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PURPOSE: Evaluate and analyze the efficacy of inferior oblique belly transposition (IOBT) in treating adult patients with diplopia and small-angle hypertropia caused by mild to moderate inferior oblique overaction (IOOA) secondary to acquired superior oblique palsy (SOP). METHODS: Nine adult patients with diplopia and small-angle hypertropia associated with mild to moderate IOOA secondary to unilateral acquired SOP were included in the current retrospective study. All patients received the IOBT procedure between February 2019 and May 2023 at The Second People's Hospital of Jinan and were followed up for more than 6 months after the surgery. During the procedure, the belly of the inferior oblique muscle was fixed to the sclera at 5 mm posterior to the temporal insertion of the inferior rectus muscle. The following indicators were reviewed pre- and post-surgery: the vertical deviation (VD) in the primary position and in the Bielschowsky test, the fovea disc angle (FDA) of the affected eye, changes in IOOA, and diplopia. RESULTS: After IOBT, the VD in the primary position decreased from 7.22â³ ± 1.72â³ (range 4â³-10â³) to 1.22â³ ± 1.30â³ (range 0â³-3â³). The VD in the Bielschowsky test decreased from 13.00â³ ± 1.80â³ to 3.22â³ ± 1.09â³. The FDA decreased from 10.02° ± 3.34° to 6.26° ± 1.91°. The grade of IOOA was reduced from 2.00 (1.00, 2.00) to 0.00 (0.00, 1.00). All changes were statistically significant (P < 0.001 or P = 0.006). Diplopia was resolved completely for all patients. CONCLUSIONS: IOBT can effectively treat adults with diplopia and small-angle hypertropia caused by mild to moderate IOOA secondary to acquired SOP.
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Músculos Oculomotores , Procedimentos Cirúrgicos Oftalmológicos , Humanos , Estudos Retrospectivos , Músculos Oculomotores/cirurgia , Músculos Oculomotores/fisiopatologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Oftalmológicos/métodos , Estrabismo/cirurgia , Estrabismo/fisiopatologia , Estrabismo/etiologia , Visão Binocular/fisiologia , Movimentos Oculares/fisiologia , Diplopia/etiologia , Diplopia/cirurgia , Diplopia/fisiopatologia , Diplopia/diagnóstico , Seguimentos , Resultado do Tratamento , Adulto Jovem , Doenças do Nervo Troclear/cirurgia , Doenças do Nervo Troclear/fisiopatologia , Doenças do Nervo Troclear/diagnósticoRESUMO
The blast crisis (BC) of chronic myeloid leukemia (CML) has poor efficacy against existing treatments and extremely short survival. However, the molecular mechanism of CML-chronic phase (CP) transformation to CML-BC is not yet fully understood. Here, we show that Lin28B, a RNA binding protein, acted as an activator enhancing the transformation to CML-BC by mediating excessive cell proliferation. The level of Lin28B expression was apparently elevated in CML-BC patients compared with newly diagnosed CML-CP patients. The overexpression of Lin28B promoted the proliferation of leukemia cells. Mechanistically, we identified Lin28B as a DNA binding protein by binding to the promoter region of miR-181d and upregulating its expression, which inhibited the expression of Programmed cell death 4 (PDCD4) by binding to the PDCD4 3'UTR region, thereby enhancing the proliferation of CML cells. Overall, the "Lin28B-miR-181d-PDCD4" regulatory axis promoted CML blast crisis. Implications: Our findings highlight the oncogenic role of Lin28B in CML blast crisis, acting as a DNA binding protein which transcriptionally upregulates miR-181d expression.
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Neural stem cells (NSCs) play crucial roles in neurological disorders and tissue injury repair through exerting paracrine effects. However, the effects of NSC-derived factors on glioma progression remain unclear. This study aimed to evaluate the effects of human NSC-conditioned medium (NSC-CM) on the behaviour of glioma cells using an in vitro co-culture system. Cell counting kit-8 and 5-ethynyl-2'-deoxyuridine assays revealed that NSC-CM inhibited glioma cell proliferation and growth in a fetal bovine serum (FBS)-independent manner. In addition, our wound-healing assay demonstrated that NSC-CM repressed glioma cell migration, while results from transwell and 3D spheroid invasion assays indicated that NSC-CM also reduced the invasion capacity of glioma cells. Flow cytometry showed that NSC-CM prevented cell cycle progression from the G1 to S phase and promoted apoptosis. Western blotting was used to show that the expression of Wnt/ß-catenin pathway-related proteins, including ß-catenin, c-Myc, cyclin D1, CD44 and Met, was remarkably decreased in NSC-CM-treated glioma cells. Furthermore, the addition of a Wnt/ß-catenin pathway activator, CHIR99021, significantly induced the expression of ß-catenin and Met and increased the proliferative and invasive capabilities of control medium-treated glioma cells but not those of NSC-CM-treated glioma cells. The use of enzyme-linked immunosorbent assays (ELISA) revealed the secretion of some antitumour factors in human and rat NSCs, including interferon-α and dickkopf-1. Our data suggest that NSC-CM partially inhibits glioma cell progression by downregulating Wnt/ß-catenin signalling. This study may serve as a basis for developing future antiglioma therapies based on NSC derivatives.
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Glioma , Células-Tronco Neurais , Humanos , Ratos , Animais , beta Catenina/metabolismo , Glioma/metabolismo , Proliferação de Células , Proteínas Wnt/metabolismoRESUMO
BACKGROUND: Refractory and relapsed acute myeloid leukemia (r/rAML) is associated with a difficult prognosis; clinical trials are typically suggested despite lack of a recognized standard of care. Combinatorial chemotherapy regimens utilized for r/rAML salvage play a crucial role in battling this invasive phase. Although it is characterized by a low response rate, CLAG is a traditional regimen used in r/rAML. We aimed to compare the efficacy and toxicity of CLAG+PLD to explore whether there was any improvement with the addition of pegylated liposomal doxorubicin (PLD) to CLAG METHODS: A total of 110 r/rAML patients were retrospectively analyzed from February 2017 to June 2020 at the Medical Center of Hematology, XinQiao Hospital, the 303rd Hospital of the Chinese People's Liberation Army, and Central Hospital of Chang Sha, Hunan Province. The response, overall survival (OS), disease-free survival (DFS), and side effects in 110 r/rAML patients were evaluated retrospectively. Of these, 55 patients were administered CLAG+PLD, while 55 patients received CLAG alone as salvage therapy. RESULTS: In the CLAG+PLD group, there were 27 (49.1%) cases of complete response (CR) with no measurable residual disease (MRD-), 12 (21.8%) cases of CR with positive MRD (MRD+), 5 (9.1%) cases of partial response (PR), 11 (20%) cases of no response (NR), and no cases of death during the cycles. The response rates in the CLAG group were lower: CR was reached in 24 (46.6%) patients with MRD-, 6 (10.9%) patients with MRD+, 10 (18.2%) patients with PR, 13 (23.6%) patients with NR, and 2 (3.6%) patients who passed away, one from infection and the other from cerebral hemorrhage. The median OS and DFS were not attained in the CLAG+PLD group during the 2-year OS and DFS follow-up, while both values were 10 months in the CLAG group (p = 0.023 and p = 0.045, respectively). The results of the Cox regression analysis for the CLAG+PLD group were strongly illustrative of the importance of hematopoietic stem cell transplantation (HSCT) following salvage therapy. No increased toxicity was observed in the CLAG+PLD group. CONCLUSION: CLAG+PLD is a potential salvage regimen for r/r AML that has a similar toxicity profile to CLAG and that improves response rates, 2-year OS, and DFS relative to CLAG.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Estudos Retrospectivos , Citarabina , Prognóstico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Background: Observational studies have reported that educational attainment has been related to the risk of esophageal cancer (EC) and its precancerous lesions. However, the causal relationship remains controversial. We aimed to apply the Mendelian randomization (MR) design to determine the causal associations between genetically predicted educational attainment and EC, Barrett's esophagus (BE), and gastroesophageal reflux disease (GERD), and to explore whether modifiable risk factors play a mediating role. Methods: Using summary statistics from genome-wide association studies (GWASs) based on European ancestry individuals of several years in education (EduYears, primary analysis, n = 293,723), college completion (College, secondary analysis, n = 95,427), EC (n = 420,531), BE (n = 361,194), and GERD (n = 420,531), genetic associations between two education phenotypes and EC, BE, and GERD were tested by two-sample MR analyses. Then, two-step MR mediation analyses were used to assess the proportion of the aforementioned association that might be mediated by body mass index (BMI), major depressive disorder (MDD), smoking, drinking, carbohydrates, fat, and protein intake. Results: Genetically predicted EduYears was negatively associated with the risk of EC, BE, and GERD {odds ratio (OR), 0.64 [95% confidence interval (CI) 0.44-0.94], 0.86 (95% CI, 0.75-0.99), and 0.62 (95%CI, 0.58-0.67)}. EduYears was negatively associated with BMI, MDD, and smoking (range of OR: 0.76-0.84). There were positive associations between BMI, smoking with EC, BE, and GERD, as well as between MDD with GERD (range of OR: 1.08-1.50). For individual mediating effect, BMI and smoking mediated 15.75 and 14.15% of the EduYears-EC association and 15.46 and 16.85% of the EduYears-BE association. BMI, MDD, and smoking mediated 5.23, 4.98, and 4.49% of the EduYears-GERD association. For combined mediation, the aforementioned mediators explained 26.62, 28.38, and 11.48% of the effect of EduYears on EC, BE, and GERD. The mediating effects of drinking and dietary composition were not significant in the effect of education on EC, BE, and GERD. Conclusion: Our study supports that genetically predicted higher educational attainment has a protective effect on EC, BE, and GERD, and is partly mediated by reducing adiposity, smoking, and depression.
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Esôfago de Barrett , Transtorno Depressivo Maior , Neoplasias Esofágicas , Refluxo Gastroesofágico , Humanos , Esôfago de Barrett/genética , Esôfago de Barrett/complicações , Transtorno Depressivo Maior/complicações , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Estudos de Casos e Controles , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/genética , Refluxo Gastroesofágico/epidemiologia , Refluxo Gastroesofágico/complicações , EscolaridadeRESUMO
BACKGROUND: Growing evidence suggests that environmental factors probably play important roles in the development of gastroesophageal cancers (GOC), however, the effects of trace elements on GOC remain unclear. OBJECTIVE: To assess the effect of trace elements on GOC and the effect modification by other factors. METHODS: Hair and fingernail samples were collected from GOC cases and controls in a population-based case-control study in Taixing, China, and were used to detect the concentrations of 12 trace elements using inductively coupled plasma mass spectrometry. Unconditional logistic regression models were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for concentrations of 12 trace elements in association with GOC after adjusting the other factors. RESULTS: A total of 830 hair samples (581 controls and 249 cases) and 895 fingernail samples (559 controls and 336 cases) were included. Compared to the lowest-tertile concentration, the higher tertiles of Ca, Zn, Fe, Al, Cr, Pb, Se, and V were positively associated with GOC, while the higher tertiles of Mg, Mn, Sr, and As were inversely associated with GOC. Significant interactions between the hair level of Cr and two other risk factors, including smoking (P for interaction = 0.044) and alcohol drinking (P for interaction = 0.028), were observed in association with GOC. SIGNIFICANCE: The current study reveals that these 12 trace elements in hair and fingernails are associated with GOC to varying degrees. Further studies and animal experiments are needed to clarify the associations and explore potential mechanisms. IMPACT STATEMENT: The role of trace elements in the development or inhibition of gastroesophageal cancers (GOC) remains unclear. In this study, we further explored the associations between 12 trace elements and GOC based on a population-based case-control study conducted in Taixing, China. Higher levels of Ca, Zn, Fe, Al, Cr, Pb, Se, and V were positively associated with increased GOC, while inverse associations between higher levels of Mg, Mn, Sr, As, and GOC were observed. Observed associations were consistent in hair and fingernail samples. Moreover, interaction effects between hair level of Cr and smoking or alcohol drinking were identified.
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Gastroenteropatias , Neoplasias , Oligoelementos , Humanos , Oligoelementos/análise , Unhas/química , Estudos de Casos e Controles , Chumbo , Cabelo/químicaRESUMO
OBJECTIVE: This study aimed to identify and project the epidemiological trends and the burden of lung cancer in China. METHODS: We extracted incidence, mortality, disability-adjusted life-years (DALYs) and age-standardized rates of lung cancer in China, between 1990 and 2019, from the Global Burden of Disease Study (2019). The estimated annual percentage change (EAPC) was applied to quantify the trends of lung cancer burden. Furthermore, we used the Bayesian age-period-cohort model to project the incidence and mortality in the next decade. RESULTS: From 1990 to 2019, the estimated national number of lung cancer incident cases increased by 224.0% to 832,920, deaths increased by 195.4% to 757,170 and DALYs increased by 146.1% to 17,128,580, respectively. Meanwhile, the ASIR, ASMR and ASDR showed an upward trend (EAPC of 1.33, 0.94 and 0.42, respectively). The ASIR and ASMR among males were about 2 times more than females, but the increase in ASIR in females (EAPC = 2.24) was more obvious than those in males (EAPC = 0.10) from 2020 to 2030. In China, smoking remained responsible for the highest burden of lung cancer, but the contribution of ambient particulate matter pollution to DALYs increased from 10.6% in 1990 to 22.5% in 2019 in total population. Moreover, we predicted that the number of deaths from lung cancer will increase by 42.7% in China by 2030. CONCLUSION: In China, the burden of lung cancer has been increasing over the past three decades, which highlights more targeted intervention measures are needed to reduce the burden of lung cancer.
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Neoplasias Pulmonares , Feminino , Masculino , Humanos , Teorema de Bayes , Neoplasias Pulmonares/epidemiologia , Fatores de Risco , China/epidemiologia , Fumar , IncidênciaRESUMO
Background: Traditional Chinese medicine (TCM) body constitution (BC), primarily determined by physiological and clinical characteristics, is an important process for clinical diagnosis and treatment and play a critical role in precision medicine in TCM. The purpose of the study was to explore whether the distributions of BC types differed by obesity status. Methods: We conducted a study to evaluate BC type in US population during 2012-2016. A total of 191 White participants from Personalized Prevention of Colorectal Cancer Trial (PPCCT) completed a self-administered Traditional Chinese Medicine Questionnaire (TCMQ, English version). In this study, we further compared the distribution of major types of TCM BC in the PPCCT to those Chinese populations stratified by obesity status. Results: We found the Blood-stasis frequency was higher in US White adults, 22.6% for individuals with BMI <30 and 11.2% for obese individuals, compared to 1.4% and 1.8%, respectively, in Chinese populations. We also found the percentages Inherited-special and Qi-stagnation were higher in US White adults than those in Chinese populations regardless of obesity status. However, the proportions of Yang-deficiency were higher in Chinese populations than those in our study conducted in US White adults regardless of obesity status. Conclusions: These new findings indicate the difference in distribution of BC types we observed between US and Chinese populations cannot be explained by the differences in prevalence of obesity. Further studies are needed to confirm our findings and understand the potential mechanism including genetic background and/or environmental factors.
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The blast crisis (BC) is the final deadly phase of chronic myeloid leukemia (CML), which remains a major challenge in clinical management. However, the underlying molecular mechanism driving blastic transformation remains unclear. Here, we show that ASF1A, an essential activator, enhanced the transformation to CML-BC by mediating cell differentiation arrest. ASF1A expression was aberrantly increased in bone marrow samples from CML-BC patients compared with newly diagnosed CML-chronic phase (CP) patients. ASF1A inhibited cell differentiation and promoted CML development in vivo. Mechanistically, we identified ASF1A as a coactivator of the Notch transcriptional complex that induces H3K56ac modification in the promoter regions of Notch target genes, and subsequently enhanced RBPJ binding to these promoter regions, thereby enhancing Notch signaling activation to mediate differentiation arrest in CML cells. Thus, our work suggests that targeting ASF1A might represent a promising therapeutic approach and a biomarker to detect disease progression in CML patients.
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Crise Blástica , Leucemia Mielogênica Crônica BCR-ABL Positiva , Crise Blástica/genética , Proteínas de Ciclo Celular/genética , Diferenciação Celular/genética , Chaperonas de Histonas , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Chaperonas Moleculares/genéticaRESUMO
Blend oils composed by leaf lard (LL) and cottonseed oil stearin (COS) were prepared and the thermal property, microstructure and crystallization of these blends were investigated in the present study. Solid fat content (SFC), thermal behaviors, triacylglycerols composition, crystal structure and morphology of the LL and COS blends were determined by pulsed nuclear magnetic resonance (pNMR), differential scanning calorimetry (DSC), high-performance liquid chromatography (HPLC), X-ray diffractometer (XRD) and polarized light microscope (PLM), respectively. SFC profiles and iso-solid diagrams indicated that SFCs of all blends were almost close to the weighted averages of the fat components at temperatures beyond 20°C; however, below 20°C, SFCs of blends exhibited higher than those of the weighted averages of the fat components. With the content of COS increasing, palmitic acid and linoleic acid in the blends increased, while stearic acid and oleic acid decreased; monounsaturated-disaturated (USS) and triunsaturated (UUU) glycerides in the blends enhanced, while monosaturated-diunsaturated (UUS) glycerides declined. The melting temperature of the blends decreased with the increase of COS content. The crystal forms in LL were ß' and ß, and the packing pattern was double and triple chain length (2L and 3L). With COS in blends increasing, ß' form crystals and 3L pattern reduced. Polarized light micrographs showed that the number of crystal particles in the blends raised with the increase of COS content, meanwhile, the grainsize of the sample gradually decreased. Visual appearances of the blends indicated that blending LL with COS could efficiently reduce the graininess of LL. The addition of COS had a significant effect on the crystallization behavior of LL. LL presented one-step crystallization at 10°C and 20°C, while COS showed two-step crystallization at 10°C and one-step crystallization at 20°C. However, the blends exhibited obvious two-step crystallization at 10°C, one-step or slight two-step crystallization at 20°C.
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Óleo de Sementes de Algodão , Ácido Oleico , Cristalização , Gorduras na Dieta , Glicerídeos/química , Ácido Linoleico , Óleo de Palmeira/química , Ácido Palmítico , Folhas de Planta/química , Óleos de Plantas/química , Triglicerídeos/químicaRESUMO
Molecular mechanisms and observational studies have found that diet-derived antioxidants are associated with digestive system cancers, whereas there is a lack of causal evidence from randomized clinical trials. In this study, we aimed to assess the causality of these associations through a Mendelian randomization (MR) study. Single nucleotide polymorphisms of diet-derived circulating antioxidants (i.e., α- and γ-tocopherol, ascorbate, retinol, ß-carotene, lycopene, and urate), accessed by absolute levels and relative metabolite concentrations, were used as genetic instruments. Summary statistics for digestive system cancers were obtained from the UK Biobank and FinnGen studies. Two-sample MR analyses were performed in each of the two outcome databases, followed by a meta-analysis. The inverse-variance weighted MR was adopted as the primary analysis. Five additional MR methods (likelihood-based MR, MR-Egger, weighted median, penalized weighted median, and MR-PRESSO) and replicate MR analyses for outcomes from different sources were used as sensitivity analyses. Genetically determined antioxidants were not significantly associated with five digestive system cancers, after correcting for multiple tests. However, we found suggestive evidence that absolute ascorbate levels were negatively associated with colon cancer in UK Biobank-the odds ratio (OR) per unit increase in ascorbate was 0.774 (95% confidence interval [CI] 0.608-0.985, p = 0.037), which was consistent with the results in FinnGen, and the combined OR was 0.764 (95% CI 0.623-0.936, p = 0.010). Likewise, higher absolute retinol levels suggestively reduced the pancreatic cancer risk in FinnGen-the OR per 10% unit increase in ln-transformed retinol was 0.705 (95% CI 0.529-0.940, p = 0.017), which was consistent with the results in UK Biobank and the combined OR was 0.747 (95% CI, 0.584-0.955, p = 0.020). Sensitivity analyses verified the above suggestive evidence. Our findings suggest that higher levels of antioxidants are unlikely to be a causal protective factor for most digestive system cancers, except for the suggestive protective effects of ascorbate on colon cancer and of retinol on pancreatic cancer.
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Antioxidantes , Neoplasias do Sistema Digestório , Antioxidantes/uso terapêutico , Ácido Ascórbico/uso terapêutico , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/genética , Neoplasias do Colo/prevenção & controle , Dieta , Neoplasias do Sistema Digestório/epidemiologia , Neoplasias do Sistema Digestório/genética , Neoplasias do Sistema Digestório/prevenção & controle , Alimentos , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana/métodos , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/prevenção & controle , Polimorfismo de Nucleotídeo Único , Reino Unido/epidemiologia , Vitamina A/uso terapêuticoRESUMO
OBJECTIVES: Understanding epidemiology trends and patterns of pancreatic cancer in China from 1990 to 2019 and predicting the burden to 2030 will provide foundations for future policies development. METHODS: We collected incidence, mortality, and disability-adjusted life-years (DALYs) data of pancreatic cancer in China from 1990 to 2019 based on the Global Burden of Disease Study 2019. We calculated the estimated annual percentage change (EAPC) to depict the trends of pancreatic cancer burden and predicted the incidence and mortality in the next decade by using a Bayesian age-period-cohort analysis. RESULTS: The number of incident cases sharply increased from 26.77 thousand in 1990 to 114.96 thousand in 2019, the age-standardized incidence rate (ASIR) nearly doubled from 3.17 per 100,000 in 1990 to 5.78 per 100,000 in 2019, with an EAPC of 2.32 (95% confidence interval [CI]: 2.12, 2.51). The mortality and DALYs presented a similar pattern with incidence. The dominant risk factor for pancreatic cancer was smoking, but the contribution of high body-mass index increased from 1990 to 2019. We projected that the incident cases and deaths of pancreatic cancer would increase to 218.79 thousand and 222.97 thousand, respectively, in 2030 with around 2 times growth. CONCLUSIONS: During the past three decades, the incidence, mortality and DALYs of pancreatic cancer gradually increased in China, and the absolute number and rate of pancreatic cancer burden would continue to rise over the next decade. Comprehensive policies and strategies need to be implemented to reduce the incidence and mortality.
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Carga Global da Doença , Neoplasias Pancreáticas , Teorema de Bayes , China/epidemiologia , Saúde Global , Humanos , Incidência , Neoplasias Pancreáticas/epidemiologia , Anos de Vida Ajustados por Qualidade de Vida , Fatores de Risco , Neoplasias PancreáticasRESUMO
BACKGROUND: To assess the spatiotemporal variation in female breast cancer attributable to low physical activity (LPA) at a global scale from 1990 to 2019, which is essential to promote physical activity, as well as prevent and control breast cancer. METHODS: The number of deaths and disability-adjusted life years (DALYs), and the corresponding age-standardized rates (ASMR and ASDR) of LPA-related breast cancer in 204 countries and territories from 1990 to 2019 were retrieved from the Global Burden of Disease Study 2019 to measure the related breast cancer burden by age and region. The estimated annual percentage change (EAPC) was calculated to quantify the secular trend in breast cancer burden rates. RESULTS: From 1990 to 2019, globally, both breast cancer deaths and DALYs attributable to LPA nearly doubled, although the corresponding ASMR and ASDR decreased slightly, with EAPC of -0.46 (95% confidence interval: -0.52, -0.40) and -0.44 (95% confidence interval: -0.49, -0.39), respectively. The LPA-related breast cancer burden varied considerably across the world, with the highest-burden rates in Oceania, Tropical Latin America and Caribbean, and the fastest growth in North Africa and Middle East. The ASMR and ASDR showed a logarithmic association with the Socio-demographic Index, and a temporally upward trend in most of 204 countries regardless of the Socio-demographic Index or the ASMR in 1990. CONCLUSIONS: Despite a decline in LPA-related breast cancer burden achieved in many countries during the last 3 decades like Bermuda, Myanmar, USA and China, an increase still occurred in most of 204 countries and territories, such as Solomon Islands, Equatorial Guinea, Japan and India. The findings can bring greater awareness to the importance of promoting physical activity for the local government to control the attributable breast cancer burden.
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Neoplasias da Mama , Carga Global da Doença , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Efeitos Psicossociais da Doença , Exercício Físico , Feminino , Saúde Global , Humanos , Anos de Vida Ajustados por Qualidade de VidaRESUMO
Prostate cancer (PCa) causes significant mortality and morbidity, with advanced metastasis. WNT signaling is a promising therapeutic target for metastatic PCa. GIPC2 is a GIPC1 paralog involved in WNT signaling pathways associated with tumor progression, but its role in PCa metastasis remains unclear. Herein, we demonstrated that high GIPC2 expression in PCa tissues was significantly associated with distant metastasis and poor prognosis. Functional studies demonstrated that high GIPC2 expression due to CpG-island demethylation promoted increased metastatic capabilities of PCa cells. Conversely, silencing GIPC2 expression significantly inhibited PCa metastasis in vitro and in vivo. Furthermore, GIPC2 directly bound the WNT co-receptor Fzd7 through its PDZ domain, which enabled activation of WNT-ß-catenin cascades, thereby stimulating PCa metastasis. Interestingly, GIPC2 protein was also identified as a component of exosomes and that it robustly stimulated PCa adhesion, invasion, and migration. The presence of GIPC2 in tumor-derived exosomes and ability to impact the behavior of tumor cells suggest that GIPC2 is a novel epigenetic oncogene involved in PCa metastasis. Our findings identified GIPC2 as a novel exosomal molecule associated with WNT signaling and may represent a potential therapeutic target and biomarker for metastatic PCa.
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Exossomos , Neoplasias da Próstata , Proteínas de Transporte , Linhagem Celular Tumoral , Exossomos/patologia , Receptores Frizzled/genética , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Via de Sinalização WntRESUMO
BACKGROUND: Uterine cancer is one of the most common female cancers worldwide, with huge heterogeneity in morbidity and mortality. Although a high body-mass index (BMI) has been linked to uterine cancer, systematic reports about the influence of high BMI and its temporal trends are scarce. METHODS: The annual morbidity, mortality, and disability-adjusted life years (DALYs) of uterine cancer in 204 countries or territories were retrieved from the GBD 2019 study. To reflect trends in disease burden, we also calculated the estimated annual percentage change (EAPC) based on the age-standardized rates of uterine cancer from 1990 to 2019. RESULTS: The global incident cases of uterine cancer increased 2.3 times from 187,190 in 1990 to 435,040 in 2019. Although the age-standardized incidence rate (ASIR) of uterine cancer increased worldwide from 8.67/100,000 in 1990 to 9.99/100,000 in 2019, the age-standardized death rate (ASDR) and DALY rate decreased during the same period. High socio-demographic index (SDI) countries tended to have a higher ASIR than developing regions, and their increasing trend in ASIR was also more pronounced. The disease was rare before 40 years old, but its risk rose sharply among women aged 50-70. A high BMI was linked to more than one-third of deaths from uterine cancer in 2019. CONCLUSIONS: The incidence in developed areas was significantly higher than in developing areas and also increased much more rapidly. Elderly females, especially those with a high BMI, have a higher risk of uterine cancer. Therefore, more health resources may be needed to curb the rising burden in specific populations.
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Carga Global da Doença , Neoplasias Uterinas , Adulto , Idoso , Índice de Massa Corporal , Feminino , Saúde Global , Humanos , Incidência , Anos de Vida Ajustados por Qualidade de Vida , Neoplasias Uterinas/epidemiologiaRESUMO
Acute myeloid leukemia (AML) is a genetically heterogeneous and frequently fatal malignancy. The ten-eleven translocation (TET)-mediated DNA demethylation is known to be critically associated with AML pathogenesis. Through chemical compound screening, we find that the opioid receptor agonist, loperamide hydrochloride (OPA1), significantly suppresses AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, are verified in AML cells in vitro and mouse and human AML models in vivo. OPA1-induced activation of OPRM1 signaling enhances the transcription of TET2 and thus activates both catalytic-dependent and -independent functions of TET2. Notably, AMLs with TET2 mutations or chemotherapy resistance are sensitive to OPA1 as well. Our results reveal the OPRM1-TET2 regulatory axis in AML and suggest that opioid agonists, particularly OPA1, a US Food and Drug Administration (FDA)-approved antidiarrheal drug, have therapeutic potential in AML, especially in TET2-mutated and chemotherapy-resistant AMLs, which have a poor prognosis.
Assuntos
Analgésicos Opioides/farmacologia , Proteínas de Ligação a DNA/metabolismo , Dioxigenases/metabolismo , Leucemia Mieloide Aguda/patologia , Receptores Opioides mu/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Loperamida/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Opioides mu/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This study aimed to estimate the latest magnitudes and temporal trends of melanoma burden at the national, regional, and global levels. The data on melanoma incidence, deaths, and disability-adjusted life-years (DALYs) in 204 countries and territories between 1990 and 2019 came from the Global Burden of Disease 2019 Study. Estimated annual percentage change (EAPC) was calculated to depict the temporal trends and Spearman rank correlation was used to analyze the influential factors of EAPC. From 1990 to 2019, the incident cases of melanoma increased by 170% to 289,950, death increased by 90% to 62,840, and DALYs increased by 67% to 1,707,800 globally. The age-standardized incidence rate (ASIR) of melanoma increased globally by an average of 1.13 [95% confidence interval (CI): 0.93-1.32], while the age-standardized rates of death and DALYs both declined with the EAPC of -0.27 (95% CI: -0.36 to -0.19) and -0.49 (95% CI: -0.57 to -0.41). In 2019, the highest burden of melanoma was observed in Australasia, followed by high-income North America and Europe regions, which all presented an incremental growth in ASIR. The positive association between the EAPC in ASIR and socio-demographic index (SDI) in 2019 (ρ = 0.600, P < 0.001) suggested that countries with higher SDI have experienced a more rapid increase in ASIR of melanoma. In conclusion, the burden of melanoma is increasing globally but differed greatly across the world. Notably, the high burden areas are facing a continuing increase in incidence, which implies more targeted strategies should be taken for reducing the increasing melanoma burden.
Assuntos
Melanoma/epidemiologia , Bases de Dados Factuais , Feminino , Geografia Médica , Carga Global da Doença/história , Carga Global da Doença/tendências , Saúde Global , História do Século XX , História do Século XXI , Humanos , Incidência , Masculino , Melanoma/história , Vigilância da População , Fatores de Risco , Análise Espaço-TemporalRESUMO
BACKGROUND: Poor oral health may be a significant risk factor for gastric cancer (GC); however, previous results are not consistent. Here, we investigated the effect of oral health on GC and effect modification by other factors. METHODS: We conducted a population-based case-control study in Taixing, China. Participants aged between 40 and 85 years and who had lived in Taixing for at least 5 years were included. The GC cases were confirmed by endoscopy and pathological diagnosis, and the controls were randomly selected using the frequency-matching method. Unconditional logistic regression models were used to derive odds ratios (ORs) and 95% confidence intervals (CIs) of oral health for GC risk after adjusting for confounders and risk factors. RESULTS: Overall, 901 GC cases and 1972 controls were included. Tooth loss was not significantly associated with an increased risk of GC (yes vs. no, OR = 1.08, 95% CI 0.88 to 1.33). Compared with toothbrushing at least twice per day, toothbrushing once per day or less was associated with an increased risk of GC (OR = 2.39, 95% CI 1.94 to 2.94), and was more pronounced in esophagogastric junction cancer and intestinal-type GC. There was no significant interaction between the indicators of oral health and age, sex, tobacco smoking, alcohol drinking, and Helicobacter pylori seropositivity. CONCLUSION: Poor oral hygiene behavior is associated with an increased risk of GC, and this positive association is consistent across all GC subgroups classified by anatomy and histology. Further studies are needed to explore the possible mechanisms behind this association.