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1.
Cell ; 168(5): 878-889.e29, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28235199

RESUMO

Design of small molecules that disrupt protein-protein interactions, including the interaction of RAS proteins and their effectors, may provide chemical probes and therapeutic agents. We describe here the synthesis and testing of potential small-molecule pan-RAS ligands, which were designed to interact with adjacent sites on the surface of oncogenic KRAS. One compound, termed 3144, was found to bind to RAS proteins using microscale thermophoresis, nuclear magnetic resonance spectroscopy, and isothermal titration calorimetry and to exhibit lethality in cells partially dependent on expression of RAS proteins. This compound was metabolically stable in liver microsomes and displayed anti-tumor activity in xenograft mouse cancer models. These findings suggest that pan-RAS inhibition may be an effective therapeutic strategy for some cancers and that structure-based design of small molecules targeting multiple adjacent sites to create multivalent inhibitors may be effective for some proteins.


Assuntos
Antineoplásicos/farmacologia , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/química , Animais , Antineoplásicos/química , Calorimetria , Linhagem Celular , Fibroblastos/metabolismo , Xenoenxertos , Humanos , Camundongos , Transplante de Neoplasias , Neoplasias/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras , Transdução de Sinais , Bibliotecas de Moléculas Pequenas
2.
Haemophilia ; 30(1): 51-58, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38111119

RESUMO

BACKGROUND: Haemophilia is a haematological disease, although most haemorrhages occur in the locomotor system. Patients are physically disabled from an early age and have a poorer perception of quality of life. In the day-to-day lives of patients and their families, psychosocial well-being, the disease's physical, personal, and social impact, as well as work-related problems are the most complicated aspects of the disease that need to be addressed. OBJECTIVE: To identify the role of occupational therapy in managing patients with haemophilia and to analyse the therapeutic potential of occupational therapy in treating these patients. METHODS: A scoping review was conducted to identify the role of occupational therapy in managing patients with haemophilia and to analyse the therapeutic potential of occupational therapy in treating these patients. The review was registered in the international registry PROSPERO (Id: CRD42022319637). The databases consulted were SCOPUS, PubMed, PsycINFO, Web of Science and Science Direct, including all studies published until 14 August 2023. RESULTS: No single study was found that specifically developed an occupational therapy intervention for patients with haemophilia. Measurement instruments have been identified, specific for patients with haemophilia and generic, that can be useful for the functional evaluation of these patients in the occupational therapy approach. Different studies showed the importance of multidisciplinary treatment, including occupational therapy. CONCLUSIONS: The use of occupational therapy could be effective in improving autonomy and quality of life in haemophilia patients. Therefore, it is of paramount importance to conduct research studies within the field of occupational therapy.


Assuntos
Hemofilia A , Terapia Ocupacional , Humanos , Hemofilia A/tratamento farmacológico , Qualidade de Vida
3.
Nature ; 553(7689): 511-514, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-29342136

RESUMO

Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis. Gain-of-function mutations in the 5'-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present in relapsed ALL. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during the initiation of leukaemia, disease progression and relapse remain unknown. Here we use a conditional-and-inducible leukaemia model to demonstrate that expression of NT5C2(R367Q), a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukaemia cell growth and leukaemia-initiating cell activity. The loss-of-fitness phenotype of NT5C2+/R367Q mutant cells is associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool. Consequently, blocking guanosine synthesis by inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) induced increased cytotoxicity against NT5C2-mutant leukaemia lymphoblasts. These results identify the fitness cost of NT5C2 mutation and resistance to chemotherapy as key evolutionary drivers that shape clonal evolution in relapsed ALL and support a role for IMPDH inhibition in the treatment of ALL.


Assuntos
5'-Nucleotidase/genética , 5'-Nucleotidase/metabolismo , Evolução Clonal , Resistencia a Medicamentos Antineoplásicos/genética , Mutação/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animais , Proliferação de Células , Modelos Animais de Doenças , Feminino , Mutação com Ganho de Função/genética , Guanosina/biossíntese , Células HEK293 , Humanos , IMP Desidrogenase/antagonistas & inibidores , IMP Desidrogenase/metabolismo , Masculino , Mercaptopurina/farmacologia , Mercaptopurina/uso terapêutico , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Purinas/metabolismo , Receptor Notch1/metabolismo , Recidiva , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Ann Hepatol ; 29(3): 101489, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38403068

RESUMO

INTRODUCTION AND OBJECTIVES: Different patterns of liver injury have been reported in association with the SARS-CoV-2 vaccines. The aim of this study was to describe a nationwide cohort of patients with SARS CoV-2 vaccine-induced liver injury, focusing on treatment and the evolution after further booster administration. PATIENTS AND METHODS: multicentre, retrospective-prospective study, including subjects who developed abnormal liver tests within 90 days after administration of SARS-CoV-2 vaccination. RESULTS: 47 cases were collected: 17 after prime dose and 30 after booster. Age was 57 years, 30 (63.8 %) were female, and 7 (14.9 %) had a history of prior autoimmune hepatitis (AIH). Most cases were non-severe, though 9 (19.1 %) developed acute liver injury or failure (ALF). Liver injury tended to be more severe in those presenting after a booster (p=0.084). Pattern of liver injury was hepatocellular (80.9 %), mixed (12.8 %) and 3 (6.4 %) cholestatic. Liver biopsy was performed on 33 patients; 29 showed findings of AIH. Forty-one (87.2 %) patients received immunosuppressants, mostly corticosteroids (35/41). One required liver transplantation and another died due to ALF. Immunosuppression was discontinued in 6/41 patients without later rebound. Twenty-five subjects received at least one booster and 7 (28.0 %) relapsed from the liver injury, but all were non-severe. Recurrence was less frequent among patients on immunosuppressants at booster administration (28.6 % vs. 88.9 %, p=0.007). CONCLUSIONS: SARS CoV-2 vaccine-induced liver injury is heterogeneous but mostly immune-mediated. Relapse of liver injury after re-exposure to vaccine is frequent (28.0 %) but mild. Immunosuppression at booster administration is associated with a lower risk of liver injury.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Recidiva , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Vacinas contra COVID-19/efeitos adversos , Estudos Retrospectivos , COVID-19/prevenção & controle , COVID-19/epidemiologia , Estudos Prospectivos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , SARS-CoV-2 , Idoso , Adulto , Imunização Secundária , Fatores de Risco , Transplante de Fígado , Imunossupressores/efeitos adversos
5.
Rev Esp Enferm Dig ; 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38305672

RESUMO

Hepatic focal lesions are a heterogeneous group of lesions that can be either benign or malignant in nature. They are typically diagnosed through ultrasound in all cases needing to rule out a metastatic nature. We present the case of a 51-year-old male from Morocco diagnosed with hepatic SOLs in the context of abdominal pain and constitutional syndrome.

6.
Reprod Biomed Online ; 46(2): 371-378, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36428176

RESUMO

RESEARCH QUESTION: Is a low platelet count related to an increased risk of severe disease in pregnant women with active severe acute respiratory syndrome coronavirus 2 infection? DESIGN: A cross-sectional multicentre study in pregnant women with COVID-19 confirmed by polymerase chain reaction, antigen test, antibody test, or all. RESULTS: A total of 153 pregnant women with COVID-19 were included in the study, of whom 12.4% had thrombocytopaenia. Pregnant women with thrombocytopaenia were on average 3.1 years older (95% CI 0.18 to 6.38) than women without thrombocytopaenia. Pregnant smokers had a higher risk of thrombocytopaenia than non-smokers (OR 6.55, CI 95% 1.29 to 33.13). B Rh negative (B Rh-) pregnant women had a much higher risk of thrombocytopaenia than pregnant women with other blood groups (OR 16.83, CI 95% 1.42 to 199.8). Pregnant women with thrombocytopaenia had a much higher risk of suffering from preeclampsia (OR 16.2, CI 95% 1.35 to 193.4). CONCLUSIONS: COVID-19 infection is not a risk factor for a low platelet count in pregnant women, although the risk is increased by smoking and in women with blood group B Rh-. In case of pregnancy with thrombocytopaenia, COVID-19 infection leads to an increased risk of preeclampsia.


Assuntos
COVID-19 , Pré-Eclâmpsia , Complicações Infecciosas na Gravidez , Trombocitopenia , Gravidez , Feminino , Humanos , COVID-19/complicações , Pré-Eclâmpsia/epidemiologia , Estudos Transversais , Trombocitopenia/complicações
7.
Appl Microbiol Biotechnol ; 107(24): 7673-7684, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37815614

RESUMO

Sustainable approaches to circular economy in animal agriculture are still poorly developed. Here, we report an approach to reduce gaseous emissions of CO2 and NH3 from animal housing while simultaneously using them to produce value-added biomass. To this end, a cone-shaped, helical photobioreactor was developed that can be integrated into animal housing by being freely suspended, thereby combining a small footprint with a physically robust design. The photobioreactor was coupled with the exhaust air of a chicken house to allow continuous cultivation of a mixed culture of Arthrospira spec. (Spirulina). Continuous quantification of CO2 and NH3 concentration showed that the coupled algae reactor effectively purifies the exhaust air from the chicken house while producing algal biomass. Typical production rates of greater than 0.3 g/l*day dry mass were obtained, and continuous operation was possible for several weeks. Morphological, biochemical, and genomic characterization of Spirulina cultures yielded insights into the dynamics and metabolic processes of the microbial community. We anticipate that further optimization of this approach will provide new opportunities for the generation of value-added products from gaseous CO2 and NH3 waste emissions, linking resource-efficient production of microalgae with simultaneous sequestration of animal emissions. KEY POINTS: • Coupling a bioreactor with exhaust gases of chicken coop for production of biomass. • Spirulina mixed culture removes CO2 and NH3 from chicken house emissions. • High growth rates and biodiversity adaptation for nitrogen metabolism. Towards a sustainable circular economy in livestock farming. The functional coupling of a helical tube photobioreactor with exhaust air from a chicken house enabled the efficient cultivation of Spirulina microalgae while simultaneously sequestering the animals' CO2 and NH3 emissions.


Assuntos
Microalgas , Spirulina , Animais , Gases/metabolismo , Dióxido de Carbono/metabolismo , Fotobiorreatores , Biomassa , Abrigo para Animais , Galinhas , Microalgas/metabolismo
8.
Nanomedicine ; 53: 102699, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37572769

RESUMO

Spinal cord injury is a dramatic disease leading to severe motor, sensitive and autonomic impairments. After injury the axonal regeneration is partly inhibited by the glial scar, acting as a physical and chemical barrier. The scarring process involves microglia, astrocytes and extracellular matrix components, such as collagen, constructing the fibrotic component of the scar. To investigate the role of collagen, we used a multimodal label-free imaging approach combining multiphoton and atomic force microscopy. The second harmonic generation signal exhibited by fibrillar collagen enabled to specifically monitor it as a biomarker of the lesion. An increase in collagen density and the formation of more tortuous fibers over time after injury are observed. Nano-mechanical investigations revealed a noticeable hardening of the injured area, correlated with collagen fibers' formation. These observations indicate the concomitance of important structural and mechanical modifications during the fibrotic scar evolution.


Assuntos
Cicatriz , Traumatismos da Medula Espinal , Camundongos , Animais , Cicatriz/patologia , Microscopia de Força Atômica , Fibrose , Astrócitos/patologia , Medula Espinal/patologia
9.
Pain Manag Nurs ; 24(5): 535-541, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37248125

RESUMO

BACKGROUND: Physical activity's established health benefits include pain control, yet there is no consensus on the required dosage according to the literature. AIM: To test the influence of exercise on perceived health in patients whose daily activities are limited due to pain. Besides, analyze the possible moderating effect of age and find a formula for exercise dosage based on the perceived level of health. METHODS: Cross-sectional study based on the 2017 Spanish National Health Survey with 4,123 participants reporting activity limitations in their daily activities due to pain. The International Physical Activity Questionnaire (short version) was used to calculate energy expenditure. Data included age, sex, leisure-time physical activity, sitting time, pain-related impairments, pain medication, and perceived health. Mediation regression analysis was conducted using the SPSS PROCESS 4.0 macro. RESULTS: Results indicate a decline in perceived health with age. The relationship between exercise (energy expenditure) and perceived health was highly significant (d=-0.224, p<0.001). Age moderated the association between pain and energy expenditure up to 75.61 years (0.1568, p=0.05) and between energy expenditure and perceived health up to 75.74 years (-0.289, p=0.05), but this effect diminished afterwards. A formula was developed to estimate energy expenditure based on the desired level of health. CONCLUSIONS: The perception of health in people who are limited in their daily activities due to pain (moderate to very much) is mediated by the amount of physical activity they perform. Besides, this perception is moderated by age, up to 76 years.


Assuntos
Exercício Físico , Dor , Humanos , Idoso , Estudos Transversais
10.
Int J Mol Sci ; 24(4)2023 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-36834513

RESUMO

Premature ageing of the placenta in pregnancy outcomes is associated with the persistent presence of oxidative stress and placental insufficiency reducing its functional capacity. In this study, we investigated cellular senescence phenotypes of pre-eclampsia and IUGR pregnancies by simultaneously measuring several biomarkers of senescence. Maternal plasma and placental samples were collected at term gestation from nulliparous women undergoing pre-labour elective caesarean section with pre-eclampsia without intrauterine growth restriction (PE; n = 5), pre-eclampsia associated with intrauterine growth restriction (n = 8), intrauterine growth restriction (IUGR < 10th centile; n = 6), and age-matched controls (n = 20). Placental absolute telomere length and senescence gene analysis was performed by RTqPCR. The expression of cyclin-dependent kinase inhibitors (p21 and p16) was determined by Western blot. Senescence-associated secretory phenotypes (SASPs) were evaluated in maternal plasma by multiplex ELISA assay. Placental expression of senescence-associated genes showed significant increases in CHEK1, PCNA, PTEN, CDKN2A, and CCNB-1 (p < 0.05) in pre-eclampsia, while TBX-2, PCNA, ATM, and CCNB-1 expression were evident (p < 0.05) and were significantly decreased in IUGR compared with controls. Placental p16 protein expression was significantly decreased in pre-eclampsia only compared with controls (p = 0.028). IL-6 was significantly increased in pre-eclampsia (0.54 pg/mL ± 0.271 vs. 0.3 pg/mL ± 0.102; p = 0.017) while IFN-γ was significantly increased in IUGR (4.6 pg/mL ± 2.2 vs. 2.17 pg/mL ± 0.8; p = 0.002) compared with controls. These results provide evidence of premature senescence in IUGR pregnancies, and while cell cycle checkpoint regulators are activated in pre-eclampsia, the cellular phenotype is one of cell repair and subsequent proliferation rather than progression to senescence. The heterogeneity of these cellular phenotypes highlights the complexity of characterising cellular senescence and may equally be indicative of the differing pathophysiological insults unique to each obstetric complication.


Assuntos
Retardo do Crescimento Fetal , Pré-Eclâmpsia , Humanos , Gravidez , Feminino , Retardo do Crescimento Fetal/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Cesárea , Antígeno Nuclear de Célula em Proliferação/metabolismo , Biomarcadores/metabolismo , Senescência Celular , Fenótipo
11.
Int J Mol Sci ; 24(3)2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36768672

RESUMO

Approximately 10 million individuals have blindness due to limbal stem cell (LSCs) deficiency, one of the most challenging problems in ophthalmology. To replenish the LSC pool, an autologous extraocular cell source is appropriate, thereby avoiding the risk of immune rejection, the need for immunosuppression and the risk of damaging the contralateral eye. In recent years, adipose-derived mesenchymal stem cells (ADSCs) have been a key element in ocular regenerative medicine. In this study, we developed a protocol for deriving human LSCs from ADSCs compatible with the standard carrier human amniotic membrane, helping provide a stem cell pool capable of maintaining proper corneal epithelial homeostasis. The best protocol included an ectodermal induction step by culturing ADSCs with media containing fetal bovine serum, transforming growth factor-ß inhibitor SB-505124, Wnt inhibitor IWP-2 and FGF2 for 7 days, followed by an LSC induction step of culture in modified supplemental hormonal epithelial medium supplemented with pigment epithelium-derived factor and keratinocyte growth factor for 10 additional days. The optimal differentiation efficiency was achieved when cells were cultured in this manner over vitronectin coating, resulting in up to 50% double-positive αp63/BMI-1 cells. The results of this project will benefit patients with LSC deficiency, aiding the restoration of vision.


Assuntos
Limbo da Córnea , Células-Tronco Mesenquimais , Humanos , Adulto , Células-Tronco do Limbo , Córnea , Células-Tronco/metabolismo , Células Cultivadas
12.
Int J Mol Sci ; 24(14)2023 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-37511180

RESUMO

Despite a multimodal radical treatment, mortality of advanced epithelial ovarian cancer (AEOC) remains high. Host-related factors, such as systemic inflammatory response and its interplay with the immune system, remain underexplored. We hypothesized that the prognostic impact of this response could vary between patients undergoing primary debulking surgery (PDS) and those undergoing interval debulking surgery (IDS). Therefore, we evaluated the outcomes of two surgical groups of newly diagnosed AEOC patients according to the neutrophil, monocyte and platelet to lymphocyte ratios (NLR, MLR, PLR), taking median ratio values as cutoffs. In the PDS group (n = 61), low NLR and PLR subgroups showed significantly better overall survival (not reached (NR) vs. 72.7 months, 95% confidence interval [CI]: 40.9-95.2, p = 0.019; and NR vs. 56.1 months, 95% CI: 40.9-95.2, p = 0.004, respectively) than those with high values. Similar results were observed in progression free survival. NLR and PLR-high values resulted in negative prognostic factors, adjusting for residual disease, BRCA1/2 status and stage (HR 2.48, 95% CI: 1.03-5.99, p = 0.043, and HR 2.91, 95% CI: 1.11-7.64, p = 0.03, respectively). In the IDS group (n = 85), ratios were not significant prognostic factors. We conclude that NLR and PLR may have prognostic value in the PDS setting, but none in IDS, suggesting that time of surgery can modulate the prognostic impact of baseline complete blood count (CBC).


Assuntos
Neutrófilos , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário , Monócitos , Proteína BRCA1 , Prognóstico , Procedimentos Cirúrgicos de Citorredução , Estudos Retrospectivos , Proteína BRCA2 , Linfócitos , Neoplasias Ovarianas/diagnóstico
13.
BMC Nurs ; 22(1): 209, 2023 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-37332015

RESUMO

BACKGROUND: Despite an existing body of literature on anxiety reduction using multi-component methods, little is known about the effect of active student participation in research and communication of scientific information on anxiety and fear reduction. The aim of this study is to evaluate the impact of quality scientific information research and the production of informative videos on the preventive aspects of COVID-19 on fear and anxiety reduction. METHODS: A randomised controlled trial was conducted with 220 undergraduate nursing students in the first year of the nursing degree. The participating students were randomised into two groups. The experimental group carried out an intervention based on a database search for information on preventing COVID-19 and production of a video giving scientific reasons why prevention measures should be followed. In the control group, students created posters and videos about theoretical aspects of one module of the nursing degree. Both groups were surveyed before and after the intervention, measuring their state of resilience, preventive behaviours, level of anxiety, and fear of COVID-19. RESULTS: The intervention group showed a greater decrease in fear levels after the intervention than those in the control group. There were no differences between the groups in terms of resilience, preventive behaviours, or anxiety. In the experimental group, there was a significant decrease in anxiety levels and fear levels after the intervention compared to the baseline levels. CONCLUSIONS: An intervention based on active participation in searches for high-quality scientific information and production of information videos on COVID-19 prevention reduced fear and anxiety caused by COVID-19 among nursing students. TRIAL REGISTRATION: We have retrospectively registered the trial in Open Science Framework and the identification number is https://doi.org/10.17605/OSF.IO/6QU5S .

14.
Rev Esp Enferm Dig ; 115(5): 223-224, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37114390

RESUMO

Gastrointestinal (GI) Endoscopy is a basic competence for the management of gastrointestinal diseases. However, it should not be regarded as an independent training technique. Rather it is a part of a continuous and accredited process that requires clinical knowledge from the gastroenterologist to keep skills up-to-date in a constantly evolving medical subspecialty. Thus, the only official accredited way for training in GI endoscopy is through the Specialized Health Training program in the Management of the Digestive Diseases administered by the Spanish Ministry of Health.


Assuntos
Gastroenterologistas , Gastroenteropatias , Humanos , Endoscopia Gastrointestinal/métodos , Currículo , Gastroenteropatias/diagnóstico por imagem , Gastroenteropatias/terapia , Competência Clínica
15.
Rev Esp Enferm Dig ; 115(3): 128-132, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36514974

RESUMO

Back in January 2022, an EASL-Lancet Commission on the impact of liver disorders in the European region commissioned by the WHO demonstrated that this condition is, actually, the second leading cause of loss of labor years in Europe after ischemic heart disease (1). This is a very relevant piece of information since this is something that is going to impact the new generations of Europeans unless a significant change is made in public health policies. Despite the advances made over the last few years in hepatitis C virus clearance-understood as a significant reduction of morbidity and mortality associated with Hepatitis B and C viruses-there are still challenges ahead to improve liver health due to the high use of alcohol, and the inseparable triad obesity / diabetes mellitus / metabolic associated fatty liver disease. Also, access to healthcare for several population groups at risk of presenting higher rates of liver disease has become a problem.


Assuntos
Hepatite C , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepacivirus , Hepatite C/diagnóstico , Hepatite C/epidemiologia , Nível de Saúde
16.
Medicina (Kaunas) ; 59(2)2023 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-36837606

RESUMO

Electrical storm is a medical emergency characterized by ventricular arrythmia recurrence that can lead to hemodynamic instability. The incidence of this clinical condition is rising, mainly in implantable cardioverter defibrillator patients, and its prognosis is often poor. Early acknowledgment, management and treatment have a key role in reducing mortality in the acute phase and improving the quality of life of these patients. In an emergency setting, several measures can be employed. Anti-arrhythmic drugs, based on the underlying disease, are often the first step to control the arrhythmic burden; besides that, new therapeutic strategies have been developed with high efficacy, such as deep sedation, early catheter ablation, neuraxial modulation and mechanical hemodynamic support. The aim of this review is to provide practical indications for the management of electrical storm in acute settings.


Assuntos
Ablação por Cateter , Desfibriladores Implantáveis , Humanos , Qualidade de Vida , Arritmias Cardíacas , Antiarrítmicos/uso terapêutico , Prognóstico
17.
Biogerontology ; 23(4): 499-514, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35851632

RESUMO

Increased frequency of DNA double strand breaks (DSBs) with aging suggests an age-associated decline in DSB repair efficiency, which is also influenced by the epigenetic landscape. H4 acetylation at lysine 16 (H4K16Ac) has been related to DSB repair since deacetylation of this mark is required for efficient 53BP1 recruitment to DSBs. Although age-associated changes in H4K16Ac levels have been studied, their contribution to age-related DSB accumulation remains unknown. In vitro aged Human Dermal Fibroblasts (HDFs) display lower levels of H4K16A that correlate with reduced recruitment of 53BP1 to basal DSBs. Following DNA damage induction, early passage (EP) cells suffered from a transient H4K16 deacetylation that allowed proper 53BP1 recruitment to DSBs. In contrast, to reach this specific and optimum level, aged cells responded by increasing their overall lower H4K16Ac levels. Induced hyperacetylation of late passage (LP) cells using trichostatin A increased H4K16Ac levels but did not ameliorate 53BP1 recruitment. Instead, deacetylation induced by MOF silencing reduced H4K16Ac levels and compromised 53BP1 recruitment in both EP and LP cells. Age-associated decrease of H4K16Ac levels contributes to the repair defect displayed by in vitro aged cells. H4K16Ac responds to DNA damage in order to reach a specific, optimum level that allows proper 53BP1 recruitment. This response may be compromised with age, as LP cells depart from lower H4K16Ac levels. Variations in H4K16Ac following the activation of the DNA damage response and aging point at this histone mark as a key mediator between DNA repair and age-associated chromatin alterations.


Assuntos
Quebras de DNA de Cadeia Dupla , Histonas , Acetilação , Idoso , Reparo do DNA , Histonas/metabolismo , Humanos , Processamento de Proteína Pós-Traducional
18.
N Engl J Med ; 379(4): 341-351, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-29863979

RESUMO

BACKGROUND: No systemic therapies have been approved for the treatment of advanced cutaneous squamous-cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous-cell carcinoma. METHODS: We report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review. RESULTS: In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event. CONCLUSIONS: Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT02383212 and NCT02760498 .).


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/secundário , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Cutâneas/patologia
19.
Aging Clin Exp Res ; 33(8): 2355-2359, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34164799

RESUMO

BACKGROUND: Older age has been reported as a risk factor for severe SARS-CoV-2 disease (COVID-19). The impact of immunosuppressants (IMS) on COVID-19 is still under debate. AIM: To describe the incidence and severity of COVID-19 in elderly patients with inflammatory bowel disease (IBD) in relation to the use of IMS. METHODS: IBD patients over 65 years of age were selected and grouped in terms of IMS use. Confirmed COVID-19, adherence to IST, comorbidities and concomitant non-IBD-related treatments between 1st of March 2020 to 1st of March 2021 were recorded. RESULTS: Out of 418 patients included, 89 (21.3%) were on IMS. Thirty-two patients (7.7%) had COVID-19, 7 of whom were on IMS (7.6% not on IMS vs. 7.9% on IMS; P = 0.933) and 7 (22%) patients died. CONCLUSIONS: Incidence of COVID-19 among elderly IBD patients was similar to that reported in the background population, regardless of the use of IMS.


Assuntos
COVID-19 , Doenças Inflamatórias Intestinais , Idoso , Humanos , Imunossupressores/efeitos adversos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/epidemiologia , Fatores de Risco , SARS-CoV-2
20.
Lasers Med Sci ; 36(2): 437-445, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32621128

RESUMO

Photobiomodulation (PBM) has been shown to improve cell proliferation and cell migration. Many cell types have been investigated, with most studies using deep penetrating red light irradiation. Considering the interest of surface biostimulation of oral mesenchymal cells after surgical wound, the present study aimed to assess green light irradiation effects on Dental Pulp Stem Cells' (DPSC) proliferation and migration. To understand the mechanisms underlying these effects, we investigated cytoskeleton organization and subsequent cell shape and stiffness. A 532-nm wavelength Nd:YAG laser (30 mW) was applied between 30 and 600 s on DPSC in vitro. Cell proliferation was analyzed at 24, 48, and 72 h after irradiation, by cell counting and enzymatic activity quantification (paranitrophenylphosphate phosphatase (pNPP) test). A wound healing assay was used to study cell migration after irradiation. Effects of PBM on cytoskeleton organization and cell shape were assessed by actin filaments staining. Elasticity changes after irradiation were quantified in terms of Young's modulus measured using Atomic Force Microscopy (AFM) force spectroscopy. Green light significantly improved DPSC proliferation with a maximal effect obtained after 300-s irradiation (energy fluence 5 J/cm2). This irradiation had a significant impact on cell migration, improving wound healing after 24 h. These results were concomitant with a decrease of cells' Young's modulus after irradiation. This cell softening was explained by actin cytoskeleton reorganization, with diminution of cell circularity and more abundant pseudopodia. This study highlights the interest of green laser PMB for the proliferation and migration of mesenchymal stem cells, with encouraging results for clinical application, especially for surgical wound healing procedures.


Assuntos
Citoesqueleto/efeitos da radiação , Polpa Dentária/citologia , Terapia com Luz de Baixa Intensidade , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos da radiação , Cicatrização/efeitos da radiação , Adolescente , Adulto , Fenômenos Biomecânicos/efeitos da radiação , Movimento Celular/efeitos da radiação , Proliferação de Células/efeitos da radiação , Forma Celular/efeitos da radiação , Células Cultivadas , Humanos , Adulto Jovem
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