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1.
J Environ Manage ; 301: 113828, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34583283

RESUMO

The application of CPB (Cemented Paste Backfill) can realize the clean, efficient, and safe mining of underground metal mines. Clear understanding on the triaxial mechanical properties of CPB is important to the CPB design and the stability analysis of the backfilled CPB structure. The triaxial mechanical properties of CPB can be significantly affected by the different curing conditions. In this research, triaxial compression tests of the CPB samples were carried out using the GCTS (Geotechnical Consulting & Testing System), and the considered curing conditions include different curing time (1, 3, 7 and 28 days), drainage conditions (drained and undrained) and curing temperatures (20 °C, 35 °C and 45 °C). The measured mechanical parameters were compared and analyzed against the framework of the Mohr-Coulomb criterion. Then, the vertical stress distribution of the backfilled CPB structure was calculated and discussed using the measured mechanical parameters. The results show that with the increase of the lateral constraint ratio (σc/Sd0), the elastoplastic stage of the measured deviator stress versus axial strain curve of CPB sample is gradually obvious. The peak deviator stress (Sdp) and the ultimate axial strain (εu) show the linear and negative exponential increase with the σc/Sd0 respectively. The number of cracks on the fractured surface of the CPB samples gradually decreased with the increase of σc/Sd0. The failure types of CPB samples were changed from tensile failure (σc/Sd0 = 0%) to the mixed tensile-shear failure (σc/Sd0≈10%) and compression-shear failure (σc/Sd0≥20%). Moreover, with the increase of curing time and curing temperature or under the drained curing condition, the peak deviator stress and cohesion (cb) of CPB can be significantly increased, but the corresponding internal friction angle (ϕb) is decreased. The shear mechanical parameters of CPB can significantly affect the vertical stress distribution inside the CPB structure. Therefore, when estimating the vertical stress distribution inside the backfilled CPB structure in engineering practices, it is necessary to focus on the changes of CPB shear parameters (cb and ϕb) caused by different curing conditions.


Assuntos
Materiais de Construção , Sulfetos , Mineração , Temperatura
2.
Ann Hematol ; 2021 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-34735613

RESUMO

Persistent thrombocytopenia (PT) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with an increased risk of bleeding and poor survival. The exact pathogenesis underlying PT remains unclear, and its management is difficult. Here we conducted a retrospective study to evaluate the efficacy and safety of eltrombopag (EPAG) in 34 patients with PT after allo-HSCT. Seven patients suffered from prolonged isolated thrombocytopenia (PIT), and 27 had secondary failure of platelet recovery (SFPR). For most patients, the initial dose was 25 mg or 50 mg daily, then adjusted to the maximum dose of 50-100 mg per day according to the response of platelet recovery and toleration of patients. The cumulative incidence (CI) of platelet recovery to at least 20 × 109/L and 50 × 109/L without transfusion support for at least 7 days was 72.1% and 60.7%, respectively. Nineteen (86.4%) of 22 responders were able to taper off the medication; furthermore, the platelet counts remained stable 1 month after withdrawal of EPAG. Although two patients discontinued EPAG during treatment due to headache and nausea, no patients developed grade 3 or 4 toxicities. Hypoplasia of bone marrow and decreased megakaryocytes (MKs) were found to be risk factors for overall response (OR) and complete response (CR) in multivariate analysis, respectively. Overall, our results indicated that EPAG can be used in the treatment of PT and that continuous exposure to EPAG may not be necessary.

3.
Front Neurol ; 12: 682448, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34721252

RESUMO

Background: Restless legs syndrome (RLS) is a common neurological disorder with unpleasant leg sensations and serious negative effects on mental and physical health. Many observational studies showed that people with RLS had a high risk of vascular diseases, including cerebrovascular and cardiovascular diseases (CVD), but the findings were conflicting. The Jidong RLS Cohort Study is a prospective cohort study designed to mainly examine whether or not RLS is associated with an increased risk of CVD. Methods and Design: The study recruited 8,867 healthy participants older than 18 years from October 2014 to December 2015. Participants received a physical examination in the Staff Hospital, Jidong Oilfield Branch, China National Petroleum Corporation. Baseline data and blood samples were collected. Restless legs syndrome was assessed using the international RLS diagnostic criteria. All of subjects would be followed up until December 2025. Major cardiovascular/cerebrovascular events including cardiac death, myocardial infarction, ischemic heart disease, heart failure, atrial fibrillation, ischemic, and hemorrhagic stroke will be the primary outcomes. Secondary outcomes include all-cause mortality, the decline in quality of life, cognitive impairment, and depression. Discussion: This study will contribute to the scientific evidence on the association between RLS and cardiovascular risks and also provide an unprecedented opportunity for early detection and prevention of CVD.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34677765

RESUMO

The employment effect of enterprises embedded in global value chains (GVCs) has important theoretical value, but existing research has ignored the impact of environmental costs on employment under the division of labor system within the value chain. By constructing a GVC-embedded index considering environmental costs, this study investigates the impact of Chinese industrial enterprises' embedding into GVCs on employment at both the theoretical and empirical levels. It is found that when the environmental cost is considered, the improvement of GVC embeddedness has a significant inhibiting effect on employment, especially for female laborers, lower-skilled laborers, state-owned enterprises, private enterprises, and enterprises in the eastern region of China. The research also shows that when considering environmental costs, the labor cost increase effect enhances the negative effect of increased GVC embeddedness on employment, while the innovation promotion effect and the foreign direct investment effect serve to mitigate the negative effect. The results provide a reference for developing countries seeking to effectively protect people's livelihood and employment while achieving a leap in the division of labor along the green value chain.

5.
J Cell Mol Med ; 25(22): 10575-10590, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34655278

RESUMO

Metastasis is the main cause of colon cancer-related deaths. RBP-Jκ is involved in colon cancer development, but its function in colon cancer metastasis is still unclear. Tumour-associated macrophages are the main cell components in tumour microenvironments. Here, we aimed to determine the function of RBP-Jκ in colon cancer metastasis and its underlying mechanisms for modulating interactions between colon cancer cell and tumour-associated macrophages. Through bioinformation analysis, we found that RBP-Jκ was overexpressed in colon cancer tissues and associated with advanced colon cancer phenotypes, macrophage infiltration and shorter survival overall as confirmed by our patients' data. And our patients' data show that RBP-Jκ expression and tumour-associated macrophages infiltration are associated with colon cancer metastasis and are independent prognostic factors for colon cancer patients. Tumour-associated macrophages induced colon cancer cell migration, invasion and epithelial-mesenchymal transition through secreting TGF-ß1. Colon cancer cells with high RBP-Jκ expression induced the expression of TGF-ß1 in tumour-associated macrophages by secreting CXCL11. Our research revealed that colon cancer cells secreted CXCL11 via overexpression of RBP-Jκ to enhance the expression of TGF-ß1 in tumour-associated macrophages to further promote metastasis of colon cancer cells.

6.
Arch Public Health ; 79(1): 179, 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663478

RESUMO

BACKGROUND: Since 2013, China launched descending resources reform, which is a new attempt to correct unbalanced allocation of health resources through human capital spillovers and brand implantation from high-level hospitals. The purpose of this paper is to explore the patients' hospital selection response to this reform with the focus of low-level hospitals to better understand the effect of this reform on correcting regional inequality of health resources allocation. METHODS: The European Consumer Satisfaction Index model (ECSI) was used to design a questionnaire, and cross-sectional data from 17 hospitals were collected through 1287 questionnaires from Zhejiang Province. Patient hospital selection (loyalty) is measured using ordinary variables by considering patient willingness to choose a low-level hospital when suffering an illness or severe illness. Analysis of variance (ANOVA) and the structure equation model are applied to examine the effect of reforms on patient behavior. RESULTS: The descending resources reform promotes improvements in the capabilities and medical environment of low-level hospitals, and descending doctors also have high accessibility. Perceived quality, patient expectations, and hospital image have significant positive effects on patient satisfaction, and the explanatory power of brand implantation from cooperative high-level hospitals and descending doctors is stronger than the image of the low-level hospital itself. And descending resources reform and patient satisfaction have significant positive impacts on patient's choice for low-level hospitals with the existence of mediating effect of satisfaction. CONCLUSIONS: This paper provides supporting empirical evidence of the descending resources reform's impact on patients' low-level hospital selection. This reform has been effective in improving the capabilities of low-level hospitals, and brand implantation of high-level hospitals shows strong explanatory power. China's reform offers a distinct and valuable approach to correcting the uneven allocation of health resources. Besides, the findings also suggest that policymakers could pay more attention to the importance of information channels in impacting patient awareness, responses, and hospital selection.

7.
Fish Physiol Biochem ; 47(5): 1565-1583, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34415453

RESUMO

Pearlscale angelfish Centropyge vrolikii is a kind of protogynous hermaphrodite fish with a natural sexual reversion. Under appropriate social conditions, a female fish can transform into a male fish spontaneously. It is an important prerequisite for artificial breeding to understand the process of its gonadal development and sexual reversion. Gonadal development is regulated by many sex-related genes. In this study, we used unreferenced RNA-Seq technology to sequence the ovary at the perinucleolus stage (OII), ovary at the yolk vesicle stage (OIV),IV and testis (T), respectively; screened the gonadal differential expression genes (DEGs); and analyzed the expression of these genes in different developmental stages of ovary and different sex gonads. The results showed that a total of 142,589 all-unigene samples were assembled, and gene annotation was performed by COG, GO, KEGG, KOG, Pfam, Swissprot, eggNOG, and NR functional database. Comparative analysis revealed that there were 1919 genes that were up-regulated and 1289 genes were down-regulated in comparison to OIV vs OII, while there were 3653 genes that were up-regulated and 2874 genes were down-regulated in comparison of OIV vs T, there were 3345 genes that were up-regulated and 2995 genes were down-regulated in comparison of the OII vs the T. At the same time, the results verified by RT-qPCR were consistent with the variation trend of transcriptome data. Among the results, amh, sox9b, dmrt1, dmrt2, cyp11a, cyp17a, and cyp19a were significantly expressed in the testes, while sox3, sox4, sox11, sox17, and hsd3b7 were significantly expressed in the ovaries. And, the expression of the amh, sox9b, dmrt2, and dmrt1 were low in the OII and OIV, while significantly increased during the ovotestis in the hermaphroditic period (OT), and finally reached the highest level in pure testis after sex reversal. The expression of sox3, sox4, hsd3b7, sox11, and sox17 was significantly reduced during the hermaphroditic period (OT). These results suggested that these genes may play an important role in the process of sex reversal. This study is helpful to further understand the molecular regulation mechanism of gonadal development and sexual reversion in Pearlscale angelfish and also provide important clues for future studies.

8.
Andrologia ; 53(10): e14195, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34374107

RESUMO

Hexachlorobenzene is a widespread endocrine disruptor. However, the effect of hexachlorobenzene on the reproductive toxicity of male animals is not described in detail. To investigate the toxic effects of hexachlorobenzene in mouse testes, hexachlorobenzene (100, 400 and 1,600 mg/kg) is fed to mice. The morphology of the testes was analysed by haematoxylin and eosin staining. We also investigated the expression of biomarkers for oxidative stress. Database screening identified proteins that interact with hexachlorobenzene and the aryl hydrocarbon receptor, a weak ligand of hexachlorobenzene. Gene enrichment analysis and protein-protein interaction analyses were also performed. Real-time PCR detected the expression levels of the aryl hydrocarbon receptor in four different stages of testicular cells. We identified significantly increased activity levels of superoxide dismutase (p < 0.05) and catalase (p < 0.05) in mouse testes that had been subjected to oxidative damage. The cell thickness and the number of cell layers in the seminiferous tubules had decreased by varying degrees after the hexachlorobenzene treatment. Particularly, cytokines and proteins involved in transcriptional regulation showed enrichment. The highest levels of aryl hydrocarbon receptor expression were detected in the spermatocytic cell line. Hexachlorobenzene exposure caused testicular damage in mice. The toxicity characteristics of hexachlorobenzene were not dose-dependent.


Assuntos
Disruptores Endócrinos , Hexaclorobenzeno , Animais , Disruptores Endócrinos/toxicidade , Hexaclorobenzeno/toxicidade , Masculino , Camundongos , Estresse Oxidativo , Túbulos Seminíferos , Testículo
9.
FASEB J ; 35(9): e21667, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34405442

RESUMO

Long noncoding RNAs (lncRNAs) are central regulators of the inflammatory response and play an important role in inflammatory diseases. PINT has been reported to be involved in embryonic development and tumorigenesis. However, the potential functions of PINT in the innate immune system are largely unknown. Here, we revealed the transcriptional regulation of inflammatory genes by PINT, whose expression is primarily dependent on the NF-κB signaling pathway in human and mouse macrophage and intestinal epithelial cell lines. Functionally, PINT selectively regulates the expression of TNF-α in basal and LPS-stimulated cells. Mechanistically, PINT acts as a modular scaffold of p65 and EZH2 to coordinate their localization and specify their binding to the target genes. Further, a high expression level of PINT was detected in intestinal mucosal tissues from patients with ulcerative colitis (UC). Together, these findings demonstrate that PINT acts as an activator of inflammatory responses, highlighting the importance of this lncRNA as a potential therapeutic target in infectious diseases and inflammatory diseases.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação da Expressão Gênica , RNA Longo não Codificante/genética , Fator de Transcrição RelA/metabolismo , Transcrição Genética , Fator de Necrose Tumoral alfa/genética , Animais , Linhagem Celular , Colite Ulcerativa/genética , Colite Ulcerativa/patologia , Citocinas/genética , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , Ligação Proteica , Transcrição Genética/genética
12.
Front Surg ; 8: 663377, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34150839

RESUMO

It is commonly observed that patients with bone fracture concomitant with traumatic brain injury (TBI) had significantly increased fracture healing, but the underlying mechanisms were not fully revealed. Long non-coding RNAs (lncRNAs) are known to play complicated roles in bone homeostasis, but their role in TBI accelerated fracture was rarely reported. The present study was designed to determine the role of lncRNAs in TBI accelerated fracture via transcriptome sequencing and further bioinformatics analyses. Blood samples from three fracture-only patients, three fracture concomitant with TBI patients, and three healthy controls were harvested and were subsequently subjected to transcriptome lncRNA sequencing. Differentially expressed genes were identified, and pathway enrichment was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. High-dimensional data visualization by self-organizing map (SOM) machine learning was applied to further interpret the data. An xCell method was then used to predict cellular behavior in all samples based on gene expression profiles, and an lncRNA-cell interaction network was generated. A total of 874 differentially expressed genes were identified, of which about 26% were lncRNAs. Those identified lncRNAs were mainly enriched on TBI-related and damage repair-related pathways. SOM analyses revealed that those differentially expressed lncRNAs could be divided into three major module implications and were mainly enriched on transcriptional regulation and immune-related signal pathways, which promote us to further explore cellular behaviors based on differentially expressed lncRNAs. We have predicted that basophils, CD8+ T effector memory cells, B cells, and naïve B cells were significantly downregulated, while microvascular endothelial cells were predicted to be significantly upregulated in the Fr/TBI group, was the lowest and highest, respectively. ENSG00000278905, ENSG00000240980, ENSG00000255670, and ENSG00000196634 were the most differentially expressed lncRNAs related to all changes of cellular behavior. The present study has revealed for the first time that several critical lncRNAs may participate in TBI accelerated fracture potentially via regulating cellular behaviors of basophils, cytotoxic T cells, B cells, and endothelial cells.

13.
Cancer Med ; 10(10): 3165-3176, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33932107

RESUMO

Relapse is the main cause of treatment failure for leukaemia patients with unfavourable gene mutations who receive allogeneic haematopoietic stem cell transplantation (allo-HSCT). There is no consensus on the indication of donor lymphocyte infusion (DLI) for prophylaxis of relapse after allo-HSCT. To evaluate the tolerance and efficacy of prophylactic DLI in patients with unfavourable gene mutations such as FLT3-ITD, TP53, ASXL1, DNMT3A or TET2, we performed a prospective, single-arm study. Prophylactic use of decitabine followed by DLI was planned in patients with TP53 or epigenetic modifier gene mutations. The prophylaxis was planned in 46 recipients: it was administered in 28 patients and it was not administered in 18 patients due to contraindications. No DLI-associated pancytopenia was observed. The cumulative incidences of grade II-IV and III-IV acute graft-versus-host disease (GVHD) at 100 days post-DLI were 25.8% and 11.0%, respectively. The rates of chronic GVHD, non-relapse mortality and relapse at 3 years post-DLI were 21.6%, 25.0% and 26.1%, respectively. The 3-year relapse-free survival and overall survival (OS) rates were 48.9% and 48.2%, respectively. Acute GVHD (HR: 2.30, p = 0.016) and relapse (HR: 2.46, p = 0.003) after DLI were independently associated with inferior OS. Data in the current study showed the feasibility of prophylactic DLI with/without decitabine in the early stage after allo-HSCT in patients with unfavourable gene mutations.


Assuntos
Decitabina/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Neoplasias Hematológicas/genética , Linfócitos/efeitos dos fármacos , Mutação/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Adolescente , Adulto , Aloenxertos/efeitos dos fármacos , Doença Crônica/tratamento farmacológico , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Transfusão de Linfócitos/métodos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Estudos Prospectivos , Taxa de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Adulto Jovem
14.
Cancer Manag Res ; 13: 3651-3661, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981164

RESUMO

Introduction: This study aims at exploring the expression and significance of recombination signal-binding protein for immunoglobulin kappa J region (RBP-Jκ) and C-X-C motif chemokine 11 (CXCL11) in human colon cancer tissues. Methods: The RBP-Jκ and CXCL11 expression levels were assessed by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) in patients with colon cancer, and their prognostic significance was evaluated. Results: Through analyzing 342 samples of colon cancer patients treated at our institution, increased expression of RBP-Jκ and CXCL11 was found in human colon cancer specimens compared with matched paratumorous normal specimens (P<0.001). A positive correlation was found between RBP-Jκ expression and CXCL11 expression (P<0.001). High RBP-Jκ expression was significantly associated with poorly differentiated tumors (P=0.005), invasion beyond propria muscularis (P=0.025), lymph node metastases (P=0.005), distant metastasis (P<0.001), advanced tumor-node-metastasis (TNM) stage (P=0.004), and a shorter overall survival (P<0.001). An increase in CXCL11 protein expression was associated with poorly differentiated tumors (P=0.015), invasion beyond propria muscularis (P=0.029), lymph node metastases (P=0.031), distant metastasis (P=0.045), advanced TNM stage (P=0.026), and a shorter overall survival of patients (P<0.001). In multivariate Cox regression analysis, RBP-Jκ protein expression (P=0.036), CXCL11 protein expression (P=0.001), differentiation (P<0.001), depth of invasion (P=0.009), distant metastasis (P<0.001), and TNM stage (P<0.001) were independent prognostic indicators of colon cancer. Conclusion: High expression of RBP-Jκ is closely associated with high CXCL11 expression, which represents a risk factor for the poor overall survival of colon cancer patients.

15.
J Healthc Eng ; 2021: 6630643, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34055274

RESUMO

Automatic classification of ECG is very important for early prevention and auxiliary diagnosis of cardiovascular disease patients. In recent years, many studies based on ECG have achieved good results, most of which are based on single-label problems; one record corresponds to one label. However, in actual clinical applications, an ECG record may contain multiple diseases at the same time. Therefore, it is very important to study the multilabel ECG classification. In this paper, a multiscale residual deep neural network CSA-MResNet model based on the channel spatial attention mechanism is proposed. Firstly, the residual network is integrated into a multiscale manner to obtain the characteristics of ECG data at different scales and then increase the channel spatial attention mechanism to better focus on more important channels and more important ECG data fragments. Finally, the model is used to classify multilabel in large databases. The experimental results on the multilabel CCDD show that the CSA-MResNet model has an average F1 score of 88.2% when the multilabel classification of 9 ECGs is performed. Compared with the benchmark model, the F1 score of CSA-MResNet in the multilabel ECG classification increased by up to 1.7%. And, in the model verification on another database HF-challenge, the final average F1 score is 85.8%. Compared with the state-of-the-art methods, CSA-MResNet can help cardiologists perform early-stage rapid screening of ECG and has a certain generalization performance, providing a feasible analysis method for multilabel ECG classification.

16.
Ying Yong Sheng Tai Xue Bao ; 32(4): 1479-1488, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33899417

RESUMO

In this study, we investigated whether Zoanthus sp. feed on two common microalgae, Platymonas subcordiformis and Isochrysis galbana, using the methods of carbon clearance rate, DNA marker, and histological analyses. The results showed that carbon clearance rate of I. galbana by Zoanthus sp. was significantly higher than that of P. subcordiformis, which were 0.44 and 0.11 pg·mL-1·polyp-1·h-1, respectively. 162 bp of 18S rRNA gene from P. subcordiformis and 442 bp of enoyl-ACP reductase gene from I. galbana were used as molecular nutrition markers, both of them were successfully amplified from the Zoanthus sp. fed by both algae species. Results of the histological analyses demonstrated that pholyp from feeding group showed a widen mesentery. Lots of food vacuoles presented in tissues of mesentery and gastrodermis. Undigested cell body of P. subcordiformis and I. galbana could also be found in some food vacuoles around siphonoglyphe as well as the gastrodermis in body wall. Therefore, results from carbon clearance rate, histological and DNA marker results all indicated that Zoanthus sp. could feed on P. subcordiformis and I. galbana.


Assuntos
Antozoários , Microalgas , Animais
17.
Environ Sci Pollut Res Int ; 28(33): 45402-45413, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33864560

RESUMO

This study explores the driving forces of natural capital demand to help solve the new problems faced by China's regional sustainable development and formulate relevant policies on resource utilization, ecological compensation, and energy structural adjustment. We find a significant and inverted U-shaped relationship between income and natural capital demand. Both economic development and environmental protection can only be improved beyond the inflection point. Energy efficiency is also closely related to natural capital demand, and its continuous improvement can slow down the rise in natural capital demand. This research provides important implications for the spread and allocation of natural capital regionally. It recommends the national allocation of natural capital, formulation of differentiated environmental policies, and improvement in energy efficiency by improving scale, technology, and structure.


Assuntos
Conservação de Recursos Energéticos , Desenvolvimento Econômico , China , Conservação dos Recursos Naturais , Eficiência , Política Ambiental
18.
Medicine (Baltimore) ; 100(8): e24725, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663084

RESUMO

BACKGROUND: High incidence of chronic graft-versus-host disease (GVHD) has been a major drawback of matched sibling donor peripheral blood stem cell transplantation (MSD -PBSCT). This study aimed to investigate the safety and efficacy of antithymocyte globulin (ATG) as a standardized part of GVHD prophylaxis in patients receiving MSD -PBSCT. METHODS: A total of 72 patients with hematological malignancies receiving MSD -PBSCT who displayed similar baseline characteristics were either given rabbit ATG ( n = 42) or no ATG (n = 30), in addition to cyclosporine, methotrexate, and mycophenolate mofetil as a standard GVHD prophylaxis regimen. Either patients or donors aged ≥40 years were included in the study. Thymoglobulin was administered at a daily dose of 1.5 mg/kg on day -5 and 3.5 mg/kg on day -4 prior to transplant (the total dose was 5 mg/kg). RESULTS: After a median follow-up of 874 days, the 3-year cumulative incidence of chronic GVHD (cGVHD) was 37.3% in the ATG group and 52.1% in the non -ATG group. The 3-year overall and disease-free survival probability were 71.0% and 62.0% (ATG versus non -ATG, P = .262) and 66.7% and 58.4% (ATG versus non -ATG, P = .334). No difference was found in the 2-year cumulative incidence of nonrelapse mortality and relapse between the ATG and non -ATG groups. This significant reduction in the incidence of cGVHD without increased relapse risk and nonrelapse mortality led to a 3-year GVHD-free, relapse-free survival probability of 66.7% and 40.0% in the ATG and non-ATG groups, respectively. CONCLUSIONS: These data suggested that rabbit antithymocyte globulin in the current protocol for GVHD prophylaxis was well tolerable and efficacious.The clinical trial was registered on January 1, 2016 (ClinicalTrials.gov Identifier NCT02677181). https://clinicaltrials.gov/ct2/show/NCT02677181.


Assuntos
Soro Antilinfocitário/administração & dosagem , Doença Enxerto-Hospedeiro/prevenção & controle , Imunossupressores/administração & dosagem , Transtornos Linfoproliferativos/cirurgia , Transplante de Células-Tronco de Sangue Periférico/métodos , Adulto , Idoso , Animais , Intervalo Livre de Doença , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Coelhos , Irmãos , Condicionamento Pré-Transplante/métodos
19.
Sci Transl Med ; 13(579)2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536281

RESUMO

Eosinophils are a myeloid cell subpopulation that mediates type 2 T helper cell immune responses. Unexpectedly, we identified a rapid accumulation of eosinophils in 22 human liver grafts after hepatic transplantation. In contrast, no eosinophils were detectable in healthy liver tissues before transplantation. Studies with two genetic mouse models of eosinophil deficiency and a mouse model of antibody-mediated eosinophil depletion revealed exacerbated liver injury after hepatic ischemia and reperfusion. Adoptive transfer of bone marrow-derived eosinophils normalized liver injury of eosinophil-deficient mice and reduced hepatic ischemia and reperfusion injury in wild-type mice. Mechanistic studies combining genetic and adoptive transfer approaches identified a critical role of suppression of tumorigenicity (ST2)-dependent production of interleukin-13 by eosinophils in the hepatoprotection against ischemia-reperfusion-induced injury. Together, these data provide insight into a mechanism of eosinophil-mediated liver protection that could serve as a therapeutic target to improve outcomes of patients undergoing liver transplantation.


Assuntos
Eosinófilos , Traumatismo por Reperfusão , Transferência Adotiva , Animais , Humanos , Interleucina-13 , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
20.
Oncogene ; 40(11): 1974-1987, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33603170

RESUMO

Smoking is one of the most impactful lifestyle-related risk factors in many cancer types including esophageal squamous cell carcinoma (ESCC). As the major component of tobacco and e-cigarettes, nicotine is not only responsible for addiction to smoking but also a carcinogen. Here we report that nicotine enhances ESCC cancer malignancy and tumor-initiating capacity by interacting with cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) and subsequently activating the JAK2/STAT3 signaling pathway. We found that aberrant CHRNA7 expression can serve as an independent prognostic factor for ESCC patients. In multiple ESCC mouse models, dextromethorphan and metformin synergistically repressed nicotine-enhanced cancer-initiating cells (CIC) properties and inhibited ESCC progression. Mechanistically, dextromethorphan non-competitively inhibited nicotine binding to CHRNA7 while metformin downregulated CHRNA7 expression by antagonizing nicotine-induced promoter DNA hypomethylation of CHRNA7. Since dextromethorphan and metformin are two safe FDA-approved drugs with minimal undesirable side-effects, the combination of these drugs has a high potential as either a preventive and/or a therapeutic strategy against nicotine-promoted ESCC and perhaps other nicotine-sensitive cancer types as well.


Assuntos
Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Janus Quinase 2/genética , Fatores de Transcrição SOXB1/genética , Fator de Transcrição STAT3/genética , Receptor Nicotínico de Acetilcolina alfa7/genética , Animais , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Metilação de DNA/efeitos dos fármacos , Dextrometorfano/farmacologia , Reposicionamento de Medicamentos , Sistemas Eletrônicos de Liberação de Nicotina , Carcinoma de Células Escamosas do Esôfago/induzido quimicamente , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Masculino , Metformina/farmacologia , Camundongos , Nicotina/toxicidade
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