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1.
ACS Appl Mater Interfaces ; 13(33): 39003-39017, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433253

RESUMO

Improving tumor immunogenicity is critical for increasing the responsiveness of triple-negative breast cancer (TNBC) to anti-PD-(L)1 treatment. Here, we verified that chidamide (CHI), an epigenetic modulator, could elicit immunogenic cell death within TNBC to enhance cancer immunogenicity and elicit an antitumor immune response. Additionally, CHI increased the expression level of PD-L1, MHC I, and MHC II on cancer cells, which contributed to T-cell recognition and PD-1/PD-L1 blockade therapy response. The synergistic antitumor efficacy of CHI and PD-L1 blockade therapy was further explored through liposomes co-delivering CHI and BMS-202 (a small-molecule PD-L1 inhibitor). The liposomes possessed good biocompatibility, security, and controllable drug release and endowed therapeutics drugs with favorable tumor accumulation. Furthermore, the drug-loaded liposomes could obviously boost the antitumor immunity of TNBC through CHI-enhanced tumor immunogenicity and BMS-202-mediated PD-L1 blockade, thereby effectively inhibiting the growth of primary and metastatic tumors with an inhibitory rate of metastasis of up to 96%. In summary, this work provided a referable and optional approach for clinical antitumor therapy based on the combination of an epigenetic modulator and PD-1/PD-L1 blockade therapy.


Assuntos
Acetamidas/química , Aminopiridinas/química , Antineoplásicos/farmacologia , Benzamidas/química , Portadores de Fármacos/química , Inibidores de Checkpoint Imunológico/química , Piridinas/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/imunologia , Acetamidas/farmacologia , Aminopiridinas/farmacologia , Animais , Benzamidas/farmacologia , Materiais Biocompatíveis/química , Linhagem Celular Tumoral , Terapia Combinada/métodos , Liberação Controlada de Fármacos , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Lipossomos/química , Camundongos , Camundongos Endogâmicos BALB C , Piridinas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Distribuição Tecidual , Resultado do Tratamento
2.
Am Fam Physician ; 104(2): 171-178, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34383430

RESUMO

Breast cancer is the leading cause of death from cancer in women worldwide, and the second most common cause of death from cancer in women in the United States. Risk assessment tools can identify the risk of breast cancer, and patients at high risk may be candidates for risk-reducing medications. The choice of medication varies with menopausal status. Breast cancer treatment depends on the stage. Stage 0 is ductal carcinoma in situ, which is noninvasive but progresses to invasive cancer in up to 40% of patients. Ductal carcinoma in situ is treated with lumpectomy and radiation or with mastectomy. If ductal carcinoma in situ is estrogen receptor-positive, patients may also receive endocrine therapy. Early invasive stages (I, IIa, IIb) and locally advanced stages (IIIa, IIIb, IIIc) are nonmetastatic and have three treatment phases. The preoperative phase uses systemic endocrine or immunotherapies when tumors express estrogen, progesterone, or ERBB2 receptors. Preoperative chemotherapy may also be used and is the only option when tumors have none of those three receptors. There are two options for the surgical phase with similar survival rates; a lumpectomy with radiation if the tumor can be excised completely with good cosmetic results, or a mastectomy. Sentinel lymph node biopsy is also performed when there is suspected nodal disease. The postoperative phase includes radiation, endocrine therapy, immunotherapy, and chemotherapy. Postmenopausal women should also be offered postoperative bisphosphonates. Stage IV (metastatic) breast cancer is treatable but not curable. Treatment goals include improving the length and quality of life.


Assuntos
Neoplasias da Mama/terapia , Gerenciamento Clínico , Neoplasias da Mama/diagnóstico , Terapia Combinada/métodos , Feminino , Humanos , Estadiamento de Neoplasias
3.
Medicine (Baltimore) ; 100(31): e26833, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397848

RESUMO

ABSTRACT: To compare the outcomes of patients with high-risk prostate cancer treated by primary radical prostatectomy (RP) and primary androgen deprivation therapy (ADT).The study included patients with high-risk or very high-risk prostate cancer. Patients treated with definitive radiation therapy and those with clinical N1 and M1 disease were excluded. The RP group was divided into sub-cohorts of patients treated with ADT and those who received ADT after biochemical recurrence post-RP. Cancer-specific survival (CSS) and overall survival (OS) were analyzed using the Kaplan-Meier method and the Cox proportional hazards model.The study analyzed 859 patients divided into the RP group (n = 654) and ADT group (n = 205). Castration-resistant prostate cancer was detected in 23 (3.5%) patients in the RP group and 43 (21.0%) patients in the ADT group. Mortality cases included 63 (9.6%) patients in the RP group and 91 (44.4%) patients in the ADT group. CSS (P = .0002) and OS (P < .0001) were significantly higher in the RP group than in the ADT group. In the sub-cohort, CSS did not differ significantly between the RP and ADT groups, whereas OS was significantly higher in the RP group than in the ADT group (P < .0001). In the multivariate analysis, primary ADT increased CSS (hazard ratio, 2.068; P = .0498) and OS (hazard ratio, 3.218; P < .0001) compared with RP.In clinically localized high-risk prostate cancer patients, primary RP was associated with better CSS and OS than primary ADT. Comprehensive counseling in this cohort of patients will help the selection of treatment.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Prostatectomia , Neoplasias da Próstata , Radioterapia , Idoso , Biomarcadores Tumorais/sangue , Terapia Combinada/métodos , Humanos , Estimativa de Kaplan-Meier , Masculino , Estadiamento de Neoplasias , Avaliação de Processos e Resultados em Cuidados de Saúde , Seleção de Pacientes , Modelos de Riscos Proporcionais , Antígeno Prostático Específico/sangue , Prostatectomia/efeitos adversos , Prostatectomia/métodos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/epidemiologia , Radioterapia/efeitos adversos , Radioterapia/métodos , República da Coreia/epidemiologia , Medição de Risco
4.
Undersea Hyperb Med ; 48(3): 297-321, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34390634

RESUMO

Refractory osteomyelitis is defined as a chronic osteomyelitis that persists or recurs after appropriate interventions have been performed or where acute osteomyelitis has not responded to accepted management techniques [1]. To date, no randomized clinical trials examining the effects of hyperbaric oxygen (HBO2) therapy on refractory osteomyelitis exist, and the number of new osteomyelitis clinical trials conducted over the past decade has been limited. However, based on a comprehensive review of the scientific literature, the addition of HBO2 therapy to routine surgical and antibiotic treatment of previously refractory osteomyelitis appears to be both safe and ultimately improves infection resolution rates. In most cases, the best clinical results are obtained when HBO2 treatment is administered in conjunction with culture-directed antibiotics and initiated soon after clinically indicated surgical debridement. Where extensive surgical debridement or removal of fixation hardware is relatively contraindicated (e.g., cranial, spinal, sternal, or pediatric osteomyelitis), a trial of culture-directed antibiotics and HBO2 therapy prior to undertaking more than limited surgical interventions provides a reasonable prospect for osteomyelitis cure. HBO2 therapy is ordinarily delivered on a once daily basis, five-seven days per week, for 90-120 minutes using 2.0-3.0 atmospheres absolute (ATA) pressure. Where prompt clinical improvement is seen, the existing regimen of antibiotics and HBO2 therapy should be continued for approximately four to six weeks. Typically, 20-40 HBO2 sessions are required to achieve sustained therapeutic benefit. In contrast, if prompt clinical response is not noted or osteomyelitis recurs after this initial treatment period, then continuation of the current antibiotic and HBO2 treatment regimen is unlikely to be effective. Instead, clinical management strategies should be reassessed and additional surgical debridement and/or modification of antibiotic therapy considered. Subsequent reinstitution of HBO2 therapy will again help maximize the overall chances for treatment success in these persistently refractory patients.


Assuntos
Antibacterianos/uso terapêutico , Oxigenação Hiperbárica/métodos , Osteomielite/terapia , Adulto , Animais , Criança , Doença Crônica , Estudos de Coortes , Terapia Combinada/métodos , Desbridamento , Humanos , Oxigenação Hiperbárica/estatística & dados numéricos , Osteomielite/classificação , Osteomielite/microbiologia , Seleção de Pacientes , Recidiva , Fatores de Tempo
5.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204583

RESUMO

Fabry disease (FD) is a lysosomal storage disease caused by mutations in the gene for the α-galactosidase A (GLA) enzyme. The absence of the enzyme or its activity results in the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), in different tissues, leading to a wide range of clinical manifestations. More than 1000 natural variants have been described in the GLA gene, most of them affecting proper protein folding and enzymatic activity. Currently, FD is treated by enzyme replacement therapy (ERT) or pharmacological chaperone therapy (PCT). However, as both approaches show specific drawbacks, new strategies (such as new forms of ERT, organ/cell transplant, substrate reduction therapy, or gene therapy) are under extensive study. In this review, we summarize GLA mutants described so far and discuss their putative application for the development of novel drugs for the treatment of FD. Unfavorable mutants with lower activities and stabilities than wild-type enzymes could serve as tools for the development of new pharmacological chaperones. On the other hand, GLA mutants showing improved enzymatic activity have been identified and produced in vitro. Such mutants could overcome several complications associated with current ERT, as lower-dose infusions of these mutants could achieve a therapeutic effect equivalent to that of the wild-type enzyme.


Assuntos
Doença de Fabry/genética , Predisposição Genética para Doença , Mutação , alfa-Galactosidase/genética , Alelos , Animais , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Gerenciamento Clínico , Ativação Enzimática , Doença de Fabry/diagnóstico , Doença de Fabry/metabolismo , Doença de Fabry/terapia , Humanos , Relação Estrutura-Atividade , Resultado do Tratamento , alfa-Galactosidase/química , alfa-Galactosidase/metabolismo
6.
Int J Lab Hematol ; 43 Suppl 1: 103-108, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34288437

RESUMO

TTP is a life-threatening disorder diagnosed using a combination of clinical information and laboratory results. ADAMTS13 activity and antibody testing represent a major advance in the field, but results can sometimes be difficult to interpret due to technical aspects of the tests and characteristics of the causative antibodies in acquired TTP. Genetic testing for ADAMTS13 mutations is also now available to assist with the diagnosis of inherited TTP. This review will focus on ADAMTS13 testing and will highlight patient and laboratory aspects that can lead to diagnostic difficulty. The effects of TTP therapies on test results will also be discussed.


Assuntos
Proteína ADAMTS13/sangue , Testes de Coagulação Sanguínea , Púrpura Trombocitopênica Trombótica/sangue , Púrpura Trombocitopênica Trombótica/diagnóstico , Autoanticorpos/sangue , Autoanticorpos/imunologia , Coagulação Sanguínea , Testes de Coagulação Sanguínea/métodos , Testes de Coagulação Sanguínea/tendências , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Mutação , Púrpura Trombocitopênica Trombótica/etiologia , Púrpura Trombocitopênica Trombótica/terapia , Resultado do Tratamento
7.
Cochrane Database Syst Rev ; 7: CD013307, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34280303

RESUMO

BACKGROUND: Delirium is an acute neuropsychological disorder that is common in hospitalised patients. It can be distressing to patients and carers and it is associated with serious adverse outcomes. Treatment options for established delirium are limited and so prevention of delirium is desirable. Non-pharmacological interventions are thought to be important in delirium prevention.  OBJECTIVES: To assess the effectiveness of non-pharmacological interventions designed to prevent delirium in hospitalised patients outside intensive care units (ICU). SEARCH METHODS: We searched ALOIS, the specialised register of the Cochrane Dementia and Cognitive Improvement Group, with additional searches conducted in MEDLINE, Embase, PsycINFO, CINAHL, LILACS, Web of Science Core Collection, ClinicalTrials.gov and the World Health Organization Portal/ICTRP to 16 September 2020. There were no language or date restrictions applied to the electronic searches, and no methodological filters were used to restrict the search. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of single and multicomponent non-pharmacological interventions for preventing delirium in hospitalised adults cared for outside intensive care or high dependency settings. We only included non-pharmacological interventions which were designed and implemented to prevent delirium.  DATA COLLECTION AND ANALYSIS: Two review authors independently examined titles and abstracts identified by the search for eligibility and extracted data from full-text articles. Any disagreements on eligibility and inclusion were resolved by consensus. We used standard Cochrane methodological procedures. The primary outcomes were: incidence of delirium; inpatient and later mortality; and new diagnosis of dementia. We included secondary and adverse outcomes as pre-specified in the review protocol. We used risk ratios (RRs) as measures of treatment effect for dichotomous outcomes and between-group mean differences for continuous outcomes. The certainty of the evidence was assessed using GRADE. A complementary exploratory analysis was undertaker using a Bayesian component network meta-analysis fixed-effect model to evaluate the comparative effectiveness of the individual components of multicomponent interventions and describe which components were most strongly associated with reducing the incidence of delirium. MAIN RESULTS: We included 22 RCTs that recruited a total of 5718 adult participants. Fourteen trials compared a multicomponent delirium prevention intervention with usual care. Two trials compared liberal and restrictive blood transfusion thresholds. The remaining six trials each investigated a different non-pharmacological intervention. Incidence of delirium was reported in all studies.  Using the Cochrane risk of bias tool, we identified risks of bias in all included trials. All were at high risk of performance bias as participants and personnel were not blinded to the interventions. Nine trials were at high risk of detection bias due to lack of blinding of outcome assessors and three more were at unclear risk in this domain.  Pooled data showed that multi-component non-pharmacological interventions probably reduce the incidence of delirium compared to usual care (10.5% incidence in the intervention group, compared to 18.4% in the control group, risk ratio (RR) 0.57, 95% confidence interval (CI) 0.46 to 0.71, I2 = 39%; 14 studies; 3693 participants; moderate-certainty evidence, downgraded due to risk of bias).  There may be little or no effect of multicomponent interventions on inpatient mortality compared to usual care (5.2% in the intervention group, compared to 4.5% in the control group, RR 1.17, 95% CI 0.79 to 1.74, I2 = 15%; 10 studies; 2640 participants; low-certainty evidence downgraded due to inconsistency and imprecision).  No studies of multicomponent interventions reported data on new diagnoses of dementia.  Multicomponent interventions may result in a small reduction of around a day in the duration of a delirium episode (mean difference (MD) -0.93, 95% CI -2.01 to 0.14 days, I2 = 65%; 351 participants; low-certainty evidence downgraded due to risk of bias and imprecision). The evidence is very uncertain about the effect of multicomponent interventions on delirium severity (standardised mean difference (SMD) -0.49, 95% CI -1.13 to 0.14, I2=64%; 147 participants; very low-certainty evidence downgraded due to risk of bias and serious imprecision). Multicomponent interventions may result in a reduction in hospital length of stay compared to usual care (MD -1.30 days, 95% CI -2.56 to -0.04 days, I2=91%; 3351 participants; low-certainty evidence downgraded due to risk of bias and inconsistency), but little to no difference in new care home admission at the time of hospital discharge (RR 0.77, 95% CI 0.55 to 1.07; 536 participants; low-certainty evidence downgraded due to risk of bias and imprecision). Reporting of other adverse outcomes was limited.  Our exploratory component network meta-analysis found that re-orientation (including use of familiar objects), cognitive stimulation and sleep hygiene were associated with reduced risk of incident delirium. Attention to nutrition and hydration, oxygenation, medication review, assessment of mood and bowel and bladder care were probably associated with a reduction in incident delirium but estimates included the possibility of no benefit or harm.  Reducing sensory deprivation, identification of infection, mobilisation and pain control all had summary estimates that suggested potential increases in delirium incidence, but the uncertainty in the estimates was substantial.  Evidence from two trials suggests that use of a liberal transfusion threshold over a restrictive transfusion threshold probably results in little to no difference in incident delirium (RR 0.92, 95% CI 0.62 to 1.36; I2 = 9%; 294 participants; moderate-certainty evidence downgraded due to risk of bias).  Six other interventions were examined, but evidence for each was limited to single studies and we identified no evidence of delirium prevention.  AUTHORS' CONCLUSIONS: There is moderate-certainty evidence regarding the benefit of multicomponent non-pharmacological interventions for the prevention of delirium in hospitalised adults, estimated to reduce incidence by 43% compared to usual care. We found no evidence of an effect on mortality. There is emerging evidence that these interventions may reduce hospital length of stay, with a trend towards reduced delirium duration, although the effect on delirium severity remains uncertain. Further research should focus on implementation and detailed analysis of the components of the interventions to support more effective, tailored practice recommendations.


Assuntos
Delírio/prevenção & controle , Pacientes Internados , Idoso , Idoso de 80 Anos ou mais , Viés , Transfusão de Sangue , Terapia Combinada/métodos , Delírio/epidemiologia , Mortalidade Hospitalar , Humanos , Incidência , Tempo de Internação , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Anticancer Res ; 41(7): 3253-3260, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230119

RESUMO

Epithelial ovarian cancer is the second most common malignancy of the female genital tract, with approximately 7,400 new cases annually in Germany. With 5,500 deaths per year, ovarian cancer is the leading gynecologic cause of death. Epithelial ovarian cancer is characterized by morphologic heterogeneity with 4 molecular biological subtypes (immunoreactive-like, differentiated-like, proliferative-like, mesenchymal-like) with different prognosis. Significantly improved survival is achieved by optimal debulking with no residual disease (R0). Systematic lymphonodectomy of clinical negative lymph nodes has no effect on overall survival in advanced ovarian cancer. Interval debulking in advanced ovarian cancer after three cycles of neoadjuvant chemotherapy with carboplatin/paclitaxel is controversial. Standard chemotherapy for advanced ovarian cancer consists of six cycles of carboplatin AUC5 and paclitaxel 175 mg/m2, in a three-week cycle. Intraperitoneal chemotherapy is not a standard therapy. Anti-hormonal therapy with an aromatase inhibitor plays a minor role in therapy of both low grade serous ovarian cancer (LGSOC) and high grade serous ovarian cancer (HGSOC). A major achievement in ovarian cancer therapy has been the results of the SOLO-1 trial, in which olaparib as a first line maintenance monotherapy resulted in an overall 70% lower risk of disease progression in patients with advanced Breast Cancer Gene (BRCA)-mutated ovarian cancer.


Assuntos
Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada/métodos , Feminino , Alemanha , Humanos , Terapia Neoadjuvante/métodos
9.
Lancet Oncol ; 22(8): 1093-1102, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34237249

RESUMO

BACKGROUND: There is paucity of investigations into immunotherapy or targeted therapy for postoperative locally recurrent pancreatic cancer. We aimed to assess the efficacy of stereotactic body radiotherapy (SBRT) plus pembrolizumab and trametinib in these patients. METHODS: In this open-label, randomised, controlled, phase 2 study, participants were recruited from Changhai Hospital affiliated to Naval Medical University, Shanghai, China. Eligible patients were aged 18 years or older with histologically confirmed pancreatic ductal adenocarcinoma characterised by mutant KRAS and positive immunohistochemical staining of PD-L1, Eastern Cooperative Oncology Group performance status of 0 or 1, and documented local recurrence after surgery followed by chemotherapy (mFOLFIRINOX or 5-fluorouracil). Eligible participants were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive SBRT with doses ranging from 35-40 Gy in five fractions, intravenous pembrolizumab 200 mg once every 3 weeks, and oral trametinib 2 mg once daily or SBRT (same regimen) and intravenous gemcitabine (1000 mg/m2) on day 1 and 8 of a 21-day cycle for eight cycles until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the as-treated population in all participants who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02704156, and is now complete. FINDINGS: Between Oct 10, 2016, and Oct 28, 2017, 198 patients were screen, of whom 170 patients were enrolled and randomly assigned to receive SBRT plus pembrolizumab and trametinib (n=85) or SBRT plus gemcitabine (n=85). As of the clinical cutoff date (Nov 30, 2020), median follow-up was 23·3 months (IQR 20·5-27·4). Median overall survival was 24·9 months (23·3-26·5) with SBRT plus pembrolizumab and trametinib and 22·4 months (95% CI 21·2-23·6) with SBRT plus gemcitabine (hazard ratio [HR] 0·60 [95% CI 0·44-0·82]; p=0·0012). The most common grade 3 or 4 adverse effects were increased alanine aminotransferase or aspartate aminotransferase (ten [12%] of 85 in SBRT plus pembrolizumab and trametinib group vs six [7%] of 85 in SBRT plus gemcitabine group), increased blood bilirubin (four [5%] vs none), neutropenia (one [1%] vs nine [11%]), and thrombocytopenia (one [1%] vs four [5%]). Serious adverse events were reported by 19 (22%) participants in the SBRT plus pembrolizumab and trametinib group and 12 (14%) in the SBRT plus gemcitabine group. No treatment-related deaths occurred. INTERPRETATION: The combination of SBRT plus pembrolizumab and trametinib could be a novel treatment option for patients with locally recurrent pancreatic cancer after surgery. Phase 3 trials are needed to confirm our findings. FUNDING: Shanghai Shenkang Center and Changhai Hospital. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Ductal Pancreático/terapia , Terapia Combinada/métodos , Neoplasias Pancreáticas/terapia , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Idoso , China , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radiocirurgia/métodos
10.
Int J Mol Sci ; 22(12)2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-34202978

RESUMO

Niemann-Pick type C (NPC) disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol in the late endo-lysosomal system of cells. Progressive neurological deterioration and the onset of symptoms, such as ataxia, seizures, cognitive decline, and severe dementia, are pathognomonic features of the disease. In addition, different pathological similarities, including degeneration of hippocampal and cortical neurons, hyperphosphorylated tau, and neurofibrillary tangle formation, have been identified between NPC disease and other neurodegenerative pathologies. However, the underlying pathophysiological mechanisms are not yet well understood, and even a real cure to counteract neurodegeneration has not been identified. Therefore, the combination of current pharmacological therapies, represented by miglustat and cyclodextrin, and non-pharmacological approaches, such as physical exercise and appropriate diet, could represent a strategy to improve the quality of life of NPC patients. Based on this evidence, in our review we focused on the neurodegenerative aspects of NPC disease, summarizing the current knowledge on the molecular and biochemical mechanisms responsible for cognitive impairment, and suggesting physical exercise and nutritional treatments as additional non-pharmacologic approaches to reduce the progression and neurodegenerative course of NPC disease.


Assuntos
Suscetibilidade a Doenças , Degeneração Neural/etiologia , Doença de Niemann-Pick Tipo C/etiologia , Doença de Niemann-Pick Tipo C/terapia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Tomada de Decisão Clínica , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/terapia , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Gerenciamento Clínico , Humanos , Degeneração Neural/diagnóstico , Doença de Niemann-Pick Tipo C/diagnóstico , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Resultado do Tratamento
11.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299373

RESUMO

Melanoma is the deadliest type of skin cancer, due to its invasiveness and limited treatment efficacy. The main therapy for primary melanoma and solitary organ metastases is wide excision. Adjuvant therapy, such as chemotherapy and targeted therapies are mainly used for disseminated disease. Radiotherapy (RT) is a powerful treatment option used in more than 50% of cancer patients, however, conventional RT alone is unable to eradicate melanoma. Its general radioresistance is attributed to overexpression of repair genes in combination with cascades of biochemical repair mechanisms. A novel sophisticated technique based on synchrotron-generated, spatially fractionated RT, called Microbeam Radiation Therapy (MRT), has been shown to overcome these treatment limitations by allowing increased dose delivery. With MRT, a collimator subdivides the homogeneous radiation field into an array of co-planar, high-dose microbeams that are tens of micrometres wide and spaced a few hundred micrometres apart. Different preclinical models demonstrated that MRT has the potential to completely ablate tumours, or significantly improve tumour control while dramatically reducing normal tissue toxicity. Here, we discuss the role of conventional RT-induced immunity and the potential for MRT to enhance local and systemic anti-tumour immune responses. Comparative gene expression analysis from preclinical tumour models indicated a specific gene signature for an 'MRT-induced immune effect'. This focused review highlights the potential of MRT to overcome the inherent radioresistance of melanoma which could be further enhanced for future clinical use with combined treatment strategies, in particular, immunotherapy.


Assuntos
Melanoma/radioterapia , Animais , Terapia Combinada/métodos , Humanos , Imunidade/imunologia , Imunoterapia/métodos , Melanoma/imunologia , Melanoma/terapia , Radioterapia/métodos , Síncrotrons
12.
BMJ ; 374: n1648, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312178

RESUMO

Since its emergence in Wuhan, China, covid-19 has spread and had a profound effect on the lives and health of people around the globe. As of 4 July 2021, more than 183 million confirmed cases of covid-19 had been recorded worldwide, and 3.97 million deaths. Recent evidence has shown that a range of persistent symptoms can remain long after the acute SARS-CoV-2 infection, and this condition is now coined long covid by recognized research institutes. Studies have shown that long covid can affect the whole spectrum of people with covid-19, from those with very mild acute disease to the most severe forms. Like acute covid-19, long covid can involve multiple organs and can affect many systems including, but not limited to, the respiratory, cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. The symptoms of long covid include fatigue, dyspnea, cardiac abnormalities, cognitive impairment, sleep disturbances, symptoms of post-traumatic stress disorder, muscle pain, concentration problems, and headache. This review summarizes studies of the long term effects of covid-19 in hospitalized and non-hospitalized patients and describes the persistent symptoms they endure. Risk factors for acute covid-19 and long covid and possible therapeutic options are also discussed.


Assuntos
COVID-19/complicações , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/etiologia , COVID-19/terapia , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Terapia Combinada/normas , Reposicionamento de Medicamentos , Carga Global da Doença , Humanos , Incidência , Guias de Prática Clínica como Assunto , Fatores de Risco , Índice de Gravidade de Doença
13.
J Clin Neurosci ; 90: 39-47, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34275579

RESUMO

The optimal timing of adjuvant radiochemotherapy (RCT) in glioblastoma (GBM) patients remains unknown and the paradigm of 'the sooner, the better' has been challenged by many recent publications. In this study, we present unique data on the outcomes of patients with significant treatment delays. The study group consisted of 346 GBM patients (median age 56.8 years) who received surgical treatment (total or subtotal resection) and then underwent adjuvant concurrent RCT at one institution. The main endpoint was overall survival (OS). The Univariate and multivariate Cox Proportional-Hazard Model, log-rank test, and Kaplan-Meier method were used for the analysis. The median OS was 18.7 months and the 5-year overall survival was 8.5%. The median time interval from surgery to RCT was 9.8 weeks. The Cox regression showed that the time interval had no statistically significant impact on OS both in uni- and multivariate analysis. The explorative analysis suggested a positive trend for improved survival for patients in the 1st quartile of the time interval, especially for patients with residual disease or local recurrence prior to RCT, However, considering the 6.9 weeks median interval in the 1st quartile, this subgroup should still be regarded as 'moderate delay' compared with other literature data. The results indicate that the time interval is not a clear prognostic factor in the treatment of GBM. Prospective trials are highly warranted, as data suggest that moderate delays in the initiation of adjuvant treatment might be associated with survival benefit.


Assuntos
Neoplasias Encefálicas/terapia , Quimiorradioterapia Adjuvante/métodos , Glioblastoma/terapia , Procedimentos Neurocirúrgicos/métodos , Tempo para o Tratamento , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Terapia Combinada/métodos , Feminino , Glioblastoma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia/tratamento farmacológico , Prognóstico , Modelos de Riscos Proporcionais
14.
Medicine (Baltimore) ; 100(22): e26210, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087895

RESUMO

BACKGROUND: Osteonecrosis of the femeral head (ONFH) occurs predominantly in young- and middle-aged people, and the disability rate is high in the late stage of the disease and most patients have to undergo total hip replacement. Clinically, increasing attention is paid to intervening early and middle-stage ONFH so as to delay its progress. Acupuncture and moxibustion (AM) is a unique method for treating ONFH in China. This study aims to summarize the advantages of AM for the treatment of ONFH. METHODS: A comprehensive literature search was conducted on the database with languages of English and Chinese. The medical subject titles used are "Osteonecrosis of the femoral head" and "acupuncture and moxibustion." Related words in the title or abstract including but were not limited to "necrosis of the femoral head," "avascular necrosis of the femoral head," "ischemic necrosis of the femoral head," "caput femoris necrosis," "bone paralysis," "bone erosion," and "bone atrophy." RESULTS: Nine randomized controlled trials were identified in this meta-analysis that included 630 subjects. Meta-analysis showed that the trial group that treated with conventional therapy combined with AM had a higher effective rate (Z = 2.27 P = 0.02) and excellent and good rate (Z = 4.85 P < 0.00001) and Harris hip function score (HHS) (Z = 2.31 P = 0.02) and lower incidence of related adverse reactions during treatment (Z = 2.82 P = 0.005) compared with the control group that treated with conventional therapy alone. CONCLUSIONS: AM for early and middle-stage ONFH is an effective and relatively safe intervention, which can improve the effective rate and excellent and good rate and HHS, and reduce the adverse reaction rate. Clinically, early and middle-stage ONFH can be intervened by combining with AM while taking conventional therapy to improve the efficacy.


Assuntos
Terapia por Acupuntura/métodos , Necrose da Cabeça do Fêmur/terapia , Cabeça do Fêmur/patologia , Moxibustão/métodos , Terapia por Acupuntura/efeitos adversos , Adulto , Idoso , Estudos de Casos e Controles , China/epidemiologia , Terapia Combinada/métodos , Feminino , Cabeça do Fêmur/irrigação sanguínea , Necrose da Cabeça do Fêmur/classificação , Articulação do Quadril/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Moxibustão/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
15.
Medicine (Baltimore) ; 100(25): e26412, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160427

RESUMO

BACKGROUND: Hypertension is a kind of cardiovascular syndrome with the main clinical manifestation of continuous increase of systemic arterial blood pressure. Hypertension coexists with other cardiovascular risk factors and is an important risk factor for cardiovascular and cerebrovascular diseases. Acupuncture is an important part of Traditional Chinese Medicine intervention. The antihypertensive effect of acupuncture on hypertension is based on the neuroendocrine system, characterized by multichannel and multitarget. This study aims to provide latest and updated proof of systematic review to assess the effectiveness and safety of acupuncture for hypertension. METHODS: We will systematically search 9 databases from their inceptions to February 2021. Only randomized controlled trials of acupuncture combined with western medicine in the treatment of hypertension will meet the inclusion criteria. The main outcome measures we focus on include clinical efficacy, syndrome efficacy, Traditional Chinese Medicine syndrome score, diastolic and systolic blood pressure changes, blood pressure variability, heart rate variability, pulse rate variability, and adverse reactions. The research screening, data extraction, and risk of bias assessment will be employed by 2 reviewers independently, and disagreement will be decided by a third senior reviewer. The Revman 5.3 software will be used for meta-analysis. The confidence of proof will be rated adopting grading of recommendations assessment, development and evaluation tool and methodological quality of this research will be assessed using assessment of multiple systematic reviews-2 and risk of bias in systematic reviews. The publication quality will be evaluated by preferred reporting items for systematic reviews and meta-analyses (PRISMA). RESULTS: This systematic review (SR) will provide evidence-based medical evidence for hypertension therapy by acupuncture combined with western medicine and we will submit the findings of this SR for peer-review publication. CONCLUSIONS: This SR will provide latest and updated summary proof for assessing the effectiveness and safety of acupuncture for hypertension. REGISTRATION NUMBER: INPLASY 202150047.


Assuntos
Terapia por Acupuntura/métodos , Anti-Hipertensivos/administração & dosagem , Diuréticos/administração & dosagem , Medicina Baseada em Evidências/métodos , Hipertensão/tratamento farmacológico , Terapia por Acupuntura/efeitos adversos , Adulto , Anti-Hipertensivos/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Terapia Combinada/métodos , Diuréticos/efeitos adversos , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Metanálise como Assunto , Sistemas Neurossecretores/efeitos dos fármacos , Sistemas Neurossecretores/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisões Sistemáticas como Assunto , Resultado do Tratamento
16.
Medicine (Baltimore) ; 100(25): e26426, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160431

RESUMO

INTRODUCTION: Esophagectomy is a major surgery with a high degree of catabolic and post-surgical inflammatory response accompanied by high morbidity and significant mortality. Post-surgical nutritional support via enteral administration of ω-3 fatty acids has been seen to be effective although its bad tolerance. There are few clinical trials with parenteral ω-3 fatty acids in these patients. We propose to investigate the effect of combining a parenteral fish oil lipid emulsion with the standard enteral nutrition (EN) support. MATERIALS AND METHODS: Prospective, single-center, randomized, double-blind study in esophagectomized patients, and treated after surgery with parenteral lipid emulsions of ω-3 fatty acids or a mixture of ω-6 long-chain triglycerides/short-chain triglycerides 50%. These emulsions will be added to the standard nutritional support in continuous infusion until 5 days of treatment have been completed. Patients will be randomized 1:1:1 in Group A receiving 0.4 g/kg/d of fish-oil lipid emulsion and 0.4 g/kg/d of a lipid emulsion mixture of ω-6 long-chain fatty acids (LCT) plus medium-chain fatty acids (MCT) (total dose of 0.8 g/kg/d of lipid emulsion); Group B receiving 0.8 g/kg/d of fish oil lipid emulsion and Group C receiving 0.8 g/kg/d of LCT/MCT emulsion.The main objective is to determine whether 5 days administration of intravenous ω-3 fatty acid lipid emulsion is effective in normalizing interleukin-6 levels compared with LCT/MCT emulsions, and whether a 0.8 g/kg/d dose is more effective than 0.4 g/kg/d. Secondary outcomes include other inflammatory markers such as C-reactive protein, tumor necrosis factor alpha and interleukin-10, and parameters of morbidity, safety, nutrition and mortality.Samples will be collected at the time when surgery is indicated and on days 0, 1, 3, 5 and 21 to determine inflammatory, nutritional, hepatic and safety parameters. In addition, clinical follow-up will be continued throughout the hospital admision and up to 1 year after surgery. DISCUSSION: Studies of ω-3 fatty acids administered parenterally in esophagectomized patients are scarce. This study proposes to investigate the effect of combining fish-oil lipid emulsions administered parenterally with EN support. Potential benefits include fast incorporation of lipids to the cellular membranes and to the inflammatory cascade, and the use of only 1 pharmaconutrient. TRIAL REGISTRATION: FAR-NP-2017-01 EudraCT number: 2016-004978-17.https://reec.aemps.es/reec/public/detail.html searching the EudraCT number. VERSION IDENTIFIER: Version 2, 08/06/2017.


Assuntos
Esofagectomia/reabilitação , Emulsões Gordurosas Intravenosas/administração & dosagem , Óleos de Peixe/administração & dosagem , Cuidados Pós-Operatórios/métodos , Complicações Pós-Operatórias/terapia , Adulto , Terapia Combinada/métodos , Método Duplo-Cego , Nutrição Enteral , Neoplasias Esofágicas/cirurgia , Esofagectomia/efeitos adversos , Feminino , Humanos , Interleucina-6/sangue , Interleucina-6/imunologia , Masculino , Nutrição Parenteral/métodos , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/imunologia , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
17.
Theranostics ; 11(14): 6860-6872, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093858

RESUMO

Background: Immunotherapy has profoundly changed the landscape of cancer management and represented the most significant breakthrough. Yet, it is a formidable challenge that the majority of cancers - the so-called "cold" tumors - poorly respond to immunotherapy. To find a general immunoregulatory modality that can be applied to a broad spectrum of cancers is an urgent need. Methods: Magnetic hyperthermia (MHT) possesses promise in cancer therapy. We develop a safe and effective therapeutic strategy by using magnetism-mediated targeting MHT-immunotherapy in "cold" colon cancer. A magnetic liposomal system modified with cell-penetrating TAT peptide was developed for targeted delivery of a CSF1R inhibitor (BLZ945), which can block the CSF1-CSF1R pathway and reduce M2 macrophages. The targeted delivery strategy is characterized by its magnetic navigation and TAT-promoting intratumoral penetration. Results: The liposomes (termed TAT-BLZmlips) can induce ICD and cause excessive CRT exposure on the cell surface, which transmits an "eat-me" signal to DCs to elicit immunity. The combination of MHT and BLZ945 can repolarize M2 macrophages in the tumor microenvironment to relieve immunosuppression, normalize the tumor blood vessels, and promote T-lymphocyte infiltration. The antitumor effector CD8+ T cells were increased after treatment. Conclusion: This work demonstrated that TAT-BLZmlips with magnetic navigation and MHT can remodel tumor microenvironment and activate immune responses and memory, thus inhibiting tumor growth and recurrence.


Assuntos
Neoplasias do Colo/terapia , Terapia Combinada/métodos , Hipertermia , Imunoterapia/métodos , Lipossomos/química , Terapia de Campo Magnético/métodos , Nanopartículas de Magnetita/química , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Benzotiazóis/farmacocinética , Benzotiazóis/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/imunologia , Feminino , Humanos , Lipossomos/metabolismo , Lipossomos/efeitos da radiação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/terapia , Ácidos Picolínicos/farmacocinética , Ácidos Picolínicos/farmacologia , Ratos , Microambiente Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Theranostics ; 11(14): 7057-7071, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093871

RESUMO

Rationale: Development of nanosystems that can be integrated with macrophages (MAs), an emerging carrier system, for effective tumor therapy remains to be challenging. We report here the development of MAs specifically loaded with hyaluronic acid (HA) nanogels (NGs) encapsulated with a photothermal agent of polypyrrole (PPy) and anticancer drug doxorubicin (DOX) (HA/DOX@PPy NGs) for tumor homing and combination photothermo-chemotherapy. Methods: Cystamine dihydrochloride-crosslinked HA NGs were first prepared through a double emulsification method, then loaded with PPy via an in-situ oxidization polymerization and physically encapsulated with DOX. The created HA/DOX@PPy NGs were well characterized and subjected to be endocytosed by MAs (MAs-NGs). The MAs-mediated tumor-homing property, phenotype changes and photothermal performance of MAs-NGs were investigated in vitro, and a subcutaneous tumor model was also established to confirm their targeting capability and enhanced antitumor therapy effect in vivo. Results: The generated hybrid NGs possess a size around 77 nm and good colloidal stability, and can be specifically endocytosed by MAs without appreciably affecting their normal biofunctionalities. In particular, NG-loaded MAs display excellent in-vitro cancer cell and in-vivo tumor homing property. Systemic administration of the MAs-NGs leads to the significant inhibition of a subcutaneous tumor model through combination photothermo-chemotherapy under laser irradiation. Conclusions: The developed hybrid HA-based NG nanosystem incorporated with PPy and DOX fully integrates the coordination and heating property of PPy to regulate the optimized DOX release in the tumor region with the assistance of MA-mediated tumor homing, providing a promising cell therapy strategy for enhanced antitumor therapy.


Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Tratamento Farmacológico/métodos , Ácido Hialurônico/química , Macrófagos/efeitos dos fármacos , Nanogéis/química , Terapia Fototérmica/métodos , Polímeros/química , Pirróis/química , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Terapia Combinada/métodos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Endocitose , Lasers , Macrófagos/efeitos da radiação , Camundongos , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Nanogéis/efeitos da radiação , Nanogéis/ultraestrutura
20.
Lancet Respir Med ; 9(9): 957-968, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34147142

RESUMO

BACKGROUND: The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. METHODS: This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10). FINDINGS: Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76-1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27-0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26-1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63-1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events. INTERPRETATION: The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. FUNDING: Amsterdam Medical Center Foundation, Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ZonMW, and the European Union Innovative Medicines Initiative 2.


Assuntos
COVID-19/terapia , Mesilato de Imatinib/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Respiração Artificial/estatística & dados numéricos , Insuficiência Respiratória/terapia , Idoso , COVID-19/complicações , COVID-19/diagnóstico , COVID-19/virologia , Permeabilidade Capilar/efeitos dos fármacos , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Método Duplo-Cego , Feminino , Humanos , Mesilato de Imatinib/efeitos adversos , Masculino , Pessoa de Meia-Idade , Países Baixos , Oxigênio/administração & dosagem , Placebos/administração & dosagem , Placebos/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/virologia , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
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