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1.
Georgian Med News ; (343): 38-43, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38096513

RESUMO

Loss of muscle mass is a typical symptom of cancer and it is strongly correlated with poor prognosis. Cancer-related Sarcopenia is unresponsive to conventional dietary changes and exercise, in contrast to age-associated muscle atrophy. This particular type of weakness differs from different kinds of muscle loss in that it is triggered by a number of interrelated mechanisms, notably inflammatory processes, abnormal metabolic processes, proteolysis, and autophagy. This research is to examine evidence supporting the theory that tumors have a causal role in causing muscular atrophy. It seeks to investigate the precise regulators that the tumour generates and how they affect the processes that result in muscle waste. The evaluation looks for new directions for further studies and medical treatments. The analysis is based on a thorough examination of the scientific literature and research that shows how tumor and muscle atrophy are related. It concentrates on studies that clarify the numerous strategies by which malignancies cause the loss of muscle. This article highlights particular mechanisms by which these tumor-derived substances affect the development of muscle loss, including inflammatory processes, metabolic disturbance, proteolysis, and autophagy. The discovery of such targets offers hope for the creation of efficient treatment strategies that can enhance the long-term outlook and quality of life of cancer sufferers who are experiencing muscle loss.


Assuntos
Neoplasias , Sarcopenia , Humanos , Sarcopenia/complicações , Sarcopenia/diagnóstico , Músculo Esquelético/metabolismo , Qualidade de Vida , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Neoplasias/patologia
3.
ESMO Open ; 8(6): 101830, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37979325

RESUMO

BACKGROUND: Cancer survivors are at increased risk for cardiovascular (CV) disease, although additional data are needed to better understand the incidence of CV events across different malignancies. This study sought to characterize the incidence of major adverse CV events [myocardial infarction, stroke, unstable angina (MACE), or heart failure (HF)] across multiple cancer types after cancer diagnosis. PATIENTS AND METHODS: Patients were identified from a USA-based administrative claims database who had index cancer diagnoses of breast, lung, prostate, melanoma, myeloma, kidney, colorectal, leukemia, or lymphoma between 2011 and 2019, with continuous enrollment for ≥12 months before diagnosis. Baseline CV risk factors and incidence rates of CV events post-index were identified for each cancer. Multivariable Cox hazards models assessed the cumulative incidence of MACE, accounting for baseline risk factors. RESULTS: Among 839 934 patients across nine cancer types, CV risk factors were prevalent. The cumulative incidence of MACE was highest in lung cancer and myeloma, and lowest in breast cancer, prostate cancer, and melanoma. MACE cumulative incidence for lung cancer was 26% by 4 years (2.7-fold higher relative to breast cancer). The incidence of stroke was especially pronounced in lung cancer, while HF was highest in myeloma and lung cancer. CONCLUSIONS: CV events were especially increased following certain cancer diagnoses, even after accounting for baseline risk factors. Understanding the variable patient characteristics and associated CV events across different cancers can help target appropriate CV risk factor modification and develop strategies to minimize adverse CV events and improve patient outcomes.


Assuntos
Neoplasias Pulmonares , Melanoma , Mieloma Múltiplo , Infarto do Miocárdio , Acidente Vascular Cerebral , Masculino , Humanos , Incidência , Medição de Risco , Infarto do Miocárdio/epidemiologia , Acidente Vascular Cerebral/epidemiologia
4.
Brain Inform ; 10(1): 18, 2023 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-37524933

RESUMO

Human behaviour reflects cognitive abilities. Human cognition is fundamentally linked to the different experiences or characteristics of consciousness/emotions, such as joy, grief, anger, etc., which assists in effective communication with others. Detection and differentiation between thoughts, feelings, and behaviours are paramount in learning to control our emotions and respond more effectively in stressful circumstances. The ability to perceive, analyse, process, interpret, remember, and retrieve information while making judgments to respond correctly is referred to as Cognitive Behavior. After making a significant mark in emotion analysis, deception detection is one of the key areas to connect human behaviour, mainly in the forensic domain. Detection of lies, deception, malicious intent, abnormal behaviour, emotions, stress, etc., have significant roles in advanced stages of behavioral science. Artificial Intelligence and Machine learning (AI/ML) has helped a great deal in pattern recognition, data extraction and analysis, and interpretations. The goal of using AI and ML in behavioral sciences is to infer human behaviour, mainly for mental health or forensic investigations. The presented work provides an extensive review of the research on cognitive behaviour analysis. A parametric study is presented based on different physical characteristics, emotional behaviours, data collection sensing mechanisms, unimodal and multimodal datasets, modelling AI/ML methods, challenges, and future research directions.

5.
Med J Armed Forces India ; 78(4): 422-429, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36267515

RESUMO

Background: Atherosclerotic carotid plaques are one of the most important causes of stroke. Apart from the severity of stenosis, there are certain plaque characteristics such as neovascularization and, surface ulceration which makes a plaque vulnerable. This study was performed to study the plaque characteristics using contrast-enhanced ultrasound (CEUS) and evaluate their association with presence of ischemic cerebrovascular symptoms in these patients. Methods: This study included patients presenting at a tertiary care center, having carotid plaques causing >60% stenosis. CEUS was performed for assessment of intraplaque neovascularity and plaque surface characteristics. These plaque features were then evaluated for their association with presence of ischemic cerebrovascular symptoms in patients. Results: Sixty plaques were studied in 50 patients. Thirty-two plaques were associated with ischemic cerebrovascular symptoms. On CEUS, intraplaque neovascularization was seen in 38 of the 60 plaques studied (63.3%). There was statistically significant association of intraplaque neovascularity and plaque surface characteristics with presence of ischemic cerebrovascular symptoms. Conclusion: CEUS allows better characterization of plaque surface characteristics and also depicts plaque neovascularization, which helps in determining the plaque vulnerability. It should be used as an adjunct to ultrasound and doppler assessment of carotid plaques.

6.
Sci Total Environ ; 852: 158421, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36058330

RESUMO

Wastewater-based surveillance (WBS) has been an effective tool for monitoring and understanding potential SARS-CoV-2 transmission across small and large-scale communities. In this study at the University of Saskatchewan, the assessment of SARS-CoV-2 was done over eight months during the 2021-2022 academic year. Wastewater samples were collected using passive samplers that were deployed in domestic sewer lines near adjacent campus residences and extracted for viral RNA, followed by Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR). The results showed similar trends for SARS-CoV-2 detection frequencies and viral loads across university residences, the whole campus, and from related WBS at Saskatoon Wastewater Treatment Plant. The maximum daily detection frequency for seven dormitories considered was about 75 %, while maximum daily case numbers for the residences and campus-wide were about 11 and 75 people, respectively. In addition, self-reported rates of infection on campus peaked during similar time frames as increases in viral load were detected at the Saskatoon wastewater treatment plant. These similarities indicate the usefulness and cost-effectiveness of monitoring the spread of COVID-19 in small-scale communities using WBS.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Águas Residuárias/análise , COVID-19/epidemiologia , RNA Viral , Universidades , Vigilância Epidemiológica Baseada em Águas Residuárias
7.
Neurochirurgie ; 68(6): 562-568, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35932885

RESUMO

BACKGROUND: Dementia following spine fusions is not described in the literature. Also, the impact of new onset dementia on long-term health care utilization is not described. The aim of our study was to define the incidence of new onset dementia and its long-term health care utilization in elderly patients. MATERIALS AND METHODS: MarketScan database were queried using the ICD-9/10 and CPT 4th edition, from 2001 to 2019. We included patients≥55 of age who underwent spine fusions with at least 5years follow-up. Outcomes were new onset dementia (>6months after the procedure) length of stay (LOS), discharge disposition, hospital readmissions, outpatient services, and medication refills. RESULTS: Of 45,129 patients who underwent spine fusions, 1283 patients (2.84%) were diagnosed to have new onset dementia. There was no difference in the reoperation rates among the dementia and non-dementia cohort at 1-, 2- and 5-years following the index procedure. Patients in the dementia cohort incurred higher number of hospital readmissions up to 5-years after the index procedure. In terms of combined index procedure and post-discharge utilization payments, significant differences were noted among the dementia vs. non-dementia cohorts at 5-years ($126,628 vs. $77,098), following the index procedure. CONCLUSION: Elderly age, higher comorbidities, Medicare insurance, multilevel lumbosacral fusions were identified as risk markers for developing dementia following spine fusions. Dementia resulted in significantly higher health care utilization with no increased rate of reoperations for up to 5-years following the index procedure.


Assuntos
Assistência ao Convalescente , Medicare , Idoso , Estados Unidos/epidemiologia , Humanos , Pré-Escolar , Incidência , Pontuação de Propensão , Alta do Paciente , Aceitação pelo Paciente de Cuidados de Saúde
8.
Lett Appl Microbiol ; 74(5): 707-717, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35060159

RESUMO

Due to awareness and benefits of goat rearing in developing economies, goats' significance is increasing. Unfortunately, these ruminants are threatened via multiple bacterial pathogens such as enteropathogenic Escherichia coli (EPEC). In goat kids and lambs, EPEC causes gastrointestinal disease leading to substantial economic losses for farmers and may also pose a threat to public health via the spread of zoonotic diseases. Management of infection is primarily based on antibiotics, but the need for new therapeutic measures as an alternative to antibiotics is becoming vital because of the advent of antimicrobial resistance (AMR). The prevalence of EPEC was established using bfpA gene, uspA gene and Stx1 gene, followed by phylogenetic analysis using Stx1 gene. The lytic activity of the isolated putative coliphages was tested on multi-drug resistant strains of EPEC. It was observed that a PCR based approach is more effective and rapid as compared to phenotypic tests of Escherichia coli virulence. It was also established that the isolated bacteriophages exhibited potent antibacterial efficacy in vitro, with some of the isolates (16%) detected as T4 and T4-like phages based on gp23 gene. Hence, bacteriophages as therapeutic agents may be explored as an alternative to antibiotics in managing public, livestock and environmental health in this era of AMR.


Assuntos
Bacteriófagos , Escherichia coli Enteropatogênica , Infecções por Escherichia coli , Proteínas de Escherichia coli , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bacteriófagos/genética , Escherichia coli Enteropatogênica/genética , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/veterinária , Proteínas de Escherichia coli/genética , Cabras/microbiologia , Filogenia , Ovinos
9.
Artigo em Inglês | MEDLINE | ID: mdl-36798522

RESUMO

Background: COVID-19 disease, a pandemic for more than two years, has major morbidity and mortality related to pulmonary involvement. Chest radiography is the main imaging tool for critically ill patients. As the availability of arterial blood gas analysis is limited in the Level I and II healthcare centres, which are major partners in providing healthcare in resource-limited times, we planned the present study. Objectives: To assess the role of chest radiography in predicting the need for oxygen/ventilator support in critically ill COVID-19 patients. Methods: This hospital-based, retrospective study included 135 patients who needed oxygen/ventilator support and had optimal-quality chest radiographs at admission. All the chest X-rays were evaluated and a severity score was calculated on a predesigned pro forma. Statistical evaluation of the data obtained was done using appropriate tools and methods. Results: Males outnumbered females, with a mean age of 54.35 ± 14.49 years. More than 72% of patients included in our study needed ventilator support while the rest needed oxygen support. There was a significant statistical correlation between the chest radiograph severity score and SPO2 /PaO2 levels in our study. Using a cut-off value >8 for the chest radiograph severity score in predicting the need for ventilator support in a Covid-19 patient, the sensitivity, specificity and accuracy was 85.7%, 92.5% and 89.5%, respectively. Conclusion: Chest radiography remains the mainstay of imaging in critically ill COVID-19 patients when they are on multiple life-support systems. Though arterial blood gas analysis is the gold standard tool for assessing the need for oxygen/ventilator support in these patients, the severity score obtained from the initial chest radiograph at the time of admission may also be used as a screening tool. Chest radiography may predict the need for oxygen/ventilator support, allowing time for patients to be moved to an appropriate-level healthcare centre, thus limiting morbidity and mortality.

10.
Public Health ; 202: 93-99, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34933205

RESUMO

OBJECTIVES: The Government of India prohibited the sale of tobacco products during the COVID-19 lockdown to prevent the spread of the SARS-CoV-2 virus. This study assessed the tobacco cessation behaviour and its predictors among adult tobacco users during the initial COVID-19 lockdown period in India. METHODS: A cross-sectional study was conducted with 801 adult tobacco users (both smoking and smokeless tobacco) in two urban metropolitan cities of India over a 2-month period (July to August 2020). The study assessed complete tobacco cessation and quit attempts during the lockdown period. Logistic and negative binomial regression models were used to study the correlates of tobacco cessation and quit attempts, respectively. RESULTS: In total, 90 (11.3%) tobacco users reported that they had quit using tobacco after the COVID-19 lockdown period. Overall, a median of two quit attempts (interquartile range 0-6) was made by tobacco users. Participants with good knowledge on the harmful effects of tobacco use and COVID-19 were significantly more likely to quit tobacco use (odds ratio [OR] 2.2; 95% confidence interval [CI] 1.2-4.0) and reported more quit attempts (incidence risk ratio 5.7; 95% CI 2.8-11.8) compared to those with poor knowledge. Participants who had access to tobacco products were less likely to quit tobacco use compared to those who had no access (OR 0.3; 95% CI 0.2-0.5]. CONCLUSIONS: Access restrictions and correct knowledge on the harmful effects of tobacco use and COVID-19 can play an important role in creating a conducive environment for tobacco cessation among users.


Assuntos
COVID-19 , Abandono do Hábito de Fumar , Abandono do Uso de Tabaco , Adulto , Controle de Doenças Transmissíveis , Estudos Transversais , Humanos , Índia , SARS-CoV-2
11.
Diabetes Metab Syndr ; 15(6): 102317, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34695772

RESUMO

BACKGROUND: Very few studies have reported on association of postprandial lipids and endothelial dysfunction among patients with diabetes. Whether endothelial dysfunction particularly postprandial FMD is worse in patients with T2DM with macrovascular disease compared to those without and whether this difference is related to postprandial hypertriglyceridemia (PPHTg) is unclear. Therefore, present study was aimed to assess the relationship between PPHTg and endothelial function in patients with T2DM with and without macrovascular disease. METHOD: Endothelial dysfunction by FMD and CIMT were compared in patients with T2DM with and without macrovascular disease (n = 13 each group) and 13 age, sex and BMI matched healthy individuals after an oral fat challenge. RESULTS: There was significant postprandial deterioration of FMD 4-hr after fat challenge in patients with diabetes (P < 0.001) as well as healthy individuals (P = 0.004). Patients with diabetes with macrovascular disease had significantly lower fasting (5.7 ± 6.1% vs. 22.7 ± 10.0% and vs. 24.7 ± 5.3%) as well as postprandial (4-hr) (3.1 ± 5.0% vs. 15.3 ± 8.1% and vs. 15.4 ± 5.7%) FMD compared to other two groups. Fasting, postprandial as well as change in FMD and CIMT in patients with diabetes correlated significantly with fasting as well as postprandial triglycerides with stronger correlation in those with macrovascular disease. CONCLUSION: Study found significant endothelial dysfunction by FMD that shows substantial further deterioration postprandially following high fat meal in patients with diabetes with macrovascular disease compared to patients with diabetes without macrovascular disease and healthy individuals. Study also indicates that PPHTg is a contributor to endothelial dysfunction. However, more studies are required to corroborate these findings.


Assuntos
Espessura Intima-Media Carotídea , Diabetes Mellitus Tipo 2/sangue , Gorduras na Dieta/administração & dosagem , Endotélio Vascular/metabolismo , Período Pós-Prandial/fisiologia , Doenças Vasculares/sangue , Administração Oral , Adulto , Espessura Intima-Media Carotídea/tendências , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/epidemiologia , Hipertrigliceridemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doenças Vasculares/epidemiologia , Doenças Vasculares/fisiopatologia
12.
Diabetes Metab Syndr ; 14(6): 1837-1840, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32961516

RESUMO

BACKGROUND AND AIMS: Iron deficiency anaemia, although well reported in diabetic nephropathy, has not been well studied in type 2 diabetes patients in the absence of nephropathy. We studied the prevalence of anaemia and iron deficiency in type 2 diabetes patients without nephropathy. MATERIAL AND METHODS: A total of 89 patients were selected for this study. 24 h urine protein less than 500 mg was used as the criteria to rule out diabetic nephropathy. Complete hemogram, iron profile and high sensitivity C reactive protein (hs CRP) levels were performed in each patient.Functional iron deficiency (FID) was defined as serum ferritin more than 100 µg/l with serum transferrin less than 20% and total iron deficiency state was defined as serum ferritin less than 100 µg/l. RESULTS: Fifteen patients (16.8%)had anaemia out of which 13 had total iron deficiency and one each had functional iron deficiency and normal iron status respectively. Assessment of the iron status overall showed that 49 patients had TID (55.05%), 16 had FID (17.9%)and 24 (27.05%) had normal iron status. The hs-CRP was significantly higher in those with iron deficiency. CONCLUSIONS: The present study found a high prevalence of iron deficiency anaemia in type 2 diabetic patients even in the absence of nephropathy. Most of the diabetic subjects also displayed an iron deficiency state the cause of which needs further investigation.


Assuntos
Anemia Ferropriva/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/patologia , Anemia Ferropriva/metabolismo , Anemia Ferropriva/patologia , Biomarcadores/análise , Glicemia/análise , Feminino , Ferritinas/metabolismo , Seguimentos , Hemoglobinas/análise , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico
13.
J Mycol Med ; 29(1): 71-74, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30630667

RESUMO

Hormographiella aspergillata, a basidiomycete is a rare cause of human infection. We report a case of 70-year-old female with corneal ulcer and endophthalmitis caused by this agent. The patient had an intraocular implantation of lens following a cataract surgery. Corneal tissue obtained during therapeutic penetrating keratoplasty showed presence of septate hyphae on microscopy and culture grew H. aspergillata which was confirmed by sequencing of ITS region. Patient was started on systemic voriconazole and topical natamycin, however the eye could not be salvaged. To our knowledge, this is the first report of ocular infection caused Hormographiella aspergillata in an immunocompetent patient.


Assuntos
Agaricales/isolamento & purificação , Infecções Oculares Fúngicas/diagnóstico , Infecções Oculares/microbiologia , Agaricales/efeitos dos fármacos , Idoso , Antifúngicos/uso terapêutico , Transplante de Córnea , Úlcera da Córnea/microbiologia , Endoftalmite/tratamento farmacológico , Endoftalmite/microbiologia , Infecções Oculares Fúngicas/tratamento farmacológico , Feminino , Humanos , Hifas , Imunocompetência
15.
Clin Radiol ; 74(1): 79.e11-79.e14, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30322707

RESUMO

AIM: To assess the quality of YouTube videos explaining transrectal ultrasound (TRUS)-guided biopsies of the prostate. MATERIALS AND METHODS: A search of YouTube was made for the terms "TRUS", "TRUS biopsy", "transrectal ultrasound", and "prostate biopsy". Videos were selected from the first 10 pages of results and reviewed by three authors against criteria based on written information from the British Association of Urological Surgeons. They were given a qualitative rating based on how well they provided information on factors such as preparation for the procedure, mechanism of the procedure and possible side effects. Data were also collected on view count, country of origin, likes, and dislikes. RESULTS: A total of 41 videos were reviewed, with no videos achieving an "excellent" rating, 32 being rated as "very poor", and only one rated as "good". Despite the poor-quality information, 39 of the videos were from healthcare organisations or individual surgeons. Videos often lacked specific information, or were targeted at healthcare professionals instead of patients. CONCLUSION: The information about TRUS-guided prostate biopsies on YouTube was not of a sufficiently high standard to allow patients to make informed decisions. Healthcare professionals hence have a duty to point patients towards adequate sources of reputable information online. Furthermore, there remains an opportunity to produce high-quality, informative, patient-focussed medical YouTube videos.


Assuntos
Biópsia Guiada por Imagem , Educação de Pacientes como Assunto/métodos , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Mídias Sociais , Humanos , Biópsia Guiada por Imagem/métodos , Biópsia Guiada por Imagem/psicologia , Masculino , Neoplasias da Próstata/patologia , Ultrassonografia , Gravação em Vídeo
17.
Ann R Coll Surg Engl ; 100(3): e49-e50, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29493352

RESUMO

Heterotrophic ossification in tumours is an uncommon phenomenon. The presence of ossification in renal cell carcinomas is extremely rare. In this report, we present a unique case of type II papillary renal cell carcinoma associated with heterotrophic ossification.


Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Ossificação Heterotópica/patologia , Carcinoma de Células Renais/diagnóstico , Humanos , Neoplasias Renais/diagnóstico , Masculino , Pessoa de Meia-Idade , Ossificação Heterotópica/diagnóstico
18.
Haemophilia ; 24(2): 245-252, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29436077

RESUMO

INTRODUCTION: Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources. AIM: Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high-titre inhibitors. METHODS: Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI. RESULTS: Of 19 patients, 7 were first-time ITI and 12 were rescue ITI. Of 7 first-time patients, 6 had at least 1 high-risk feature for ITI failure. Four of 7 first-time patients were tolerized in a median of 7.8 months. The remaining 3 patients continue on rFVIIIFc ITI. Of 12 rescue patients, 7 initially achieved a negative Bethesda titre (≤0.6) in a median of 3.3 months, 1 had a decrease in Bethesda titre and continues on rFVIIIFc ITI and 4 have not demonstrated a decrease in Bethesda titre. Of these 4, 3 continue on rFVIIIFc ITI and 1 switched to bypass therapy alone. Two initially responsive patients transitioned to other factors due to recurrence. Overall, 16 of 19 patients remain on rFVIIIFc (prophylaxis or ITI). For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events reported. CONCLUSIONS: Recombinant factor VIII Fc fusion protein demonstrated rapid time to tolerization in high-risk first-time ITI patients. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI with other products. These findings highlight the need to further evaluate the use of rFVIIIFc for ITI.


Assuntos
Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Criança , Pré-Escolar , Fator VIII/farmacologia , Humanos , Fragmentos Fc das Imunoglobulinas/farmacologia , Lactente , Proteínas Recombinantes de Fusão/farmacologia , Estudos Retrospectivos
19.
Leukemia ; 32(3): 663-674, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28690315

RESUMO

Anthracyclines have been a cornerstone in the cure of diffuse large B-cell lymphoma (DLBCL) and other hematological cancers. The ability of anthracyclines to eliminate DLBCL depends on the presence of topoisomerase-II-alpha (TopIIA), a DNA repair enzyme complex. We identified nucleolin as a novel binding partner of TopIIA. Abrogation of nucleolin sensitized DLBCL cells to TopIIA targeting agents (doxorubicin/etoposide). Silencing nucleolin and challenging DLBCL cells with doxorubicin enhanced the phosphorylation of H2AX (γH2AX-marker of DNA damage) and allowed DNA fragmentation. Reconstitution of nucleolin expression in nucleolin-knockdown DLBCL cells prevented TopIIA targeting agent-induced apoptosis. Nucleolin binding to TopIIA was mapped to RNA-binding domain 3 of nucleolin, and this interaction was essential for blocking DNA damage and apoptosis. Nucleolin silencing decreased TopIIA decatenation activity, but enhanced formation of TopIIA-DNA cleavable complexes in the presence of etoposide. Moreover, combining nucleolin inhibitors: aptamer AS1411 or nucant N6L with doxorubicin reduced DLBCL cell survival. These findings are of clinical importance because low nucleolin levels versus high nucleolin levels in DLBCL predicted 90-month estimated survival of 70% versus 12% (P<0.0001) of patients treated with R-CHOP-based therapy.


Assuntos
Antineoplásicos/farmacologia , Linfoma Difuso de Grandes Células B/metabolismo , Fosfoproteínas/antagonistas & inibidores , Proteínas de Ligação a RNA/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Dano ao DNA , DNA Topoisomerases Tipo II/metabolismo , Feminino , Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Terapia de Alvo Molecular , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Nucleolina
20.
Leukemia ; 32(4): 960-970, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28972595

RESUMO

Ibrutinib, a covalent inhibitor of Bruton Tyrosine Kinase (BTK), is approved for treatment of patients with relapsed/refractory or treatment-naïve chronic lymphocytic leukemia (CLL). Besides directly inhibiting BTK, ibrutinib possesses immunomodulatory properties through targeting multiple signaling pathways. Understanding how this ancillary property of ibrutinib modifies the CLL microenvironment is crucial for further exploration of immune responses in this disease and devising future combination therapies. Here, we investigated the mechanisms underlying the immunomodulatory properties of ibrutinib. In peripheral blood samples collected prospectively from CLL patients treated with ibrutinib monotherapy, we observed selective and durable downregulation of PD-L1 on CLL cells by 3 months post-treatment. Further analysis showed that this effect was mediated through inhibition of the constitutively active signal transducer and activator of transcription 3 (STAT3) in CLL cells. Similar downregulation of PD-1 was observed in CD4+ and CD8+ T cells. We also demonstrated reduced interleukin (IL)-10 production by CLL cells in patients receiving ibrutinib, which was also linked to suppression of STAT3 phosphorylation. Taken together, these findings provide a mechanistic basis for immunomodulation by ibrutinib through inhibition of the STAT3 pathway, critical in inducing and sustaining tumor immune tolerance. The data also merit testing of combination treatments combining ibrutinib with agents capable of augmenting its immunomodulatory effects.


Assuntos
Linfócitos B Reguladores/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Receptor de Morte Celular Programada 1/metabolismo , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Adenina/análogos & derivados , Idoso , Linfócitos B Reguladores/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Feminino , Humanos , Tolerância Imunológica/efeitos dos fármacos , Imunossupressores/uso terapêutico , Leucemia Linfocítica Crônica de Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Piperidinas , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos
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