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Supercooling is a critical issue of phase change liquid metal composites in their application as stiffness-tuning and shape memory materials because of the thermal hysteresis during heating–cooling cycles. Right now, researchers still have a poor understanding of the supercooling behavior of liquid metal composites; and there have not been any successful attempts to suppress their supercooling effect. The aims of this work are to investigate factors that affect supercooling of Field's metal particles and composites and to find methods that can suppress this supercooling effect. We found that the supercooling behavior is strongly affected by particle sizes, polymer matrix, alloy compositions, and oxide impurities.

Background The clinical outcome of B-cell lymphoma has improved dramatically due to hematopoietic stem cell transplantation (HSCT) and biological agents. However, treatment of high-risk B cell lymphoma in the elderly remains a challenge because of their ineligibility for HSCT, high mortality and relapse rates. Maintenance therapy to improve the prognosis of B cell lymphoma in the elderly might be feasible. Methods We analyzed the efficacy of a combination of human recombinant granulocyte-macrophage colony-stimulating factor (rhGM-CSF) with the R2 regimen in maintenance therapy in high-risk B cell lymphoma in the elderly of our center. A total of 83 elderly patients, who were ineligible for auto-HSCT and had a response after 6 cycles of induction therapy above a partial response, were divided into two groups: observation (n = 44) and R2 + GM-CSF (n = 39) by enrollment time. Results The clinical data, survival outcome, and the number of peripheral blood mononuclear cells were analyzed and compared. The numbers of lymphocytes (1.19 × 109/L vs. 1.03 × 109/L, P = 0.0062) and leukocyte (6.46 × 109/L vs. 4.85×109/L, P = 0.0048) increased after receipt of maintenance therapy, particularly the number of natural killer cells (0.131 × 109/L vs. 0.061 × 109/L, P = 0.0244). Patients receiving R2 + GM-CSF for maintenance had longer-term remission (duration of response (DOR): 18.9 months vs. 11.3 months, P = 0.001), and longer-term progression free survival (PFS) (not reached (NR) vs. 31.7 months, P = 0.037), and overall survival (OS) (NR vs. NR, P = 0.015). The new R2 regimen was safe and well tolerated. The elderly, high-risk, and high tumor burden seemed to have tendency to be independent prognostic factors for a better PFS (P = 0.060, 0.012, 0.005). Conclusions The new R2 regimen prolonged progression-free survival and overall survival among elderly patients with high-risk B cell lymphoma, appeared to lead to improve response without compromising its tolerability profile in elderly patients who are ineligible to receive HSCT. The number of patients in this trial was limited and the conclusions should be verified in larger, prospective, multicenter studies. Retrospectively registered: The ethical committee of Huadong Hospital (approval number: 2021K186).

Background: Lymphoma has been identified as the most common cause of non-infectious fever of unknown origin (FUO). However, clinical characteristics and prognostic factors in lymphoma patients with FUO are lacking. Methods: From January 1, 2013 to December 31, 2019, our center enrolled 185 patients who initially presented with FUO but were later diagnosed with lymphoma in Huadong Hospital of Fudan University. The FUO and matched non-FUO groups were compared in terms of clinical symptoms, laboratory examinations, overall survival (OS), and progression-free survival (PFS). The prognostic factors of OS and PFS in patients with FUO were assessed by Cox analyses. Results: In the FUO group (180 in total), B cell non-Hodgkin’s lymphoma (B-NHL) cases were 88 (48.9%), T cell non-Hodgkin’s lymphoma (T-NHL) was 60 (33.3%), NK/T cell lymphoma (NK/T-CL) was 24 (13.3%), and Hodgkin’s lymphoma (HL) was 8 (4.4%). During the hospitalization, the maximum body temperature of the FUO group diagnosed with B-NHL, T-NHL, or NK/T-CL was statistically higher than that of the non-FUO group (P < 0.05). The differences in OS between the FUO and non-FUO groups were significant for HL (P = 0.006), B-NHL (P = 0.007), and T-NHL (P = 0.013). In the multivariate analyses, the log(10) serum ferritin was an independent risk factor for all-cause death in patients with FUO (hazard ratio, 9.578; 95% confidence interval, 1.382-66.365; P = 0.022). Conclusion: We found that the subtypes of lymphoma initially presenting with FUO were mostly B-NHL and T-NHL. The detection of ferritin levels during the hospital stay may help predict the long-term survival rate in patients with FUO.

Background: High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) remains controversial as a front-line therapy for high-risk diffuse large B cell lymphoma (DLBCL). Moreover, whether modifying the conditioning regimen with anthracyclines for DLBCL will improve the effect and achieve a deeper response in upfront HSCT remains unexplored. Methods: In the present study, we retrospectively compared the outcomes of 156 high-risk DLBCL patients treated with non-HSCT, upfront HSCT or salvage HSCT with a conditioning regimen consisting of mitoxantrone, etoposide, and cyclophosphamide (MCE). Result: We found that an MCE conditioning regimen achieved a complete hematopoietic engraftment and well-tolerated, the incidence of grade 1–2 cardiac toxicity was 3.1%. Transplant-related mortality did not occur. The overall survival (OS) and progression-free survival (PFS) of the upfront group (117.8 and 92.9 months) were substantially longer than that of the non-HSCT group (78.1 and 48.9 months) (P = 0.001 vs P = 0.009), also much longer than that of salvage HSCT group (58.3 m and 21.5 m) (P = 0.00 vs P = 0.00). The multivariate analysis that AnnArbor Stage was related to PFS and OS in upfront HSCT with the MCE regimen. Conclusions: The upfront HSCT with MCE regimen was well-tolerated and exhibited intriguing data in front line therapy to improve the high-risk DLBCL prognosis. However, whether high-risk DLBCL should receive consolidation HSCT with an MCE regimen after an initial CR requires a prospective, large-scale, long-term clinical trials to validate.Retrospectively registered: This study was approved by the Ethical Committee of Huadong Hospital with the Ethical number of 2021K126.

BackgroundLymphoma is found to be the main source of non-infectious fever of unknown origin (FUO). However, there is a lack of clinical features and outcomes in lymphoma patients initially presenting as FUO.MethodsFrom January 1, 2013 to December 31, 2019, our center enrolled 185 patients who initially presented as FUO then confirmed to be lymphoma in Huadong Hospital of Fudan University. During the same study period, 332 lymphoma patients without FUO received treatment in our center. After the exclusion, 509 patients were included in the retrospectively study. The differences in clinical manifestations, laboratory examinations, overall response rates and survival rates between the FUO and non-FUO groups were analyzed. The clinical endpoints were overall survival (OS) and progress-free survival (PFS).ResultsIn the non-FUO group (329 in total), Hodgkin’s lymphoma (HL) was 17 (5.2%), B cell non-Hodgkin’s lymphoma (B-NHL) was 276 (83.9%), T cell non-Hodgkin’s lymphoma (T-NHL) was 32 (9.7%) and NK/T cell lymphoma (NK/T-CL) was 4 (1.2%). In the FUO group (180 in total), B-NHL was 88 (48.9%), T-NHL was 60 (33.3%), NK/T-CL was 24 (13.3%) and HL was 8 (4.4%). During the hospitalization, the maximum body temperature of the FUO group diagnosed with B-NHL, T-NHL and NK/T-CL was statistically higher than that of the non-FUO group (all P0.05).Conclusion We found that the major subtypes of lymphoma initially presenting as FUO were B-NHL and T-NHL. The main diagnostic biopsy sites were subcutaneous lymphnodes, bone marrow and spleen for lymphoma patients with FUO. Patients with FUO suffered from a higher risk of all-cause death in the long term.

Summary A hallmark of acute myeloid leukemia (AML) is the inability of self-renewing malignant cells to mature into a non-dividing terminally differentiated state. This differentiation block has been linked to dysregulation of multiple cellular processes, including transcriptional, chromatin, and metabolic regulation. The transcription factor HOXA9 and the histone demethylase LSD1 are examples of such regulators that promote differentiation blockade in AML. To identify metabolic targets that interact with LSD1 inhibition to promote myeloid maturation, we screened a small molecule library to identify druggable substrates. We found that differentiation caused by LSD1 inhibition is enhanced by combined perturbation of purine nucleotide salvage and de novo lipogenesis pathways, and identified multiple lines of evidence to support the specificity of these pathways and suggest a potential basis of how perturbation of these pathways may interact synergistically to promote myeloid differentiation. In sum, these findings suggest potential drug combination strategies in the treatment of AML., Graphical abstract, Highlights • Combined epigenetic and metabolic perturbations induce myeloid differentiation • Combination treatment alters nucleotide, lipid, and gene expression profiles • Combination treatment induces differentiation of human acute myeloid leukemia cells, Molecular biology; Stem cells research; Systems biology

BACKGROUND: Diagnostic splenectomy is often performed on patients with suspected splenic lymphoma. However, unnecessary splenectomy entails more harm than benefit for patients. Therefore, a preliminary screening method for patients with suspected splenic lymphoma that has high sensitivity and specificity is urgently needed. METHODS: From the pathology database at Huadong and Huashan Hospital, we retrospectively identified 60 patients of suspected splenic lymphoma who underwent fluorodeoxyglucose (FDG)-positron emission tomography (PET) before receiving a splenectomy and did not show any increase in FDG uptake except in the spleen. We compared the indicators of PET-CT, such as the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and the SUVmax of 18F-FDG uptake ratios between the spleen/liver, spleen/bone marrow, and liver/bone marrow. RESULTS: No significant differences were detected in SUVmax, TLG, MTV, or the SUVmax ratio of the liver/bone marrow between the lymphoma and benign groups. However, the SUVmax ratios of the spleen/liver and spleen/bone marrow were significantly higher in the lymphoma group than in the benign group (P=0.001; P=0.001). Receiver operating characteristic (ROC) curve analysis determined a spleen/liver SUVmax ratio of >2.42 and a spleen/bone marrow SUVmax ratio of >1.45 to be the indications for requiring a diagnostic splenectomy for lymphoma. Parallel testing increased the specificity and sensitivity of the test. CONCLUSIONS: Patients whose PET-CT results are inconclusive regarding the need for splenectomy may benefit from our prediction model. Future large-scale prospective clinical trials are required to verify these findings.

Accumulating evidence from clinical trials indicates chronic hepatitis B virus (HBV) infection is associated with the incidence of diffuse large B-cell lymphoma (DLBCL) and may be associated with the prognosis of DLBCL, though this suggestion remains controversial. We performed a meta-analysis to assess whether HBV infection is associated with prognosis and response to chemotherapy in DLBCL. After a strict literature search strategy, a total of 809 HBV surface antigen (HBsAg) seropositive patients with DLBCL and 2849 HBsAg seronegative patients with DLBCL from twelve trials were included. DLBCL patients with chronic HBV infection had significantly poorer 2- and 5-year overall survival (OS) (HR 1.54, 95% CI 1.23-1.92, P

Background Decitabine are used in the treatment of myelodysplastic syndrome (MDS), but none trials reported overall survival improvement. Methods High-risk MDS and MDS transformed AML (sAML) patients (IPSS-R > 4.5, age above 60 years) in 6 medical centers of China were treated and compared a new regimen (decitabine with CEG) consisted of low dose decitabine (15 mg/m2, days 1-3), low dose etoposide (30 mg/m2, days 4,6,8,10,12), cytarabine (10 mg/m2 per day, days 4-12) and granulocyte colony-stimulating factor (G-CSF, 5ug/kg, adjusted by patients’ WBC level, 12 hours prior to decitabine administration) with decitabine alone. The endpoints were death and disease progression. Results The baseline characteristics of these 2 groups were equivalent and none patients received prior chemotherapy. The treatment response rate (P= .048) and progression free survival (PFS, P = .030) all demonstrated significant improvement compared with decitabine alone. Decitabine with CEG regimen had attained a CR rate of 45.7%, a median OS of 36 (19-53) months and a median PFS of 34 (16.7-51.3) months in high-risk MDS patients, a CR rate of 40% in sAML. While decitabine alone only attained a median OS of 26 (24.5-27.5) months and a CR rate of 18.2% as well as a median progression free survival of 20 (17.6-22.4) months in MDS patients. Treatment response to CR or PR and TP53 mutation were 2 prognostic factor for OS and PFS in decitabine with CEG regimen. Conclusion Decitabine with CEG regimen showed some promising advantage in elderly, high-risk MDS.

Wensi Qian, 1,* Li Wang, 2,* Pei Li, 3,* Yingwei Hu, 1 Qian Wang, 3 Ke Yi, 1 Min Wu, 1 Yu Xu, 1 Jin Song, 1 Pingping Chen, 1 Hongdi Zhang, 1 Jiexian Ma, 1, 4 Yanhui Xie 1 1Department of Hematology, Huadong Hospital Affiliated with Fudan University, Shanghai, People’s Republic of China; 2Department of Hematology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Qingdao, People’s Republic of China; 3Department of Hematology, Huashan Hospital Affiliated with Fudan University, Shanghai, People’s Republic of China; 4Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated with Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yanhui Xie; Jiexian MaDepartment of Hematology, Huadong Hospital Affiliated with Fudan University, Ma 221 West Yan’an Road, Shanghai 200040, People’s Republic of ChinaTel +86-21-62483180 Ext.80216; +86-21-62483180 Ext.81303Fax +86-21-62495490Email xyh@medmail.com.cn jiexianma@hotmail.comPurpose: This study was aimed at comparing the efficacy and tolerability of an arsenic trioxide/bortezomib/ascorbic acid/dexamethasone (ABCD) regimen with efficacy and tolerability of a bortezomib/dexamethasone (BD) regimen in patients with newly diagnosed myeloma.Patients and Methods: Fifty-seven and sixty-four patients were treated with the ABCD and BD regimens, respectively. Eligible and agreeable patients received autologous hematopoietic stem cell transplantation followed by consolidation.Results: The response rates (above VGPR) were 74.1% and 32.8% in the ABCD- and BD-treated groups, respectively (P = 0.000). Compared to BD regimen, ABCD regimen significantly improved PFS (P = 0.026) and OS (P = 0.000) in newly diagnosed patients. Patients with a high tumor burden, low or standard risk, and without auto-HSCT seemed to especially benefit compared to the same group with BD regimen. ABCD also showed better tolerability with lower bone marrow suppression (P = 0.026). Furthermore, complete response or near CR after induction therapy was a good prognostic factor for ABCD-associated OS and PFS.Conclusion: ABCD is an effective and tolerable regimen compared with BD regimen in newly diagnosed myeloma patients. ABCD regimen could be an economical, effective, and tolerable choice in low- and standard-risk patients.Keywords: multiple myeloma, arsenic trioxide, bortezomib, overall survival, treatment response

There is still a lack of effective treatments for elderly AML/MDS patients, especially those with TP53 mutation. We conducted a prospective, multicenter clinical trial to evaluate decitabine and etoposide based regimen in elderly AML/MDS patients and found the median OS of TP53 mutation AML/MDS was improved to 31 months. Moreover, the administration of decitabine and etoposide greatly reduced TP53 mutant AML tumor burden in NSG mice model. Decitabine and etoposide induced significant apoptosis and differentiation of TP53 mutant myeloid tumor cells in vitro. RNA sequencing data and CRISPR-Cas9 gene editing indicated that drug-induced apoptosis and differentiation, were predominantly dependent on Notch1 signaling pathway. We also found that normal p53 function could inhibit Notch1 activation, whereas decitabine and etoposide could activate Notch1 in dysfunctional TP53 mutant AML/MDS. These findings indicate that treatment of elderly AML/MDS patients may need to be developed into a more precise, personalized chemotherapy in the future.

At our center, relapsed mantle cell lymphoma (MCL) can be treated with maintenance therapy composed of consecutive low-dose lenalidomide and short-term, high-dose dexamethasone (LD regimen), which achieves good responses (longer overall survival and progression-free survival) and low toxicity. Cereblon is probably targeted by both lenalidomide and dexamethasone, which leads to synergistic cytotoxicity in MCL by inhibiting the interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3), phosphatidylinositol 3-kinase (PI3K)/AKT and AKT2/Forkhead box O3 (FOXO3A)/BCL2-like 11 (BIM) pathways. The two drugs synergistically inhibit the same pathways, but through different sites. Cereblon was found expressed in most of the MCL tissues (91.3% positivity). Moreover, cereblon expression is positively correlated with LD regimen sensitivity: long-term lenalidomide exposure downregulates cereblon and induces multi-drug resistance against lenalidomide, dexamethasone, cytarabine, cisplatin, and methotrexate in vitro. Removal of lenalidomide resensitizes lenalidomide-resistant MCL cells to lenalidomide and dexamethasone. Our work suggests that rotating the LD regimen with other regimens would improve MCL maintenance therapy., Highlights • Synergistic inhibition of IL-6/STAT3, PI3K/AKT, and AKT2/FOXO3A/BIM pathways by lenalidomide and dexamethasone • CRBN expression in MCL may account for the effectiveness of the LD regimen • Long-term lenalidomide exposure downregulates CRBN expression and induces drug resistance; Lena removal resensitized MCL cells • Intermittent use of the LD regimen would avoid drug resistance Consecutive low-dose lenalidomide and short-term, high-dose dexamethasone (LD) maintenance therapy showed good response in relapsed mantle cell lymphoma. The synergistic effect of the two drugs might involve cereblon and such signaling pathways as IL-6/STAT3, PI3K/Akt and Akt2/FoxO3a/Bim. Cereblon expression positively correlated with LD regimen sensitivity. Expression of cereblon in mantle cell lymphoma probably accounts for the effectiveness of the LD regimen.

Glucocorticoids (GCs) are widely used drugs in the treatment of lymphoid malignancies; resistance of GCs in lymphocytes confers poor prognosis and the mechanisms are poorly understood. Here, we found T-acute lymphoblastic leukemia (T-ALL) cells acquire resistance to dexamethasone (DEX)-mediated killing through abnormal activation of Akt, resulting in inhibition of the FoxO3a/Bim pathway. The resistant state was reported to be associated with increased glycolysis, NOTCH1 activating mutations and activated PI3K/ serum GS regulated kinases (SGK) pathway. Use of aforementioned pathway inhibitors blocked FoxO3a-phosphorylation and partially improved DEX-mediated killing of GC-resistant T-ALL cells, further revealing the essential role of the FoxO3a/Bim pathway in the development of GC resistance. Inhibition of Akt is most effective at restoring sensitivity to DEX of GC-resistant lymphocytes in vitro and in vivo, but shows significant hepatotoxicity in vivo. A significantly elevated expression of Akt2 not Akt1 in intrinsically, secondarily GC-resistant lymphocytes and relapsed/refractory ALL patients implicates a more specific target for GC resistance. Mechanistically, Akt2 has a stronger binding capacity with FoxO3a compared to Akt1, and acts as a direct and major negative regulator of FoxO3a activity driving GC resistance. Pharmacologic inhibition of Akt2 more effectively restores sensitivity to GCs than inhibition of Akt1 in vitro, shows higher synergistic effect acting with DEX, and reverses GC resistance in GC-resistant T- or B- lymphoid tumors in vivo with reduced liver toxicity. In summary, these results suggest that Akt2 might serve as a more direct and specific kinase mediating GC resistance through FoxO3a/Bim signaling pathway, and Akt2 inhibition may be explored as a promising target for treating GC-resistant hematopoietic malignancies.

In order to compute the optimal dowel length in cement concrete pavement, semi-infinite beam on elastic foundation was deduced and modified for the analysis of dowel bars. The dowel deflection, bending moment and shearing were analyzed for dowel bars under the traffic loading, dowel length based on the second inflexion distance was computed and a relationship between dowel length and dowel diameter was established. The theoretical analysis found that the dowel length in Chinese specification is conservative. A finite element model was also established to simulate the dowel load system. Based on the result of maximum value and variation tendency of mises stress for different dowel diameters and dowel lengths, it is feasible to shorten dowel length specified in JTG D40-2002 by 50%. However, considering the construction tolerances in the making and sawing of joints in new pavement construction, which might add 50–150 mm to the required overall dowel length, it’s more appropriate to reduce the dowel length by 20% in practice. Keywords: Dowel bar, Mechanical analysis, Length design, Cement concrete pavement, Finite element model

In this study, to overcome the high cost of accelerated loading test, a small-scale laboratory experiments were developed and conducted toward the potential dowel bar alternatives. Similarity theory and Accelerated Pavement Analyzer were used to evaluate dowel bars with different materials and cross-sections. The test results showed that larger FRP dowel is required to produce the same load transfer efficiency and differential deflection which would be produced with given size of round steel dowel. Moreover, steel dowel with large diameter can effectively improve the ability of joints to transfer vertical shear forces and reduce the internal stress, thereby extending the service life of dowel load transfer system.

In this study, a small-scaled accelerated loading test based on similarity theory and Accelerated Pavement Analyzer was developed to evaluate dowel bars with different materials and cross-sections. Jointed concrete specimen consisting of one dowel was designed as scaled model for the test, and each specimen was subjected to 864 thousand loading cycles. Deflections between jointed slabs were measured with dial indicators, and strains of the dowel bars were monitored with strain gauges. The load transfer efficiency, differential deflection, and dowel-concrete bearing stress for each case were calculated from these measurements. The test results indicated that the effect of the dowel modulus on load transfer efficiency can be characterized based on the similarity model test developed in the study. Moreover, round steel dowel was found to have similar performance to larger FRP dowel, and elliptical dowel can be preferentially considered in practice.

Whether TLX3 is a predictor of prognosis of pediatric T cell acute lymphocytic leukemia (T-ALL) is controversial, with some studies concluding that it is and others concluding the opposite. Therefore, a systematic review was performed to explore the relationship of TLX3 expression with the prognosis of pediatric T-ALL. The PubMed database, The Cochrane Library, conference proceedings, EMBASE databases, and references of published trials and review articles were searched. Two reviewers independently assessed the quality of the trials and extracted data. Hazard ratios (HRs) for disease-free survival (DFS) and odds ratios (OR) for 5-year DFS were pooled using the STATA package. Ultimately, six trials involving 515 patients with pediatric T-ALL were analyzed. The pooled HR (1.07 [0.32, 3.56], p = 0.91) for DFS and OR (1.30 [0.52, 3.27], p = 0.57) for 5-year DFS showed that the TLX3-positive group showed no statistically significant difference with the TLX3-negative group. Our results suggested that TLX3 expression is not an indicator for the prognosis of pediatric T-ALL.

The number of elderly myelodysplastic syndrome/acute leukemia(MDS/AML) patients is increasing every year while the treatment is limited and outcome is poor, which is also faced with the lack of basic research and breakthrough. The expectation of better life quality and longer survival in elderly patients is increasing with the improvement of living standards. We compared two different regimens decitabine with CEG as well as decitabine with CAG in random clinical trials(ChiCTR-INR-16009337) enrolled 72 elderly MDS/AML patients and conducted multivariate factor regression to determine the independent prognostic factor of decitabine with CEG regimen. We also compared the sensitivity of different cell lines to etoposide, decitabine and aclarubicin in vitro and explored the possible molecular mechanism as well as signaling pathway by RNA-seq. We found TP53 mutation is an independent prognostic factor(HR for OS: 3.4(1.2-9.9)) in decitabine with CEG group, with a significant prolonged survival of 31 months(p=0.019) and progression free survival of 24 months(p=0.034) among these patients. While TP53 wild type patients could get benefit from decitabine with CAG regimen, with a prolonged overall survival(p=0.034) and progression free survival(p=0.009). We also found decitabine with etoposide could greatly reduce tumor burden and prolong T53 mutation leukemic mice survival in NOD/SCID mice.TP53 mutation cells were sensitive to etoposide-induced apoptosis, while TP53 wide type cells were relatively sensitive to Aclarubicin-induced apoptosis in vitro. Etoposide and decitabine could induce differentiation in TP53 mutation clones, while aclarubicin didn't have such effect. RNA-sequence data gave us a hint that etoposide might activate Notch1 signaling pathway. We then use CRISPR to knockout Notch1 and find drug induced apoptosis and differentiation were reduced to a half of before(p Decitabine with CEG regimen significantly prolonged TP53 mutation MDS/AML survival. TP53 mutational clone might be sensitive to etoposide, which was dependent on Notch1 signaling pathway. p53 function presence would affect Notch1 activation. We will consider how to make decision on elderly MDS/AML patients treatment by TP53 status in larger clinical trials. Figure Disclosures No relevant conflicts of interest to declare.

Regulatory T (Treg) cells play an important role in allergic airway diseases and upregulation of Treg cells is a potential therapeutic strategy for asthma. In this study, we show that short-term intratracheal use of IL-2 combined with glucocorticoid alleviates antigen-induced airway inflammation and reduces airway hyperresponsiveness by expanding antigen-nonspecific Treg cells, with a decrease in T helper 2 (Th2) cells and Th2-associated cytokines. We also designed a long-acting polyethylene glycol (PEG)-modified IL-2 and demonstrated that the optimal dosage form is IL-2(PEG) plus budesonide, which can upregulate Treg cells and ameliorate asthma at a lower dose. The therapeutic effect was faster than treatment with dexamethasone and was effective at a low dose suitable for humans that could last for at least 6 weeks. This study unveils a new therapeutic regimen and suggests that such endogenous Treg therapy could be a useful tool to persistently alleviate asthma.

Glucocorticoid (GC) resistance in lymphoblastic malignancies is related to treatment failure and is a marker of poor prognosis. Previous studies have suggested that microRNA-182 (miR-182) functions as an oncogene and plays a role in tumorigenesis, through regulation of FOXO3A. FOXO3A has been implicated in tumor suppression and GC-induced apoptosis, suggesting that FOXO3A has potential as a therapeutic target. Herein we investigated the role of miR-182 in GC sensitivity in lymphoblastic malignancies. Expression of miR-182 was consistently higher in human and mouse GC-resistant cell lines than in GC-sensitive cell lines. Furthermore, increased expression of miR-182 reduced total FOXO3A expression but had no significant effect on phospho-FOXO3A. Additionally Bim, as a downstream target of FOXO3A, was reduced by overexpression of miR-182, and increased by down-regulation of miR-182. These results demonstrate that miR-182 is involved in glucocorticoid resistance, via targeting of FOXO3A, and that restoration of miR-182 is a potentially promising therapeutic strategy in lymphoblastic malignancies.

To explore the relationship of Notch1 mutation in T-ALL with the survival rate of T-ALL patients. The PubMed database, the Cochrane Library, conference proceedings, EMBASE databases, and references of published trials and review articles were searched. Two reviewers independently assessed the quality of the trials and extracted data. Hazard ratios (HRs) for event-free survival (EFS) were pooled by STATA package. Seven trials involving 964 patients with T-ALL were ultimately analyzed. Seven hundred and eleven patients were children (age

Background: Glucocorticoids (GCs) are common components in chemotherapeutic protocols for acute lymphoblastic leukemia (ALL). A major obstacle in GC therapy, however, is the gradual acquisition of apoptotic resistance in ALL cells repeatedly treated with these hormones. Previous reports indicate that 15-30% of pediatric ALL samples are resistant to GCs, while in refractory childhood ALL, the prevalence of GC resistance is as high as 70%. Identification of specific molecular mechanisms driving resistance to GC and targeting downstream molecules may lead to the development of new therapeutic strategies. Results: FoxO transcription factor FoxO3a has been shown to regulate apoptosis in lymphocytes. Unphosphorylated FoxO3a can be upregulated by dexamethasone (DEX), which subsequently translocates into the nucleus, upregulates Bim expression and induces apoptosis. In our current study, we cultured a GC-sensitive T-ALL cell line CCRF-CEM with a specific concentration of DEX over multiple passages and obtained a highly resistant cell line, designated CEM-DR. We observed this T-ALL cell line acquires resistance to DEX-mediated killing through abnormal activation of Akt, resulting in inhibition of the FoxO3a/Bim pathway (A). Pharmacologic inhibition of Akt with Akt inhibitor IV effectively restores sensitivity to DEX of CEM-DR by enhancing the FoxO3a/Bim pathway, but shows significant hepatotoxicity with increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in vivo (B). Common hematologic toxicities and hepatic toxicities with increased AST and ALT of Akt inhibitor have also been reported in the treatment of solid tumors in humans, partially limiting their clinical applicability (Becher OJ et al, Pediatr Blood Cancer 2017). There are two closely related, highly conserved homologues of Akt: Akt-1 and -2, which differ in enzyme function. Our study aimed to investigate the potential role of Akt isoforms Akt1 and Akt2 in the mechanism of GC resistance and explore a more direct and specific target for resistance reversal. By western blot analysis we observed the expression of Akt2 in intrinsically resistant T-ALL cells Jurkat was significantly higher than that in sensitive CCRF-CEM cells, while Akt1 expression in aforementioned cell lines was similar. The expression of Akt2 also increased synchronously with the increase of half maximal inhibitory concentration (IC50) of DEX in CEM-DR cells, further indicating that Akt2 expression increases in secondarily resistant lymphocytes. A significantly elevated expression of Akt2 not Akt1 were shown in relapsed/refractory ALL patients when compared with the newly diagnosed patients. To detect if Akt2 was able to directly interact with FoxO3a, co-immunoprecipitation assay was employed. MYC-FoxO3a was co-transfected with Flag-Akt1 or Flag-Akt2 into HEK293T cells. The result demonstrated the more presence of Flag-AKT2 than Flag-Akt1 in MYC-FoxO3a immunoprecipitates, suggesting that AKT2 as the major regulator directly interacting with FoxO3a. Reciprocal immunoprecipitation experiments confirmed the closer association between Flag-Akt2 and MYC-FoxO3a (C). Then we used siRNA to down-regulate Akt1 or Akt2 expression in resistant T-ALL cells; we observed GC-induced apoptosis increased significantly (D) after down-regulation of Akt2 expression, along with the expression of p-FoxO3a decreased (E) . To examine the therapeutic role of Akt isoform specific inhibitors, we treated resistant T-ALL cell with A-674563 (Akt1 inhibitor), CCT128930 (Akt2 inhibitor) or Akti1/2 (Akt1/2 inhibitor). Selective inhibition of Akt2 with CCT128930 more significantly enhances the FoxO3a/Bim signaling pathway, increases DEX-mediated killing of resistant T-ALL cells (F) and effectively reverses GC resistance than Akt1 inhibitor in vitro and in vivo. When exploring the potential influence on viscera by Akt isoform inhibitors in vivo, we found Akt2 inhibitor did not significantly influence hematopoiesis, cardiac and renal functions. Notably, Akt2 inhibitor did not show hepatic toxicities of increased serum ALT, AST and total bilirubin which appear in Akt1 or Akt1/2 inhibition. Conclusions: Akt2 might serve as a more direct and specific kinase mediating GC resistance through FoxO3a/Bim-signaling pathway in ALL, and targeting Akt2 with CCT128930 may be explored as a promising therapeutic strategy for resistance reversal. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

To study the function of a miRNA, it is necessary to identify its target genes. The most common methods to reveal miRNA target genes rely on ectopically expressed tagged Ago2 and nonphysiological overexpression or inhibition of the miRNA of interest. To uncover the natural association between miRNAs and their target genes, we isolated endogenous Ago2 protein followed by a selective strategy, which only amplified target genes of the selected miRNA from the purified RNA-induced silencing complex by miRNA specific primers. This enabled us to identify the mRNAs regulated by miRNAs of interest. Our data demonstrated that this strategy is effective and highly credible. Moreover, our results showed the evidence of efficient miRNA target sites in 5' untranslated regions and open reading frames of target mRNAs.

Dexamethasone (DEX) induces apoptosis in lymphocytes, while protecting some cancer cells from apoptosis, by a poorly understood mechanism. In this study, we examined the potential role of the forkhead transcription factor (FOXO3A) in DEX-induced apoptosis. Unphosphorylated FOXO3A, the active form of FOXO3A, can translocate into nucleus and induce apoptosis. In lymphocytes, FOXO3A is upregulated by DEX treatment, while phospho-FOXO3A was downregulated. In several different types of cancer cells, we found that sensitivity to DEX correlated negatively to expression of phospho-FOXO3A. We conclude that DEX might maintain FOXO3A in its unphosphorylated, active form. Knockdown of FOXO3A expression using a small interfering RNA (siRNA) significantly reduces apoptosis in lymphocytes. This study suggests that FOXO3A has a pivotal role in DEX-induced apoptosis. Increased phospho-FOXO3A levels in cancer cells may explain, in part, their resistance to apoptosis. Therefore, FOXO3A may be a potential target for cancer therapy.

The objective of this study was to investigate the feasibility of TiO2 waterborne epoxy resin as fog seal and exhaust degradation material in asphalt pavement. To achieve this objective, a commercial anatase/rutile mixed-phase nano-TiO2 was added to waterborne epoxy resin at various percentages. Prepared TiO2 coating was characterized with the use of adhesive shear strength test and laboratory photocatalytic performance test, which was performed with a newly developed apparatus for the study of vehicle exhaust decomposition. In addition, the impact of TiO2 coating on skid resistance and permeability of asphalt pavement was analyzed, with the British Pendulum, sand patch method, and pavement permeability test. The results of the experiments indicated that TiO2 waterborne epoxy resin coating was very effective in decomposing NO, HC, and CO pollutants from automobile exhaust. Moreover, application of waterborne epoxy resin as fog seal could maintain the skid resistance and improve the impermeability of the pavement.

Background microRNAs (miRNAs) are small noncoding RNAs that regulate cognate mRNAs at the post-transcriptional stage. Several studies have shown that miRNAs modulate gene expression in mammalian cells by base pairing to complementary sites in the 3′-untranslated region (3′-UTR) of the target mRNAs. Methodology/Principal Findings In the present study, miR-24 was found to target fas associated factor 1(FAF1) by binding to its amino acid coding sequence (CDS) region, thereby regulating apoptosis in DU-145 cells. This result supports an augmented model whereby animal miRNAs can exercise their effects through binding to the CDS region of the target mRNA. Transfection of miR-24 antisense oligonucleotide (miR-24-ASO) also induced apoptosis in HGC-27, MGC-803 and HeLa cells. Conclusions/Significance We found that miR-24 regulates apoptosis by targeting FAF1 in cancer cells. These findings suggest that miR-24 could be an effective drug target for treatment of hormone-insensitive prostate cancer or other types of cancers. Future work may further develop miR-24 for therapeutic applications in cancer biology.

Regulatory T (Treg) cells are a subpopulation of T cells that not only prevent autoimmunity, but also control a wide range of T cell-dependent immune responses. Glucocorticoid treatment (dexamethasone, or Dex) has been reported to amplify IL-2-mediated selective in vivo expansion of Treg cells. We simultaneously administered Dex and IL-2 to the donor in a murine allogeneic lymphocyte transplantation model to expand functional suppressive CD4(+)CD25(+)FOXP3(+) T cells in the graft and to raise the regulatory T cell/effector T cell (Treg/ Teff ) ratio to prevent graft-versus-host disease (GVHD). After combined treatment of the donor with Dex (5 mg/kg/day) and IL-2 (300,000 IU/mouse/day) for 3 days, grafts were subjected to flow cytometric analysis, and transplantation was carried out from male C57BL/6 mice to female BALB/c mice aged 8-12 weeks. Results showed that short-term simultaneous administration of Dex and IL-2 markedly expanded functional suppressive CD4(+)CD25(+)FOXP3(+) T cells in the murine spleen. In this murine allogeneic transplantation model, the grafts from donors with Dex and IL-2 pre-treatment led to a longer survival time for the recipients than for the control group (median survival time60 day vs. 12 day, P=0.0002). The ratio of Treg/Teff also increased remarkably (0.43+/-0.15 vs. 0.14+/-0.01, P=0.01). This study demonstrated that co-stimulation with Dex and IL-2 selectively expanded functional CD4(+)CD25(+)FOXP3(+) T cells in vivo, and that grafts from donors pre-treated with Dex and IL-2 led to longer survival time and greater suppression of GVHD after allogeneic transplantation. Thus, GVHD can be suppressed by the specific expansion of regulatory T cells with Dex and IL-2 in graft donors.