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1.
Front Immunol ; 12: 749266, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621279

RESUMO

Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT). Corticosteroid is the first-line treatment for aGVHD, but its response rate is only approximately 50%. At present, no uniformly accepted treatment for steroid-refractory aGVHD (SR-aGVHD) is available. Blocking interleukin-2 receptors (IL-2Rs) on donor T cells using pharmaceutical antagonists alleviates SR-aGVHD. This meta-analysis aimed to compare the efficacy and safety of four commercially available IL-2R antagonists (IL-2RAs) in SR-aGVHD treatment. A total of 31 studies met the following inclusion criteria (1): patients of any race, any sex, and all ages (2); those diagnosed with SR-aGVHD after HSCT; and (3) those using IL-2RA-based therapy as the treatment for SR-aGVHD. The overall response rate (ORR) at any time after treatment with basiliximab and daclizumab was 0.81 [95% confidence interval (CI): 0.74-0.87)] and 0.71 (95% CI: 0.56-0.82), respectively, which was better than that of inolimomab 0.54 (95% CI: 0.39-0.68) and denileukin diftitox 0.56 (95% CI: 0.35-0.76). The complete response rate (CRR) at any time after treatment with basiliximab and daclizumab was 0.55 (95% CI: 0.42-0.68) and 0.42 (95%CI: 0.29-0.56), respectively, which was better than that of inolimomab 0.30 (95% CI: 0.16-0.51) and denileukin diftitox 0.37 (95% CI: 0.24-0.52). The ORR and CRR were better after 1-month treatment with basiliximab and daclizumab than after treatment with inolimomab and denileukin diftitox. The incidence of the infection was higher after inolimomab treatment than after treatment with the other IL-2RAs. In conclusion, the efficacy and safety of different IL-2RAs varied. The response rate of basiliximab was the highest, followed by that of daclizumab. Prospective, randomized controlled trials are needed to compare the efficacy and safety of different IL-2RAs.

2.
Lancet Haematol ; 8(10): e688-e699, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34560012

RESUMO

BACKGROUND: High-dose dexamethasone is the standard initial treatment for patients with immune thrombocytopenia, but many patients still relapse and require further treatments. All-trans retinoic acid has been shown to exert immunomodulatory effects and promote thrombopoiesis, and so we aimed to assess the activity and safety of all-trans retinoic acid plus high-dose dexamethasone as a first-line treatment for newly diagnosed patients with immune thrombocytopenia. METHODS: This multicentre, open-label, randomised, controlled, phase 2 trial was done at six different tertiary medical centres in China. Eligible participants were adults (aged >18 years) with treatment-naive, newly diagnosed, primary immune thrombocytopenia who had either a platelet count of less than 30 × 109 platelets per L or a platelet count of less than 50 × 109 platelets per L and clinically significant bleeding. We randomly assigned (1:1) participants to receive either all-trans retinoic acid (10 mg orally twice daily for 12 weeks) plus high-dose dexamethasone (40 mg/day intravenously for 4 consecutive days) or high-dose dexamethasone alone using a central, web-based randomisation system. If patients did not respond by day 14, the 4-day course of dexamethasone was repeated. The primary endpoint was 6-month sustained response, defined as the maintenance of a platelet count of at least 30 × 109 platelets per L and at least 2-times higher than the baseline count and the absence of bleeding, with no need for rescue medication at this time. The primary endpoint was analysed by intention-to-treat and safety was assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT04217148, and is now completed. FINDINGS: Between Jan 1, 2020, and June 30, 2020, 132 patients were randomly assigned to either all-trans retinoic acid plus high-dose dexamethasone (n=66) or high-dose dexamethasone alone (n=66). Three patients did not receive their allocated treatment, leaving 129 in the safety analysis set. At 6 months, a significantly higher proportion of participants in the all-trans retinoic acid plus high-dose dexamethasone group (45 [68%] of 66) than in the high-dose dexamethasone monotherapy group (27 [41%] of 66) had a sustained response (OR 3·095, 95% CI 1·516-6·318; p=0·0017). The most common adverse events were dry skin (31 [48%] of 64 patients), headaches (12 [19%]), and insomnia (12 [19%]) in the combination group, and insomnia (ten [15%] of 65 patients) and anxiety or mood disorders (eight [12%]) in the monotherapy group. Both treatments were well tolerated and no grade 4 or worse adverse events occurred. There were no treatment-related deaths. INTERPRETATION: The combination of all-trans retinoic acid and high-dose dexamethasone was safe and active in newly diagnosed patients with primary immune thrombocytopenia, providing a sustained response. This regimen represents a potential first-line treatment in this setting, but further studies are needed to validate its efficacy and safety. FUNDING: The Beijing Municipal Science and Technology Commission, the National Natural Science Foundation of China, the Beijing Natural Science Foundation, the National Key Research and Development Program of China, and the Foundation for Innovative Research Groups of the National Natural Science Foundation of China.


Assuntos
Dexametasona/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Tretinoína/uso terapêutico , Adulto , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Masculino , Púrpura Trombocitopênica Idiopática/diagnóstico , Resultado do Tratamento
3.
Blood Adv ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34507352

RESUMO

Transplant-associated thrombotic microangiopathy (TA-TMA) is a potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Information on markers for early prognostication remains limited, and no predictive tools for TA-TMA are available. We attempt to develop and validate a prognostic model for TA-TMA. A total of 507 patients who developed TA-TMA following allo-HSCT were retrospectively identified and separated into a derivation cohort and a validation cohort according to the time of transplantation to perform external temporal validation. Patient age (OR 2.371, 95% CI 1.264-4.445), anemia (OR 2.836, 95% CI 1.566-5.138), severe thrombocytopenia (OR 3.871, 95% CI 2.156-6.950), elevated total bilirubin (OR 2.716, 95% CI 1.489-4.955) and proteinuria (OR 2.289, 95% CI 1.257-4.168) were identified as independent prognostic factors for the 6-month outcome of TA-TMA. A risk score model termed BATAP (Bilirubin, Age, Thrombocytopenia, Anemia, Proteinuria) was then constructed according to the regression coefficients. The validated c-statistics were 0.816 (95% CI 0.766-0.867) and 0.756 (95% CI 0.696-0.817) in the internal and external validation, respectively. Calibration plots indicated that the model-predicted probabilities correlated well with the actual observed frequencies. This predictive model may facilitate the prognostication of TA-TMA and contribute to the early identification of high-risk patients.

4.
J Hematol Oncol ; 14(1): 145, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526099

RESUMO

The consensus recommendations in 2018 from The Chinese Society of Hematology (CSH) on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation (allo-HSCT) facilitated the standardization of clinical practices of allo-HSCT in China and progressive integration with the world. There have been new developments since the initial publication. To integrate recent developments and further improve the consensus, a panel of experts from the CSH recently updated the consensus recommendations, which are summarized as follows: (1) there is a new algorithm for selecting appropriate donors for allo-HSCT candidates. Haploidentical donors (HIDs) are the preferred donor choice over matched sibling donors (MSDs) for patients with high-risk leukemia or elderly patients with young offspring donors in experienced centers. This replaces the previous algorithm for donor selection, which favored MSDs over HIDs. (2) Patients with refractory/relapsed lymphoblastic malignancies are now encouraged to undergo salvage treatment with novel immunotherapies prior to HSCT. (3) The consensus has been updated to reflect additional evidence for the application of allo-HSCT in specific groups of patients with hematological malignancies (intermediate-risk acute myeloid leukemia (AML), favorable-risk AML with positive minimal residual disease, and standard-risk acute lymphoblastic leukemia). (4) The consensus has been updated to reflect additional evidence for the application of HSCT in patients with nonmalignant diseases, such as severe aplastic anemia and inherited diseases. (5) The consensus has been updated to reflect additional evidence for the administration of anti-thymocyte globulin, granulocyte colony-stimulating factors and post-transplantation cyclophosphamide in HID-HSCT.

5.
Ann Palliat Med ; 10(8): 9304-9308, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34488417

RESUMO

Hypercalcemia is a clinical emergency which can cause hypercalcemic crisis and even endanger patients' lives. The increase of serum calcium concentration is caused by the redistribution of calcium in bone and the inhibition of parathyroid secretion, which is known as non-parathyroid hypercalcemia. In this report, we presented a rare case of non-parathyroid hypercalcemia during lactation in order to optimize the diagnosis and treatment of this condition. A 27-year-old female patient was admitted to Wuxi People's Hospital on July 11, 2019 due to "fatigue, anorexia, and pain in both knees for half a month". The patient had fatigue and discomfort, accompanied by pain in both knees without obvious inducement. At the same time, the patient had decreased food intake. In the past 3 days, the symptoms worsened, accompanied by limb numbness. The serum calcium level was increased and the parathyroid hormone (PTH) level was decreased. The patient was diagnosed with hypercalcemia, and was treated with calcitonin and lactation termination. The knee pain disappeared and serum calcium returned to normal during a 2-week follow-up. To conclude, the correlation between hypercalcemia and lactation needs to be considered for non-parathyroid hypercalcemia during lactation. After excluding other possible causes, lactation termination therapy may be an effective therapeutic strategy for non-parathyroid hypercalcemia caused by excessive lactation.


Assuntos
Hipercalcemia , Adulto , Cálcio , Feminino , Humanos , Hipercalcemia/etiologia , Lactação , Dor , Hormônio Paratireóideo
6.
Med Sci Monit ; 27: e930421, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34415897

RESUMO

BACKGROUND In a previous study, we reported that pro-brain-derived neurotrophic factor (proBDNF) was involved in the pathology of alcohol dependence, and the single-nucleotide polymorphism (SNP) Val66Met was located at the prodomain of the brain-derived neurotrophic factor gene (BDNF). This polymorphism has been reported to affect intracellular trafficking and activity-dependent secretion of BDNF. Our present research investigated the relationships between the BDNF Val66Met polymorphism and the plasma levels of proBDNF and mature brain-derived neurotrophic factor (mBDNF) in patients with alcohol dependence. MATERIAL AND METHODS The BDNF gene Val66Met polymorphism was genotyped in 59 alcohol-dependent patients and 37 age- and sex-matched controls, and the plasma levels of proBDNF and mBDNF were assessed by enzyme-linked immunosorbent assay in all participants. RESULTS No association was found between the BDNF gene Val66Met polymorphism and alcohol dependence (P>0.05). In comparison with the control group, the level of plasma proBDNF in the alcohol-dependence group was notably increased (Z=-2.228, P=0.026), while the level of mBDNF was remarkedly decreased (Z=-2.014, P=0.044). In the alcohol-dependence group, significant associations were not found between the Val66Met polymorphisms and proBDNF and mBDNF plasma levels (P>0.05). The plasma level of proBDNF was positively correlated with the average daily alcohol consumption in the last month (r=0.344, P=0.008) and drinking history (r=0.317, P=0.014), while the plasma level of mBDNF had negative effects (r=-0.361, P=0.005, with the average daily alcohol consumption; r=-0.427, P=0.001, with drinking history). CONCLUSIONS The BDNF gene Val66Met polymorphism does not appear to affect the secretion of proBDNF and mBDNF in Chinese patients with alcohol dependence. Furthermore, this study reconfirmed that the plasma levels of proBDNF and mBDNF were correlated with the average daily alcohol consumption in the last month and with drinking history.

7.
Blood Adv ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34448835

RESUMO

Intracranial hemorrhage (ICH) is a rare but fatal central nervous system complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, factors that are predictive of early mortality in patients who develop ICH after undergoing allo-HSCT have not been systemically investigated. From January 2008 to June 2020, 70 allo-HSCT patients with ICH diagnosis formed the derivation cohort. Forty-one allo-HSCT patients with ICH diagnosis were collected from 12 other medical centers during the same period, and they comprised the external validation cohort. We used these 2 cohorts to develop and validate a grading scale that enables the prediction of 30-day mortality from ICH in all-HSCT patients. Four predictors, lactate dehydrogenase level, albumin level, white blood cell count and disease status, were retained in the multivariable logistic regression model, and a simplified grading scale, termed the LAWS score, was developed. The LAWS score was adequately calibrated (Hosmer-Lemeshow test, p>0.05) in both cohorts. It had good discrimination power in both the derivation cohort (C-statistic of 0.859, 95% CI 0.776-0.945) and the external validation cohort (C-statistic of 0.795, 95% CI 0.645-0.945). The LAWS score is the first scoring system capable of predicting the 30-day mortality from ICH in allo-HSCT patients. It showed good performance in identifying allo-HSCT patients at increased risk of early mortality after ICH diagnosis. We anticipate that it would help risk-stratify allo-HSCT patients with ICH and facilitate future studies on developing individualized and novel interventions for patients within different LAWS risk groups.

8.
Clin Exp Immunol ; 206(2): 196-207, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34382213

RESUMO

Elderly individuals exhibit unbalanced bone marrow (BM) effector T cell subset differentiation, such as increased T helper type 1 (Th1) and T cytotoxic type 1 (Tc1) cell frequencies, but the underlying mechanism is still unclear. Endothelial cells (ECs), which are instructive components of the BM microenvironment, exhibit the phenotype of semi-professional antigen-presenting cells and regulate T cell recruitment and activation. Thus, we compared the frequency and function of BM ECs, especially their capacity to regulate effector T cell subsets, between young and elderly healthy individuals, and explored the underlying mechanism of this immunomodulatory discrepancy. Although the young and elderly EC percentages were comparable, young ECs showed fewer reactive oxygen species and better migratory and tube-forming abilities than elderly ECs. Notably, increased T cell activation molecules and inflammatory cytokines were found in elderly ECs which regulated T cells to differentiate into more proinflammatory T cells, including Th1 and Tc1 cells, than young ECs.

9.
Cell Death Dis ; 12(8): 780, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34373449

RESUMO

FANCI is an essential component of Fanconi anemia pathway, which is responsible for the repair of DNA interstrand cross-links (ICLs). As an evolutionarily related partner of FANCD2, FANCI functions together with FANCD2 downstream of FA core complex. Currently, growing evidences showed that the essential role of FA pathway in male fertility. However, the underlying mechanisms for FANCI in regulating spermatogenesis remain unclear. In the present study, we found that the male Fanci-/- mice were sterile and exhibited abnormal spermatogenesis, including massive germ cell apoptosis in seminiferous tubules and dramatically decreased number of sperms in epididymis. Besides, FANCI deletion impaired maintenance of undifferentiated spermatogonia. Further investigation indicated that FANCI was essential for FANCD2 foci formation and regulated H3K4 and H3K9 methylation on meiotic sex chromosomes. These findings elucidate the role and mechanism of FANCI during spermatogenesis in mice and provide new insights into the etiology and molecular basis of nonobstructive azoospermia.

10.
J Am Soc Mass Spectrom ; 32(10): 2546-2551, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34463497

RESUMO

The proportional content of the phenylpropanoid monomeric units (4-hydroxyphenyl (H), guaiacyl (G), and syringyl (S)) in lignin is of paramount importance in germ plasm screening and for evaluating the results of plant breeding and genetic engineering. This content is usually determined using a tedious and slow (2 days/sample) method involving derivatization followed by reductive cleavage (DFRC) combined with GC/MS or NMR analysis. We report here a fast mass spectrometric method for the determination of the monomer content. This method is based on the fast pyrolysis of a lignin sample inside the ion source area of a linear quadrupole ion trap mass spectrometer. The evaporated pyrolysis products are promptly deprotonated via negative-ion mode atmospheric pressure chemical ionization ((-)APCI) and analyzed by the mass spectrometer to determine the monomer content. The results obtained for the wild-type and six genetic variants of poplar were consistent with those obtained by the DFRC method. However, the mass spectrometry method requires only a small amount of sample (50 µg) and the use of only small amounts of three benign chemicals, methanol, water, and ammonium hydroxide, as opposed to DFRC that requires substantially larger amounts of sample (10 mg or more) and large amounts of several hazardous chemicals. Furthermore, the mass spectrometry method is substantially faster (3 min/sample), more precise, and the data interpretation is more straightforward as only nine ions measured by the mass spectrometer are considered.

11.
Front Cell Infect Microbiol ; 11: 665406, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34350129

RESUMO

Gut microbiota has been proved to be involved in the occurrence and development of many diseases, such as type 2 diabetes, obesity, coronary heart disease, etcetera. It provides a new idea for the pathogenesis of polycystic ovary syndrome (PCOS). Our study showed that the gut microbial community of PCOS with high low-density lipoprotein cholesterol (LDLC) has a noticeable imbalance. Gut microbiota of PCOS patients was significantly changed compared with CON, and these changes were closely related to LDLC. Gut microbiota may affect the metabolic level of PCOS patients through multiple metabolic pathways, and lipid metabolism disorder may further aggravate the imbalance of gut microbiota. Actinomycetaceae, Enterobacteriaceae and Streptococcaceae had high accuracy in the diagnosis of PCOS and the differentiation of subgroups, suggesting that they may play an important role in the diagnosis and treatment of PCOS in the future. Also, the model we built showed good specificity and sensitivity for distinguishing PCOS from CON (including L_CON and L_PCOS, H_CON and H_PCOS). In conclusion, this is the first report on the gut microbiota of PCOS with high LDLC, suggesting that in the drug development or treatment of PCOS patients, the difference of gut microbiota in PCOS patients with different LDLC levels should be fully considered.


Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Síndrome do Ovário Policístico , Colesterol , HDL-Colesterol , LDL-Colesterol , Feminino , Humanos
12.
Biomed Res Int ; 2021: 9952463, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34337065

RESUMO

Previous studies on the relationship between the circulating level of interleukin-17 (IL-17) and disease activity in systemic lupus erythematosus (SLE) were contradictory. This study is aimed at quantitatively assessing the correlation between the circulating IL-17 level and disease activity in SLE patients. A systematic search for related literature was conducted via PubMed, Web of Science, EMBASE, and Cochrane Library (up to January 26, 2021). The relationship between circulating IL-17 levels and SLE activity was evaluated using Fisher's z value, which was then converted to r. The standardized mean difference (SMD) and its 95% confidence interval (CI) were used to describe the difference between the circulating IL-17 level in patients with active and inactive SLE. STATA 16.0 was used to perform statistical analysis. Random-effects model was performed to synthesize data. Twenty-six studies involving 1,560 SLE patients were included in this review. The pooled r value was 0.38 (95% CI: 0.25-0.50; I 2 = 83.8%, P < 0.001) between the SLE activity and circulating level of IL-17. Patients with active SLE had higher level of circulating IL-17 than that of inactive (pooled SMD = 0.95, 95% CI: 0.38-1.53; I 2 = 90.5%, P < 0.001). The subgroup analysis suggested that the region and detection method of circulating IL-17 might not be a source of heterogeneity. No significant publication bias was found. In summary, circulating IL-17 level has a low positive relationship with SLE activity. It is necessary to carefully consider the use of circulating IL-17 as a biomarker of the disease activity in SLE patients. The relationship between the circulating level of IL-17 and SLE activity should be further confirmed in randomized controlled studies.


Assuntos
Interleucina-17/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/patologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Viés de Publicação , Adulto Jovem
13.
Front Immunol ; 12: 687961, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335589

RESUMO

Graft-versus-host disease (GVHD) is a pathology in which chemokines and their receptors play essential roles in directing the migration of alloreactive donor T cells into GVHD organs, thereby leading to further target tissue damage. Currently, acute GVHD (aGVHD) remains a major cause of high morbidity and mortality in patients who underwent allogeneic hematopoietic cell transplantation (alloHCT). The identification of immune cells that correlate with aGVHD is important and intriguing. To date, the involvement of innate-like γδ T cells in the pathogenesis of aGVHD is unclear. Herein, we found that primary human γδ T cells did not directly trigger allogeneic reactions. Instead, we revealed that γδ T cells facilitated the migration of CD4 T cells via the SDF-1-CXCR4 axis. These results indicate indirect regulation of γδ T cells in the development of aGVHD rather than a direct mechanism. Furthermore, we showed that the expression of CXCR4 was significantly elevated in γδ T cells and CD4 and CD8 T cells in recipients who experienced grades II-IV aGVHD after alloHCT. Consistently, CXCR4-expressing γδ T cells and CD4 T cells were induced in the target organs of mice suffering aGVHD. The depletion of γδ T cells in transplant grafts and treatment with AMD3100, an inhibitor of CXCR4 signaling, delayed the onset of aGVHD and prolonged survival in mice. Taken together, these findings suggest a role for γδ T cells in recruiting alloreactive CD4 T cells to target tissues through the expression of CXCR4. Our findings may help in understanding the mechanism of aGVHD and provide novel therapeutic targets.

14.
Artigo em Inglês | MEDLINE | ID: mdl-34433917

RESUMO

Between 2008 and 2019, 58,914 hematopoietic stem cell transplantations (HSCTs) were reported to the Chinese Blood and Marrow Transplantation Registry Group (CBMTRG) throughout China. In this report, we focus on 2019 data and describe current trends in HSCT in China. There was continued growth in transplant activity in China, with a rapid increase in haploidentical HSCT. In 2019, a total of 12,323 cases of HSCT were reported from 149 transplant teams, 78% (9597 cases) were allogeneic HSCTs. Haploidentical donor (HID) HSCT accounted for 60% (5771 cases) of allogeneic HSCT. The most common indications for allogeneic HSCT for malignant disease were acute myeloid leukemia (AML) (37%) and acute lymphoblastic leukemia (ALL) (24%), and the largest proportion of non-malignant diseases comprised aplastic anemia (AA) (13%). Multiple stem cell source composed 70% of HID and 28% of MSD, which was typical in China. The BuCy based regimen (59%) was the most popular conditioning regimen for allogeneic HSCT, followed by the BuFlu based regimen (23%) and TBI-based regimen (12%). This survey clearly shows comprehensive information about the current state and recent trends for HSCT in China. Further efforts should be made to obtain detailed information.

15.
Am J Hematol ; 96(11): 1407-1419, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34350623

RESUMO

Idiopathic inflammatory demyelinating diseases (IIDDs) of the central nervous system (CNS) are rare but serious neurological complications of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). However, the risk factors and a method to predict the prognosis of post-transplantation CNS IIDDs are not available. This retrospective study first reviewed data from 4532 patients who received haplo-HSCT during 2008-2019 in our center, and 184 patients (4.1%) with IIDDs after haplo-HSCT were identified. Grades II to IV acute graft-versus-host disease (aGVHD) (p < 0.001) and chronic GVHD (cGVHD) (p = 0.009) were identified as risk factors for developing IIDDs after haplo-HSCT. We then divided the 184 IIDD patients into a derivation cohort and validation cohort due to transplantation time to develop and validate a model for predicting the prognosis of IIDDs. In the multivariate analysis of the derivation cohort, four candidate predictors were entered into the final prognostic model: cytomegalovirus (CMV) infection, Epstein-Barr virus (EBV) infection, IgG synthesis (IgG-syn) and spinal cord lesions. The prognostic model had an area under the receiver operating characteristic curve of 0.864 (95% CI: 0.803-0.925) in the internal validation cohort and 0.871 (95% CI: 0.806-0.931) in the external validation cohort. The calibration plots showed a high agreement between the predicted and observed outcomes. Decision curve analysis indicated that IIDD patients could benefit from the clinical application of the prognostic model. The identification of IIDD patients after allo-HSCT who have a poor prognosis might allow timely treatment and improve patient survival and outcomes.

16.
Materials (Basel) ; 14(15)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34361327

RESUMO

To clarify the understanding and analysis of arc molten marks in electrical faults of aluminum alloy wires, this paper simulates overcurrent faults of aluminum alloy wires at currents of 128 A-224 A and uses thermogravimetry-differential scanning calorimetry (TG-DSC), optical microscope (OM), scanning electron microscope (SEM) and X-ray energy spectroscopy (EDS) to characterize the effects of current on the microstructure of arc beads. The results show that there are small and large amounts of Al-Si and Al-Fe binary phases in the metallographic structure of the aluminum alloy wires at the rated current, the grains are fine, and there are no significant grain boundaries. After an overcurrent fault occurs in the wires, a high-temperature arc causes the second phase in the aluminum alloy to disappear, a cellular dendritic metallographic structure appears, the grain boundaries become more well-defined, and composition segregation occurs at the grain boundaries. Using Image-Pro-Plus software to quantify the grain characteristics, the average grain size is found to gradually decrease as the current increases. In addition, by comparing and analyzing the characteristics of arc beads in aluminum wires and aluminum alloy wires under the same conditions, alloying elements are found to have a refining effect on the grain boundaries, and there are coarse precipitates at the grain boundaries in the aluminum wire arc beads.

17.
J Immunother Cancer ; 9(8)2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34373258

RESUMO

BACKGROUND: The phosphatidylinositol 3-kinase (PI3K) is frequently hyperactivated in cancer and plays important roles in both malignant and immune cells. The effect of PI3Kα inhibitors on the tumor microenvironment (TME) remains largely unknown. Here, we investigated the modulation of the TME by a clinical PI3Kα-specific inhibitor CYH33. METHODS: The activity of CYH33 against a panel of murine tumors in the immune-competent context or athymic mice was detected. Single-cell RNA sequencing and multi-parameter flow cytometry were performed to determine the immune profiling of TME. The effect of CYH33 on immune cells was conducted with primary murine cells. RESULTS: CYH33 exhibited more potent antitumor activity in immune-competent context. CYH33 enhanced the infiltration and activation of CD8+T and CD4+T cells, while attenuating M2-like macrophages and regulatory CD4+T cells. Increase in memory T cells was confirmed by the induction of long-term immune memory on CYH33 treatment. Mechanistically, CYH33 relieved the suppressed expansion of CD8+T cells via preferential polarization of the macrophages to the M1 phenotype. CYH33 promoted fatty acid (FA) metabolism in the TME, while FA enhanced the activity of CD8+T cells in vitro. The combination of CYH33 with the FA synthase (FASN) inhibitor C75 synergistically inhibited tumor growth with enhanced host immunity. CONCLUSIONS: CYH33 induces immune activation and synergizes with FASN inhibitor to further promote the antitumor immunity, which gains novel insights into how PI3K inhibitors exert their activity by modulating TME and provides a rationale for the concurrent targeting of PI3K and FASN in breast cancer treatment.

18.
Pharm Biol ; 59(1): 1117-1125, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34403300

RESUMO

CONTEXT: Panax japonicus is the dried rhizome of Panax japonicus C.A. Mey. (Araliaceae). Saponins from Panax japonicus (SPJ) exhibit anti-inflammatory and antioxidative effects. OBJECTIVE: To explore the neuroprotective effect of SPJ on natural ageing of rat. MATERIALS AND METHODS: Sprague-Dawley (SD) rats 18-month-old were divided into ageing control, ageing treated with SPJ 10 or 30 mg/kg (n = 8). Five-month-old rats were taken as the adult control (n = 8). Rats were fed regular feed or feed containing SPJ for 4 months. Cognitive level was evaluated by Morris water maze (MWM) test. The mechanisms of SPJ's neuroprotection were evaluated by transmission electron microscope, western blot analysis, and immunofluorescence in vivo and in vitro. RESULTS: SPJ attenuated ageing-induced cognitive impairment as indicated by elevated number of times crossing the target platform (from 1.63 to 3.5) and longer time spent in the target platform quadrant (from 1.33 to 1.98). Meanwhile, SPJ improved the morphology of microglia and synapse, and activated M2 microglia polarisation including increased hippocampus levels of CD206 (from 0.98 to 1.47) and YM-1 (from 0.67 to 1.1), and enhanced autophagy-related proteins LC3B (from 0.48 to 0.82), Beclin1 (from 0.32 to 0.51), Atg5 (from 0.22 to 0.89) whereas decreased p62 level (from 0.71 to 0.45) of ageing rats. In vitro study also showed that SPJ regulated the microglial polarisation and autophagy. DISCUSSION AND CONCLUSIONS: SPJ improved cognitive deficits of ageing rats through attenuating microglial inflammation and enhancing microglial autophagy, which could be used to treat neurodegenerative disorders.

20.
Transplant Cell Ther ; 27(10): 870.e1-870.e7, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34229053

RESUMO

Late-onset severe pneumonia (LOSP) is defined as severe pneumonia developing during the late phase of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because of the high mortality in patients with LOSP, it is important to identify prognostic factors. In this study, we aimed to develop a risk score system with broad applicability that can help predict the risk of LOSP-associated mortality. We retrospectively analyzed 100 patients with LOSP after allo-HSCT between June 2009 and July 2017. The assessment variables included immune, nutritional, and metabolic parameters at the onset of LOSP. Of these 100 patients, 45 (45%) eventually died, and 55 (55%) were positive for organisms, most commonly viruses. In the multivariate analysis, higher monocyte count (≥0.20 × 109/L versus <0.20 × 109/L; P = .001), higher albumin level (≥30.5 g/L versus <30.5 g/L; P = .044), lower lactic dehydrogenase level (<250 U/L versus ≥250 U/L; P = .008) and lower blood urea nitrogen concentration (<7.2 mmol/L versus ≥7.2 mmol/L; P = .026) at the onset of LOSP were significantly associated with better 60-day survival. A risk score system based on the foregoing results showed that the probability of 60-day survival decreased with increasing risk factors, from 96.3% in the low-risk group to 49.1% in the intermediate-risk group and 12.5% in the high-risk group. Our results indicate that this scoring system using 4 variables can stratify patients with different probabilities of survival after LOSP, which suggests that patients' immune, nutritional, and metabolic status are crucial factors in determining outcome.

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