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HDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%–35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.

Background Increasing evidence suggests that hepatitis C virus (HCV) infection is associated with non-Hodgkin’s lymphoma (NHL). However, no clear consensus has been reached about the clinical features and effective treatment of HCV-associated NHL patients. We therefore performed a systematic review and meta-analysis to explore the clinical characteristics and effectiveness of antiviral treatment or rituximab administration among NHL patients with HCV infection. Methods Eight electronic databases, including PubMed, OVID, EMBASE, Cochrane Library, ClinicalTrials, WANFANG, CNKI, and VIP, were searched for eligible studies up to July 31, 2021. The hazard ratio (HR) or odds ratio (OR) corresponding to the 95% confidence interval (CI) was calculated to estimate the outcomes. Publication bias was assessed by Egger’s and Begg’s tests. Statistical analysis was performed with RevMan 5.4 software and Stata version 15. Results There were 27 shortlisted articles out of a total of 13,368 NHL patients included in the current meta-analysis. Our results demonstrated that NHL patients with HCV infection had a significantly shorter overall survival (OS: HR 1.89; 95% CI 1.42–2.51, P Conclusions The current study provided compelling evidence about an inferior prognosis and distinct clinical characteristics among HCV-associated NHL patients. Antiviral treatment and rituximab-containing regimens were shown to be efficacious in improving the clinical outcomes of NHL patients with HCV infection.

Ribosome biogenesis is a fundamental activity in cells. Ribosomal dysfunction underlies a category of diseases called ribosomopathies in humans. The symptomatic characteristics of ribosomopathies often include abnormalities in craniofacial skeletons, digestive organs, and hematopoiesis. Consistently, disruptions of ribosome biogenesis in animals are deleterious to embryonic development with hypoplasia of digestive organs and/or impaired hematopoiesis. In this study, ltv1, a gene involved in the small ribosomal subunit assembly, was knocked out in zebrafish by clustered regularly interspaced short palindromic repeats (CRISPRs)/CRISPR associated protein 9 (Cas9) technology. The recessive lethal mutation resulted in disrupted ribosome biogenesis, and ltv1Δ14/Δ14 embryos displayed hypoplastic craniofacial cartilage, digestive organs, and hematopoiesis. In addition, we showed that the impaired cell proliferation, instead of apoptosis, led to the defects in exocrine pancreas and hematopoietic stem and progenitor cells (HSPCs) in ltv1Δ14/Δ14 embryos. It was reported that loss of function of genes associated with ribosome biogenesis often caused phenotypes in a P53-dependent manner. In ltv1Δ14/Δ14 embryos, both P53 protein level and the expression of p53 target genes, Δ113p53 and p21, were upregulated. However, knockdown of p53 failed to rescue the phenotypes in ltv1Δ14/Δ14 larvae. Taken together, our data demonstrate that LTV1 ribosome biogenesis factor (Ltv1) plays an essential role in digestive organs and hematopoiesis development in zebrafish in a P53-independent manner.

FMS-like tyrosine kinase 3 (FLT3) mutant acute myeloid leukemia (AML) occurs in approximately 30% of all AML patients and still has a poor prognosis. This study is directed to investigate gilteritinib in combination with homoharringtonine (HHT) on FLT3-ITD-mutant AML cell lines. In our study, we found that cell proliferation was dramatically suppressed by the combination of gilteritinib and HHT. This combination therapy decreased the mitochondrial membrane potential, finally inducing apoptosis. We demonstrated that gilteritinib downregulated the expression of FLT3 and downstream signaling, further decreased the mRNA level of myeloid cell leukemia-1 (Mcl-1). HHT and combination therapy could upregulate UBE2L6, which induced the degradation of Mcl-1 via ubiquitin-proteasome system. Knockdown of UBE2L6 could protect Mcl-1 from deprivation through the ubiquitin-proteasome system. These findings may provide a novel theoretical basis for the treatment of AML patients with FLT3-ITD mutations.

Habitat use of the tapertail anchovy (Coilia mystus Linnaeus, 1758) from the Oujiang River Estuary and the Zhujiang (Pearl) River Estuary was studied by examining the environmental signatures of Sr and Ca in otoliths using electron probe microanalysis. Individuals from the Oujiang River had higher and varied Sr:Ca ratios (expressed as (Sr:Ca)×1 000, 3.83-13.0 average) in the otolith core regions, suggesting that they were born in brackish or sea waters, and that a freshwater habitat might not be necessary for egg hatching and larval growth. While, individuals from the Zhujiang River had lower Sr:Ca ratios (0.39–2.51 average) in the core regions, suggesting a freshwater origin. After hatching, anchovies from the Zhujiang River migrate downstream to the river estuary close to brackish water. Our results demonstrated varied habitat use for spawning during stages of early life history between the two populations, and suggested that such variations are promoting diversity of life history strategies of this species.

Summary: The seasonal patterns of the denitrifiers (denitrifying bacteria) in the sediment of Daya Bay, southern China, were examined using quantitative PCR and high-throughput MiSeq sequencing methods in spring, summer and winter. The abundance and diversity of nirS-encoding denitrifiers were much higher than that of nirK-encoding denitrifiers, indicating that the former probably dominated the denitrification processes in sediments of Daya Bay. The average abundance and diversity of nirS-encoding denitrifiers were much higher in spring than that in summer and winter, on the other hand, the abundance of nirK-encoding denitrifiers showed the opposite pattern. The species composition of nirS-encoding denitrifiers community in spring differed significantly from that in summer and winter, whereas, no significant difference existed between summer and winter. The dominant environmental drivers for the diversity of community species were NO2−, NO3− and DO concentrations. The abundances of dominant genera of nirS- encoding denitrifiers, Accumulibacter sp. and Cuprizvidus sp., were significantly higher in summer and winter than that in spring, and were negatively correlated with NO2−, NO3−, and DO concentrations (p

GenX, a substitute for perfluorooctanoic acid, has been widely detected in surface water. Due to its bioaccumulation, toxicity and persistence, GenX can cause adverse effects such as oxidative damage on aquatic organisms. To investigate the toxicity of GenX and the anti-oxidant mechanism of algae under acute exposure, the growth, photosynthetic activity and gene expression of Chlorella pyrenoidosa (C. pyrenoidosa) were tested. Results showed that the growth of C. pyrenoidosa was inhibited under acute GenX exposure. The toxicity of GenX increased with time and concentration but was lower than that of the traditional perfluoroalkyl and polyfluoroalkyl substances (PFASs). Furthermore, with the increase of GenX concentration, the production of reactive oxygen species increased, while the level of the anti-oxidant enzyme first increased and then decreased. Changes in photosynthetic parameters also indicated that the photosynthetic system of C. pyrenoidosa was negatively affected by GenX exposure. Transcription analysis revealed that the up-regulation of genes related to the glutathione-ascorbate cycle and photosynthesis is a positive strategy to cope with the oxidative stress caused by acute GenX exposure. Our findings provide new insights into the interactions between emerging PFASs and aquatic organisms at the molecular level.

The polar body, with haploid DNA, is a small cell produced during the meiosis of an oocyte. Here, we describe the detailed procedures for the detection of the second polar body in zebrafish (Danio rerio) embryos after 10 min post fertilization. A polar body can be easily distinguished as a small dot with a DAPI-stained nucleus surrounded by Phalloidin-labeled F-actin in each fertilized zebrafish embryo.

The hepatopancreatic duct (HPD) system links the liver and pancreas to the intestinal tube and is composed of the extrahepatic biliary duct, gallbladder, and pancreatic duct. Haematopoietically expressed-homeobox (Hhex) protein plays an essential role in the establishment of HPD; however, the molecular mechanism remains elusive. Here, we show that zebrafish hhex-null mutants fail to develop the HPD system characterized by lacking the biliary marker Annexin A4 and the HPD marker sox9b. The hepatobiliary duct part of the mutant HPD system is replaced by an intrahepatic intestinal tube characterized by expressing the intestinal marker fatty acid-binding protein 2a (fabp2a). Cell lineage analysis showed that this intrahepatic intestinal tube is not originated from hepatocytes or cholangiocytes. Further analysis revealed that cdx1b and pdx1 are expressed ectopically in the intrahepatic intestinal tube and knockdown of cdx1b and pdx1 could restore the expression of sox9b in the mutant. Chromatin-immunoprecipitation analysis showed that Hhex binds to the promoters of pdx1 and cdx1b genes to repress their expression. We therefore propose that Hhex, Cdx1b, Pdx1, and Sox9b form a genetic network governing the patterning and morphogenesis of the HPD and digestive tract systems in zebrafish.

Introduction: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. In the global phase 3 ALCYONE trial, the addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) resulted in improved outcomes over bortezomib, melphalan, and prednisone (VMP) alone in transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). At a median follow-up of 16.5 months, the median progression-free survival (PFS) was not reached (NR) for the D-VMP group versus 18.1 months for the VMP group (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.38-0.65; P Methods: Eligible pts in OCTANS and ALCYONE were ≥18 years of age, had NDMM, and were not eligible for autologous stem cell transplant due to age (≥65 years) or comorbidities. All pts received up to 9 (42-day) cycles of bortezomib 1.3 mg/m 2 subcutaneously twice weekly on Weeks 1, 2, 4, and 5 of Cycle 1 and once weekly on Weeks 1, 2, 4, and 5 of Cycles 2-9; melphalan 9 mg/m 2 orally once daily on Days 1-4 of each cycle; and prednisone 60 mg/m 2 orally once daily on Days 1-4 of each cycle. For pts in the D-VMP group, daratumumab 16 mg/kg intravenously was administered once weekly in Cycle 1, once every 3 weeks in Cycles 2-9, and once every 4 weeks thereafter until disease progression or unacceptable toxicity. Cytogenetic risk was determined at baseline via local fluorescence in situ hybridization or karyotype analysis; pts with high cytogenetic risk had a del17p, t(4;14), or t(14;16) abnormality. Results: In total, 220 Asian pts were randomized (D-VMP, n=146; VMP, n=74) in the OCTANS study and 706 global pts were randomized (D-VMP, n=350; VMP, n=356) in the ALCYONE study. The median age was 69 (range, 57-84) years in OCTANS and 71 (range 40-93) years in ALCYONE. Among pts with available cytogenetic results, 48/219 (21.9%) pts in OCTANS and 98/616 (15.9%) pts in ALCYONE had high-risk cytogenetic abnormalities. At a median follow-up of 12.3 months in OCTANS and 16.5 months in ALCYONE, in the pooled intent-to-treat (ITT) population from OCTANS and ALCYONE, the estimated 12-month PFS rate was 86.2% in the D-VMP group (n=496) versus 74.6% in the VMP group (n=430), and the estimated 18-month PFS rate was 73.3% versus 50.3%, respectively; the median PFS was NR in the D-VMP group versus 18.1 months in the VMP group (HR, 0.48; 95% CI, 0.38-0.61; P Conclusion: In a pooled analysis of Asian pts from OCTANS and global pts from ALCYONE, D-VMP demonstrated clinical benefit versus VMP in transplant-ineligible pts with NDMM. The benefit of D-VMP versus VMP was observed across clinically relevant subgroups. These results support the use of D-VMP in transplant-ineligible pts with NDMM. Figure 1 Figure 1. Disclosures Kim: BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Li: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Chim: Janssen, Takeda & Amgen: Other: received sponsorship for overseas meetings. Rodriguez-Otero: Clínica Universidad de Navarra: Current Employment; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria. Dimopoulos: Takeda: Honoraria; BMS: Honoraria; Janssen: Honoraria; Beigene: Honoraria; Amgen: Honoraria. Wroblewski: Janssen: Current Employment, Current equity holder in publicly-traded company. Carson: Janssen: Current Employment. Qi: Janssen: Current Employment, Current equity holder in publicly-traded company. Wang: Janssen: Current Employment. Song: Janssen: Current Employment. Jia: Janssen: Current Employment. Yang: Janssen: Current Employment, Current equity holder in publicly-traded company. Liu: Janssen: Ended employment in the past 24 months. Li: Janssen: Current Employment. Zhang: Janssen: Current Employment. Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

Introduction: Daratumumab is a human IgGκ monoclonal antibody that targets CD38 with a direct on-tumor and immunomodulatory mechanism of action. In the primary analysis (median follow-up, 16.5 months) of the global phase 3 ALCYONE trial, daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) significantly improved progression-free survival (PFS) versus VMP alone in patients with newly diagnosed multiple myeloma (NDMM) who were ineligible for transplant (median PFS, not reached vs 18.1 months; hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.38-0.65; P Methods: Eligible patients in OCTANS and ALCYONE were ≥18 years of age, were diagnosed with NDMM, and were not eligible for autologous stem cell transplant due to age (≥65 years) or comorbidities. All patients received up to 9 cycles (42-days) of bortezomib (1.3 mg/m 2; subcutaneous) twice weekly on Weeks 1, 2, 4, and 5 of Cycle 1 and once weekly on Weeks 1, 2, 4, and 5 of Cycles 2 to 9; melphalan (9 mg/m 2; oral) once daily on Days 1 to 4 of each cycle; prednisone (60 mg/m 2; oral) once daily on Days 1 to 4 of each cycle. For patients in the D-VMP group, daratumumab (16 mg/kg, intravenous) was administered once weekly in Cycle 1, once every 3 weeks in Cycles 2 to 9, and once every 4 weeks thereafter until disease progression or unacceptable toxicity. Response over time (at 6, 12, 18, 24, 54 weeks) and disease progression were assessed by a validated computer algorithm in accordance with the IMWG criteria. Minimal residual disease (MRD) negativity (10 -5) was assessed by multi-parameter flow cytometry in OCTANS and by next-generation sequencing in ALCYONE. Results: In the OCTANS study, 220 Asian patients were randomized (D-VMP, n=146; VMP, n=74); in the ALCYONE study, 706 global patients were randomized (D-VMP, n=350; VMP, n=356). Median age in OCTANS was 69 (range, 57-84) years and 71 (range 40-93) years in ALCYONE. Patients were pooled from both studies (D-VMP, n=496; VMP, n=430). D-VMP increased the rate of complete response or better (≥CR; 10.2% vs 5.6%) and the rate of very good partial response or better (≥VGPR; 58.5% vs 38.1%) versus VMP after 18 weeks of treatment (Figure A). Responses deepened over time among patients in both the D-VMP and VMP groups, as shown by the ≥CR rate (D-VMP, 38.8%; VMP, 21.6%) and the ≥VGPR rate (D-VMP, 74.0%; VMP, 50.7%) at 54 weeks. At a median follow-up of 12.3 months for OCTANS and 16.5 months for ALCYONE, among patients who achieved a VGPR (D-VMP: n=145 [29.2%]; VMP: n=109 [25.3%]), the median PFS was not reached in the D-VMP group versus 19.9 months in the VMP group (HR, 0.61; 95% CI, 0.36-1.00; P=0.0499; Figure B). All patients who achieved ≥CR with or without MRD negativity (10 -5) demonstrated prolonged PFS, regardless of treatment (≥CR: HR, 1.54; 95% CI, 0.65-3.65; P=0.3210; ≥CR+MRD negativity: HR, 0.67; 95% CI, 0.13-3.40; P=0.6225; Figure B); however, more patients treated with D-VMP achieved this level of response (≥CR: D-VMP , n=212 [42.7%]; VMP, n=100 [23.3%]; ≥CR+MRD negativity: D-VMP, n=116 [23.4%]; VMP, n=27 [6.3%]; Figure B). Conclusion: In a pooled analysis of OCTANS and ALCYONE, more patients with transplant-ineligible NDMM achieved deeper responses with D-VMP versus VMP. More patients treated with D-VMP achieved ≥CR with or without MRD negativity compared with those treated with VMP alone, leading to prolonged PFS regardless of treatment. These results support the use of daratumumab in addition to VMP in transplant-ineligible Asian patients with NDMM. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding. Kim: BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Li: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Chim: Janssen, Takeda & Amgen: Other: received sponsorship for overseas meetings. Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria; Clínica Universidad de Navarra: Current Employment. Liberati: abbvie, amgen, archigen, beigene, BMS, celgene, DR REDDY'S LABORATORIES SPA, fibrogen, glaxo, Janssen, Karyopharm, Morphosys, Novartis, Onconova, Oncopeptides ab, Roche, Sanophi, Secura Bio, Takeda, Verastem,: Research Funding. Takamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; SRL: Consultancy; Adaptive Biotechnologies, Eisai: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Dimopoulos: BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Wroblewski: Janssen: Current Employment, Current equity holder in publicly-traded company. Carson: Janssen: Current Employment. Qi: Janssen: Current Employment, Current equity holder in publicly-traded company. Wang: Janssen: Current Employment. Song: Janssen: Current Employment. Jia: Janssen: Current Employment. Yang: Janssen: Current Employment, Current equity holder in publicly-traded company. Liu: Janssen: Ended employment in the past 24 months. Li: Janssen: Current Employment. Zhang: Janssen: Current Employment.

Background Daratumumab (DARA), a human IgGκ monoclonal antibody targeting CD38, is approved by the FDA and EMA for the treatment of newly diagnosed multiple myeloma (NDMM) in combination with standard-of-care regimens. DARA in combination with VMP (D-VMP) was approved based on results of the phase 3 ALCYONE trial. The phase 3 OCTANS study investigated the efficacy and safety of D-VMP in Asian NDMM patients (NCT03217812). Here, we present a subgroup analysis of D-VMP in Chinese patients in OCTANS. Methods Asian patients with NDMM who were ineligible for ASCT were randomized (2:1) to D-VMP or VMP. Patients received 9 (42-day) cycles of bortezomib (1.3 mg/m2 SC) twice weekly in Cycle 1 (Weeks 1, 2, 4, 5) then once weekly (QW) in Cycles 2-9 (Weeks 1, 2, 4, 5); melphalan (9 mg/m2 PO) and prednisone (60 mg/m2 PO) once daily on Days 1-4 of each cycle. DARA (16 mg/kg IV) was administered to patients in the D-VMP arm QW in Cycle 1, Q3W in Cycles 2-9, and Q4W thereafter until disease progression or unacceptable toxicity. The primary endpoint was the very good partial response or better (≥VGPR) rate. Key secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and safety. Minimal residual disease (MRD) negativity (10–5) rate was an exploratory endpoint. Results A total of 167 Chinese patients were enrolled (D-VMP [n=114]; VMP [n=53]). Baseline characteristics were balanced between arms; median age was 69 (range, 57-81) years and 35 (21.0%) patients had high-risk cytogenetics. At the time of data analysis (clinical cutoff 2 July 2020), 31 (27.2%) patients in the D-VMP arm had discontinued treatment vs 19 (36.5%) patients in the VMP arm. At a median follow-up of 12.3 (range, 0-29.3) months for the overall study population, ≥VGPR rate was significantly improved with D-VMP vs VMP (74.6% vs 45.3%; odds ratio, 3.51; 95% CI 1.76-7.00; P=0.0003). ORR was 90.4% with D-VMP and 83.0% with VMP. Patients in the D-VMP arm achieved significantly higher MRD-negativity rates (29.8% vs 5.7%; P=0.0003). Median PFS was not reached with D-VMP vs 18.2 months with VMP (HR 0.41; 95% CI 0.21-0.78; P=0.0049); the estimated 12-month PFS rate was 83.4% vs 62.6%, respectively. The most frequent (≥10%) grade 3/4 treatment-emergent adverse events (TEAEs) for the D-VMP/VMP arms were thrombocytopenia (47.4%/44.2%), leukopenia (39.5%/48.1%), lymphopenia (38.6%/28.8%), neutropenia (37.7%/51.9%), pneumonia (32.5%/17.3%), anemia (26.3%/25.0%), hypokalemia (16.7%/3.8%), and hypertension (10.5%/11.5%). Infusion-related reactions occurred in 36 (31.6%) patients, the majority of which were mild. A total of 5 TEAE-related deaths (D-VMP, n=3; VMP, n=2) were reported. Conclusion The addition of DARA to VMP significantly improved efficacy in Chinese NDMM patients and showed a safety profile consistent with the global ALCYONE trial. No new safety concerns were identified. These data support the use of D-VMP for the treatment of Chinese NDMM patients.

We aimed to evaluate the efficacy of five oral nucleos(t)ide analogues (NAs), including lamivudine, entecavir, adefovir, telbivudine and tenofovir, for the prevention of hepatitis B virus (HBV) reactivation and HBV-related complications in chronic hepatitis B virus (CHB) infected patients with hematological malignancies receiving chemotherapy or hematopoietic stem cell transplantation (HSCT) by network meta-analysis.The search identified 28 articles involving 5 different prophylactic regimens covering 1478 participants.Among five prophylactic regimes, tenofovir (predicted probability, 90%), was the most effective intervention followed by entecavir (88%) in preventing HBV reactivation. There was no significant difference between tenofovir and entecavir for preventing HBV reactivation. With regards to other outcomes, tenofovir and telbivudine was not included to evaluate due to lack of relevant studies. Entecavir was the most effective intervention in reducing the risk of HBV related hepatitis (100%), HBV related death (61%) and all other causes of hepatitis (98%).Tenofovir and entecavir might be the most potent regimes in prevention of HBV reactivation for CHB infected patients with hematological malignancies undergoing chemotherapy or HSCT.

Objective: Outcome of patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) remains poor, highlighting the need for novel treatment regimens. Lenalidomide is an immunomodulatory drug that could reverse rituximab refractoriness in lymphoma patients. This study aimed to explore the efficacy and safety of lenalidomide, rituximab combined with second-line chemotherapy (R2-chemo) in patients with r/r DLBCL. Methods: In this study, r/r DLBCL patients received R2-chemo as second-line salvage therapy. The treatment plan was as follows: lenalidomide 10mg/day, day 1-14; rituximab 375mg/m2, day 1; chemo-regimen in combination with R2 as per Investigator's discretion. The overall response rate (ORR), complete remission rate (CR rate), duration of remission (DOR), disease-free survival (PFS) and overall survival (OS) were evaluated. Results: As of Aug 1, 2020, 15 patients with r/r DLBCL were enrolled in this study with median age 65 years (range, 49 to 74 years), and 60% female. 20% (3/15) was transformed DLBCL, 33.3% (5/15) was relapse and 46.7% (7/15) had refractory disease. All received at least 1 prior line of immune-chemotherapy including rituximab, and 1 case was recurrence after autologous hematopoietic stem cell transplantation. 6.7% (1/15) had double-hit lymphoma, 66.7% (10/15) had MYC or BCL-2 high expression by IHC, of whom 26.7% (4/15) had co-expression of the MYC and BCL2. Cell of origin features using the Hans algorithm: 26.7% (4/15) were GCB, and 73.3% (11/15) were non-GCB. The chemo-regimens in combination with R2 were as follows: 5 cases of GEMOX or GCD, 7 cases of DICE or ICE, 2 cases of DHAP, 1 case of CHOPE regimen. As of the cutoff date, 13 cases were evaluable for efficacy. The ORR (CR+PR) was 61.5%, with 53.8% achieving a CR, and the median DOR was 9.7m (range, 2.9 to 23.7m). With a median time to follow-up of 15.3m (95%CI, 12.2 to 18.4m), median PFS and OS had not yet reached. The estimated 2-year PFS and OS rates were 53.8% and 75.2%, respectively. The most common treatment-related adverse event was hematological toxicity, and no treatment-related deaths occurred. Conclusion: The R2 combined with second-line salvage chemotherapy regimen has a significant efficacy in the treatment of patients with r/r DLBCL, and can be well- tolerated with no significant additive toxicities. The efficacy and safety of this regimen and the choice of chemo-regimen as an optimal combination partner for R2 need to be further verified by prospective clinical studies with a larger sample size. Figure Disclosures No relevant conflicts of interest to declare.

Ikzf1 is a Kruppel-like zinc-finger transcription factor that plays indispensable roles in T and B cell development. Although the function of Ikzf1 has been studied extensively, the molecular mechanism underlying T lymphopoiesis remains incompletely defined during the embryonic stage. Here we report that the genetic ablation of ikzf1 in mutant zebrafish resulted in abrogated embryonic T lymphopoiesis. This was ascribed to impaired thymic migration, proliferation, and differentiation of hematopoietic stem/progenitor cells (HSPCs). Ccr9a and Irf4a, two indispensable factors in T lymphopoiesis, were the direct targets of Ikzf1 and were absent in the ikzf1 mutants. Genetic deletion of either ccr9a or irf4a in the corresponding mutant embryos led to obvious T cell development deficiency, which was mainly caused by disrupted thymic migration of HSPCs. Restoration of ccr9a in ikzf1 mutants obviously promoted HSPC thymus homing. However, the HSPCs then failed to differentiate into T cells. Additional replenishment of irf4a efficiently induced HSPC proliferation and T cell differentiation. Our findings further demonstrate that Ikzf1 regulates embryonic T lymphopoiesis via Ccr9 and Irf4 and provide new insight into the genetic network of T lymphocyte development.

Myosin phosphatase targeting subunit 1 (Mypt1) is the regulatory subunit of myosin phosphatase which dephosphorylates the light chain of myosin II to inhibit its contraction. Although biochemical properties of Mypt1 have been characterized in detail, its biological functions in organisms are not well understood. The zebrafish mypt1 sq181 allele was found defective in the ventral pancreatic bud and extrapancreatic duct development, resulting in dysplasia of exocrine pancreas. In mypt1 sq181 mutant, the early growth of the ventral pancreatic bud was initiated but failed to expand due to impaired cell proliferation and increased cell apoptosis. As Mypt1 is essential for cell migration, the loss-of-function of Mypt1 in the mutant disrupted the lateral plate mesoderm migration during gut looping, therefore, altering the Bmp2a expression pattern within it, and eventually leading to impaired Bmp signaling in the adjacent exocrine pancreas. Overexpression of bmp2a could rescue the development of exocrine pancreas, suggesting that the impaired Bmp2a signaling is responsible for the pancreatic development defects. Bmp2a has been reported to promote the early specification of the ventral pancreatic bud, and our study reveals that it continues to serve as a cell proliferation/survival signal to ensure pancreatic bud growth properly in zebrafish.

The mechanisms that ensure fertilization of egg by a sperm are not fully understood. In all teleosts, a channel called the ‘micropyle’ is the only route of entry for sperm to enter and fertilize the egg. The micropyle forms by penetration of the vitelline envelope by a single specialized follicle cell, the micropylar cell. The mechanisms underlying micropylar cell specification and micropyle formation are poorly understood. Here, we show that an effector of the Hippo signaling pathway, the Transcriptional co-activator with a PDZ-binding domain (Taz), plays crucial roles in micropyle formation and fertilization in zebrafish (Danio rerio). Genome editing mutants affecting taz can grow to adults. However, eggs from homozygous taz females are not fertilized even though oocytes in mutant females are histologically normal with intact animal-vegetal polarity, complete meiosis and proper ovulation. We find that taz mutant eggs have no micropyle. Taz protein is specifically enriched in mid-oogenesis in the micropylar cell located at the animal pole of wild type oocyte, where it might regulate the cytoskeleton. Taz protein and micropylar cells are not detected in taz mutant ovaries. Our work identifies a novel role for the Hippo/Taz pathway in micropylar cell specification in zebrafish, and uncovers the molecular basis of micropyle formation in teleosts., Author summary In many fish, sperm enters eggs through a specialized channel called the ‘micropyle’. The micropyle is formed by a special follicle cell, the ‘micropylar cell’, which sits on the top of the developing egg during oogenesis, and forms the sperm entry canal. The underlying mechanisms of this process are unknown. We find that Taz, an effector of an important signaling pathway, the Hippo pathway, is specifically enriched in micropylar cells in zebrafish, and regulates formation of the micropyle. Loss of Taz function in females results in no micropylar cells, failure to form a micropyle on eggs, which are consequently, not fertilized. Our study identifies a new role for the Hippo/Taz pathway in cell fate specification in the ovary, and reveals a potential mechanism for forming the sperm entry port. Similar mechanisms might operate in other fish as well.

Follicular dendritic cell sarcoma (FDCS) is a rare lymphoid neoplasm with indolent clinical process. However, we presented here a rare case of FDCS in aggressive pace. The case was a 48-year-old female complaining of dysphagia for half a year. She was found gastric fundus bulge under gastroscopy and diagnosed as low-differentiated gastric adenocarcinoma in the local hospital. After three courses of chemotherapy with paclitaxel combined with oxaliplatin and 5-fluorouracil, PET-CT showed progressive disease (PD) with not only gastric bulk but also invasion to the liver and multiple lymph nodes in the abdomen. The patient was admitted to the Department of Surgery of our hospital. Total gastrectomy and liver tumor resection were performed and postoperative pathology demonstrated FDCS. The patient was transferred to our department for chemotherapy. After three courses of CHOP, PET-CT showed tumor in the anastomotic site, partial liver resection margin and left adrenal gland. The patient was sent for radiotherapy. After radiation, PET-CT demonstrated PD and the puncture of left supraclavicular lymph node confirmed FDCs. Thalidomide and prednisone were given orally. At the same time, the whole exome sequencing (WES) was performed, based on which therapy response index (TRI) was analyzed by Cellworks software. According to TRI, the regimen of etoposide, carboplatin, bendamustine and chidamide was chosen for the patient. After the chemotherapy, the patient developed repeated vomiting and diarrhea. Abdominal CT showed intussusception and intestinal obstruction. She was sent for gastrointestinal surgery to relieve obstruction and postoperative pathology again confirmed FDCS. However, her abdominal pain and diarrhea occurred again one month after operation. The patient was discharged voluntarily and went to local hospital for supportive care. During a year from the onset to abandon of tumor therapy, the case was administered operation, radiotherapy and chemotherapy. The regimens of chemotherapy included paclitaxel-based chemotherapy for solid tumors, CHOP for lymphoma, and formulated regimen according to the analysis of WES. However, all of these therapeutic strategies were unable to control the progress of her disease. Hitherto, there is no guideline or consensus to guide the treatment of FDCS. The diagnosis and treatment process of this relapsed and refractory case can provide reference for clinicians to manage FDCS. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: FDCS of this case was in the aggressive manner. Routine therapeutic strategies, including operation, radiotherapy and chemotherapy based on paclitaxel or CHOP, were not able to control the progress. Therefore, the whole exome sequencing (WES) was performed, based on which therapy response index (TRI) was analyzed by Cellworks software. According to TRI, the regimen of etoposide, carboplatin, bendamustine and chidamide was chosen for the patient under the consent of her and her family for off-label use.

The hepatopancreatic duct (HPD) system links the liver and pancreas to the intestinal tube and is composed of the extrahepatic biliary duct, gallbladder and pancreatic duct. Haematopoietically-expressed-homeobox (Hhex) protein plays an essential role in the establishment of HPD, however, the molecular mechanism remains elusive. Here we show that zebrafish hhex-null mutants fail to develop the HPD system characterized by lacking the biliary marker Annexin A4 and the HPD marker sox9b. The mutant HPD system is replaced by an intrahepatic intestinal tube characterized by expressing the intestinal marker fatty-acid-binding–protein 2a (fabp2a). Cell lineage analysis showed that this intrahepatic intestinal tube is not originated from hepatocytes or cholangiocytes. Further analysis revealed that cdx1b and pdx1 were expressed ectopically in the intrahepatic intestinal tube and knockdown of cdx1b and pdx1 restored the expression of sox9b in the mutant. Chromatin-immunoprecipitation analysis shows that Hhex binds to the promoters of pdx1 and cdx1b genes to repress their expression. We therefore propose that Hhex, Cdx1b and Pdx1 form a genetic network governing the patterning and morphogenesis of the HPD and digestive tract systems in zebrafish.

This paper represents the first effort to study the environmental Sr and Ca signatures in otolith of spinyhead croaker Collichthys lucidus, an economically important sciaenid fish in China, by means of Electron Probe Microanalysis. Results from life-history transect analyses and X-ray intensity maps suggested that all croakers in this study collected from the Yangtze River Estuary were estuarine-resident individuals, in contrast to previous reports that C. lucidus is a marine fish. However, the high Sr core suggested that the stimulation of relatively high salinity water seemed to be required for spawning, embryogenesis and early larval growth of C. lucidus.

Background: Multiple myeloma (MM) is the second most common hematological malignancy. This disease remains incurable as nearly all patients will relapse and become refractory to established MM therapy. Thus, new treatment option for relapsed or refractory (R/R) MM is needed, particularly those with different mechanisms of action. One such approach is to inhibit histone deacetylase (HDAC) and produce synergistic anti-myeloma activity via mechanisms of epigenetic modulations. In 2015, panobinostat was approved by US FDA as the first HDACi to treat R/R MM in combination with bortezomib and dexamethasone. Bisthianostat is a novel bisthiazole-based HDACi evolved from the thiazole-thiazoline cap group in natural product Largazole (Nan et al., ACS Med Chem Lett. 2014). It is orally available and displayed inhibition against a series of MM cell lines. Here we presented preliminary in-human findings from CH-020PI study, an ongoing phase 1 study of bisthianostat. (Trial registered at ClinicalTrial.gov: NCT03618602) Methods: CH-020PI is a first-in-human study to investigate the safety, tolerability, pharmacokinetics, and efficacy of bisthianostat in R/R MM patients. It is a single center, open-label, single arm, dose escalating phase I study. A standard 3+3 cohort design with 100mg as the starting dose was used to determine the maximum tolerated dose of bisthianostat. This study comprised two phases: a pharmacokinetics phase and an expansion phase. In the pharmacokinetics phase, a single-dose of bisthianostat was administered on day 1, and then multiple-dose was administered on a twice-weekly schedule for 4 consecutive weeks. Patients in the expansion phase received continuous bisthianostat twice weekly until progressive disease or unacceptable toxicities. Results: Until 30 June 2019, 8 patients were enrolled at 3 dose levels from 100 to 400mg. The median age at enrollment was 62 years (range, 51-70 years). The median number of previous lines of therapy was 5 (range, 2-6). Per protocol, all of 8 patients were evaluable for pharmacokinetics, toxicities and efficacy. In the pharmacokinetic evaluation, for all the 8 patients tested at day 1, the peak concentration of bisthianostat was reached within 2.3 hours; half life time were around 4 hours; bisthianostat uptake represented by AUClast were in good proportion to the level of dose as 100, 200 and 400mg, respectively. Similar results were observed at day 28. Any grade hematological treatment-related adverse events (AEs) occurred in 4 of 8 patients (50%), while grade 3/4 hematological AEs occurred in 2 (25%) patients. Any grade non-hematological treatment-emergent AEs were observed in 3 (37.5%) patients; no grade 3/4 non-hematological AEs were reported. No patient discontinued the treatment of bisthianostat due to AEs. Except patient 007 (200mg cohort) experienced a grade 2 nausea, no patients experienced diarrhea, nausea, or vomiting. It is worthy to note that gastrointestinal toxicity is common with the use of panobinostat, a FDA-approved HDAC inhibitor. Overall single-agent efficacy was modest, and stable disease (SD) was observed in 4 (50%) patients. At the time of data cut-off for statistical analysis, no dose-limiting toxicity has been observed. Conclusions: Bisthianostat proved to be well absorbed and tolerated. It exhibited modest anti-tumor efficacy in our cohort of heavily pretreated patients with R/R MM. This phase I clinical trial is currently ongoing, and future trials should compare different doses and schedules of the combination in order to optimize the treatment tolerability and enhance its efficacy. Disclosures No relevant conflicts of interest to declare.

Interferon regulatory factor (IRF)-8 is a critical transcription factor involved in the pathogenesis of myeloid neoplasia. However, the underlying mechanisms in vivo are not well known. Investigation of irf8-mutant zebrafish in this study indicated that Irf8 is evolutionarily conserved as an essential neoplastic suppressor through tight control of the proliferation and longevity of myeloid cells. Surviving irf8 mutants quickly developed a myeloproliferative neoplasm (MPN)-like disease with enhanced output of the myeloid precursors, which recurred after transplantation. Multiple molecules presented notable alteration and Mertk signaling was aberrantly activated in the hematopoietic cells in irf8 mutants. Transgenic mertk overexpression in Tg(coro1a:mertk) zebrafish recapitulated the myeloid neoplasia-like syndrome in irf8 mutants. Moreover, functional interference with Mertk, via morpholino knockdown or genetic disruption, attenuated the myeloid expansion phenotype caused by Irf8 deficiency. Therefore, Mertk signaling is a critical downstream player in the Irf8-mediated regulation of the progression of myeloid neoplasia. Our study extends the understanding of the mechanisms underlying leukemogenesis.

// Mingge Zhou 1 , Yumei Chen 1 , Honghui Huang 2 , Xiang Zhou 1 , Jianjun Liu 1 , Gang Huang 1 1 Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China 2 Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Correspondence to: Gang Huang, email: huang2802@163.com Jianjun Liu, email: nuclearj@163.com Keywords: DLBCL, prognosis, PET/CT, TLG, MTV Received: September 18, 2016 Accepted: October 14, 2016 Published: November 07, 2016 ABSTRACT Purpose : We evaluated the prognostic value of total lesion glycolysis (TLG) measured in baseline 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) in diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Methods: A total of 91 patients with newly diagnosed DLBCL underwent 18 F-FDG PET/CT scans before R-CHOP therapy. Metabolic tumor volume (MTV) was measured with the marginal threshold of normal liver mean standard uptake value (SUVmean) plus 3 standard deviations (SD). TLG was the sum of the products of MTV and SUVmean in all measured lesions. The predictive value was estimated by Log-rank test and Cox-regression analysis. Results: Median follow-up was 30 months (range, 5-124 months). The 5-year estimated progression-free survival (PFS) of the low and high TLG group were 83% and 34%, respectively (p

Background Significant attention has been directed toward the high incidence of malignant tumours that occur post-transplantation. However, there are few reports of myeloid sarcomas (MSs) following renal transplantation. Case presentation This case report describes a 26-year-old male patient who presented with repeatedly high creatinine levels and hydronephrosis six months post-renal transplantation. Surgical pathology revealed ureteral MS; however, the tumour recurred following resection. Bone marrow biopsy indicated that the patient also had acute promyelocytic leukaemia. The tumour was treated with local radiotherapy, and the leukaemia was treated with systemic chemotherapy. The patient’s conditions were satisfactory at the one-year follow-up. Conclusions This report is the first to describe a ureteral MS post-renal transplantation. Our findings suggest that surgical resection combined with radiotherapy and chemotherapy can help control the status of patients with this condition.

// Min-Yue Zhang 1, * , Gui-Qi Zhu 2, 3, * , Ke-Qing Shi 2, 4 , Ji-Na Zheng 2, 3 , Zhang Cheng 2, 3 , Zhuo-Lin Zou 5 , Hong-Hui Huang 1 , Fang-Yuan Chen 1 , Ming-Hua Zheng 2, 4 1 Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China 2 Department of Hepatology, Liver Research Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China 3 School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou 325000, China 4 Institute of Hepatology, Wenzhou Medical University, Wenzhou 325000, China 5 Department of Infection Diseases, the First Hospital of Jiaxing, Jiaxing 314000, China * Co-first authors, these author contributed equally to this work Correspondence to: Ming-Hua Zheng, e-mail: zhengmh@wmu.edu.cn Fang-Yuan Chen, e-mail: chenfangyuan62@163.com Keywords: hepatitis B virus reactivation, chemotherapy, nucleos(t)ide analogues prophylaxis, network meta-analysis, indirect comparison Received: February 28, 2016 Accepted: April 02, 2016 Published: April 21, 2016 ABSTRACT Objectives: Currently, no consensus exists regarding the optimal oral prophylactic regimens for hepatitis B surface antigen seropositive patients undergoing chemotherapy. We aimed to compare the efficacy of oral nucleos(t)ide analogues (NAs), including lamivudine, entecavir, adefovir, telbivudine and tenofovir, for the prevention of chemotherapy-induced hepatitis B virus (HBV) reactivation and its related morbidity and mortality in patients with chronic HBV (CHB) infection. Results: Fifty-two eligible articles consisting of 3892 participants were included. For HBV reactivation, prophylactic treatment with NAs were all significantly superior to no prophylaxis, with odds ratio (OR) from 0.00 (95% confidence interval [CI] 0.00~0.04) for the most effective intervention (tenofovir) to 0.10 (95% CI 0.06~0.14) for the least effective intervention (lamivudine). For secondary outcomes, prophylaxis with NAs also significantly outperformed observation. The results suggested that entecavir reduced the risk of HBV related hepatitis (predicted probability, 83%), HBV related death (68%) and all causes of hepatitis (97%) most efficaciously. It ranked second in decreasing all causes of death (34%). Materials and Methods: PubMed, Embase and Cochrane Library database were searched for controlled trials up to March 31, 2015. Primary outcome was the incidence of HBV reactivation. Secondary outcomes included the incidence of HBV-related hepatitis and death, all causes of hepatitis and death. Network meta-analysis combined direct and indirect evidence to estimate ORs for the clinical outcomes. A mean ranking and the probability of optimal therapeutic regime was obtained for each treatment based on clinical outcomes. Conclusions: Available evidence suggests that prophylatic therapy with tenofovir and entecavir may be the most potent interventions in prevention of HBV reactivation and HBV-related morbidity and mortality for CHB infection patients undergoing chemotherapy.

Both the intestine and liver develop from the endoderm, yet little is known how these two digestive organs share and differ in their developmental programs, at the molecular level. A classical forward genetic screen, with no gene bias, is an effective way to address this question by examining the defects of the intestine and liver in obtained mutants to assess mutated genes responsible for the development of either organ or both. We report here such a screen in zebrafish. ENU was used as the mutagen because of its high mutagenic efficiency and no site preference. Embryos were collected at 3.5 dpf for RNA whole mount in situ hybridization with a cocktail probe of the intestine marker ifabp and the liver marker lfabp to check phenotypes and determine their parental heterozygosis. A total of 52 F2 putative mutants were identified, and those with general developmental defects were aborted. To rule out non-inheritable phenotypes caused by high mutation background, F2 putative mutants were outcrossed with wild type fish and a re-screen in F3 generations was performed. After complementation tests between F3 mutants with similar phenotypes originating from the same F2 families, a total of 37 F3 mutant lines originated from 22 F2 families were identified after screening 78 mutagenized genomes. Classification of mutant phenotypes indicated that 31 out of the 37 mutants showed defects in both the intestine and liver. In addition, four "intestine specific mutants" and two "liver specific mutants" showed selectively more severe phenotype in the intestine and liver respectively. These results suggested that the intestine and liver share a substantial number of essential genes during both organs development in zebrafish. Further studies of the mutants are likely to shed more insights into the molecular basis of the digestive system development in the zebrafish and vertebrate.

The mechanisms underlying gut development, especially peristalsis, are widely studied topics. However, the causes of gut peristalsis-related diseases, especially Opioid-Induced Bowel Dysfunction (OIBD) disorder, have not been well defined. Therefore, our study used zebrafish, a popular model for studying both gut development and peristalsis, and DCFH-DA, a dye that clearly labels the live fish gut lumen, to characterize the formation process of gut lumen as well as the gut movement style in vivo. By applying Loperamide Hydrochloride (LH), the μ-opioid receptor-specific agonist, we established an OIBD-like zebrafish model. Our study found that acetylcholine (ACh) was a key transmitter that derepressed the phenotype induced by LH. Overall, the study showed that the antagonistic role of ACh in the LH-mediated opioid pathway was evolutionarily conserved; moreover, the OIBD-like zebrafish model will be helpful in the future dissection of the molecular pathways involved in gut lumen development and pathology.

Objective: Application of high-throughput genomics technology to analysis the differences in lncRNA/mRNA expression profiles between the patients with diffuse large B cell lymphoma (DLBCL) and reactive hyperplasia of lymph node (RLN), and between different disease states of DLBCL, in order to explore the role of the aberrantly expressed lncRNAs in the pathogenesis of DLBCL. Materials and methods: Tumor tissue samples from five newly diagnosed DLBCL, 3 relapsed DLBCL patients and 4 samples of RLN were collected. Agilent Human lncRNA/mRNA Microarray (4×180K) was used to profile differentially expression of lncRNA/mRNAs. Bioinformatics methods were performed for data analysis, including screening of differentially expressed lncRNA/mRNAs, gene ontology (GO) and KEGG pathway enrichment analysis, and lncRNA/mRNA co-expression network construction. Portion of dysregulated lncRNAs from the microarray data analysis was selected for validation using quantitative real-time polymerase chain reaction (qRT-PCR). Results: (1) In patients with newly diagnosed DLBCL, compared to RLN, a total of 5,806 dysregulated lncRNAs were identified (P (2) In patients with primary refractory DLBCL, compared with chemo-sensitive patients, a total of 425 dysregulated lncRNAs were identified(P (3) In patients with relapsed DLBCL, compared with newly diagnosed patients, a total of 605 dysregulated lncRNAs were identified(P (4) Fourteen dysregulated lncRNAs expressions were analyzed in the same sample series using qRT-PCR to validate the microarray analysis results. In all but one lncRNA, consistent trend of expression changes was observed in two methods. Conclusions: In patients with newly diagnosed DLBCL versus RLN, and between different disease states of DLBCL, the lncRNA/mRNA expression profiles were significantly altered. Differentially expressed mRNAs are involved in a number of biological functions and signaling pathways. It prompt lncRNA may play an important role in the mechanism of occurrence, drug resistance and relapse of DLBCL. The above results provide the theory basis for the further study on the role of differentially expressed lncRNA in the development of DLBCL and its potential application as the possible biomarkers of early diagnosis and prognosis. Disclosures No relevant conflicts of interest to declare.

The co-existence of de novo myelodysplastic syndrome (MDS) and non-Hodgkin lymphoma (NHL) prior to therapy is an extremely unusual finding. We report here a case of co-existent de novo MDS-refractory cytopenia with multilineage dysplasia and T-cell NHL, including clinical features, histopathological findings, molecular assessment, treatment course and outcomes. Other cases from the literature showing co-existence of both disorders are also reviewed; to date 19 similar cases have been reported. Among all cases (including the present patient), eight cases were diagnosed with de novo MDS and NHL simultaneously, which were considered to be true coincidences. The mechanisms responsible for the appearance of co-existence have not yet been ascertained, however in the present case a common chromosomal abnormality (20q deletion) was found in bone marrow and lymph node preparations. We conclude, therefore, that the co-existent de novo MDS and T-cell NHL seen in the present case may have a common origin.

Hematopoiesis is a complex process which gives rise to all blood lineages in the course of an organism's lifespan. However, the underlying molecular mechanism governing this process is not fully understood. Here we report the isolation and detailed study of a newly identified zebrafish ugly duckling (Udu) mutant allele, Udusq1. We show that loss-of-function mutation in the udu gene disrupts primitive erythroid cell proliferation and differentiation in a cell-autonomous manner, resulting in red blood cell (RBC) hypoplasia. Positional cloning reveals that the Udu gene encodes a novel factor that contains 2 paired amphipathic α-helix–like (PAH-L) repeats and a putative SANT-L (SW13, ADA2, N-Cor, and TFIIIB–like) domain. We further show that the Udu protein is predominantly localized in the nucleus and deletion of the putative SANT-L domain abolishes its function. Our study indicates that the Udu protein is very likely to function as a transcription modulator essential for the proliferation and differentiation of erythroid lineage.