Genome sequencing of Sitopsis species provides insights into their contribution to the B subgenome of bread wheat.

Wheat (Triticum aestivum, BBAADD) is an allohexaploid species that originated from two polyploidization events. The progenitors of the A and D subgenomes have been identified as Triticum urartu and Aegilops tauschii, respectively. Current research suggests that Aegilops speltoides is the closest but not the direct ancestor of the B subgenome. However, whether Ae. speltoides has contributed genomically to the wheat B subgenome and which chromosome regions are conserved between Ae. speltoides and the B subgenome remain unclear. Here, we assembled a high-quality reference genome for Ae. speltoides, resequenced 53 accessions from seven species (Aegilops bicornis, Aegilops longissima, Aegilops searsii, Aegilops sharonensis, Ae. speltoides, Aegilops mutica [syn. Amblyopyrum muticum], and Triticum dicoccoides) and revealed their genomic contributions to the wheat B subgenome. Our results showed that centromeric regions were particularly conserved between Aegilops and Triticum and revealed 0.17 Gb of conserved blocks between Ae. speltoides and the B subgenome. We classified five groups of conserved and non-conserved genes between Aegilops and Triticum, revealing their biological characteristics, differentiation in gene expression patterns, and collinear relationships between Ae. speltoides and the wheat B subgenome. We also identified gene families that expanded in Ae. speltoides during its evolution and 789 genes specific to Ae. speltoides. These genes can serve as genetic resources for improvement of adaptability to biotic and abiotic stress. The newly constructed reference genome and large-scale resequencing data for Sitopsis species will provide a valuable genomic resource for wheat genetic improvement and genomic studies.

Carbon nanotube bridged nickel hexacyanoferrate architecture for high-performance hybrid capacitive deionization.

Although widely used as hybrid capacitive deionization (HCDI) electrode material, the low intrinsic conductivity of metal hexacyanometalate (MHCF) severely hinders the fast insertion/extraction of Na+ in/from its 3D framework structure, damaging its desalination performance. Herein, we design a carbon nanotube (CNT) bridged nickel hexacyanoferrate architecture (NiHCF). The highly conductive CNT not only acts as the skeleton for the uniform growth of NiHCF to provide more ion-accessible surface and active sites but also serves as the conductive bridge to connect the NiHCF particles, which prevents the agglomeration of NiHCF particles and facilitates the charge transfer and ion diffusion during the desalination process. Therefore, the HCDI cell assembled by NiHCF/CNT cathode and AC anode exhibits an excellent desalination performance with a high desalination capacity of 29.1 mg g-1 and a superior desalination rate of 7.2 mg g-1 min-1 in 500 mg L-1 NaCl solution. This work provides a facile method for preparing high-performance MHCF-based electrodes for desalination application.

Discovery of Novel Pyrazolopyrimidines as Potent, Selective, and Orally Bioavailable Inhibitors of ALK2.

Activin receptor-like kinase 2 (ALK2) is a transmembrane kinase receptor that mediates the signaling of the members of the TGF-ß superfamily. The aberrant activation of ALK2 has been linked to the rare genetic disorder fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) that are associated with severely reduced life expectancy in pediatric patients. ALK2 has also been shown to play an essential role in iron metabolism by regulating hepcidin levels and affecting anemia of chronic disease. Thus, selective inhibition of ALK2 has emerged as a promising strategy for the treatment of multiple disorders. Herein, we report the discovery of a novel pyrazolopyrimidines series as highly potent, selective, and orally bioavailable inhibitors of ALK2. Structure-based drug design and systematic structure-activity relationship studies were employed to identify potent inhibitors displaying high selectivity against other ALK subtypes with good pharmacokinetic profiles.

Efficient induction of neural progenitor cells from human ESC/iPSCs on Type I Collagen.

A stable, rapid and effective neural differentiation method is essential for the clinical applications of human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) in treating neurological disorders and diseases. Herein, we established a novel and robust monolayer differentiation method to produce functional neural progenitor cells (NPCs) from human ESC/iPSCs on Type I Collagen. The derived cells not only displayed the requisite markers, but also behaved similarly to classic NPCs both in vitro and in vivo. Upon transplantation into traumatic brain injury model, the derived NPCs facilitated recovery from injury. We also found that SMAD signaling stayed down throughout the differentiation process on Type I Collagen, and the pluripotent signals were rapidly downregulated along with raising up of neural early markers on the third day. Meanwhile, ATAC-seq data showed the related mediation of distinct transcriptome and global chromatin dynamics during NPC induction. Totally, our results thus provide a convenient way to generate NPCs from human ESC/iPSCs for neural diseases' treatment.

Identification of pAKT as a pharmacodynamic marker for MER kinase in human melanoma G361 cells.

BACKGROUND: The MER signaling pathway represents an attractive therapeutic target for human cancers. Growth arrest-specific protein 6 (GAS6)-induced MER phosphorylation is often unstable and difficult to detect without pervanadate pretreatment in human cancer cells, posing a challenge for the development of selective MER kinase inhibitors. Here, we identified phosphorylated AKT (pAKT) as a specific pharmacodynamic marker for MER kinase inhibitors in human melanoma G361 cells. METHODS: The expression of MER, TYRO3, and AXL were profiled among multiple human cancer cells. To determine whether they play a role in the activation of pAKT, MER and TYRO3 were selectively depleted by small, interfering RNA knockdown. In addition, using AKT phosphorylation as a readout, a high-throughput cell-based assay was established in G361 cells for evaluation of the potency of potential inhibitors of MER pathway activation. RESULTS: We demonstrated that high levels of MER and TYRO3, but not AXL, were expressed in G361 cells. In these cells, pAKT was induced by GAS6 treatment, which could be reversed by AXL/MER inhibitors. We showed that GAS6-induced pAKT is only dependent on MER kinase, but not TYRO3, in G361 cells. Furthermore, we observed a correlation in potency between inhibition of pAKT in G361 cells and pMER in MER-overexpressing Ba/F3 cells by these inhibitors. CONCLUSIONS: In summary, we have demonstrated that GAS6-induced pAKT is a possible pharmacodynamic marker for the inhibition of MER kinase, and we have successfully developed a cell-based functional assay for screening small-molecule inhibitors of MER kinase for potential therapeutic utility in treating GAS6/MER-deregulated human cancers.

The telomerase inhibitor AZT enhances differentiation and prevents overgrowth of human pluripotent stem cell-derived neural progenitors.

Human pluripotent stem cell (hPSC)-based cell-replacement therapy has emerged as a promising approach for addressing numerous neurological diseases. However, hPSC transplantation has the potential to cause human cell overgrowth and cancer, which represents a major obstacle to implementing hPSC-based therapies. Inhibition of the overgrowth of transplanted cells could help reduce the risk for hPSC transplantation-induced tumorigenesis. In this study, we report that the telomerase inhibitor azidothymidine (3'-azido-3'-deoxythymidine; AZT) enhances the differentiation of cortical neurons and significantly suppresses the proliferation of hPSC-derived cortical progenitors. Using human embryonic stem cells and induced pluripotent stem cells in culture, we found that AZT effectively reduces the number of dividing progenitors without inducing cell death. Furthermore, AZT promoted differentiation of cortical progenitors and maturation of cortical neurons. Of note, AZT-pretreated, hPSC-derived neural progenitors exhibited decreased proliferation and increased differentiation into cortical neurons when transplanted into the mouse brain. In summary, our findings indicate that AZT prevents the overgrowth of hPSC-derived neural precursors and enhances the differentiation of cortical neurons in both cell cultures and hPSC-transplanted mouse brain. We propose that our work could inform clinical applications of hPSC-based cell therapy.

Targeting PFKFB3 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitor.

Resistance to the BCR-ABL tyrosine kinase inhibitor (TKI) remains a challenge for curing the disease in chronic myeloid leukemia (CML) patients as leukemia cells may survive through BCR-ABL kinase activity-independent signal pathways. To gain insight into BCR-ABL kinase activity-independent mechanisms, we performed an initial bioinformatics screen and followed by a quantitative PCR screen of genes that were elevated in CML samples. A total of 33 candidate genes were identified to be highly expressed in TKIs resistant patients. Among those genes, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), controlling the limiting step of glycolysis, was found to be strongly associated with TKIs resistance. PFKFB3 knockdown or pharmacological inhibition of its kinase activity markedly enhanced the sensitivity of CML cells to TKIs. Furthermore, pharmacological inhibition of PFKFB3 inhibited CML cells growth and significantly prolonged the survival of both allograft and xenograft CML mice. ChIP-seq data analysis combined with subsequent knockdown experiment showed that the Ets transcription factor PU.1 regulated the elevated expression of PFKFB3 in TKIs-resistant CML cells. Therefore, our results showed that targeting PFKFB3 sensitizes CML cells to TKIs and PFKFB3 may be a potential BCR-ABL kinase activity-independent mechanism in CML.

The synergy of Vitamin C with decitabine activates TET2 in leukemic cells and significantly improves overall survival in elderly patients with acute myeloid leukemia.

BACKGROUND: Decitabine is widely used in the treatment of acute myeloid leukemia (AML) in elderly patients. Low-dose Vitamin C has also been indicated to induce DNA demethylation at the cellular level. However, little is known whether low-dose Vitamin C has a synergistic effect with decitabine in clinic. METHODS: The effect of combined low-dose Vitamin C and decitabine on cell proliferation, the cell cycle, apoptosis and the expression level and activity of TET2 was investigated in HL60 and NB4 human leukemic cells. Additionally, we analyzed the clinical outcomes of 73 elderly AML patients who received A-DCAG (intravenous Vitamin C [IVC] plus DCAG [n = 39]) or DCAG (n = 34) treatment. RESULTS: We found that low-dose Vitamin C and decitabine has a synergistic efficacy on proliferation, apoptosis, TET2 expression and activity, compared to drug-alone treatment in HL60 and NB4 cell lines in vitro. In clinic, feasibility and safety evaluations revealed that patients who received A-DCAG regimen have a higher complete remission (CR) rate than those who received the DCAG regimen (79.92% vs. 44.11%; P = 0.004) after one cycle of chemotherapy. The median overall survival (OS) was better in the A-DCAG group compared with the DCAG group (15.3 months vs. 9.3 months, P = 0.039). Patients with adverse cytogenetics did benefit from CR. There was no clinically significant additional toxicity observed with the addition of IVC. CONCLUSION: On the basis of these results, the addition of IVC at low doses to DCAG appeared to improve CR and prolong OS, compared with DCAG, in elderly patients with AML.

[Analysis of prognosis of acute myeloid leukemia patients based on genetic mutations].

OBJECTIVE: To correlate the clinical features of patients with acute myeloid leukemia (AML) with mutations of FLT3-ITD, NPM1, CEBPA, c-KIT, DNMT3A and ND4 genes as well as chromosomal aberrations. METHODS: Somatic mutations of aforementioned genes in 412 newly diagnosed AML patients were detected with PCR and direct sequencing. All patients were also subjected to R-banding chromosomal analysis. The results were correlated with the clinical features and prognosis of the patients. RESULTS: The mutation rates of FLT3-ITD, NPM1, CEBPA, c-KIT, DNMT3A and ND4 were 9.0% (26/289), 19.1% (50/262), 18.9% (34/180), 3.4% (7/208), 6.6% (9/137) and 6.9% (4/58), respectively. Patients with poor prognosis based on genetic mutations had lower blood platelet count than those with intermediate and good prognosis (P=0.001 and P=0.001, respectively). None of the three groups attained median overall survival (OS) (P> 0.05). The complete remission (CR) was similar among the three groups (P> 0.05). For patients with different prognosis based on cytogenetic findings, white blood cell count in those with intermediate prognosis was higher than those with good and poor prognosis (P< 0.001 and P=0.004, respectively), while the blood platelet count of the intermediate group was higher than that of the group with good prognosis (P=0.018). No significant difference was found among the three groups in terms of hemoglobin level (P> 0.05). The group with poor prognosis has attained shorter OS compared with those with good and intermediate prognosis (P< 0.001 and P=0.003, respectively). However, the CR rate of the group with good prognosis was higher than that of the intermediate group (P=0.001). For the group with intermediate prognosis, presence of genetic mutations did not correlate with the clinic characteristics such as white blood cell count, blood platelet count, hemoglobin level, OS and CR rate (P> 0.05 for all comparisons). CONCLUSION: Genetic mutations combined with cytogenetic analysis can facilitate the prognosis and personalized treatment for patients with AML.

GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and PI3K/AKT pathways.

Available therapeutic options for advanced B cell precursor acute lymphoblastic leukemia (pre-B ALL) are limited. Many lead to neutropenia, leaving patients at risk of life-threatening infections and result in bad outcomes. New treatment options are needed to improve overall survival. We previously showed that GZD824, a novel BCR-ABL tyrosine kinase inhibitor, has anti-tumor activity in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia cells and tumor models. Here, we show that GZD824 decreases cell viability, induces cell-cycle arrest, and causes apoptosis in pre-B ALL cells. Furthermore, Ph- pre-B ALL cells were more sensitive to GZD824 than Ph+ pre-B ALL cells. GZD824 consistently reduced tumor loads in Ph- pre-B ALL xenografts but failed to suppress Ph+ pre-B ALL xenografts. GZD824 decreased phosphorylation of SRC kinase, STAT3, RB and C-myc. It also downregulated the expression of BCL-XL, CCND1 and CDK4 and upregulated expression of CCKN1A. Expression of IRS1 was decreased in GZD824-treated pre-B ALL cells, blocking the PI3K/AKT pathway. These data demonstrate that GZD824 suppresses pre-B ALL cells through inhibition of the SRC kinase and PI3K/AKT pathways and may be a potential therapeutic agent for the management of pre-B ALL.

The molecular basis of targeting PFKFB3 as a therapeutic strategy against cancer.

6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatases (PFKFBs) are bifunctional enzymes which regulate the transformation between fructose-2, 6-bisphosphate (F2, 6BP) and fructose-6-phosphate (F6P) in the process of glucose metabolism. Among the four isozymes (PFKFB1-4), PFKFB3 has stronger kinase activity than phosphatase activity, resulting in the synthesis of F2, 6BP and the promotion of glycolysis. Additionally, PFKFB3 plays a key role in cell cycle regulation. It has been confirmed that PFKFB3 is upregulated in a variety of tumor cells, and inhibition of it results in suppression of the growth of tumor cells by downregulating the glycolytic flux. It is expected to release drug resistance and prevent disease progression by PFKFB3 inhibition. Recent studies have also shown that the efficacy of PFKFB3 inhibition in tumor cells is not only related to glycolysis, but also autophagy. Here, we have reviewed the biological characteristics of PFKFB3, the regulation pathway of glucose metabolism manipulated by PFKFB3, and other regulatory mechanisms in hematologic and non-hematologic malignant tumor cells.

Decitabine before Low-Dose Cytarabine-Based Chemotherapy Combined with Human Leukocyte Antigen-Mismatched Stem Cell Microtransplantation Improved Outcomes in Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia.

The optimal treatment for elderly patients with acute myeloid leukemia (AML) remains a great challenge. Establishing a more feasible, acceptable, accessible and safe treatment strategy for elderly patients is urgently needed. We conducted a prospective study of 23 elderly patients (median age, 68 years; range, 60 to 87 years) with newly diagnosed AML to evaluate the efficacy and toxicity of decitabine plus granulocyte colony-stimulating factor priming, low-dose aclarubicin, and cytarabine (DCAG) chemotherapy combined with HLA-mismatched stem cell microtransplantation (SC-MST) without graft-versus-host disease (GVHD) prophylaxis. After the first cycle, the overall response and the complete remission (CR) rates were 86.4% and 81.8%, respectively. CR was achieved in 90.9% of the normal karyotype group and in 80.0% of patients with unfavorable karyotypes at baseline. The median overall survival (OS) and disease-free survival rates were 17 and 13 months, respectively, with a 2-year OS of 34.8%. The median OS of the patients who received ≥3 cycles of SC-MST was significantly longer than those who received only 1 or 2 cycles of treatment. The regimen was well tolerated with a 4-week mortality of 4.3%, and no GVHD was observed. The most common adverse events were hematologic toxicities. Our data suggest that the innovative combination of DCAG with SC-MST may optimize the clinical strategy for elderly patients with newly diagnosed AML.

Alox5 Blockade Eradicates JAK2V617F-Induced Polycythemia Vera in Mice.

Myeloproliferative neoplasms such as polycythemia vera (PV), which are associated with the JAK mutation V617F, remain incurable despite progress in the use of JAK2 inhibitors for treatment of some of these diseases. In this study, we employed mice that undergo JAK2V617F-induced PV as a tool to explore new candidate targets for therapy. Our investigations focused on the lipid metabolic enzyme arachidonate 5-lipoxygenase (Alox5), which we found to be strongly upregulated by JAK2V617F in hematopoietic cells in vitro and in vivo Notably, genetic deletion of Alox5 or its inhibition in mice with a bioactive small-molecule inhibitor was sufficient to attenuate PV development. This therapeutic effect was associated with induction of a blockade in cell-cycle progression and also with apoptosis in PV cells. Genetic loss exerted an inhibitory effect on PV-initiating cells. Similarly, Alox5 inhibition was sufficient to suppress colony formation in human JAK2V617F-expressing CD34+ cells. Mechanistic investigations showed that Alox5 inhibition reduced AKT activation and decreased ß-catenin expression in JAK2V617F-expressing cells. Together, our results define Alox5 as a key genetic effector of JAK2V617F in driving PV, and they identify this enzyme as a candidate therapeutic target to treat this refractory myeloproliferative neoplasm. Cancer Res; 77(1); 164-74. ©2016 AACR.

TIGAR cooperated with glycolysis to inhibit the apoptosis of leukemia cells and associated with poor prognosis in patients with cytogenetically normal acute myeloid leukemia.

BACKGROUND: Cancer cells show increased glycolysis and take advantage of this metabolic pathway to generate ATP. The TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits aerobic glycolysis and protects tumor cells from intracellular reactive oxygen species (ROS)-associated apoptosis. However, the function of TIGAR in glycolysis and survival of acute myeloid leukemia cells remains unclear. METHODS: We analyzed TIGAR expression in cytogenetically normal (CN-) AML patients and the correlations with clinical and biological parameters. In vivo and in vitro, we tested whether glycolysis may induce TIGAR expression and evaluated the combination effect of glycolysis inhibitor and TIGAR knockdown on human leukemia cell proliferation. RESULTS: High TIGAR expression was an independent predictor of poor survival and high incidence of relapse in adult patients with CN-AML. TIGAR also showed high expression in multiple human leukemia cell lines and knockdown of TIGAR activated glycolysis through PFKFB3 upregulation in human leukemia cells. Knockdown of TIGAR inhibited the proliferation of human leukemia cells and sensitized leukemia cells to glycolysis inhibitor both in vitro and in vivo. Furthermore, TIGAR knockdown in combination with glycolysis inhibitor 2-DG led leukemia cells to apoptosis. In addition, the p53 activator Nutlin-3α showed a significant combinational effect with TIGAR knockdown in leukemia cells. However, TIGAR expression and its anti-apoptotic effects were uncoupled from overexpression of exogenous p53 in leukemia cells. CONCLUSIONS: TIGAR might be a predictor of poor survival and high incidence of relapse in AML patients, and the combination of TIGAR inhibitors with anti-glycolytic agents may be novel therapies for the future clinical use in AML patients.

TP53-induced glycolysis and apoptosis regulator protects from spontaneous apoptosis and predicts poor prognosis in chronic lymphocytic leukemia.

OBJECTIVES: Circulating chronic lymphocytic leukemia (CLL) cells appear not to be overly utilizing aerobic glycolysis. However, recurrent contact with CLL cells in a stromal microenvironment leads to increased aerobic glycolysis and the cells' overall glycolytic capacity, which promotes cell survival and proliferation. TP53-induced glycolysis and apoptosis regulator (TIGAR) has been directly implicated in cellular metabolism in the control of glycolysis. TIGAR inhibits glycolysis and protects cells from intracellular reactive oxygen species (ROS)-associated apoptosis. METHODS: TIGAR mRNA expression was investigated by quantitative PCR in 102 newly diagnosed CLL patients. Furthermore, the relationship between the expression of TIGAR and its clinical characteristics and prognosis were investigated. Moreover, we also investigated the correlation between TIGAR expression and apoptosis in primary CLL cells. RESULTS: Our data revealed that TIGAR overexpression was correlated with the protection from spontaneous apoptosis in CLL cells, and is strongly associated with advanced Binet stage, unmutated immunoglobulin heavy-chain variable region (IGHV) status, CD38 positivity, ß2-microglobulin and p53 aberrations. Higher expression of TIGAR was associated with shorter treatment-free survival (median: three months vs. 51 months, P=0.0108), worse overall survival (median: 74 months vs. not reached, P=0.0242), and the diverse responses to fludarabine-based chemotherapy. TIGAR expression in patients resistant to chemotherapy was significantly higher than in patients sensitive to chemotherapy (mean: 0.3859±0.1710 vs. 0.0974±0.0291, P=0.0290). CONCLUSION: Taken together, our findings revealed that high TIGAR expression is closely correlated with worse clinical outcome in CLL patients, and depicted how bioenergetic characteristics could be therapeutically exploited in CLL.

Methotrexate therapy of T-cell large granular lymphocytic leukemia impact of STAT3 mutation.

T-cell large granular lymphocytic leukemia (T-LGLL) is a rare haematologic neoplasm. Consequntly, there are no large prospective studies of therapy and no uniform therapy recommendations. We analyzed data from 36 subjects receiving methotrexate alone (N = 27) or with prednisone (N = 9) as initial therapy. 31 subjects responded (86%, 95% confidence interval [CI], 73, 95%) with 8 complete responses and 23 partial responses. Median time-to-response was 3 months (range, 1-5 months). Median response duration was 20 months (range, 2-55 months). ß2-microoglobulin (ß2-MG) and erythrocyte sedimentation rate (ESR) decreased significantly post-therapy (P < 0.0001). Pure red cell aplasia (PRCA) was present in 18 subjects (50%) of our subjects and responded well to methotrexate. 26 subjects (72%) were tested for STAT3 mutation. 9 with a mutation had a median treatment-free survival of 5 months (range, 0.5-13 months), significantly briefer than that of 17 subjects without a STAT3 mutation (19 months, range, 3-97 months; P = 0.012; log-rank test). Methotrexate with or without prednisone is an effective initial therapy of persons with T-LGLL with wild-type STAT3.

Effects of IGF-1 on neural differentiation of human umbilical cord derived mesenchymal stem cells.

AIMS: Umbilical cord derived mesenchymal stem cells (UC-MSCs) have been demonstrated to hold the potential to be applied in the treatment of kinds of disease. In recent years, some scientists have differentiated the cells into neural progenitor cells (NPCs) successfully, providing a new cell source for neural disease therapy. However, the differentiation methods still need to be improved for the clinical studies in the future. In this study, insulin-like growth factor-1 (IGF-1) was tested to ameliorate UC-MSCs neural differentiation. MAIN METHODS: IGF-1 overexpressing UC-MSCs (UC-MSCs-IGF-1) were established through retroviral infection, and further differentiated into NPCs through neural induction. The proliferation and differentiation ability of UC-MSCs derived NPCs were evaluated respectively and the associated signaling mechanisms were further analyzed with RNA microarray, qPCR and western-blot. KEY FINDINGS: Compared with NPCs from normal UC-MSCs, the NPCs derived from UC-MSCs-IGF-1 hold better proliferation ability and more Pax6-positive cells and Nestin-positive cells. Moreover, the UC-MSCs-IGF-1 derived NPCs could differentiate into astrocyte with higher efficiency during the process of terminal differentiation in vitro. RNA microarray analysis indicated that some key genes associated with neural differentiation and NPCs proliferation were upregulated, which were also confirmed with qPCR and western-blot. Finally, NPCs from UC-MSCs-IGF-1 transfected with IGF-1-siRNA showed a decrease of proliferation ability and astrocyte differentiation. SIGNIFICANCE: This study indicated that IGF-1 could improve neural differentiation of human UC-MSCs and provided a novel strategy to enhance astrocyte differentiation of NPCs from UC-MSCs.

Prognostic significance of bone marrow infiltration detected by PET-CT in newly diagnosed diffuse large B cell lymphoma.

The aim of this study was to examine the prognostic value of bone marrow involvement (BMI) assessed by baseline PET-CT (PET(0)-BMI) in treatment-naïve patients with diffuse large B-cell lymphoma (DLBCL). All patients from a single centre diagnosed as DLBCL between 2005 and 2014 had data extracted from staging PET-CT (PET(0)-CT), bone marrow biopsy (BMB), and treatment records. The PET(3)-CT (PET-CT scan after cycle 3 of immunochemotherapy) was performed on all the patients with PET(0)-BMI positivity (PET(0)-BMI(+)). Of 169 patients, 20 (11.8%) had BMI on BMB, whereas 35 (20.7%) were PET(0)-BMI positive. Among PET(0)-BMI(+) patients, patients with maximum of standard uptake value (SUVmax) of bone marrow (SUVmax(BM)) more than 8.6 were significantly associated with high IPI score (3-5) (P=0.002), worse progression-free survival (PFS) and overall survival (OS) (P=0.025 and P=0.002, respectively). In the 68 stage IV cases, 3-year OS was higher in the patients with negative PET(0)-BMI (PET(0)-BMI(-)) than that with PET(0)-BMI(+) (84.2%±6.5% vs. 44.1%±8.6%; P=0.003), while 3-year PFS only shown a trend of statistic significance (P=0.077) between the two groups. Among the 69 patients of inter-risk of IPI (2-3), patients with PET(0)-BMI(+) had significantly inferior PFS and OS than that with PET(0)-BMI(-) (P=0.009 and P<0.001, respectively). The cut-off value of the decreased percentage of SUVmax(BM) between PET(0)-CT and PET(3)-CT (ΔSUVmax(BM)) was 70.0%, which can predict PFS (P=0.003) and OS (P=0.023). These data confirmed that along with the increased sensitivity and accuracy of identifying bone marrow by PET-CT, novel prognostic values of marrow involvement were found in patients with DLBCL.

The distinct clinical features and prognosis of the CD10⁺MUM1⁺ and CD10⁻Bcl6⁻MUM1⁻ diffuse large B-cell lymphoma.

Using an immunohistochemistry (IHC) based method, diffuse large B-cell lymphoma (DLBCL) can be classified into germinal center B-cell (GCB) and non-GCB subtypes. However, the prognostic value of Hans algorithm was contradictory in the literature. Using IHC and fluorescence in situ hybridization, we analyzed the antibodies applied in Hans algorithm and other genetic factors in 601 DLBCL patients and prognostic value of Hans algorithm in 306 cases who were treated with chemoimmunotherapy. The results showed that patients with GCB subtype have better overall survival (OS) and progression-free survival (PFS) than non-GCB cases. However, to some extent, double positive (CD10(+)MUM1(+), DP) and triple negative (CD10(-)Bcl6(-)MUM(-), TN) showed different clinical characteristics and prognosis to others that were assigned to the same cell-of-origin group. The DP group showed similar OS (median OS: both not reached, P = 0.3650) and PFS (median PFS: 47.0 vs. 32.7 months, P = 0.0878) with the non-GCB group while the TN group showed similar OS (median OS: both not reached, P = 0.9278) and PFS (median PFS: both not reached, P = 0.9420) with the GCB group. In conclusion, Recognition of specific entities in Hans algorithm could help us to accurately predict outcome of the patients and choose the best clinical management for them.

Enhanced renoprotective effect of IGF-1 modified human umbilical cord-derived mesenchymal stem cells on gentamicin-induced acute kidney injury.

The therapeutic action of umbilical cord-derived mesenchymal stem cells (UC-MSCs) against acute kidney injury (AKI) has been demonstrated by several groups. However, how to further enhance the renoprotective effect of UC-MSCs and improve the therapy effect, are still unclear. In this study, we mainly investigated whether insulin-like growth factor-1 (IGF-1)-modified UC-MSCs hold an enhanced protective effect on gentamicin-induced AKI in vivo. Our results indicated that the IGF-1 overexpression could enhance the therapeutic action of human UC-MSCs, and the AKI rats treated with IGF-1-overexpressed UC-MSCs (UC-MSCs-IGF-1) showed better recovery of biochemical variables in serum or urine associated with renal function, histological injury and renal apoptosis, compared with AKI rats treated with normal UC-MSCs. RNA microarray analysis indicated that some key genes in the signal pathways associated with anti-oxidation, anti-inflammatory, and cell migratory capacity were up-regulated in UC-MSCs-IGF-1, and the results were further confirmed with qPCR. Furthermore, a series of detection in vitro and in vivo indicated that the UC-MSCs-IGF-1 hold better anti-oxidation, anti-inflammatory, and cell migratory capacity for IGF-1 overexpression. Thus, our study indicated that enhancement of UC-MSCs bioactivities with IGF-1 overexpression could increase the UC-MSCs therapeutic potential and further developed a new therapeutic strategy for the treatment of AKI.