment In SpaiN (CHAIN) cohorts (n=722) were enrolled and followed. Age, gender, pack-years history, BMI, dyspnea, lung function measurements, exercise capacity, BODE index, history of exacerbations and survival were recorded. CT-detected comorbidities were registered in the BODE cohort. The proportion of subjects without AL by GLI criteria was determined in each cohort. The clinical, CT-detected comorbidity, and overall survival of these patients were evaluated.ResultsIn total, 18% of the BODE and 15% of the CHAIN cohort did not meet GLI AL criteria. In the BODE and CHAIN cohorts respectively, these patients had a high clinical burden (BODE≥3: 9% and 20%; mMRC≥2: 16% and 45%; exacerbations in the previous year: 31% and 9%; 6MWD<350m: 15% and 19%, respectively), and a similar prevalence of CT-diagnosed comorbidities compared with those with GLI AL. They also had a higher rate of long-term mortality – 33% and 22% respectively.ConclusionsAn important proportion of patients from 2 GOLD-defined COPD cohorts did not meet GLI AL criteria at enrolment, although they had a significant burden of disease. Caution must be taken when applying the GLI AL criteria in clinical practice. (AU)


Assuntos
Humanos , Mortalidade , Doença Pulmonar Obstrutiva Crônica , Espirometria , Comorbidade , Dispneia
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