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Prostate adenocarcinoma (CaP) patients are classified into low-, intermediate-, and high-risk groups that reflect relative survival categories. While there are accepted treatment regimens for low- and high-risk patients, intermediate-risk patients pose a clinical dilemma, as treatment outcomes are highly variable for these individuals. A better understanding of the factors that regulate the progression of CaP is required to delineate risk. For example, aberrant activation of the Hedgehog (Hh) pathway is implicated in CaP progression. Here, we identify the serine protease inhibitor protease nexin 1 (PN1) as a negative regulator of Hh signaling in prostate. Using human CaP cell lines and a mouse xenograft model of CaP, we demonstrate that PN1 regulates Hh signaling by decreasing protein levels of the Hh ligand Sonic (SHH) and its downstream effectors. Further-more, we show that SHH expression enhanced tumor growth while overexpression of PN1 inhibited tumor growth and angiogenesis in mice. Finally, using comparative genome hybridization, we found that genetic alterations in Hh pathway genes correlated with worse clinical outcomes in intermediate-risk CaP patients, indicating the importance of this pathway in CaP., Introduction Prostate adenocarcinoma (CaP) is the second leading cause of male cancer death in the Western world (1). Various risk groups (low, intermediate, high, and metastatic) that reflect relative survival [...]

Serine proteinase inhibitor, clade E member 2 (SERPINE2), also known as protease nexin-1 (PN-1), is a member of the serpin family. Despite several reported roles of SERPINE2 in tumor development the histological distribution of SERPINE2 and its expression levels in a large variety of tumors remains unclear. Through expressed sequence tag database analysis, immunohistochemical staining of tissue microarrays and a literature review, it was revealed that SERPINE2 expression varied according to growth stages and tissue types. SERPINE2 is differentially expressed in a number of tumors and their normal tissue counterparts. SERPINE2 is identified most abundantly in adenocarcinomas. SERPINE2 serves diverse roles in a variety of tumors and therefore may serve as a promising biomarker for tumor diagnosis and prognosis. [ABSTRACT FROM AUTHOR]

Objectives: Various studies have investigated the prognostic value of C-MYC aberrations in diffuse large B-cell lymphoma (DLBCL). However, the role of C-MYC as an independent prognostic factor in clinical practice remains controversial. A systematic review and meta-analysis were performed to clarify the clinical significance of C-MYC aberrations in DLBCL patients. Methods: The pooled hazard ratios (HRs) for overall survival (OS) and event-free survival (EFS) were calculated as the main effect size estimates. The procedure was conducted according to the Cochrane handbook and PRISMA guidelines, including the use of a heterogeneity test, publication bias assessment, and meta-regression, as well as subgroup analyses. Results: Twenty-four eligible studies enrolling 4662 patients were included in this meta-analysis. According to the nature of C-MYC aberrations (gene, protein, and mRNA), studies were divided into several subgroups. For DLBCL patients with C-MYC gene abnormalities, the combined HR was 2.22 (95% confidence interval, 1.89 to 2.61) for OS and 2.29 (95% confidence interval, 1.81 to 2.90) for EFS, compared to patients without C-MYC gene abnormalities. For DLBCL patients with overexpression of C-MYC protein and C-MYC mRNA, pooled HRs for OS were 2.13 and 1.62, respectively. C-MYC aberrations appeared to play an independent role among other well-known prognostic factors in DLBCL. Addition of rituximab could not overcome the inferior prognosis conferred by C-MYC. Conclusion: The present systematic review and meta-analysis confirm the prognostic value of C-MYC aberrations. Screening of C-MYC should have definite prognostic meaning for DLBCL stratification, thus guaranteeing a more tailored therapy. [ABSTRACT FROM AUTHOR]

SIL-TAL1 rearrangement is common in T-cell acute lymphoblastic leukemia (T-ALL), however its prognostic implication remains controversial. To investigate the clinical characteristics and outcome of this subtype in Chinese population, we systemically reviewed 62 patients with newly diagnosed T-ALL, including 15 patients with SIL-TAL1 rearrangement. We found that SIL-TAL1+ T-ALL was characterized by higher white blood cell count (P = 0.029) at diagnosis, predominant cortical T-ALL immunophenotype (P = 0.028) of the leukemic blasts, and a higher prevalence of tumor lysis syndrome (TLS, P<0.001) and disseminated intravascular coagulation (DIC, P<0.001), which led to a higher early mortality (P = 0.011). Compared with SIL-TAL1− patients, SIL-TAL1+ patients had shorter relapse free survival (P = 0.007) and overall survival (P = 0.002). Our NOD/SCID xenotransplantation model also demonstrated that SIL-TAL1+ mice models had earlier disease onset, higher leukemia cell load in peripheral blood and shorter overall survival (P<0.001). Moreover, the SIL-TAL1+ mice models exerted a tendency of TLS/DIC and seemed vulnerable towards chemotherapy, which further simulated our clinical settings. These data demonstrate that SIL-TAL1 rearrangement identifies a distinct subtype with inferior outcome which could allow for individual therapeutic stratification for T-ALL patients. [ABSTRACT FROM AUTHOR]

The Stress-responsive activator of p300 (Strap) is a transcription cofactor that has an important role in the control of DNA damage response through its ability to regulate p53 activity. Here, we report that Strap is inducible by heat shock and stimulates the transcription of heat-shock genes. A chromatin-associated complex involving heat-shock factor 1 (HSF1), Strap and the p300 coactivator assembles on the heat-shock protein 70 (hsp70) promoter, and Strap augments HSF1 binding and chromatin acetylation in Hsp genes, most probably through the p300 histone acetyltransferase. Cells depleted of Strap do not survive under heat-shock conditions. These results indicate that Strap is an essential cofactor that acts at the level of chromatin control to regulate heat-shock-responsive transcription. [ABSTRACT FROM AUTHOR]

Blast crisis of chronic myeloid leukemia with plasmacytoid dendritic cell phenotype associated with a rare fusion transcript, e13a3 BCR-ABL1 This 30-year-old male patient presented with a pathological fracture of the left distal femur and worsening left shoulder pain (Figure 1(A-C)). Stem cell transplantation can provide durable disease control in blastic plasmacytoid dendritic cell neoplasm: a retrospective study from the European group for blood and marrow transplantation. [Extracted from the article]

The related kinases ATM (ataxia-telangiectasia mutated) and ATR (ataxia-telangiectasia and Rad3-related) phosphorylate a limited number of downstream protein targets in response to DNA damage. Here we report a new pathway in which ATM kinase signals the DNA damage response by targeting the transcriptional cofactor Strap. ATM phosphorylates Strap at a serine residue, stabilizing nuclear Strap and facilitating formation of a stress-responsive co-activator complex. Strap activity enhances p53 acetylation, and augments the response to DNA damage. Strap remains localized in the cytoplasm in cells derived from ataxia telangiectasia individuals with defective ATM, as well as in cells expressing a Strap mutant that cannot be phosphorylated by ATM. Targeting Strap to the nucleus reinstates protein stabilization and activates the DNA damage response. These results indicate that the nuclear accumulation of Strap is a critical regulator in the damage response, and argue that this function can be assigned to ATM through the DNA damage-dependent phosphorylation of Strap. [ABSTRACT FROM AUTHOR]

Abstract We previously demonstrated the protective effect of MSCs in an adaptive transfer mouse model. However, their therapeutic potential in an allogeneic immunocompetent setting mimicking clinical context of islet transplantation remained unknown. The aim of this study was to determine whether MSCs therapy, either by itself, or combined with Rapamycin could benefit the allograft survival of fully MHC-mismatched mouse islet transplant. Combination therapy of MSCs and low-dose Rapamycin significantly prolonged the survival of islet allografts, whereas treatment of MSCs, or Rapamycin alone, had no impact. Interestingly, this protective effect was associated with an induced expansion of regulatory T cells in islet grafts and draining lymph nodes, a skewed T-cell differentiation toward immunotolerance, and a profound suppression of alloreactivity against donor antigen. Our study suggests that a combination therapy of MSCs and low-dose Rapamycin can prolong the survival and preserve the function of islet allograft in the MHC-mismatched mouse model of islet transplantation. Highlights • MSCs alone are not able to promote allogeneic islet engraft and Rapamycin has detrimental effects on islet engraftment. • MSCs combined with low-dose Rapamycin significantly prolonged the survival and enhanced the function of islet allografts. • The protective effect of combination therapy is associated with induced expansion of regulatory T cells in vivo. • The combination therapy leads to profound suppression of alloreactive response to donor specific antigen. [ABSTRACT FROM AUTHOR]

Acute Promyelocytic Leukemia (APL) is one of the most curable leukemia which shows great sensitivity to all-trans retinoic acid (ATRA) although a small number of the patients present poor prognosis and short survival. Isochromosome 17 in APL which usually bears an additional copy of RARA/PML fusion gene is considered to be a negative factor on its prognosis. Cryptic t(15;17) on i(17q) leads to an extra copy of PML/RARA rather than RARA/PML which may confer a worse prognosis. We describe here a rare APL case with complex chromosomal abnormality including isochromosome 17 bearing cryptic t(15;17) showing poor outcome. The patient lacks a classic t(15;17) and fluorescence in situ hybridization (FISH) presents 2 PML/RARA fusion signals on both long arms of the isochromosome. The patient also acquired a secondary mutation at relapse when the initial karyotype was already a complex karyotype involving chromosome 13, 17 and 22 at the same time. The poor response of this patient to traditional chemotherapy like ATRA and novel therapy like arsenic trioxide (ATO) suggests that early auto-hematological stem cell transplantation may be the choice of APL with isochromosome 17 especially with cryptic t(15;17) on i(17q). We are the first to show a clear history and evidence of FISH of these kind of cases. A small summary of cases with cryptic t(15;17) on isochromosome 17 is also made.

Ikaros6 was specifically associated with clinical and genetic features of acute lymphoblastic leukemia (ALL) and could be used for prediction of inferior survival. The present study aimed to further investigate the correlation between Ikaros6 and other prognostic factors, and to explore the novel prognosis prediction function by combining Ikaros6 and other factors in Chinese adult B-ALL. We examined the expression of Ikaros6 in 108 patients by reverse transcription polymerase chain reaction and confirmed the results by sequencing, gene scanning and real-time PCR. Ikaros6 was associated with BCR-ABL1 (P=0.010) and myeloid-associated antigens (P=0.009), but had an independent negative impact on survival. In multivariable Cox analysis, Ikaros6 was an independent prognostic marker for overall survival (P=0.013, HR=2.140), event-free survival (P=0.016, HR=1.972) and relapse-free survival (P=0.002, HR=3.636). This study indicated closed relation between BCR-ABL1, myeloid-associated antigens and Ikaros6.These three risk factors played an important role in evaluation of prognosis in Chinese adult B-ALL. Furthermore, Ikaros6 is more beneficial for the disease recurrence prediction.

Protease nexin 1 (PN1) is an endogenous serine protease inhibitor (SERPIN), expressed at high levels in the prostate, and capable of inhibiting the proliferation of prostate cancer cells. We previously showed that PN1-uPA complexes inhibited Sonic Hedgehog (SHH) signalling through engagement of the LRP receptor. Here, we describe an alternative anti-proliferative mechanism through which PN1 expression leads to apoptosis. In prostate cancer cells, increased expression of PN1 led to substantial reduction of XIAP levels and apoptosis mediated through the uPAR, but not the LRP receptor. The alterations in XIAP were effected in two ways 1) via alteration in the NF-κB pathway, a pathway known to signal XIAP transcription and 2) by promoting XIAP instability. The AKT pathway is known to phosphorylate XIAP at serine 87 leading to protein stability and PN1 expression is shown to interfere with this process. As a result of both mechanisms, programmed cell death is substantially increased. Consistent with these observations, reduced PN1 protein correlated with elevated p65/XIAP expression and with higher Gleason scores in human prostate tissue arrays. Thus, PN1 expression appears to differentially down-regulate distinct oncogenic pathways depending upon the cell surface receptor engaged by its complexes and demonstrates a novel molecular mechanism by which the protein can promote tumor cell apoptosis.

Background: Chronic myeloid leukemia (CML) with the e19a2 transcript coding for p230 is a rare disease. ABL1 kinase domain mutations in CML with the e19a2 rearrangement were seldom reported., Methods: The clinical characteristics of a 45-year-old Chinese female CML patient with e19a2 BCR/ABL1 transcript were described. The mutation on the ABL gene exons was determined by sequencing the cDNA of the μ-BCR-ABL fusion product., Results: This patient developed an acquired resistance associated with two p-BCR/ABL1 mutations (E255K and G250E) during treatment with imatinib., Conclusions: Here, we report a CML patient with e19a2 transcripts, carrying E255K and G250E mutation and experience of nilotinib treatment. The μ-BCR/ABL1 mutation should be investigated after imatinib treatment failure.

Immune escape is a fundamental trait of cancer. Dendritic cells (DC) that interact with T cells represent a crucial site for the development of tolerance to tumor antigens, but there remains incomplete knowledge about how DC-tolerizing signals evolve during tumorigenesis. In this study, we show that DCs isolated from patients with metastatic or locally advanced breast cancer express high levels of the adiponectin receptors AdipoR1 and AdipoR2, which are sufficient to blunt antitumor immunity. Mechanistic investigations of ligand-receptor interactions on DCs revealed novel signaling pathways for each receptor. AdipoR1 stimulated IL10 production by activating the AMPK and MAPKp38 pathways, whereas AdipoR2 modified inflammatory processes by activating the COX-2 and PPARγ pathways. Stimulation of these pathways was sufficient to block activation of NF-κB in DC, thereby attenuating their ability to stimulate antigen-specific T-cell responses. Together, our findings reveal novel insights into how DC-tolerizing signals evolve in cancer to promote immune escape. Furthermore, by defining a critical role for adiponectin signaling in this process, our work suggests new and broadly applicable strategies for immunometabolic therapy in patients with cancer., (©2014 American Association for Cancer Research.)

A large number of patients with advanced lymphoma become refractory or relapse after initial treatment due to the persistence of minimal residual disease. Ideal immunotherapy strategy for eradicating the minimal residual disease of lymphoma and preventing the tendency to relapse need to be developed. Here, we use a mice model mimicked the disease entities of aggressive B-cell lymphoma dynamically to analyze the host anti-lymphoma immunity during the progression of lymphoma. We have shown that STAT3 activity was gradually enhanced in host immune effector cells with the progression of lymphoma. Inhibition of the STAT3 activity with a small molecule inhibitor was able to effectively enhance the function of both host innate and adaptive immunity, and thereby delayed the progression of lymphoma. Despite the therapeutic benefits were achieved by using of the STAT3 inhibitor, disrupting of STAT3 pathway did not prevent the eventual development of lymphoma due to the presence of point mutation of β2M, which controls immune recognition by T cells. Our findings highlight the complexity of the mechanism of immune evasion; therefore a detailed analysis of genes involved in the immune recognition process should be essential before an elegant immunotherapy strategy could be conducted.

SIL-TAL1 rearrangement is common in T-cell acute lymphoblastic leukemia (T-ALL), however its prognostic implication remains controversial. To investigate the clinical characteristics and outcome of this subtype in Chinese population, we systemically reviewed 62 patients with newly diagnosed T-ALL, including 15 patients with SIL-TAL1 rearrangement. We found that SIL-TAL1(+) T-ALL was characterized by higher white blood cell count (P = 0.029) at diagnosis, predominant cortical T-ALL immunophenotype (P = 0.028) of the leukemic blasts, and a higher prevalence of tumor lysis syndrome (TLS, P<0.001) and disseminated intravascular coagulation (DIC, P<0.001), which led to a higher early mortality (P = 0.011). Compared with SIL-TAL1(-) patients, SIL-TAL1(+) patients had shorter relapse free survival (P = 0.007) and overall survival (P = 0.002). Our NOD/SCID xenotransplantation model also demonstrated that SIL-TAL1(+) mice models had earlier disease onset, higher leukemia cell load in peripheral blood and shorter overall survival (P<0.001). Moreover, the SIL-TAL1(+) mice models exerted a tendency of TLS/DIC and seemed vulnerable towards chemotherapy, which further simulated our clinical settings. These data demonstrate that SIL-TAL1 rearrangement identifies a distinct subtype with inferior outcome which could allow for individual therapeutic stratification for T-ALL patients.

Acute lymphoblastic leukemia (ALL) is a heterogeneous disorder, and primary drug resistance and relapse are thought to be the main causes for treatment failure in ALL patients. For these refractory or relapsed patients, there is an increasing demand to identify novel therapeutic approaches, which will highly rely on the use of xenotransplantation models in translational research. Given the critical role that the spleen plays in the hematopoiesis and lymphopoiesis in adult mice, intrasplenic inoculation of ALL cells into immunodeficient mice may represent a feasible route for leukemic xenotransplantation. In the present study, engraftments via intrasplenic inoculation in anti-mCD122 mAb conditioned NOD/SCID mice were achieved in 5 out of 11 cases, and the engrafted cells reconstituted a complete leukemic phenotype. The engrafted cells sustained the self-renewal capacity of leukemia-initiating cells as tested by serial xenotransplantation and can be used for evaluation of antileukemic drugs. These data suggest that the combination of intrasplenic inoculation and the targeted depletion of CD122(+) cells could provide a novel approach for the xenotransplantation of ALL cells in NOD/SCID mice. Furthermore, this model can be used for stem cell research, long-term analysis of engraftment kinetics and in vivo drug tests.

Matrix metalloproteinase-9 (MMP-9) expression is known to enhance the invasion and metastasis of tumor cells. In previous work based on a proteomic screen, we identified the serpin protease nexin-1 (PN-1) as a potential target of MMP-9. Here, we show that PN-1 is a substrate for MMP-9 and establish a link between PN-1 degradation by MMP-9 and regulation of invasion. PN-1 levels increased in prostate carcinoma cells after downregulation of MMP-9 and in tissues of MMP-9-deficient mice, consistent with PN-1 degradation by MMP-9. We identified three MMP-9 cleavage sites in PN-1 and showed that mutations in those sites made PN-1 more resistant to MMP-9. Urokinase plasminogen activator (uPA) is inhibited by PN-1. MMP-9 augmented uPA activity in the medium of PC3-ML cells by degrading PN-1. Prostate cancer cells, overexpressing PN-1 or treated with MMP-9 shRNA, had reduced cell invasion in Matrigel. PN-1 siRNA restored uPA activity and the invasive capacity. PN-1 mutated in the serpin inhibitory domain, the reactive center loop, failed to inhibit uPA and to reduce Matrigel invasion. This study shows a novel molecular pathway in which MMP-9 regulates uPA activity and tumor cell invasion through cleavage of PN-1.

Matrix metalloproteinase-9 (MMP-9) is implicated in tumor metastasis as well as a variety of inflammatory and pathological processes. Although many substrates for MMP-9, including components of the extracellular matrix, soluble mediators such as chemokines, and cell surface molecules have been identified, we undertook a more comprehensive proteomics-based approach to identify new substrates to further understand how MMP-9 might contribute to tumor metastasis. Previous proteomics approaches to identify protease substrates have depended upon differential labeling of each sample. Instead we used a label-free quantitative proteomics approach based on ultraperformance LC-ESI-high/low collision energy MS. Conditioned medium from a human metastatic prostate cancer cell line, PC-3ML, in which MMP-9 had been down-regulated by RNA interference was compared with that from the parental cells. From more than 200 proteins identified, 69 showed significant alteration in levels after depletion of the protease (>+/-2-fold), suggesting that they might be candidate substrates. Levels of six of these (amyloid-beta precursor protein, collagen VI, leukemia inhibitory factor, neuropilin-1, prostate cancer cell-derived growth factor (PCDGF), and protease nexin-1 (PN-1)) were tested in the conditioned media by immunoblotting. There was a strong correlation between results by ultraperformance LC-ESI-high/low collision energy MS and by immunoblotting giving credence to the label-free approach. Further information about MMP-9 cleavage was obtained by comparison of the peptide coverage of collagen VI in the presence and absence of MMP-9 showing increased sensitivity of the C- and N-terminal globular regions over the helical regions. Susceptibility of PN-1 and leukemia inhibitory factor to MMP-9 degradation was confirmed by in vitro incubation of the recombinant proteins with recombinant MMP-9. The MMP-9 cleavage sites in PN-1 were sequenced. This study provides a new label-free method for degradomics cell-based screening leading to the identification of a series of proteins whose levels are affected by MMP-9, some of which are clearly direct substrates for MMP-9 and become candidates for involvement in metastasis.

The Stress-responsive activator of p300 (Strap) is a transcription co-factor that has an important role in the control of DNA damage response through its ability to regulate p53 activity. Recent studies have however suggested that Strap takes on a wider role in regulating the cellular response to stress. Thus, Strap is now known to be inducible by heat shock and stimulate the transcription of heat-shock genes. A chromatin-associated complex involving heat-shock factor 1 (HSF1), Strap and the p300 co-activator assembles on the HSP70 gene promoter, and Strap augments HSF1 binding and chromatin acetylation in HSP genes, most probably through recruiting p300 acetyltransferase. Cells depleted of Strap do not survive under heat-shock conditions. It appears therefore that Strap is an essential co-factor that acts at the level of chromatin control to regulate heat-shock-responsive transcription. These recent studies underscore the central role taken on by transcription co-factors in integrating and co-ordinating different cellular stress response pathways.