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1.
Clin Appl Thromb Hemost ; 28: 10760296211068037, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35019756

RESUMO

Secondary failure of platelet recovery (SFPR) is a life-threatening complication that may affect up to 20% of patients after allogeneic hematopoietic stem cell transplantation (HSCT). In this study, to evaluate the efficacy of recombinant human thrombopoietin (rhTPO), we retrospectively analyzed 29 patients who received continuous rhTPO for the treatment of SFPR. Overall response and complete response were observed in 24 (82.8%) patients and 10 (34.5%) patients, at a median time of 21.5 days (range, 3-41 days) and 39.5 days (range, 7-53 days) after initiation of rhTPO treatment, respectively. Among the responders, the probability of keeping overall response and complete response at 1 year after response was 77.3% and 80.0%, respectively. In multivariate analysis, higher CD34+ cells (≥3 × 106/kg) infused during HSCT (HR: 7.22, 95% CI: 1.53-34.04, P = 0.01) and decreased ferritin after rhTPO treatment (HR: 6.16, 95% CI: 1.18-32.15, P = 0.03) were indicated to associate with complete response to rhTPO. Importantly, rhTPO was well tolerated in all patients without side effects urging withdrawal and clinical intervention. The results of this study suggest that rhTPO may be a safe and effective treatment for SFPR.

2.
Talanta ; 236: 122891, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34635270

RESUMO

A molecularly imprinted biosensor for lysozyme based on the polymer nanoparticles self-assembled from water-soluble and electroactive poly (γ-glutamic acid) modified with 3-aminothiophene copolymer were prepared. The water-soluble copolymer made imprinting of lysozyme in aqueous solution possible and thus facilitated improvement of the activity of LYS. Subsequent electro-polymerization not only locked the recognition site between copolymer and lysozyme but also created a conductive polymer network, which can enhance the electron transfer rate and increase the conductivity of the film. The prepared molecularly imprinted biosensor exhibited a wide linear range from 1 × 10-10 to 1 × 10-5 mg mL-1, and satisfactory selectivity, stability, repeatability for lysozyme detection.


Assuntos
Técnicas Biossensoriais , Impressão Molecular , Nanopartículas , Muramidase , Polímeros , Água
3.
JCI Insight ; 2021 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-34914637

RESUMO

Systemic hypoxia is characterized by peripheral vasodilation and pulmonary vasoconstriction. However, the system-wide mechanism for signaling hypoxia remains unknown. Accumulating evidence suggests that hemoglobin in RBCs may serve as an O2 sensor and O2-responsive NO signal transducer to regulate systemic and pulmonary vascular tone, but this remains unexamined at the integrated system level. One residue invariant in mammalian hemoglobins (Hb), ß-globin Cys93 (ßCys93), carries NO as vasorelaxant S-nitrosothiol (SNO) to autoregulate blood flow during oxygen delivery. ßCys93Ala mutant mice thus exhibit systemic hypoxia despite transporting oxygen normally. Here we show that ßCys93Ala mutant mice have reduced S-nitrosohemoglobin (SNO-Hb) at baseline and upon targeted SNO repletion, and that hypoxic vasodilation by RBCs is impaired in vitro and in vivo, recapitulating hypoxic pathophysiology. Notably, ßCys93Ala mutant mice show marked impairment of hypoxic peripheral vasodilation and develop signs of pulmonary hypertension with age. Mutant mice also die prematurely with cor pulmonale (pulmonary hypertension with right ventricular dysfunction) when living under low oxygen. Altogether, we identify a major role for RBC-SNO in clinically-relevant vasodilatory responses attributed previously to endothelial NO. We conclude that SNO-Hb transduces the integrated, system-wide response to hypoxia in the mammalian respiratory cycle, expanding a core physiological principle.

4.
J Clin Invest ; 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34793333

RESUMO

It is widely recognized that inflammation plays a critical role in cardiac hypertrophy and heart failure. However, clinical trials targeting cytokines have shown equivocal effects indicating the need for a deeper understanding of the precise role of inflammation and inflammatory cells in heart failure.Leukocytes from human subjects and a rodent model of heart failure were characterized by a marked reduction in expression of KLF2 mRNA. Using a mouse model of Angiotensin II-induced non-ischemic cardiac dysfunction, we showed that neutrophils played an essential role in the pathogenesis and progression of heart failure. Mechanistically, chronic Angiotensin II infusion activated a neutrophil KLF2-NETosis pathway that triggered sporadic thrombosis in small myocardial vessels leading to myocardial hypoxia, cell death, and hypertrophy. Conversely, targeting neutrophils, NETs or thrombosis ameliorated these pathological changes and preserved cardiac dysfunction. KLF2 regulated neutrophil activation in response to Angiotensin II at the molecular level, partly through the crosstalk with HIF1 signaling.Taken together, our data implicate neutrophil-mediated immunothrombotic dysregulation as a critical pathogenic mechanism leading to cardiac hypertrophy and heart failure. This neutrophil KLF2-NETosis-thrombosis mechanism underlying chronic heart failure can be exploited for therapeutic gain by therapies targeting neutrophils, NETosis, or thrombosis.

5.
Front Cardiovasc Med ; 8: 750067, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34778406

RESUMO

Aim: Mechanical dyssynchrony (MD) is associated with heart failure (HF) and may be prognostically important in cardiac resynchronization therapy (CRT). Yet, little is known about its patterns in healthy or diseased hearts. We here investigate and compare systolic and diastolic MD in both right (RV) and left ventricles (LV) of canine, primate and healthy and failing human hearts. Methods and Results: RV and LV mechanical function were examined by pulse-wave Doppler in 15 beagle dogs, 59 rhesus monkeys, 100 healthy human subjects and 39 heart failure (HF) patients. This measured RV and LV pre-ejection periods (RVPEP and LVPEP) and diastolic opening times (Q-TVE and Q-MVE). The occurrence of right (RVMDs) and left ventricular systolic mechanical delay (LVMDs) was assessed by comparing RVPEP and LVPEP values. That of right (RVMDd) and left ventricular diastolic mechanical delay (LVMDd) was assessed from the corresponding diastolic opening times (Q-TVE and Q-MVE). These situations were quantified by values of interventricular systolic (IVMDs) and diastolic mechanical delays (IVMDd), represented as positive if the relevant RV mechanical events preceded those in the LV. Healthy hearts in all species examined showed greater LV than RV delay times and therefore positive IVMDs and IVMDd. In contrast a greater proportion of the HF patients showed both markedly increased IVMDs and negative IVMDd, with diastolic mechanical asynchrony negatively correlated with LVEF. Conclusion: The present IVMDs and IVMDd findings have potential clinical implications particularly for personalized setting of parameter values in CRT in individual patients to achieve effective treatment of HF.

6.
Front Cell Dev Biol ; 9: 720383, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34692679

RESUMO

Hearing loss is a serious illness affecting people's normal life enormously. The acoustic properties of a tympanic membrane play an important role in hearing, and highly depend on its geometry, composition, microstructure and connection to the surrounding annulus. While the conical geometry of the tympanic membrane is critical to the sound propagation in the auditory system, it presents significant challenges to the study of the 3D microstructure of the tympanic membrane using traditional 2D imaging techniques. To date, most of our knowledge about the 3D microstructure and composition of tympanic membranes is built from 2D microscopic studies, which precludes an accurate understanding of the 3D microstructure, acoustic behaviors and biology of the tissue. Although the tympanic membrane has been reported to contain elastic fibers, the morphological characteristic of the elastic fibers and the spatial arrangement of the elastic fibers with the predominant collagen fibers have not been shown in images. We have developed a 3D imaging technique for the three-dimensional examination of the microstructure of the full thickness of the tympanic membranes in mice without requiring tissue dehydration and stain. We have also used this imaging technique to study the 3D arrangement of the collagen and elastic fibrillar network with the capillaries and cells in the pars tensa-annulus unit at a status close to the native. The most striking findings in the study are the discovery of the 3D form of the elastic and collagen network, and the close spatial relationships between the elastic fibers and the elongated fibroblasts in the tympanic membranes. The 3D imaging technique has enabled to show the 3D waveform contour of the collagen and elastic scaffold in the conical tympanic membrane. Given the close relationship among the acoustic properties, composition, 3D microstructure and geometry of tympanic membranes, the findings may advance the understanding of the structure-acoustic functionality of the tympanic membrane. The knowledge will also be very helpful in the development of advanced cellular therapeutic technologies and 3D printing techniques to restore damaged tympanic membranes to a status close to the native.

7.
Biomed Opt Express ; 12(5): 2979-2995, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34168910

RESUMO

The rupture of coronary atherosclerotic plaque (CAP) and the resulting intracoronary thrombosis account for most acute coronary syndromes. Thus, the early identification and risk assessment of CAP is crucial for timely medical intervention. In this study, we propose a quantitative and label-free method for human CAP identification using multiphoton microscopy (MPM) and three-dimensional (3D) image analysis techniques. By detecting the intrinsic MPM signals, the microstructures of collagen and elastin fibers within normal and CAP-lesioned human coronary artery walls were imaged. Using a 3D gray level co-occurrence matrix method and 3D weighted vector summation algorithm, quantitative indicators that characterize the spatial texture and orientation features of the fibers were extracted. We demonstrate that these indicators show superior accuracy and repeatability over 2D texture features in CAP discrimination. Furthermore, by combining the 3D microstructural indicators, a support vector machine model that classifies CAP from the normal arterial wall with an accuracy of >97% was established. In conjunction with advances in multiphoton endoscopy, the proposed method shows great potential in providing a quantitative, label-free, and real-time tool for the early identification and risk assessment of CAP in the future.

8.
Immunology ; 164(1): 148-160, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33934334

RESUMO

CD11c is a canonical dendritic cell (DC) marker with poorly defined functions in the immune system. Here, we found that blocking CD11c on human peripheral blood mononuclear cell-derived DCs (MoDCs) inhibited the proliferation of CD4+ T cells and the differentiation into IFN-γ-producing T helper 1 (Th1) cells, which were critical in acute graft-versus-host disease (aGVHD) pathogenesis. Using allogeneic bone marrow transplantation (allo-BMT) murine models, we consistently found that CD11c-deficient recipient mice had alleviated aGVHD symptoms for the decreased IFN-γ-expressing CD4+ Th1 cells and CD8+ T cells. Transcriptional analysis showed that CD11c participated in several immune regulation functions including maintaining antigen presentation of APCs. CD11c-deficient bone marrow-derived DCs (BMDCs) impaired the antigen presentation function in coculture assay. Mechanistically, CD11c interacted with MHCII and Hsp90 and participated in the phosphorylation of Akt and Erk1/2 in DCs after multiple inflammatory stimulations. Therefore, CD11c played crucial roles in triggering aGVHD and might serve as a potential target for the prevention and treatment of aGVHD.


Assuntos
Transplante de Medula Óssea , Antígeno CD11c/metabolismo , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Células Th1/imunologia , Doença Aguda , Animais , Apresentação do Antígeno , Antígeno CD11c/genética , Células Cultivadas , Doença Enxerto-Hospedeiro , Interferon gama/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/citologia , Transplante Homólogo
9.
Transplant Cell Ther ; 27(8): 666.e1-666.e9, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34020086

RESUMO

Marrow fibrosis (MF) is usually accompanied with primary myelodysplastic syndromes (MDS) and no consensus has been reached on the relationship between MF and prognosis. We retrospectively analyzed 239 MDS and MDS derived acute myeloid leukemia patients with known grade of MF who received allogeneic stem cell transplantation (allo-HSCT). Of these, it included 121 (50.6%) without fibrosis (MF-0), 81 (33.9%) with mild fibrosis (MF-1), 37 (15.5%) with moderate to severe fibrosis (MF-2/3). MF-2/3 was associated with more pronounced dysmegakaryopoiesis (P =.002), more frequent karyotype abnormality (P = .039) and increased leukemic transformation. Spliceosome and ras pathway mutation occurred more frequently in patients with MF-2/3. After allo-HSCT, neutrophil and platelet engraftment was significantly delayed in patients with MF-2/3 than those with MF-1 and MF-0 (P = .031, P = .05, respectively). The estimated 3-year overall survival (OS) rates and disease-free survival (DFS) rates were significantly lower in patients with MF-2/3 than in those with MF-0 or MF-1 (P = .018, P = .018, respectively). Notably, in the subgroup of patients with more than 10% bone marrow blasts, MF-2/3 was independently associated with shorter OS and DFS (P = .012, P = .012, respectively) and has improved outcomes for these patients who achieved complete remission (CR) before allo-HSCT. Overall, MF-2/3 as an additional risk factor have the inferior prognosis for MDS and MDS-AML patients with bone marrow blasts ≥10%. Using pretransplantation cytoreductive therapy to obtain CR for these patients may benefit from allo-HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Mielofibrose Primária , Medula Óssea , Humanos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Estudos Retrospectivos , Fatores de Risco , Condicionamento Pré-Transplante , Transplante Homólogo
10.
Am J Respir Cell Mol Biol ; 65(1): 70-80, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33780653

RESUMO

Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification, airway hyperreactivity, and pulmonary hypertension. In our BPD model, we have investigated the metabolism of the bronchodilator and pulmonary vasodilator GSNO (S-nitrosoglutathione). We have shown the GSNO catabolic enzyme encoded by adh5 (alcohol dehydrogenase-5), GSNO reductase, is epigenetically upregulated in hyperoxia. Here, we investigated the distribution of GSNO reductase expression in human BPD and created an animal model that recapitulates the human data. Blinded comparisons of GSNO reductase protein expression were performed in human lung tissues from infants and children with and without BPD. BPD phenotypes were evaluated in global (adh5-/-) and conditional smooth muscle (smooth muscle/adh5-/-) adh5 knockout mice. GSNO reductase was prominently expressed in the airways and vessels of human BPD subjects. Compared with controls, expression was greater in BPD smooth muscle, particularly in vascular smooth muscle (2.4-fold; P = 0.003). The BPD mouse model of neonatal hyperoxia caused significant alveolar simplification, airway hyperreactivity, and right ventricular and vessel hypertrophy. Global adh5-/- mice were protected from all three aspects of BPD, whereas smooth muscle/adh5-/- mice were only protected from pulmonary hypertensive changes. These data suggest adh5 is required for the development of BPD. Expression in the pulmonary vasculature is relevant to the pathophysiology of BPD-associated pulmonary hypertension. GSNO-mimetic agents or GSNO reductase inhibitors, both of which are currently in clinical trials for other conditions, could be considered for further study in BPD.


Assuntos
Álcool Desidrogenase/metabolismo , Displasia Broncopulmonar/metabolismo , Hipertensão Pulmonar/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Álcool Desidrogenase/genética , Animais , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/patologia , Criança , Pré-Escolar , Feminino , Humanos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Lactente , Masculino , Camundongos , Camundongos Knockout , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia
11.
J Clin Invest ; 131(4)2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33586679

RESUMO

Skeletal muscle is a major determinant of systemic metabolic homeostasis that plays a critical role in glucose metabolism and insulin sensitivity. By contrast, despite being a major user of fatty acids, and evidence that muscular disorders can lead to abnormal lipid deposition (e.g., nonalcoholic fatty liver disease in myopathies), our understanding of skeletal muscle regulation of systemic lipid homeostasis is not well understood. Here we show that skeletal muscle Krüppel-like factor 15 (KLF15) coordinates pathways central to systemic lipid homeostasis under basal conditions and in response to nutrient overload. Mice with skeletal muscle-specific KLF15 deletion demonstrated (a) reduced expression of key targets involved in lipid uptake, mitochondrial transport, and utilization, (b) elevated circulating lipids, (c) insulin resistance/glucose intolerance, and (d) increased lipid deposition in white adipose tissue and liver. Strikingly, a diet rich in short-chain fatty acids bypassed these defects in lipid flux and ameliorated aspects of metabolic dysregulation. Together, these findings establish skeletal muscle control of lipid flux as critical to systemic lipid homeostasis and metabolic health.


Assuntos
Homeostase , Fatores de Transcrição Kruppel-Like/metabolismo , Metabolismo dos Lipídeos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Animais , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Camundongos Knockout , Mitocôndrias Musculares/genética
12.
Biomaterials ; 269: 120654, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33434712

RESUMO

A variety of therapies have been developed and used for the treatment of colon cancer, however, the high mortality rate remains high and more effective strategies are still in urgent needs. In this study, an immunotherapy approach that is composed of innate immune activator Astragaloside III (As) and the photodynamic therapy (PDT) reagent chlorine e6 (Ce6) ((As + Ce6)@MSNs-PEG), was developed for colon cancer treatment. We showed that (As + Ce6)@MSNs-PEG could effectively activate NK cells and inhibit the proliferation of tumor cells in vitro. It could also effectively reach tumor sites, induce infiltration of immune cells into the tumor, and enhance the cytotoxicity of natural killer cells and CD8+ T cells in vivo. Without obvious side effects, (As + Ce6)@MSNs-PEG treatment significantly inhibited tumor growth and extended the lifespan of tumor-bearing mice. Further results revealed that treatment of (As + Ce6)@MSNs-PEG led to enhanced IFN secretion by immune cells and increased T-box transcription factor (T-bet), which is highly expressed by T cells. Therefore, (As + Ce6)@MSNs-PEG may serve as an effective and safe platform for combinatory use with nano-herb medicine and PDT to provide a new therapy for colon cancer treatment.


Assuntos
Neoplasias do Colo , Nanopartículas , Fotoquimioterapia , Porfirinas , Animais , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Imunoterapia , Camundongos , Fármacos Fotossensibilizantes/uso terapêutico
13.
Hematology ; 26(1): 65-74, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33402056

RESUMO

Objectives: To analyze the outcomes of patients who received autologous stem cell transplantation (auto-SCT), matched sibling donor stem cell transplantation (MSD-SCT) and haploidentical stem cell transplantation (haplo-SCT) and provide the basis for the choice of transplantation method in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Methods: We retrospectively investigated the outcomes of 119 adult patients with Ph+ ALL in our center. The overall survival (OS) rate, leukemia-free survival (LFS) rate, cumulative incidence of relapse (CIR) rate, non-relapse mortality (NRM) rate and the impact of achievement of complete molecular response (CMR) within 3 months and sustaining CMR up to transplantation (s3CMR) on transplantation method were explored. Results: The estimated OS, LFS, CIR and NRM rates at 3 years were not significantly different among three groups (p = 0.960, 0.917, 0.375 and 0.096, respectively). For the 65 patients who achieved s3CMR, there was no significant difference in OS (84.5% vs 72.5% vs 100%, p = 0.374), LFS (75.2% vs 64.5% vs 83.3%, p = 0.668), CIR (17.2% vs 8.1% vs 16.7%, p = 0.583) and NRM (3.1% vs 23.4% vs 0%, p = 0.055) among auto-SCT group, MSD-SCT group and haplo-SCT group. However, in patients who did not achieve s3CMR, auto-SCT recipients tended to have higher CIR (60% vs 33.2% vs 24.0%, p = 0.013) than the allo-HSCT group. Conclusions: Auto-SCT with maintenance therapy after HSCT appears to be an attractive treatment option for patients with Ph+ ALL especially for those whose s3CMR was kept up to transplantation. For non-s3CMR patients, allogeneic transplantation may be more effective from lower relapse.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Transplante de Células-Tronco , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Análise de Sobrevida , Transplante Autólogo , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
14.
Leukemia ; 35(6): 1563-1570, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33077866

RESUMO

Safety and efficacy of allogeneic anti-CD19 chimeric antigen receptor T cells (CAR-T cells) in persons with CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) relapsing after an allotransplant remain unclear. Forty-three subjects with B-ALL relapsing post allotransplant received CAR-T cells were analyzed. 34 (79%; 95% confidence interval [CI]: 66, 92%) achieved complete histological remission (CR). Cytokine release syndrome (CRS) occurred in 38 (88%; 78, 98%) and was ≥grade-3 in 7. Two subjects died from multiorgan failure and CRS. Nine subjects (21%; 8, 34%) developed ≤grade-2 immune effector cell-associated neurotoxicity syndrome (ICANS). Two subjects developed ≤grade-2 acute graft-versus-host disease (GvHD). 1-year event-free survival (EFS) and survival was 43% (25, 62%). In 32 subjects with a complete histological remission without a second transplant, 1-year cumulative incidence of relapse was 41% (25, 62%) and 1-year EFS and survival, 59% (37, 81%). Therapy of B-ALL subjects relapsing post transplant with donor-derived CAR-T cells is safe and effective but associated with a high rate of CRS. Outcomes seem comparable to those achieved with alternative therapies but data from a randomized trial are lacking.


Assuntos
Antígenos CD19/metabolismo , Transplante de Células-Tronco Hematopoéticas/mortalidade , Imunoterapia Adotiva/métodos , Recidiva Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Prognóstico , Receptores de Antígenos Quiméricos/imunologia , Estudos Retrospectivos , Taxa de Sobrevida , Doadores de Tecidos , Transplante Homólogo , Adulto Jovem
15.
Antioxid Redox Signal ; 34(12): 936-961, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32597195

RESUMO

Significance: Red blood cell (RBC)-mediated vasodilation plays an important role in oxygen delivery. This occurs through hemoglobin actions, at least in significant part, to convert heme-bound nitric oxide (NO) (in tense [T]/deoxygenated-state hemoglobin) into vasodilator S-nitrosothiol (SNO) (in relaxed [R]/oxygenated-state hemoglobin), convey SNO through the bloodstream, and release it into tissues to increase blood flow. The coupling of hemoglobin R/T state allostery, both to NO conversion into SNO and to SNO release (along with oxygen), under hypoxia supports the model of a three-gas respiratory cycle (O2/NO/CO2). Recent Advances: Oxygenation of tissues is dependent on a single, strictly conserved Cys residue in hemoglobin (ßCys93). Hemoglobin couples SNO formation/release at ßCys93 to O2 binding/release at hemes ("thermodynamic linkage"). Mice bearing ßCys93Ala hemoglobin that is unable to generate SNO-ßCys93 establish that SNO-hemoglobin is important for R/T allostery-regulated vasodilation by RBCs that couple blood flow to tissue oxygenation. Critical Issues: The model for RBC-mediated vasodilation originally proposed by Stamler et al. in 1996 has been largely validated: SNO-ßCys93 forms in vivo, dilates blood vessels, and is hypoxia-regulated, and RBCs actuate vasodilation proportionate to hypoxia. Numerous compensations in ßCys93Ala animals to alleviate tissue hypoxia (discussed herein) are predicted to preserve vasodilatory responses of RBCs but impair linkage to R/T transition in hemoglobin. This is borne out by loss of responsivity of mutant RBCs to oxygen, impaired blood flow responses to hypoxia, and tissue ischemia in ßCys93-mutant animals. Future Directions: SNO-hemoglobin mediates hypoxic vasodilation in the respiratory cycle. This fundamental physiology promises new insights in vascular diseases and blood disorders.


Assuntos
Eritrócitos/metabolismo , Hemoglobinas/metabolismo , Vasodilatação/genética , Globinas beta/genética , Animais , Eritrócitos/patologia , Técnicas de Introdução de Genes , Hemoglobinas/genética , Humanos , Camundongos , Óxido Nítrico/genética , Oxigênio/metabolismo , S-Nitrosotióis/uso terapêutico , Globinas beta/metabolismo
16.
ACS Omega ; 5(42): 27032-27042, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33134663

RESUMO

Three-dimensional porous carbon was fabricated using lotus leaves as a renewable precursor. The as-synthesized carbon had a high surface area (3601 m2/g), suitable O-N-S self-doping, and three-dimensional (3D) architecture with interconnected micro/meso/macropores, together with proper pore size distribution. Consequently, these admirable features endowed porous carbon as a superadsorbent for dye removal with ultrahigh adsorption capacity for rhodamine B (9444.39 mg/g) and reliable cyclability (>97% capacitance retention after 10 cycles). The adsorption of dye onto the as-prepared carbon was a spontaneous endothermic process and followed the pseudo-second-order kinetic model and the Langmuir isotherm model. The π-π stacking, hydrogen bond, and acid-base interactions were proposed to mainly account for the combination of the adsorbate and the adsorbent. Overall, these values indicated the high-performance biomass-derived carbon as a dye adsorbent and may boost the large-scale production and application of 3D hierarchical porous carbon with heteroatom doping in the field of wastewater treatment.

17.
Opt Lett ; 45(12): 3305-3308, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32538969

RESUMO

We present confocal fluorescence lifetime imaging microscopy in the second near-infrared (NIR-II) window to assess the morphological and biochemical information of live samples. A home-built superconducting single-photon detector (SSPD) was used to facilitate the NIR-II fluorescence lifetime measurement. The SSPD has many advantages, including high sensitivity to NIR-II signals (detection efficiency >50%), fast temporal response (∼109ps), low timing jitter (∼50ps), and low dark count rate (<100cps). We demonstrate the feasibility of the developed microscopy system by comparing fluorescence lifetimes of a range of fluorophores with emission in the NIR-II window and by performing multicolor three-dimensional fluorescence lifetime imaging of a mouse ear in vivo. The biochemical properties of the cells and tissues probed by the fluorescence lifetimes of the fluorophores provide complementary information for biomedical studies, significantly benefiting diverse applications in life science.

18.
Biomed Opt Express ; 11(5): 2366-2372, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32499929

RESUMO

NIR-II fluorescence imaging is a promising method for visualizing biological structures in deep tissue, owing to the advantages of significantly suppressed optical scattering and diminished autofluorescence in biological tissues. However, few NIR-II fluorescence imaging approaches can simultaneously achieve a large field of view, high resolution and superior penetration depth, while exhibiting optical sectioning capability. In this paper, we present a novel NIR-II fluorescence mesoscopy system based on the f-θ scanning scheme and confocal detection to overcome these limitations. When used with NIR-II fluorescent dyes, our setup performs NIR-II fluorescence imaging on samples as large as 7.5×7.5 mm2 with a lateral resolution of 6.3 µm. In addition, our system provides a depth-resolved imaging ability and zooming function. We successfully demonstrate in vivo cerebrovascular imaging of a mouse with local ischemia. Thus, our system provides new opportunities to explore the mechanism of cerebrovascular disease.

19.
Biol Blood Marrow Transplant ; 26(9): 1663-1669, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32504862

RESUMO

Cytomegalovirus (CMV) infection and graft-versus-host disease (GVHD) remain the major causes of nonrelapse mortality (NRM) in patients following alternative donor hematopoietic stem cell transplantation (HCT). Mizoribine (MZR) showed an anti-CMV effect in addition to its immunosuppressive effect in patients with renal transplantation. In this study, we aimed to evaluate the efficacy and safety of MZR combined with a calcineurin inhibitor (CNI) as a method of prophylactic immunosuppression in recipients following alternative donor HCT. Eighty patients were enrolled in the study and randomized to the MZR (n = 40) or MMF (n = 40) cohort before transplantation conditioning. Analyses involved a comparison of the outcomes between the 2 cohorts, as well as risk analyses of early nonrelapse mortality (NRM) and severe CMV infection. In contrast to MMF, MZR was associated with a lower but statistically nonsignificant median CMV DNA peak load (P = .075), significantly fewer episodes of persistent/refractory infection (odds ratio [OR], .12), and a lower failure rate of CMV treatment (OR, .82), but a significantly higher rate of hyperuricemia (OR, 2.75). Transplantation efficacy was comparable in the 2 cohorts regarding engraftment, the development of secondary poor graft function and GVHD, and the estimated OS and PFS. The 1-year NRM of the MZR cohort did not differ from that of the MMF cohort, whereas the rate of 1-year NRM caused by viral infections was reduced in the MZR cohort and was of borderline statistical significance (P = .05). In the multivariate analysis, lower doses of CD34+ cells in grafts (hazard ratio [HR], 3.65) and persistent/refractory CMV infections (versus no CMV infection: HR, 7.31; versus CMV infection that was not persistent/refractory: HR, 4.46) were predictors of increased 1-year NRM. The use of MMF (versus MZR cohort: OR, 11.54) and grade II-IV acute GVHD (OR, 15.32) were independent risk factors for developing persistent/refractory CMV infection. When combined with CNIs, MZR functioned well in terms of both immunosuppression and reduced severity of CMV infection; however, further studies are warranted to verify its use as a potential immunosuppressant for alternative donor HCT.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Inibidores de Calcineurina/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Ácido Micofenólico/uso terapêutico , Ribonucleosídeos , Condicionamento Pré-Transplante
20.
Am J Cancer Res ; 10(4): 1218-1228, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368397

RESUMO

To evaluate whether cytoreductive therapy is needed for myelodysplastic syndromes (MDS) patients with excess blasts type 2 (MDS-EB2) and acute myeloid leukemia derived from MDS (MDS-AML) before HLA-matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT), we retrospectively analyzed 80 cases of MDS-EB2 and MDS-AML patients who received MSD-PBSCT between February 2006 and December 2019 in our hospital. The 3-years overall survival (OS) rate and disease-free survival (DFS) rate were (59.1±5.8)% and (52.5±5.7)%, respectively. The 3-years non-relapse mortality (NRM) rate and relapse rate (RR) were (22.4±0.2)% and (25.4±0.2)%, respectively. Univariate analysis showed that, hematopoietic cell transplantation comorbidity index (HCT-CI) ≥ 2, poor/very poor karyotype and occurrence of grade III-IV acute graft-versus-host disease (aGVHD) are risk factors for OS. Patients received pre-transplant cytoreductive therapy (PCT) and obtained complete remission (CR) had significantly higher OS rate than those who failed to achieve CR (non-CR group) and those who did not receive PCT (non-PCT group) [(80.0±8.3)% versus (38.1±10.6)% versus (56.1±9.3)%, P=0.010]. PCT significantly increased the OS rate [(62.2±10.0)% versus (20.0±17.9)%, P=0.013] for MDS-AML patients but not for MDS-EB2 patients [(59.2±11.1)% versus (62.9±10.1)%, P=0.991]. Our findings suggest reducing tumor burden by cytoreductive therapy to obtain CR before transplant improves OS. For MDS-AML patients, PCT is beneficial, while for MDS-EB2 patients, PCT is not necessary.

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