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1.
J Am Chem Soc ; 146(14): 9819-9827, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38546207

RESUMO

Iron-based phosphate cathode of Na4Fe3(PO4)2(P2O7) has been regarded as a low-cost and structurally stable cathode material for Na-ion batteries (NIBs). However, their practical application is greatly hindered by the insufficient electrochemical performance and limited energy density. Here, we report a new iron-based phosphate cathode of Na4.5Fe3.5(PO4)2.5(P2O7) with the intergrown heterostructure of the maricite-type NaFePO4 and orthorhombic Na4Fe3(PO4)2(P2O7) phases at a mole ratio of 0.5:1. Benefited from the increased composition ratio and the spontaneous activation of the maricite-type NaFePO4 phase, the as-prepared Na4.5Fe3.5(PO4)2.5(P2O7) composites deliver a reversible capacity over 130 mA h g-1 and energy density close to 400 W h kg-1, which is far beyond that of the single-phase Na4Fe3(PO4)2(P2O7) cathode (∼120 mA h g-1 and ∼350 W h kg-1). Moreover, the kg-level products from the scale-up synthesis demonstrate a stable cycling performance over 2000 times at 3 C in pouch cells. We believe that our findings could show the way forward the practical application of the iron-based phosphate cathodes for NIBs.

2.
Heliyon ; 10(5): e27080, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38449627

RESUMO

The thyroid represents the most prevalent form of head and neck and endocrine cancer. The present investigation demonstrates the anticancer effects of Lusianthridin against cadmium (Cd)-induced thyroid cancer in rats. Swiss Wistar rats were utilized in this experimental study. Cd was employed to induce thyroid cancer, and the rats were divided into different groups, receiving oral administration of Lusianthridin (20 mg/kg) for 14 days. Thyroid parameters, deiodinase levels, hepatic parameters, lipid parameters, and antioxidant parameters were respectively estimated. The mRNA expression was assessed using real-time reverse transcriptase polymerase chain reaction (RT-PCR). Lusianthridin significantly (P < 0.001) improved protein levels, T4, T3, free iodine in urine, and suppressed the level of TSH. Lusianthridin significantly (P < 0.001) enhanced the levels of FT3, FT4, and decreased the level of rT3. Lusianthridin significantly (P < 0.001) reduced the levels of D1, D2, D3, and enhanced the levels of hepatic parameters like AST, ALT. Lusianthridin remarkably (P < 0.001) altered the levels of lipid parameters such as LDL, total cholesterol, HDL, and triglycerides; antioxidant parameters viz., MDA, GSH, CAT, and SOD. Lusianthridin significantly altered the mRNA expression of Bcl-2, Bax, MEK1, ERK1, ERK2, p-eIf2α, GRP78, eIf2α, and GRP94. The results clearly state that Lusianthridin exhibits protective effects against thyroid cancer.

3.
J Glob Health ; 14: 04014, 2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38271210

RESUMO

Background: We analysed the cancer burden among elderly Chinese people over the age of 55 years and compared them to USA and Western Europe to explore the cancer model in China. Methods: We retrieved data on 29 cancers with 34 risk factors from the 2019 Global Burden of Disease database to evaluate the cancer burden in Chinese elderly individuals aged 55 years and older. We then used the age-standardised incidence rate (ASIR), age-standardised death rate (ASDR), age-standardised disability-adjusted life year (DALY) rate, and average annual percentage change (AAPC) to compare the characteristics and change trend of cancers among China, USA, and Western Europe. Results: In 2019, the number of incident cases of 29 cancers among people aged 55 years and above in China increased more than 3-fold compared to 1990, while the number of deaths and DALYs approximately doubled. We also found that the cancer population in China was ageing; meanwhile, the cancer burden became significantly higher for men than for women, and the gap between men and women had widened. Cancers with the highest cancer DALYs were lung cancer (13 444 500; 95% uncertainty interval (UI) = 11 307 100, 15 853 700), stomach cancer (7 303 900; 95% UI = 6 094 600, 8 586 500), oesophageal cancer (4 633 500; 95% UI = 3 642 500, 5 601 200), colon and rectum cancer (4 386 500; 95% UI = 3 769 500, 5 067 200), liver cancer (2 915 100, 95% UI = 2 456 300, 3 463 900), and pancreatic cancer (2 028 400; 95% UI = 1 725 000, 2 354 900). Compared with 1990, the DALY rate and incidence rate of stomach cancer, oesophageal cancer, and liver cancer had markedly decreased. The DALY rate and incidence rate of lung, colon, rectum, and pancreatic cancer had increased significantly, as did the incidence rate of breast cancer in women. Smoking and diet were the top two cancer risk factors, and the impact of ambient particulate matter pollution on cancer increased each year. The overall 29 cancers age-standardised DALY rate and ASDR in China, USA, and Western Europe were similar, and all showed downward trend in the past 30 years. Compared with the USA and Western Europe, the age-standardised DALY rate of liver, nasopharyngeal, oesophageal, stomach, and cervical cancers in China was more prominent. The age-standardised DALY rate of lung cancer and colon and rectum cancer decreased annually in Western Europe and the USA, but increased in China. Conclusions: Over the past 30 years, China had made progress in controlling stomach, oesophageal, and liver cancer. However, lung, colon, rectum, pancreatic, and breast cancers had become more prevalent, having risen alongside economic development. The risks of smoking and dietary were major issues that need to be addressed urgently. The cancer situation in China remains serious; future cancer prevention efforts need to balance economic development with people's physical health, identify key groups, improve the health environment of residents and guide them to live a healthy life, and expand the scope of cancer screening.


Assuntos
População do Leste Asiático , Neoplasias , Idoso , Feminino , Humanos , Masculino , Europa (Continente)/epidemiologia , Carga Global da Doença , Incidência , Anos de Vida Ajustados por Qualidade de Vida , Fatores de Risco , Pessoa de Meia-Idade , China/epidemiologia , Estados Unidos/epidemiologia , Neoplasias/epidemiologia
4.
BMC Public Health ; 23(1): 2522, 2023 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-38104107

RESUMO

BACKGROUND: Primary brain and central nervous system cancer (collectively called CNS cancers) cause a significant burden to society. The purpose of this study was to evaluate the trends in the burden of CNS cancers from 1990 to 2019 and to predict the incidence and mortality rates and the corresponding numbers for the next 25 years to help countries to understand the trends in its incidence and mortality, and to make better adjustments or formulation of policies and allocation of resources thereby reducing the burden of the disease. METHODS: The 2019 Global Burden of Disease Study provided incidence rates, death rates, and disability-adjusted life year (DALY) data in Asia from 1990 to 2019. To reflect the trends in the age-standardized incidence, mortality, and DALY rates, the estimated annual percentage change (EAPC) was determined. The Bayesian age-period cohort (BAPC) model was employed to predict the burden of CNS cancers in the next 25 years. RESULTS: The incidence, death, and DALY rates of CNS cancers all increased from 1990 to 2019. The age-standardized incidence rate (ASIR) for CNS cancers increased from 9.89/100,000 in 1990 to 12.14/100,000 in 2019, with an EAPC of 0.69 (95% confidence interval (CI): 0.65, 0.73). The ASDR and the age-standardized DALY rate both decreased, with EAPCs of - 0.08 and - 0.52, respectively. Before 2005, the age-standardized DALY rate in East Asia was much greater in females than in males, while in Central Asia, the age-standardized death and DALY rates in males both increased sharply after 2000. In contrast to 1990, the caseload increased for the 55-70 years age group. The number of deaths decreased sharply among individuals aged younger than 20 years, especially in East Asia, accounting for only 5.41% of all deaths. The age group with the highest mortality rate was > 60 years, especially in Japan. The ASIR will continue to increase in Asia from 2020 to 2044, and the ASDR will gradually diminish. The incidence and number of deaths from CNS cancers in Asia are expected to increase over the next 25 years, especially among females. CONCLUSIONS: The study identified an increasing trend in morbidity, mortality and disability-adjusted life-years (DALYs), with differences in age-standardized morbidity rates for different population groups. In addition, it is noteworthy that the burden of disease (as measured by disability-adjusted life-years (DALYs)) is higher among women in Central Asia compared with other regions. ASIR will continue to increase over the next 25 years, with the increase in female cases and mortality expected to be more pronounced. This may need to be further substantiated by additional research, on the basis of which health authorities and policymakers can better utilize limited resources and develop appropriate policies and preventive measures.


Assuntos
Neoplasias , Morte Perinatal , Masculino , Humanos , Feminino , Idoso , Adulto , Pessoa de Meia-Idade , Teorema de Bayes , Anos de Vida Ajustados por Qualidade de Vida , Carga Global da Doença , Ásia/epidemiologia , Incidência , Saúde Global , Neoplasias/epidemiologia , Encéfalo , Sistema Nervoso Central
5.
Nat Genet ; 55(11): 1901-1911, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37904053

RESUMO

Genetic mutations accumulate in an organism's body throughout its lifetime. While somatic single-nucleotide variants have been well characterized in the human body, the patterns and consequences of large chromosomal alterations in normal tissues remain largely unknown. Here, we present a pan-tissue survey of mosaic chromosomal alterations (mCAs) in 948 healthy individuals from the Genotype-Tissue Expression project, augmenting RNA-based allelic imbalance estimation with haplotype phasing. We found that approximately a quarter of the individuals carry a clonally-expanded mCA in at least one tissue, with incidence strongly correlated with age. The prevalence and genome-wide patterns of mCAs vary considerably across tissue types, suggesting tissue-specific mutagenic exposure and selection pressures. The mCA landscapes in normal adrenal and pituitary glands resemble those in tumors arising from these tissues, whereas the same is not true for the esophagus and skin. Together, our findings show a widespread age-dependent emergence of mCAs across normal human tissues with intricate connections to tumorigenesis.


Assuntos
Aberrações Cromossômicas , Neoplasias , Humanos , Mutação , Neoplasias/genética , Desequilíbrio Alélico , Esôfago
6.
BMJ Open ; 13(9): e074677, 2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-37751958

RESUMO

INTRODUCTION: Sleep disorders are clinical syndromes of disturbed sleep-wake rhythms and abnormal sleep quality. They have various causes, but their main manifestations are difficulty falling asleep, sleep disruption and daytime fatigue. These are common clinical symptoms in perioperative patients, especially in gynaecological patients. There is a lack of research on the factors influencing perioperative sleep disorders in gynaecological patients. The aim of this study is to assess the prevalence of sleep disorders in gynaecological surgery patients and to analyse the possible factors influencing them to provide new ideas for improving sleep disorders in this patient population. METHODS AND ANALYSIS: This cross-sectional, descriptive and observational survey is planned to include 480 gynaecological day surgery patients. All patients who meet the inclusion criteria are eligible to join the study. The study will record preoperative diagnosis, surgical procedure, duration of surgery, type of anaesthesia, anaesthetic drugs, sleep quality, anxiety and depression levels and pain indices 30 days before and 1, 2, 3 and 30 days after surgery. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee of Beijing Shijitan Hospital Affiliated with Capital Medical University (Approval Number: sjtkyll-lx-2022(109)) before the start of recruitment. The results of the study will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ChiCTR2200064533.


Assuntos
Distúrbios do Início e da Manutenção do Sono , Transtornos do Sono-Vigília , Humanos , Estudos Transversais , Sono , Transtornos do Sono-Vigília/epidemiologia
7.
Ann Med ; 55(2): 2246996, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37607247

RESUMO

BACKGROUND: Cardiopulmonary bypass (CPB) is frequently employed for cardiac surgery, and selecting a suitable priming fluid is a prerequisite for CPB. Currently, the commonly used priming fluids in clinics are classified as crystalloids and colloids, including balanced crystalloids, albumin, dextran, gelatin and hydroxyethyl starch (HES). This network meta-analysis compared the effects of eight fluids used during CPB in adults to determine optimal priming fluid during CPB surgery. METHODS: Randomised controlled trials assessing priming fluids for CPB in adult cardiac surgery published before 13 April 2023 were searched across Ovid MEDLINE(R) ALL, OVID EMbase, and Cochrane Central Register of Controlled Trials. Various priming fluids were classified into eight categories, including balanced crystalloids, 0.9% NaCl, iso-oncotic human albumin, hyperoncotic human albumin, HES with molecular weight 130k, HES with molecular weight 200k, gelatin and dextran. RESULTS: The NMA of platelet counts revealed no significant differences in any result. In direct comparison results, only the comparison of HES with molecular weight 130k vs. gelatin (standard mean difference = -0.40, 95% confidence interval [95%CI: -0.63, -0.16) revealed a significant difference. According to the SUCRA, balanced crystalloids had the highest platelet count, followed by gelatin, and HES with a molecular weight of 130k had the lowest platelet, followed by HES with a molecular weight of 200k. CONCLUSION: Patients using dextran have a low mortality rate and a short mean CPB time, the use of balanced crystalloids is beneficial in terms of platelet count, and HES with molecular weight 130k is beneficial for postoperative urine volume at 24h. However, all priming fluids have pros and cons quite, and the optimal choice of priming fluids remains unsupported by current evidences. When performing CPB surgery, the type of priming fluid should be selected according to the actual situation in CPB for adult cardiac surgery.


When dextran was used as the CPB priming fluid, patients had the lowest mortality and shortest mean CPB time.With iso-oncotic HA, patients had the shortest length of ICU stay, the least blood loss 24h after surgery, and the lowest chest tube output 24h after surgery.The use of balanced crystalloids was beneficial for platelet count, the use of L-HES was beneficial for urine output 24h after surgery, and the use of H-HES resulted in the shortest hospital stay.In summary, each of these fluids has pros and cons quite, and an optimal choice of priming fluids during CPB surgery remains unsupported by current evidence.When performing CPB surgery, the type of priming fluids should be selected according to the actual condition of the patient's body.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Ponte Cardiopulmonar , Adulto , Humanos , Metanálise em Rede , Dextranos/uso terapêutico , Gelatina , Albumina Sérica Humana
8.
JCO Precis Oncol ; 7: e2300070, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37561983

RESUMO

PURPOSE: Clonal hematopoiesis (CH), the expansion of clones in the hematopoietic system, has been linked to different internal and external features such as aging, genetic ancestry, smoking, and oncologic treatment. However, the interplay between mutations in known cancer predisposition genes and CH has not been thoroughly examined in patients with solid tumors. METHODS: We used prospective tumor-blood paired sequencing data from 46,906 patients who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) testing to interrogate the associations between CH and rare pathogenic or likely pathogenic (P/LP) germline variants. RESULTS: We observed an enrichment of CH-positive patients among those carrying P/LP germline mutations and identified a significant association between P/LP germline variants in ATM and CH. Germline and CH comutation patterns in ATM, TP53, and CHEK2 suggested biallelic inactivation as a potential mediator of clonal expansion. Moreover, we observed that CH-PPM1D mutations, similar to somatic tumor-associated PPM1D mutations, were depleted in patients with P/LP germline mutations in the DNA damage response (DDR) genes ATM, CHEK2, and TP53. Patients with solid tumors and harboring P/LP germline mutations, CH mutations, and mosaicism chromosomal alterations might be at an increased risk of developing secondary leukemia while germline variants in TP53 were identified as an independent risk factor (hazard ratio, 36; P < .001) for secondary leukemias. CONCLUSION: Our results suggest a close relationship between inherited variants and CH mutations within the DDR genes in patients with solid tumors. Associations identified in this study might translate into enhanced clinical surveillance for CH and associated comorbidities in patients with cancer harboring these germline mutations.


Assuntos
Hematopoiese Clonal , Neoplasias , Humanos , Estudos Prospectivos , Neoplasias/genética , Mutação/genética , Mutação em Linhagem Germinativa/genética
9.
Plant Physiol ; 193(1): 708-720, 2023 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-37073495

RESUMO

Autophagy plays an important role in plant antiviral defense. Several plant viruses are reported to encode viral suppressor of autophagy (VSA) to prevent autophagy for effective virus infection. However, whether and how other viruses, in particular DNA viruses, also encode VSAs to affect viral infection in plants is unknown. Here, we report that the C4 protein encoded by Cotton leaf curl Multan geminivirus (CLCuMuV) inhibits autophagy by binding to the autophagy negative regulator eukaryotic translation initiation factor 4A (eIF4A) to enhance the eIF4A-Autophagy-related protein 5 (ATG5) interaction. By contrast, the R54A or R54K mutation in C4 abolishes its capacity to interact with eIF4A, and neither C4R54A nor C4R54K can suppress autophagy. However, the R54 residue is not essential for C4 to interfere with transcriptional gene silencing or post-transcriptional gene silencing. Moreover, plants infected with mutated CLCuMuV-C4R54K develop less severe symptoms with decreased levels of viral DNA. These findings reveal a molecular mechanism underlying how the DNA virus CLCuMuV deploys a VSA to subdue host cellular antiviral autophagy defense and uphold viral infection in plants.


Assuntos
Begomovirus , Viroses , Nicotiana/genética , Begomovirus/genética , Proteínas/metabolismo , DNA Viral/genética , DNA Viral/metabolismo , Autofagia/genética , Antivirais/metabolismo , Doenças das Plantas
10.
Nat Biotechnol ; 41(3): 417-426, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36163550

RESUMO

Genome instability and aberrant alterations of transcriptional programs both play important roles in cancer. Single-cell RNA sequencing (scRNA-seq) has the potential to investigate both genetic and nongenetic sources of tumor heterogeneity in a single assay. Here we present a computational method, Numbat, that integrates haplotype information obtained from population-based phasing with allele and expression signals to enhance detection of copy number variations from scRNA-seq. Numbat exploits the evolutionary relationships between subclones to iteratively infer single-cell copy number profiles and tumor clonal phylogeny. Analysis of 22 tumor samples, including multiple myeloma, gastric, breast and thyroid cancers, shows that Numbat can reconstruct the tumor copy number profile and precisely identify malignant cells in the tumor microenvironment. We identify genetic subpopulations with transcriptional signatures relevant to tumor progression and therapy resistance. Numbat requires neither sample-matched DNA data nor a priori genotyping, and is applicable to a wide range of experimental settings and cancer types.


Assuntos
Mieloma Múltiplo , Transcriptoma , Humanos , Transcriptoma/genética , Variações do Número de Cópias de DNA/genética , Haplótipos/genética , Filogenia , Análise de Célula Única/métodos , Microambiente Tumoral
11.
Ann Med ; 54(1): 454-463, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35107407

RESUMO

BACKGROUND: Hidradenocarcinoma is a rare malignancy of sweat gland differentiation. Published literature has reported that hidradenocarcinoma has a high recurrence and metastasis rate, and the prognosis is extremely poor. However, the sample sizes included in these studies are insufficient, and therefore, the findings are doubtful. MATERIALS AND METHODS: Clinicopathological characteristics and survival data of 289 hidradenocarcinoma patients were extracted from the SEER database (covering 18 registries, 2000-2018) released in July 2021. The distribution of clinicopathological characteristics was compared using the Pearson chi-square test. Overall survival (OS) and cancer-specific survival (CSS) were analysed using the log-rank test and univariate analysis. RESULTS: The primary site of hidradenocarcinoma in 121 patients was located in the head and neck, accounting for 41.9%, and the others were located in the trunk and limbs. For hidradenocarcinoma, the mean OS and CSS were 164 months and 165.9 months, respectively; the 10-year OS rate and CSS rate were 60.2% and 90.5%, respectively. Survival analysis showed that the primary site, sex, age, race, histologic grade, stage, and surgery are not associated with hidradenocarcinoma patients' OS or CSS. For head and neck hidradenocarcinoma or trunk and limbs hidradenocarcinoma, sex, age, race, histologic grade, AJCC stage, and primary site surgery are still not related to prognosis. Tumour size is correlated with patients' OS rather than CSS. CONCLUSIONS: Hidradenocarcinoma is a malignant tumour with a good prognosis, which is different from previous views. Tumour size is inversely proportional to patients' overall survival time affecting the OS and CSS of patients. Improving health awareness, initial histological examination and timely surgery are the keys to improving the prognosis.


Assuntos
Prognóstico , Humanos , Programa de SEER , Análise de Sobrevida , Taxa de Sobrevida
12.
Clin Cancer Res ; 28(8): 1614-1627, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35078859

RESUMO

PURPOSE: Therapy-related myelodysplastic syndrome and acute leukemias (t-MDS/AL) are a major cause of nonrelapse mortality among pediatric cancer survivors. Although the presence of clonal hematopoiesis (CH) in adult patients at cancer diagnosis has been implicated in t-MDS/AL, there is limited published literature describing t-MDS/AL development in children. EXPERIMENTAL DESIGN: We performed molecular characterization of 199 serial bone marrow samples from 52 patients treated for high-risk neuroblastoma, including 17 with t-MDS/AL (transformation), 14 with transient cytogenetic abnormalities (transient), and 21 without t-MDS/AL or cytogenetic alterations (neuroblastoma-treated control). We also evaluated for CH in a cohort of 657 pediatric patients with solid tumor. RESULTS: We detected at least one disease-defining alteration in all cases at t-MDS/AL diagnosis, most commonly TP53 mutations and KMT2A rearrangements, including involving two novel partner genes (PRDM10 and DDX6). Backtracking studies identified at least one t-MDS/AL-associated mutation in 13 of 17 patients at a median of 15 months before t-MDS/AL diagnosis (range, 1.3-32.4). In comparison, acquired mutations were infrequent in the transient and control groups (4/14 and 1/21, respectively). The relative risk for development of t-MDS/AL in the presence of an oncogenic mutation was 8.8 for transformation patients compared with transient. Unlike CH in adult oncology patients, TP53 mutations were only detectable after initiation of cancer therapy. Last, only 1% of pediatric patients with solid tumor evaluated had CH involving myeloid genes. CONCLUSIONS: These findings demonstrate the clinical relevance of identifying molecular abnormalities in predicting development of t-MDS/AL and should guide the formation of intervention protocols to prevent this complication in high-risk pediatric patients.


Assuntos
Sobreviventes de Câncer , Leucemia Mieloide Aguda , Neuroblastoma , Adulto , Medula Óssea/patologia , Criança , Células Clonais , Humanos , Leucemia Mieloide Aguda/genética , Neuroblastoma/patologia
13.
Nat Commun ; 12(1): 5975, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645798

RESUMO

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15-2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15-3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22-3.30, p = 6×10-3) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15-2.13, p = 5×10-3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.


Assuntos
COVID-19/etiologia , COVID-19/patologia , Hematopoiese Clonal/genética , Células-Tronco Hematopoéticas/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/imunologia , Criança , Pré-Escolar , Hematopoiese Clonal/imunologia , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação/imunologia , Neoplasias/genética , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença
14.
Acta Biochim Biophys Sin (Shanghai) ; 53(5): 528-537, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33674828

RESUMO

In clinic, perioperative neurocognitive disorder is becoming a common complication of surgery in old patients. Neuroinflammation and blood-brain barrier (BBB) disruption are important contributors for cognitive impairment. Atorvastatin, as a strong HMG-CoA reductase inhibitor, has been widely used in clinic. However, it remains unclear whether atorvastatin could prevent anesthesia and surgery-induced BBB disruption and cognitive injury by its anti-inflammatory property. In this study, aged C57BL/6J mice were used to address this question. Initially, the mice were subject to atorvastatin treatment for 7 days (10 mg/kg). After a simple laparotomy under 1.5% isoflurane anesthesia, Morris water maze was performed to assess spatial learning and memory. Western blot analysis, immunohistochemistry, and enzyme-linked immunosorbent assay were used to examine the inflammatory response, BBB integrity, and cell apoptosis. Terminal-deoxynucleotidyl transferase mediated nick end labeling assay was used to assess cell apoptosis. The fluorescein sodium and transmission electron microscopy were used to detect the permeability and structure of BBB. The results showed that anesthesia and surgery significantly injured hippocampal-dependent learning and memory, which was ameliorated by atorvastatin. Atorvastatin could also reverse the surgery-induced increase of systemic and hippocampal cytokines, including IL-1ß, TNF-α, and IL-6, accompanied by inhibiting the nuclear factor kappa-B (NF-κB) pathway and Nucleotide-Binding Oligomerization Domain, or Leucine Rich Repeat and Pyrin Domain Containing 3 (NLRP3) inflammasome activation, as well as hippocampal neuronal apoptosis. In addition, surgery triggered an increase of BBB permeability, paralleled by a decrease of the ZO-1, occludin, and Claudin 5 proteins in the hippocampus. However, atorvastatin treatment could protect the BBB integrity from the impact of surgery, by up-regulating the expressions of ZO-1, occludin, and Claudin 5. These findings suggest that atorvastatin exhibits neuroprotective effects on cognition in aged mice undergoing surgery.


Assuntos
Envelhecimento/metabolismo , Atorvastatina/efeitos adversos , Barreira Hematoencefálica/metabolismo , Disfunção Cognitiva/metabolismo , Inflamassomos/metabolismo , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Envelhecimento/patologia , Animais , Atorvastatina/farmacologia , Barreira Hematoencefálica/patologia , Disfunção Cognitiva/etiologia , Camundongos
15.
In Vitro Cell Dev Biol Anim ; 57(3): 342-349, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33537929

RESUMO

Hormesis describes a biphasic dose-response relationship generally characterized by a low-dose excitement and a high-dose inhibition. This phenomenon has been observed in the regulation of cell, organ, and organismic level. However, hormesis has not reported in oocytes. In this study, we observed, for the first time, hormetic responses of PIPP levels in oocytes by inhibitor of Akt1 or PKCδ. The expression of PIPP was detected by qPCR, immunofluorescent (IF), and Western Blot (WB). To observe the changes of PIPP levels, we used the inhibitors against pAkt1 (Ser473) or PKCδ, SH-6 or sotrastaurin with low and/or high-dose, treated GV oocytes and cultured for 4 h, respectively. The results showed that PIPP expression was significantly enhanced when oocytes were treated with SH-6 or sotrastaurin 10 µM, but decreased with SH-6 or sotrastaurin 100 µM. We also examined the changes of PIPP levels when GV oocytes were treated with exogenous PtdIns(3,4,5)P3 or LY294002 for 4 h. Our results showed that PIPP level was enhanced much higher under the treatment of 0.1 µM PtdIns(3,4,5)P3 than that of 1 µM PtdIns(3,4,5)P3, which is consistent with the changes of PIPP when oocytes were treated with inhibitors of pAkt1 (Ser473) or PKCδ. In addition, with PIPP siRNA, we detected that down-regulated PIPP may affect distributions of Akt, Cdc25, and pCdc2 (Tyr15). Taken together, these results show that the relationships between PIPP and Akt may follow the principle of hormesis and play a key role during release of diplotene arrest in mouse oocytes.


Assuntos
Hormese , Inositol Polifosfato 5-Fosfatases/metabolismo , Oócitos/metabolismo , Prolina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Forma Celular/efeitos dos fármacos , Cromonas/farmacologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Hormese/efeitos dos fármacos , Prófase Meiótica I/efeitos dos fármacos , Camundongos , Morfolinas/farmacologia , Oócitos/citologia , Oócitos/efeitos dos fármacos , Fosfatos de Fosfatidilinositol/metabolismo , Fosforilação/efeitos dos fármacos , Proteína Quinase C-delta/metabolismo , Regulação para Cima/efeitos dos fármacos
16.
Nat Commun ; 12(1): 338, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436578

RESUMO

Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations (n = 14,789) and mCAs (n = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7-22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6-33, P < 0.001). Our results suggest that mCA should be considered in conjunction with gene mutations in the surveillance of patients at risk of hematologic neoplasms.


Assuntos
Aberrações Cromossômicas , Evolução Clonal/genética , Hematopoiese Clonal/genética , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias Hematológicas/genética , Humanos , Pessoa de Meia-Idade , Mosaicismo , Neoplasias/genética , Medição de Risco , Seleção Genética , Adulto Jovem
17.
medRxiv ; 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33269365

RESUMO

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. 1-4 These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. 2,5,6 A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. 7,8 Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 515 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we found that CH was associated with severe Covid-19 outcomes (OR=1.9, 95%=1.2-2.9, p=0.01). We further explored the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH was significantly associated with risk of Clostridium Difficile (HR=2.0, 95% CI: 1.2-3.3, p=6×10 -3 ) and Streptococcus/Enterococcus infections (HR=1.5, 95% CI=1.1-2.1, p=5×10 -3 ). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

18.
Nat Genet ; 52(11): 1219-1226, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33106634

RESUMO

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.


Assuntos
Hematopoiese Clonal/genética , Segunda Neoplasia Primária/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/efeitos da radiação , Criança , Pré-Escolar , Evolução Clonal , Hematopoiese Clonal/efeitos dos fármacos , Estudos de Coortes , Feminino , Aptidão Genética , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide/genética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Seleção Genética , Adulto Jovem
19.
BMC Anesthesiol ; 20(1): 197, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32781985

RESUMO

BACKGROUND: Rectus sheath block (RSB) is known to attenuate postoperative pain and reduce perioperative opioid consumption. Thus, a retrospective study was performed to examine the effects of bilateral rectus sheath block (BRSB) in cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A total of 178 patients undergoing CRS/HIPEC at our hospital were included. Patient information and anaesthesia-related indicators were collected from the electronic medical record (EMR) system. All subjects were divided into the following two groups: the G group (general anaesthesia) and the GR group (RSB combined with general anaesthesia). Patients in the GR group received 0.375% ropivacaine for BRSB before surgery. The primary outcomes included the total amount of remifentanil and rocuronium, the total consumption of dezocine after surgery, the visual analogue scale (VAS) score and the patient-controlled intravenous analgesia (PCIA) input dose at 1 h (T6), 6 h (T7), 12 h (T8), 24 h (T9) and 48 h (T10) after surgery. Other outcomes were also recorded, such as patient demographic data, the intraoperative heart rate (HR) and mean arterial pressure (MAP), and postoperative complications. RESULTS: Compared with the G group, the GR group showed a shorter time to tracheal extubation (P < 0.05), a decreased total amount of remifentanil and rocuronium (P < 0.05), and a reduced VAS score, PCIA input dose and number of PCIA boluses at 1 h, 6 h and 12 h after surgery (P < 0.05). However, at 24 h and 48 h after surgery, there were no differences in the VAS score of pain at rest or during motion between the two groups (P > 0.05). Moreover, the incidence of hypertension, emergence agitation, delayed recovery, hypercapnia, and nausea and vomiting was lower in the GR group than in the G group (P < 0.05). There were no differences in the changes in MAP and HR during the surgery between the two groups (P > 0.05). No complications associated with nerve block occurred. CONCLUSION: BRSB could provide short-term postoperative analgesia, reduce perioperative opioid consumption and reduce the incidence of postoperative complications. It is an effective and safe procedure in CRS/HIPEC.


Assuntos
Procedimentos Cirúrgicos de Citorredução/métodos , Quimioterapia Intraperitoneal Hipertérmica/métodos , Bloqueio Nervoso/métodos , Reto do Abdome/diagnóstico por imagem , Reto do Abdome/inervação , Ultrassonografia de Intervenção/métodos , Adulto , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Feminino , Humanos , Quimioterapia Intraperitoneal Hipertérmica/efeitos adversos , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/prevenção & controle , Reto do Abdome/efeitos dos fármacos , Estudos Retrospectivos
20.
Int J Oncol ; 55(5): 988-1002, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31485599

RESUMO

Anaplastic thyroid carcinoma (ATC) has a poor prognosis due to its resistance to all conventional treatments. The long non­coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) serves a critical role in cancer chemoresistance; however, whether NEAT1 is associated with chemoresistance of ATC remains unclear. In the present study, reverse transcription­quantitative PCR assays were performed to detect the expression levels of NEAT1, microRNA (miR)­9­5p and sperm­associated antigen 9 (SPAG9). Western blot analysis was conducted to assess the protein expression levels of p62, microtubule­associated proteins 1A/1B light chain 3B and SPAG9. Cell proliferation was detected using the Cell Counting kit­8 assay, and cell apoptosis was determined by flow cytometry. Dual­luciferase reporter and RNA immunoprecipitation assays were performed to verify the interaction between NEAT1 and miR­9­5p, or miR­9­5p and SPAG9. Furthermore, an animal model was used to investigate the regulatory effects of NEAT1 on cisplatin (DDP)­resistance in tumors in vivo. The present results demonstrated that NEAT1 was upregulated in ATC tissues and cell lines, and NEAT1 silencing resulted in decreased DDP­resistance of ATC cells. In addition, NEAT1 suppressed miR­9­5p expression by binding to miR­9­5p and SPAG9 was a direct target of miR­9­5p. miR­9­5p overexpression sensitized ATC cells to DDP. Notably, NEAT1 silencing exerted its inhibitory effect on DDP­resistance of ATC via the miR­9­5p/SPAG9 axis in vitro and in vivo. In conclusion, the present study demonstrated that NEAT1 silencing ameliorated DDP­resistance of ATC, at least in part by reducing miR­9­5p sponging and regulating SPAG5 expression; therefore, NEAT1 may be considered a potential therapeutic target of ATC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Longo não Codificante/genética , Carcinoma Anaplásico da Tireoide/secundário , Neoplasias da Glândula Tireoide/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Cisplatino/farmacologia , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/genética , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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