Transcatheter arterial perfusion chemotherapy combined with lipiodol chemoembolization for advanced colorectal cancer complicated by obstruction.

Background: Obstruction is a common complication of advanced colorectal cancer. This study was aimed at investigating the safety, efficacy, and feasibility of transcatheter arterial perfusion chemotherapy combined with lipiodol chemoembolization for treating advanced colorectal cancer complicated by obstruction. Patients and methods: This retrospective analysis was conducted using clinical data of patients with advanced colorectal cancer who received arterial infusion chemotherapy combined with lipiodol chemoembolization treatment at our center. Treatment efficacy was evaluated in terms of obstruction-free survival and overall survival, and treatment complications were monitored. Results: Fifty-four patients with colorectal cancer complicated by obstruction were included. All patients successfully underwent transcatheter arterial infusion combined with lipiodol chemoembolization treatment. The average lipiodol dose administered was 2.62 ± 1.45 ml (0.5-5.5 ml). No serious complications such as perforation or tumor dissemination occurred. The clinical success rate was 83.3% (45/54). One month after treatment, the objective response rate (ORR) and disease control rate (DCR) were 66.67% and 88.9%, respectively. The median obstruction-free survival was 5.0 months. No serious adverse events occurred. As of the last follow-up, 6 patients survived, 44 died, and 4 were lost to follow-up. Conclusion: Our findings revealed that transcatheter arterial infusion chemotherapy combined with lipiodol chemoembolization is safe and effective for treating advanced colorectal cancer complicated by obstruction. It may serve as a new treatment strategy for patients with advanced colorectal cancer complicated by obstruction.

Development and evaluation of a human CD47/HER2 bispecific antibody for Trastuzumab-resistant breast cancer immunotherapy.

The treatment for trastuzumab-resistant breast cancer (BC) remains a challenge in clinical settings. It was known that CD47 is preferentially upregulated in HER2+ BC cells, which is correlated with drug resistance to trastuzumab. Here, we developed a novel anti-CD47/HER2 bispecific antibody (BsAb) against trastuzumab-resistant BC, named IMM2902. IMM2902 demonstrated high binding affinity, blocking activity, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and internalization degradation effects against both trastuzumab-sensitive and trastuzumab-resistant BC cells in vitro. The in vivo experimental data indicated that IMM2902 was more effective than their respective controls in inhibiting tumor growth in a trastuzumab-sensitive BT474 mouse model, a trastuzumab-resistant HCC1954 mouse model, two trastuzumab-resistant patient-derived xenograft (PDX) mouse models and a cord blood (CB)-humanized HCC1954 mouse model. Through spatial transcriptome assays, multiplex immunofluorescence (mIFC) and in vitro assays, our findings provided evidence that IMM2902 effectively stimulates macrophages to generate C-X-C motif chemokine ligand (CXCL) 9 and CXCL10, thereby facilitating the recruitment of T cells and NK cells to the tumor site. Moreover, IMM2902 demonstrated a high safety profile regarding anemia and non-specific cytokines release. Collectively, our results highlighted a novel therapeutic approach for the treatment of HER2+ BCs and this approach exhibits significant anti-tumor efficacy without causing off-target toxicity in trastuzumab-resistant BC cells.

Histone lysine demethylase KDM5B facilitates proliferation and suppresses apoptosis in human acute myeloid leukemia cells through the miR-140-3p/BCL2 axis.

The histone lysine demethylase KDM5B is frequently up-regulated in various human cancer cells. However, its expression and functional role in human acute myeloid leukemia (AML) cells remain unclear. Here, we found that the expression level of KDM5B is high in primary human AML cells. We have demonstrated that knocking down KDM5B leads to apoptosis and impairs proliferation in primary human AML and some human AML cell lines. We further identified miR-140-3p as a downstream target gene of KDM5B. KDM5B expression was inversely correlated with the miR-140-3p level in primary human AML cells. Molecular studies showed that silencing KDM5B enhanced H3K4 trimethylation (H3K4me3) at the promoter of miR-140-3p, leading to high expression of miR-140-3p, which in turn inhibited B-cell CLL/lymphoma 2 (BCL2) expression. Finally, we demonstrate that the defective proliferation induced by KDM5B knockdown (KD) can be rescued with the miR-140-3p inhibitor or enhanced by combining KDM5B KD with a BCL2 inhibitor. Altogether, our data support the conclusion that KDM5B promotes tumorigenesis in human AML cells through the miR-140-3p/BCL2 axis. Targeting the KDM5B/miR-140-3p/BCL2 pathway may hold therapeutic promise for treating human AML.

Crosstalk between colorectal CSCs and immune cells in tumorigenesis, and strategies for targeting colorectal CSCs.

Cancer immunotherapy has emerged as a promising strategy in the treatment of colorectal cancer, and relapse after tumor immunotherapy has attracted increasing attention. Cancer stem cells (CSCs), a small subset of tumor cells with self-renewal and differentiation capacities, are resistant to traditional therapies such as radiotherapy and chemotherapy. Recently, CSCs have been proven to be the cells driving tumor relapse after immunotherapy. However, the mutual interactions between CSCs and cancer niche immune cells are largely uncharacterized. In this review, we focus on colorectal CSCs, CSC-immune cell interactions and CSC-based immunotherapy. Colorectal CSCs are characterized by robust expression of surface markers such as CD44, CD133 and Lgr5; hyperactivation of stemness-related signaling pathways, such as the Wnt/ß-catenin, Hippo/Yap1, Jak/Stat and Notch pathways; and disordered epigenetic modifications, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA action. Moreover, colorectal CSCs express abnormal levels of immune-related genes such as MHC and immune checkpoint molecules and mutually interact with cancer niche cells in multiple tumorigenesis-related processes, including tumor initiation, maintenance, metastasis and drug resistance. To date, many therapies targeting CSCs have been evaluated, including monoclonal antibodies, antibody‒drug conjugates, bispecific antibodies, tumor vaccines adoptive cell therapy, and small molecule inhibitors. With the development of CSC-/niche-targeting technology, as well as the integration of multidisciplinary studies, novel therapies that eliminate CSCs and reverse their immunosuppressive microenvironment are expected to be developed for the treatment of solid tumors, including colorectal cancer.

A Quadruplex Ultrasensitive Immunoassay for Simultaneous Assessment of Human Reproductive Hormone Proteins in Multiple Biofluid Samples.

Reproductive hormones play vital roles in reproductive health and can be used to assess a woman's ovarian function and diagnose diseases associated with reproductive endocrine disorders. As these hormones are important biomarkers for reproductive health monitoring and diagnosis, a rapid, high-throughput, and low-invasive detection and simultaneous assessment of the levels of multiple reproductive hormones has important clinical applications. In this work, a quadruplex ultrasensitive immunoassay was developed for simultaneous assessment of 4 human reproductive hormone proteins (follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and anti-Müllerian hormone (AMH)) in a variety of human biofluid samples. This assay takes advantage of single-molecule imaging of microwell arrays and capture antibody beads as a reaction interface to construct multiplex bead array immunoassays. The analyte-bound beads can easily be parsed to individual wells and detected via fluorophores, emitting distinct wavelengths associated to the beads. As a result, this proposed quadruplex immunoassay exhibits four good 4-parameter logistic calibration curves ranging from 2.7 to 2000, 1.6 to 1200, 1.8 to 1300, and 0.3 to 220 pg/mL with limits of detection of 0.32, 0.28, 0.14, and 0.02 pg/mL for FSH, LH, PRL, and AMH, respectively. Furthermore, the developed quadruplex immunoassay was used to test clinical venous serum samples where it showed remarkable consistency with clinical test results in methodological comparison and the diagnosis of polycystic ovary syndrome. In addition, we successfully applied the ultrasensitive capability of this assay to the simultaneous testing and evaluation of four proteins in fingertip blood as well as urine samples, in which the urinary AMH level (1.42-156 pg/mL) was measured and assessed quantitatively for the first time.

Feasibility and tolerability of sintilimab plus anlotinib as the second-line therapy for patients with advanced biliary tract cancers: An open-label, single-arm, phase II clinical trial.

Patients with biliary tract cancer (BTC) were associated with poor prognosis and limited therapeutic options after first-line therapy currently. In this study, we sought to evaluate the feasibility and tolerability of sintilimab plus anlotinib as the second-line treatment for patients with advanced BTC. Eligible patients had histologically confirmed locally advanced unresectable or metastatic BTC and failed after the first-line treatment were recruited. The primary endpoint was overall survival (OS). Simultaneously, association between clinical outcomes and genomic profiling and gut microbiome were explored to identify the potential biomarkers for this regimen. Twenty patients were consecutively enrolled and received study therapy. The trail met its primary endpoint with a median OS of 12.3 months (95% CI: 10.1-14.5). Only four (20%) patients were observed of the grade 3 treatment-related adverse events (TRAEs) and no grade 4 or 5 TRAEs were detected. Mutation of AGO2 was correlated with a significantly longer OS. Abundance of Proteobacteria was associated with inferior clinical response. Therefore, sintilimab plus anlotinib demonstrated encouraging anti-tumor activity with a tolerable safety profile and deserved to be investigated in larger randomized trials for patients with advanced BTC subsequently.

Distinct clinical pattern of colorectal cancer patients with POLE mutations: A retrospective study on real-world data.

Objective: Studies have demonstrated an association between somatic POLE exonuclease domain mutations (EDMs) and the prognosis of colorectal cancer (CRC). However, the prognostic value of POLE non-EDMs remains unclear. This retrospective study aimed to explore the possible relationships between POLE mutation subtypes and CRC prognosis. Methods: The 272 CRC patients from the First Affiliated Hospital of Zhengzhou University (ZZ cohort) and 499 CRC patients from The Cancer Genome Atlas database (TCGA cohort) were retrospectively collected. The cases were divided into subgroups based on POLE mutation sites and microsatellite instability (MSI) status. The continuous variables were compared among three subgroups with Kruskal-Wallis tests. Pairwise comparisons between three groups were performed by Bonferroni correction method, and adjusted p < 0.05 was considered statistically significant. The categorical variables were compared with Chi-square test and Fisher's exact test. The Kaplan-Meier curves and Cox regression models were conducted to evaluate prognostic values of POLE mutations. Results: In the ZZ cohort, POLE EDMs (2.6%) were significantly associated with younger age (p = 0.018) and localized in the left colon (p = 0.001). POLE non-EDMs were significantly associated with MSI-high status (p < 0.001) and localization in the right colon (p = 0.001). In the TCGA cohort, the tumor mutation burden (TMB) of both POLE EDM tumors (p < 0.001) and POLE non-EDM tumors (p < 0.001) was significantly higher than that of POLE wild-type (WT) tumors. A similar trend was observed in the ZZ cohort, although there were no significant differences. In the ZZ cohort, the POLE EDM group had higher progression-free survival (PFS) (p = 0.002) and overall survival (OS) (p = 0.042) than the POLE non-EDM group and POLE WT group. We also report one CRC patient harboring a germline POLE mutation who received camrelizumab and exhibited long-term stable disease. Conclusion: Both POLE-EDMs and POLE non-EDMs were associated with significantly increased TMB in CRC and may be biomarkers for CRC treatment and prognosis. Current evidence does not support an effect of POLE non-EDMs on PFS and OS. A significant association between POLE EDMs and improved PFS and OS may exist, but future studies with larger sample sizes are needed. Entire coding region of the POLE gene should be screened.

Detection and clinical significance of circulating tumor cells in colorectal cancer.

Histopathological examination (biopsy) is the "gold standard" for the diagnosis of colorectal cancer (CRC). However, biopsy is an invasive method, and due to the temporal and spatial heterogeneity of the tumor, a single biopsy cannot reveal the comprehensive biological characteristics and dynamic changes of the tumor. Therefore, there is a need for new biomarkers to improve CRC diagnosis and to monitor and treat CRC patients. Numerous studies have shown that "liquid biopsy" is a promising minimally invasive method for early CRC detection. A liquid biopsy mainly samples circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), microRNA (miRNA) and extracellular vesicles (EVs). CTCs are malignant cells that are shed from the primary tumors and/or metastases into the peripheral circulation. CTCs carry information on both primary tumors and metastases that can reflect dynamic changes in tumors in a timely manner. As a promising biomarker, CTCs can be used for early disease detection, treatment response and disease progression evaluation, disease mechanism elucidation, and therapeutic target identification for drug development. This review will discuss currently available technologies for plasma CTC isolation and detection, their utility in the management of CRC patients and future research directions.

Methylation of dual-specificity phosphatase 4 controls cell differentiation.

Mitogen-activated protein kinases (MAPKs) are inactivated by dual-specificity phosphatases (DUSPs), the activities of which are tightly regulated during cell differentiation. Using knockdown screening and single-cell transcriptional analysis, we demonstrate that DUSP4 is the phosphatase that specifically inactivates p38 kinase to promote megakaryocyte (Mk) differentiation. Mechanistically, PRMT1-mediated methylation of DUSP4 triggers its ubiquitinylation by an E3 ligase HUWE1. Interestingly, the mechanistic axis of the DUSP4 degradation and p38 activation is also associated with a transcriptional signature of immune activation in Mk cells. In the context of thrombocytopenia observed in myelodysplastic syndrome (MDS), we demonstrate that high levels of p38 MAPK and PRMT1 are associated with low platelet counts and adverse prognosis, while pharmacological inhibition of p38 MAPK or PRMT1 stimulates megakaryopoiesis. These findings provide mechanistic insights into the role of the PRMT1-DUSP4-p38 axis on Mk differentiation and present a strategy for treatment of thrombocytopenia associated with MDS.

Thymosin alpha-1 blocks the accumulation of myeloid suppressor cells in NSCLC by inhibiting VEGF production.

BACKGROUND: Thymosin alpha-1 (TA) has been reported to inhibit tumor growth as an immunomodulator. However, its mechanism of action in immunosuppressive cells is unclear. The purpose of this study was to investigate whether TA can reshape the immune microenvironment by inhibiting the function of myeloid-derived suppressor cells (MDSCs) in non-small cell lung carcinoma (NSCLC). METHODS: The effects of TA on peripheral blood monocytic MDSCs (M-MDSCs) in patients with NSCLC and on the apoptosis and migration of M-MDSCs were studied. A mouse subcutaneous xenograft tumor model was constructed, and the effect of TA on M-MDSC migration was evaluated. Quantitative real-time PCR, Western blotting, flow cytometry and immunohistochemistry were used to examine the mechanism by which TA affects M-MDSCs. RESULTS: TA not only promoted the apoptosis of M-MDSCs by reducing the Bcl-2/BAX ratio but also and more importantly inhibited the migration of MDSCs to the tumor microenvironment by suppressing the production of vascular endothelial growth factor (VEGF) through the downregulation of hypoxia-inducible factor (HIF)-1α in tumor cells. CONCLUSIONS: TA may have a novel antitumor effect mediated by decreasing M-MDSC accumulation in the tumor microenvironment through reduced VEGF production.

LncRNA BC200 Promotes Esophageal Squamous Cell Cancer Migration and Invasion and Can Regulate ATF4 Expression.

Background: The main reason for esophageal squamous cell carcinoma (ESCC) treatment failure is metastasis. Little is known about the mechanisms involved in the metastasis of ESCC, and there is a lack of effective therapeutic targets. In our previous study, we found that patients with high levels of BC200 tended to have poor prognoses. Methods: First, we applied qRT-PCR to detect the expression level of BC200 in normal esophageal squamous epithelial cells and ESCC cells with different degrees of differentiation ability. Then, we changed BC200 expression by transfecting constructed lentiviruses that included BC200 shRNA (LV-BC200-shRNA, KD), negative control (CON053, NC), or BC200 gene (LV-BC200, BC200) to create BC200-deficient cell models in KYSE410 and KYSE70 cells and BC200 overexpression cell models in EC9706 cells and verified the transfection effect by qRT-PCR. Then, we examined cell migration by wound healing assay, invasion by Transwell assay, and proliferation by MTT assay and examined the metastasis ability in a xenograft mouse model. Gene expression profiling was performed to screen a panel of mRNAs following inhibition of BC200 expression. We then used ingenuity pathway analysis (IPA) to analyze the functions of the changed molecules and their interactions. The results from the microarray were validated by qRT-PCR and Western blotting. Results: In this study, we found that the expression of BC200 in poorly differentiated cell lines was significantly higher than that in well-differentiated cell lines. BC200 can significantly promote the migration and invasion but not the proliferation ability of ESCC cells in vitro and BC200 shRNA can significantly suppress tumor metastasis in vivo. Our genome-wide expression profile chip showed 406 differentially expressed genes, with 91 upregulated genes and 315 downregulated genes. The upstream regulator analysis showed that ATF4 was predicted to be strongly inhibited and 21 genes were consistently inhibited by this gene. Our qRT-PCR and Western blotting data also identified the reduced expression of ATF4 and some selected downstream genes, such as SNAIL2, GADD45A, and PSAT1, as a consequence of downregulating BC200 expression in ESCC. Conclusion: Our data showed that BC200 promoted the metastasis of ESCC cells and could regulate the expression of ATF4 and its downstream genes.

Roles of HMGB1 in regulating myeloid-derived suppressor cells in the tumor microenvironment.

Myeloid-derived suppressor cells (MDSCs) are notable contributors to the immunosuppressive tumor microenvironment (TME) and are closely associated with tumor progression; in addition, MDSCs are present in most patients with cancer. However, the molecular mechanisms that regulate MDSCs in the etiopathogenesis of human tumor immunity remain unclear. The secreted alarmin high mobility group box 1 (HMGB1) is a proinflammatory factor and inducer of many inflammatory molecules during MDSC development. In this review, we detail the currently reported characteristics of MDSCs in tumor immune escape and the regulatory role of secreted HMGB1 in MDSC differentiation, proliferation, activity and survival. Notably, different posttranslational modifications of HMGB1 may have various effects on MDSCs, and these effects need further identification. Moreover, exosome-derived HMGB1 is speculated to exert a regulatory effect on MDSCs, but no report has confirmed this hypothesis. Therefore, the effects of HMGB1 on MDSCs need more research attention, and additional investigations should be conducted.

Nanoscale dual-enzyme cascade metal-organic frameworks through biomimetic mineralization as ROS generators for synergistic cancer therapy.

Chemodynamic therapy (CDT) has been critically challenged by insufficient H2O2 in cancer tissues and inefficient reactive oxygen species (ROS) production. Herein, we have reported the facile synthesis of an efficient ROS generator (GOx@Pd@ZIF-8) that exerts synergistic anticancer activity by blocking glucose metabolism and producing ROS. Glucose oxidase (GOx) and palladium (Pd) cube nanozymes were incorporated in zeolitic imidazolate framework-8 (ZIF-8) by biomimetic mineralization. Systematic characterization indicated the successful entrapment and embedding of GOx and Pd during ZIF-8 crystal growth. The GOx@Pd@ZIF-8 composite showed favorable catalytic glucose activity and stable ROS production. In vitro experiments showed that the GOx@Pd@ZIF-8 composite effectively inhibited cancer cell proliferation, invasion, and migration and promoted apoptosis through the ROS-mediated signaling pathway, which was further confirmed by bioinformatics analyses of RNA-seq data obtained from in vitro experiments. Furthermore, the GOx@Pd@ZIF-8 composite inhibited tumor growth with few to no side effects on other tissues in vivo. This work provides a novel antitumor strategy involving the construction of a stable and highly active ROS generator that shows promise for the treatment of solid cancers.

Myeloid-derived suppressor cells-new and exciting players in lung cancer.

Lung cancer (LC) is the leading cause of cancer-related death worldwide due to its late diagnosis and poor outcomes. As has been found for other types of tumors, there is increasing evidence that myeloid-derived suppressor cells (MDSCs) play important roles in the promotion and progression of LC. Here, we briefly introduce the definition of MDSCs and their immunosuppressive functions. We next specifically discuss the multiple roles of MDSCs in the lung tumor microenvironment, including those in tumor growth and progression mediated by inhibiting antitumor immunity, and the associations of MDSCs with a poor prognosis and increased resistance to chemotherapy and immunotherapy. Finally, we also discuss preclinical and clinical treatment strategies targeting MDSCs, which may have the potential to enhance the efficacy of immunotherapy.

Long noncoding RNA DIO3OS interacts with miR-122 to promote proliferation and invasion of pancreatic cancer cells through upregulating ALDOA.

BACKGROUND: Long noncoding RNA (lncRNA) has been implicated in numerous tumors, including pancreatic cancer (PC). However, the precise cellular roles and molecular mechanisms of lncRNA DIO3OS on PC development remains to be fully clarified. METHODS: We performed the meta-analysis on PC samples and non-tumor samples retrieved from the TCGA database, and measured the levels of DIO3OS in PC cell lines and a normal pancreatic duct epithelial cell line HPDE6-C7. Cell proliferation was evaluated via CCK-8 assay. Cell invasion in vitro was investigated by transwell assay. The RNA immunoprecipitation assay and luciferase reporter assay was utilized to confirm the putative miR-122-binding site in DIO3OS. The effects of DIO3OS on PC progression were tested using in vivo subcutaneous xenografts. RESULTS: Our results showed that DIO3OS was highly expressed in human PC tissues and PC cell lines. DIO3OS exhibited oncogenic properties in stimulating PC cell proliferation and invasion in vitro and promoting cancer growth in vivo. Through online predictive tools and functional experiments, we found that DIO3OS could bind directly to microRNA-122 (miR-122) and inhibited its expression, which functioned as a tumor suppressor in PC cells. We also verified that ALDOA was the direct target of miR-122, and the tumor suppressive effects caused by DIO3OS knockdown or miR-122 overexpression could be rescued by re-expression of ALDOA in PC cells. CONCLUSIONS: Overall, our study suggested that lncRNA DIO3OS promotes PC cell growth and invasion by competing for miR-122 to modulate the expression of ALDOA. These findings yield a better understanding of the potential mechanisms by which gain of DIO3OS expression accelerates PC progression.

PRMT1-RBM15 axis regulates megakaryocytic differentiation of human umbilical cord blood CD34+ cells.

Protein arginine methyltransferase 1 (PRMT1) serves pivotal roles in various cellular processes. However, its role in megakaryocytic differentiation has not been clearly reported. The aim of the present study was to explore the role of the PRMT-RNA binding motif protein 15 (RBM15) axis in human MK differentiation and the feasibility of targeting PRMT1 for leukemia treatment. In the present study, PRMT1 was overexpressed and the RBM15 protein was knocked down in human umbilical cord blood cluster of differentiation (CD)34+ cells and the cells were then cultured in megakaryocytic differentiation medium. Flow cytometry was used to analyze CD41 and CD42 double-positive cells, as well as the protein expression levels of PRMT1 and RBM15. The results demonstrated that human cord blood CD34+ cells differentiate into mature MKs in high thrombopoitin medium, as demonstrated by CD41 and CD42 expression. Overexpression of PRMT1 in human umbilical cord blood CD34+ cells blocked the maturation of megakaryocytic cells. Knockdown of RBM15 by short hairpin RNA produced less mature MKs. PRMT1 inhibitor rescued PRMT1-blocked megakaryocytic differentiation. These results provide evidence for a novel role of PRMT1 in the negative regulation of megakaryocytic differentiation. PRMT1 may be a therapeutic target for leukemia treatment.

MMP-2 together with MMP-9 overexpression correlated with lymph node metastasis and poor prognosis in early gastric carcinoma.

The aim of this study was to correlate matrix metalloproteinase-2 and matrix metalloproteinase-9 expression with the clinicopathological features and outcome of patients with early gastric cancer and to clinically elucidate more information on the role of matrix metalloproteinase-2 and matrix metalloproteinase-9 protein overexpression with regard to lymph node metastasis of early gastric cancer. The levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 protein expression were assessed by immunohistochemistry. An association was observed between matrix metalloproteinase-2, matrix metalloproteinase-9, and matrix metalloproteinase-2/matrix metalloproteinase-9 overexpression and clinicopathological factors, such as ulceration and lymph node metastasis. Furthermore, matrix metalloproteinase-9 and matrix metalloproteinase-2/matrix metalloproteinase-9 overexpression both were strongly correlated with histological grade. In addition, matrix metalloproteinase-2/matrix metalloproteinase-9 overexpression correlated with deep invasion. Multivariate Cox regression analysis revealed that matrix metalloproteinase-2 and matrix metalloproteinase-9 expression were both independent factors of overall survival in patients with early gastric cancer. In novelty, we found that matrix metalloproteinase-2/matrix metalloproteinase-9 overexpression was an independent indicator of lymph node metastasis in early gastric cancer which will be helpful in clinic to select the appropriate treatment of these patients.

Splicing factor SF3B1K700E mutant dysregulates erythroid differentiation via aberrant alternative splicing of transcription factor TAL1.

More than 60% of myeloid dysplasia syndrome (MDS) contains mutations in genes encoding for splicing factors such as SF3B1, U2AF, SRSF2 and ZRSR2. Mutations in SF3B1 are associated with 80% cases of refractory anemia with ring sideroblast (RARS), a subtype of MDS. SF3B1K700E is the most frequently mutated site among mutations on SF3B1. Yet the molecular mechanisms on how mutations of splicing factors lead to defective erythropoiesis are not clear. SF3B1K700E mutant binds to an RNA binding protein, RBM15, stronger than the wild type SF3B1 protein in co-immunoprecipitation assays. In addition, K700E mutant alters the RNA splicing of transcription factors TAL1 and GATA1. Via alternative RNA splicing, a novel short TAL1 transcript variant (TAL1s) is generated. Enhanced interaction between SF3B1 and RBM15 promotes the production of full-length TAL1 (TAL1fl) mRNA, while reduction of RBM15 protein level via PRMT1-mediated degradation pathway changes TAL1s/TAL1fl ratio in favor of TAL1s. TAL1s contains the helix-loop-helix DNA binding domain but not the N terminal region upstream of the DNA binding domain. The TAL1s protein loses its interaction with ETO2, which represses early erythropoiesis. In this vein, overexpression of TAL1s stimulates the transcription of ß-hemoglobin in human leukemia K562 cells and promotes erythroid differentiation of human cord blood CD34+ cells cultured in erythropoietin-containing medium. Therefore, mutations of SF3B1 may block erythropoiesis via dysregulation of alternative RNA splicing of transcription factor TAL1, and targeting PRMT1 may alleviate the anemic symptoms in MDS patients.

Extranodal involvement in young patients with diffuse large B-cell lymphoma: distribution, prognostic value and treatment options.

OBJECTIVE: Extranodal involvement represents a peculiar presentation of diffuse large B-cell lymphoma (DLBCL). Previous studies have suggested that older patients are more prone to extranodal involvement. This study retrospectively addressed the distribution, prognostic value and treatment options of extranodal involvement in young patients with DLBCL. METHODS: A total of 329 patients were enrolled according to the inclusion requirements. The effects of gender, extranodal involvement, age-adjusted international prognostic index (aaIPI), rituximab infusion and radiotherapy on patient outcomes were evaluated. RESULTS: Among these patients, 59% presented extranodal involvement in 16 anatomic sites. More than one instance was linked to many poorer clinical characteristics and poorer survival compared with either nodal disease or one instance. In patients with one extranodal lesion, multivariate analysis revealed that the site of extranodal involvement, but not the aaIPI or rituximab infusion, was independently related to the outcome, and radiotherapy had a negative influence on survival. CONCLUSIONS: Extranodal involvement is common in younger patients and exhibits a ubiquitous distribution. The site of extranodal involvement is of strong prognostic significance. Radiotherapy for extranodal lesions does not improve patient outcomes.