Meta-Analysis of 5-Fraction Preoperative Radiotherapy for Soft Tissue Sarcoma.

OBJECTIVES: Studies investigating preoperative 5-fraction radiation therapy (RT) for soft tissue sarcoma (STS) are limited. We performed a meta-analysis to determine the efficacy and safety of this treatment paradigm. METHODS: This study-level meta-analysis was conducted using Bayesian methods. Statistical estimation for risk of outcome rates was conducted by posterior mean and 95% highest posterior density (HPD) intervals. Studies with 2-year local control (LC) and description of major wound complications (MWC) per the CAN-NCIC-SR2 study were included and served as the primary endpoints. Secondary endpoints included rates of acute and late toxicity. A total of 10 studies were identified and 7 met the inclusion criteria. Subgroup analyses were performed for ≥30 Gy vs <30 Gy. RESULTS: A total of 209 patients from 7 studies were included. Five studies used ≥30 Gy (n=144), and 2 studies <30 Gy (n=64). Median follow-up was 29 months (range: 21 to 57 mo). Primary tumor location was lower extremity in 68% and upper extremity in 22%. Most tumors were intermediate or high grade (95%, 160/169), and 50% (79/158) were >10 cm. The two-year LC for the entire cohort was 96.9%, and the rate of MWC was 30.6%. There was a trend toward improved LC with ≥ 30 Gy (95% HPD: 0.95 to 0.99 vs 0.84 to 0.99). There was no difference in MWC (95% HPD: 0.18 to 0.42 vs 0.17 to 0.55) or late toxicity between the groups. CONCLUSION: Preoperative 5-fraction RT for STS demonstrates excellent 2-year LC with MWC and toxicity similar to standard fractionation preoperative RT. Multi-institutional trials with a universal RT protocol are warranted.

XBP1s activates METTL3/METTL14 for ER-phagy and paclitaxel sensitivity regulation in breast cancer.

Cancer cells employ the unfolded protein response (UPR) or induce autophagy, especially selective removal of certain ER domains via reticulophagy (termed ER-phagy), to mitigate endoplasmic reticulum (ER) stress for ER homeostasis when encountering microenvironmental stress. N6-methyladenosine (m6A) is one of the most abundant epitranscriptional modifications and plays important roles in various biological processes. However, the molecular mechanism of m6A modification in the ER stress response is poorly understood. In this study, we first found that ER stress could dramatically elevate m6A methylation levels through XBP1s-dependent transcriptional upregulation of METTL3/METTL14 in breast cancer (BC) cells. Further MeRIP sequencing and relevant validation results confirmed that ER stress caused m6A methylation enrichment on target genes for ER-phagy. Mechanistically, METTL3/METTL14 increased ER-phagy machinery formation by promoting m6A modification of the ER-phagy regulators CALCOCO1 and p62, thus enhancing their mRNA stability. Of note, we further confirmed that the chemotherapeutic drug paclitaxel (PTX) could induce ER stress and increase m6A methylation for ER-phagy. Furthermore, the combination of METTL3/METTL14 inhibitors with PTX demonstrated a significant synergistic therapeutic effect in both BC cells and xenograft mice. Thus, our data built a novel bridge on the crosstalk between ER stress, m6A methylation and ER-phagy. Most importantly, our work provides novel evidence of METTL3 and METTL14 as potential therapeutic targets for PTX sensitization in breast cancer.

Transcriptome exploration of ferroptosis-related genes in TGFß- induced lens epithelial to mesenchymal transition during posterior capsular opacification development.

BACKGROUND: Posterior capsular opacification (PCO) is the main reason affecting the long-term postoperative result of cataract patient, and it is well accepted that fibrotic PCO is driven by transforming growth factor beta (TGFß) signaling. Ferroptosis, closely related to various ocular diseases, but has not been explored in PCO. METHODS: RNA sequencing (RNA-seq) was performed on both TGF-ß2 treated and untreated primary lens epithelial cells (pLECs). Differentially expressed genes (DEGs) associated with ferroptosis were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to investigate their biological function. Additionally, protein-to-protein interactions among selected ferroptosis-related genes by PPI network and the top 10 genes with the highest score (MCC algorithm) were selected as the hub genes. The top 20 genes with significant fold change values were validated using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Our analysis revealed 1253 DEGs between TGF-ß2 treated and untreated pLECs, uncovering 38 ferroptosis-related genes between two groups. Among these 38 ferroptosis-related genes,the most prominent GO enrichment analysis process involved in the response to oxidative stress (BPs), apical part of cell (CCs),antioxidant activity (MFs). KEGG were mainly concentrated in fluid shear stress and atherosclerosis, IL-17 and TNF signaling pathways, and validation of top 20 genes with significant fold change value were consistent with RNA-seq. CONCLUSIONS: Our RNA-Seq data identified 38 ferroptosis-related genes in TGF-ß2 treated and untreated pLECs, which is the first observation of ferroptosis related genes in primary human lens epithelial cells under TGF-ß2 stimulation.

[Efficacy and Survival of Venetoclax Based Regimen in the Treatment of Acute Myeloid Leukemia].

OBJECTIVE: To explore the efficacy and survival of venetoclax based (VEN-based) regimen in the treatment of acute myeloid leukemia（AML）. METHODS: A retrospective study was conducted in patients who received VEN-based regimen and completed at least 1 course of efficacy evaluation at the The First Affiliated Hospital of Nanchang University from July 2019 to July 2022. The incidence of complete remission （CR）/CR with incomplete hematologic recovery （CRi） rate, objective remission rate（ORR） and survival of patients with different risk strati- fication and gene subtypes were analyzed. RESULTS: A total of 79 patients were enrolled, including 43 patients with newly diagnosed unfit AML （unfit AML） and 36 relapsed/refractory AML (R/R AML). The median age of the patients was 62(14-83) years old. 36 out of 79 patients achieved CR/CRi and the ORR of the whole cohort was 64.6%. The CR/CRi rate of unfit AML patients was significantly higher than that of R/R AML patients (60.5% vs 27.8%, P=0.004). In unfit AML cohort, the patients with NPM1 and IDH1/2 mutations were benefited, 8 out of 9 patients ahcieved CR/CRi, 7/8 and 5/8 patients achieved minimal residual disease (MRD) negativity, respectively. Six out of 9 patients with TET2 mutation achieved CR/CRi, 3/6 patients achieved MRD negativity. In R/R AML cohort, 2 out of 3 patients with RUNX1 mutation achieved CR/CRi, without MRD negative, while the CR/CRi rate of patients with other gene mutations was lower than 40%. The median follow-up time was 10.1(95%CI: 8.6-11.6) months. In whole cohort, the median overall survival (mOS) time was 9.1 months and the relapse free survival (RFS) time was not reached. The mOS and RFS of unfit AML patients were significantly longer than those of R/R AML patients (14.1 vs 6.8 months, P=0.013; not reached vs 3.3 months, P=0.000). In unfit AML cohort, the mOS of patients with NPM1 or IDH1/2 mutations was not reached, while that of patients without NPM1 or IDH1/2 mutations was 8.0 months (P=0.009; P=0.022). Furthermore, the mOS of patients with TP53 mutaion was significantly shorter than that of patients without TP53 mutation (5.2 vs 14.1 months， P=0.049). In R/R AML cohort, there was no significant difference in mOS between patients with mutation in each gene subtype and those without gene mutation (P>0.05). All patients had hematology adverse reactions, 91.1% patients had AE grade≥3. The most common non-hematology adverse reactions was infection, with an incidence of 91.1%. VEN-based regimen was tolerable for AML patients. CONCLUSION: VEN-based regimen can achieve a high response rate, especially in unfit AML with acceptable safety, and some patients can achieve MRD negative. It is also effective in NPM1-, IDH1/2-positive patients with long survival time.

Chidamide, Decitabine, Cytarabine, Aclarubicin, and Granulocyte Colony-stimulating Factor Therapy for Patients with Relapsed/Refractory Acute Myeloid Leukemia: A Retrospective Study from a Single-Center.

OBJECTIVE: Preclinical evidence and clinical trials have suggested synergistic effects of epigenetic modifiers in combination with cytotoxic agents for the treatment of leukemia. However, their efficacy in patients with relapsed/refractory acute myeloid leukemia (R/R AML) remains unclear. METHODS: Clinical data of R/R AML patients who received a CDCAG regimen (chidamide, decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor) from July 1, 2018 to October 31, 2021 at our center were retrospectively assessed, and the safety and efficacy of the CDCAG regimen were evaluated. Patients were followed up until November 30, 2021, with a median follow-up of 21.6 months (95% CI: 10.0-33.2 months). RESULTS: A total of 67 patients were enrolled. Two patients died within 3 weeks after the initiation, and therefore only 65 patients underwent the assement for clinical response and survival. It was found that 56.9% patients achieved complete remission with a median overall survival (OS) of 9.6 months. The median OS of responders was 25.9 months, while that of non-responders was 5.0 months (P<0.0001). Patients with gene mutations had a superior overall response rate (ORR) (80.4% vs. 45.5%, P=0.043) compared to those without gene mutations. The presence of DNA methyltransferase 3 A (DNMT3A), ten-eleven translocation-2 (TET2), and isocitrate dehydrogenase 1/2 (IDH1/2) mutations did not affect the response rate (88.2% vs. 68.9%, P=0.220) and reflected a better OS (not attained vs. 9.0 months, P=0.05). The most common non-hematologic adverse events were pulmonary infection (73.1%), followed by febrile neutropenia (23.9%) and sepsis (19.4%). CONCLUSIONS: The CDCAG regimen was effective and well-tolerated in R/R AML patients, increasing the potential for allogeneic hematopoietic stem cell transplantation. Moreover, patients with DNMT3A, TET2, and IDH1/2 mutations might benefit from this regimen.

[Establishment and Clinical Significance of Prognostic Nomogram Model for Diffuse Large B-Cell Lymphoma Based on Immunohistochemistry Markers and International Prognostic Index Scores].

OBJECTIVE: To retrospectively analyze clinical characteristics and survival time of patients with diffuse large B-cell lymphoma (DLBCL), detect prognosis-related markers, and establish a nomogram prognostic model of clinical factors combined with biomarkers. METHODS: One hundred and thirty-seven patients with DLBCL were included in this study from January 2014 to March 2019 in the First Affiliated Hospital of Nanchang University. The expression of GCET1, LMO2, BCL-6, BCL-2 and MYC protein were detected by immunohistochemistry (IHC), then the influences of these proteins on the survival and prognosis of the patients were analyzed. Univariate and multivariate Cox regression analysis were used to gradually screen the prognostic factors in nomogram model. Finally, nomogram model was established according to the result of multivariate analysis. RESULTS: The positive expression of GCET1 protein was more common in patients with Ann Arbor staging I/II (P =0.011). Compared with negative patients, patients with positive expression of LMO2 protein did not often show B symptoms (P =0.042), and could achieve better short-term curative effect (P =0.005). The overall survival (OS) time of patients with positive expression of LMO2 protein was significantly longer than those with negative expression of LMO2 protein (P =0.018), though the expression of LMO2 protein did not correlate with progression-free survival (PFS) (P >0.05). However, the expression of GCET1 protein had no significant correlation with OS and PFS. Multivariate Cox regression analysis showed that nomogram model consisted of 5 prognostic factors, including international prognostic index (IPI), LMO2 protein, BCL-2 protein, MYC protein and rituximab. The C-index applied to the nomogram model for predicting 4-year OS rate was 0.847. Moreover, the calibrated curve of 4-year OS showed that nomogram prediction had good agreement with actual prognosis. CONCLUSION: The nomogram model incorporating clinical characteristics and IHC biomarkers has good discrimination and calibration, which provides a useful tool for the risk stratification of DLBCL.

Angioimmunoblastic T-cell lymphoma induced hemophagocytic lymphohistiocytosis and disseminated intravascular coagulopathy: A case report.

BACKGROUND: Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma, with heterogenous clinical manifestations and poor prognosis. Here, we report a case of AITL induced hemophagocytic lymphohistiocytosis (HLH) and disseminated intravascular coagulopathy (DIC). CASE SUMMARY: An 83-year-old man presented with fever and purpura of both lower limbs for one month. Groin lymph node puncture and flow cytometry indicated a diagnosis of AITL. Bone marrow examination and other laboratory related indexes indicated DIC and HLH. The patient rapidly succumbed to gastrointestinal bleeding and septic shock. CONCLUSION: This is the first reported case of AITL induced HLH and DIC. AITL is more aggressive in older adults. In addition to male gender, mediastinal lymphadenopathy, anaemia, and sustained high level of neutrophil-to-lymphocyte ratio may indicate a greater risk of death. Early diagnosis, early detection of severe complications, and prompt and effective treatment are vital.

[Retracted] Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog signaling pathway in breast cancer.

Following the publication of this paper, it was drawn to the Editor's attention by concerned readers that several of the cellular images shown in Figs. 6A and 8A, the scratch­wound assay images shown in Fig. 5A, the western blotting data in Figs. 2C and 7A and the Matrigel invasion assays in Fig. 5C were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 36: 204­214, 2015; DOI: 10.3892/ijmm.2015.2217].

Secondary positioning of rotationally asymmetric refractive multifocal intraocular lens in a patient with glaucoma: A case report.

BACKGROUND: Asymmetric multifocal intraocular lenses (IOLs) are now widely used in the modern cataract surgery, providing a good level of visual performance over a range of distances and high postoperative patient satisfaction. We report a case of improved visual quality after shifting the near segment of an asymmetrical multifocal IOL to the superotemporal placement in the dominant eye of a glaucoma patient. CASE SUMMARY: A 72-year-old woman with bilateral glaucoma underwent phacoemulsification in the dominant eye (left eye) with implantation of an asymmetrical multifocal IOL. Postoperative uncorrected distance visual acuity (UDVA) was 0.0 logMAR (20/20 Snellen) and uncorrected near visual acuity (UNVA) was 0.1 logMAR (20/25 Snellen). Two weeks later, the patient presented to our clinic with decreased vision due to migration of lens epithelial cells to IOL anterior surface and edema of corneal endothelial cells. Anterior capsule polishing and superotemporal placement of near segment [+3.00 diopter (D) addition (add)] of IOL were performed. As a result, UDVA at the first week and first year after reposition was 0.0 logMAR (20/20 Snellen), and compared with 0.3 logMAR (20/40 Snellen) in the first week, the UNVA was improved to 0.0 logMAR (20/20 Snellen) one year after surgery. CONCLUSION: The postoperative inflammatory reaction and lens epithelial cells proliferation were obvious in this glaucoma patient. Capsule polishing and rotation of the lens were beneficial to the patient, which not only enhanced the patient's vision, but also improved the patient's satisfaction. Therefore, glaucoma patients need to be cautious of implanting multifocal IOLs. Placement of a near segment of an asymmetrical multifocal IOL in the dominant eye should be performed on an individual basis.

Treatment of contaminants by a cathode/FeIII/peroxydisulfate process: Formation of suspended solid organic-polymers.

Treatment of highly contaminated wastewaters containing refractory or toxic organic contaminants (e.g. industrial wastewaters) is becoming a global challenge. Most technologies focus on efficient degradation of organic contaminants. Here we improve the cathode/FeIII/peroxydisulfate (PDS) technology by turning down the current density and develop an innovative mechanism for organic contaminants abatement, namely polymerization rather than degradation, which allows simultaneous contaminants removal and resource recovery from wastewater. This polymerization leads to organic-particles (suspended solid organic-polymers) formation in bulk solution, which is demonstrated by eight kinds of representative organic contaminants. Taking phenol as a representative, 83% of PDS is saved compared to degradation process, with 87.2% of DOC removal. The formed suspended solid organic-polymers occupy 59.2% of COD of the original organics in solution, and can be easily separated from aqueous solution by sedimentation or filtration. The separated organic-polymers are a series of polymers coupled by phenolic monomers, as confirmed by FTIR and ESI-MS analyzes. The energy contained in the recovered organic polymers (4.76 × 10-5 kWh for 100 mL of 1 mM phenol solution in this study) can fully compensate the consumed electrical energy (2.8 × 10-5 kWh) in the treatment process. A representative polymerization model for this process is established, in which the SO4•- and HO• generated from PDS activation initiate the polymerization and improve the polymerization degree by the production of oligomer intermediates. A practical coking wastewater treatment is carried out to verify the research results and get positive feedback, with 56.0% of DOC abatement and the suspended solid organic-polymers accounts for 42.5% of the total COD in the raw wastewater. The energy consumption (47 kWh/kg COD, including electricity and PDS cost) is lower than the values in previous reports. This study provides a novel method for industrial wastewater treatment based on polymerization mechanism, which is expected to recover resources while removing pollutants with low consumption.

Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression.

The transcriptional regulator nuclear factor of activated T-cells, cytoplasmic 3 (NFATc3) is constitutively activated in several cancer types and plays important roles in cancer development and progression. Heavily phosphorylated NFATc3 resides in the cytoplasm of resting cells, and dephosphorylated NFATc3 translocates to the nucleus to activate expression of target genes in cells exposed to stimuli, for instance, hypoxia. Apart from phosphorylation, various post-translational modifications have been reported to regulate NFAT transcriptional activity. However, the mechanisms remain elusive. Here, we have demonstrated that NFATc3 is activated in human pancreatic ductal adenocarcinoma (PDAC) cells and that excessive activation of NFATc3 is correlated to advanced stages of PDAC and short survival time of PDAC patients. NFATc3 is deSUMOylated at K384 by SENP3 under hypoxia, which impairs the interaction between NFATc3 and phosphokinase GSK-3ß, subsequently decreases NFATc3 phosphorylation and increases its nuclear occupancy. Knockdown of SENP3 greatly decreased hypoxia-induced NFATc3 nuclear occupancy. Our results highlight that SENP3-mediated deSUMOylation acts as an essential modulator of NFATc3, which is instrumental in PDAC tumor progression under hypoxia.

Microtentacle Formation in Ovarian Carcinoma.

BACKGROUND: The development of chemoresistance to paclitaxel and carboplatin represents a major therapeutic challenge in ovarian cancer, a disease frequently characterized by malignant ascites and extrapelvic metastasis. Microtentacles (McTNs) are tubulin-based projections observed in detached breast cancer cells. In this study, we investigated whether ovarian cancers exhibit McTNs and characterized McTN biology. METHODS: We used an established lipid-tethering mechanism to suspend and image individual cancer cells. We queried a panel of immortalized serous (OSC) and clear cell (OCCC) cell lines as well as freshly procured ascites and human ovarian surface epithelium (HOSE). We assessed by Western blot ß-tubulin isotype, α-tubulin post-translational modifications and actin regulatory proteins in attached/detached states. We studied clustering in suspended conditions. Effects of treatment with microtubule depolymerizing and stabilizing drugs were described. RESULTS: Among cell lines, up to 30% of cells expressed McTNs. Four McTN morphologies (absent, symmetric-short, symmetric-long, tufted) were observed in immortalized cultures as well as ascites. McTN number/length varied with histology according to metastatic potential. Most OCCC overexpressed class III ß-tubulin. OCCC/OSC cell lines exhibited a trend towards more microtubule-stabilizing post-translational modifications of α-tubulin relative to HOSE. Microtubule depolymerizing drugs decreased the number/length of McTNs, confirming that McTNs are composed of tubulin. Cells that failed to form McTNs demonstrated differential expression of α-tubulin- and actin-regulating proteins relative to cells that form McTNs. Cluster formation is more susceptible to microtubule targeting agents in cells that form McTNs, suggesting a role for McTNs in aggregation. CONCLUSIONS: McTNs likely participate in key aspects of ovarian cancer metastasis. McTNs represent a new therapeutic target for this disease that could refine therapies, including intraperitoneal drug delivery.

Microstructure and Fatigue Damage of 316L Stainless Steel Manufactured by Selective Laser Melting (SLM).

In this paper, 316L stainless steel powder was processed and formed by selective laser melting (SLM). The microstructure of the sample was studied using an optical microscope, and the fatigue failure of the sample and the characteristics of crack initiation and propagation were analyzed, providing a research basis for the application of SLM-316L. Due to the influence of microstructure and SLM process defects, the fatigue cracks of SLM-316L mainly emerged due to defects such as lack of fusion and pores, while the cracks of rolled 316L initiated at the inclusions near the surface of the specimen. After fatigue microcrack initiation of the SLM-316L specimen, due to the existence of shear stress and tear stress, the crack tip was passivated and Z-shaped propagation was formed. The existence of internal defects in SLM-316L made the microcrack initiation random and diverse. At the same time, the existence of defects affected the crack propagation in the form of bending, bifurcation and bridge, which made the main crack propagation deviate from the maximum load direction.

Study on Microstructure and Fatigue Properties of FGH96 Nickel-Based Superalloy.

In this study, using synchrotron radiation X-ray imaging, the microstructure, tensile properties, and fatigue properties of FGH96 nickel-based superalloy were tested, and the fatigue damage mechanism was analyzed. An analysis of the experimental results shows that the alloy structure is dense without voids or other defects. It was observed that the primary γ' phase is distributed on the grain boundary in a chain shape, and the secondary γ' phase is found inside the crystal grains. The X-ray diffraction (XRD) pattern indicates that no other phases were seen except for the γ and γ' phases. The tensile strength of the alloy is 1570 MPa and the elongation is 12.1%. Using data fitting and calculation, it was found that the fatigue strength of the alloy under the condition of 5 × 106 cycles is 620.33 MPa. A fatigue fracture has the characteristics of secondary crack, cleavage step, fatigue stripe, tire indentation, and dimple. The fracture is a mix of cleavage fracture and ductile fracture. Through a three-dimensional reconstruction of the alloy synchrotron radiation imaging area, it was found that the internal defects are small and mostly distributed at the edge of the sample. The dimple morphology is formed by cavity aggregation and cavity germination resulting from defects in the material itself, fracture of the second-phase particles, and separation of the second-phase particles from the matrix interface. By analyzing the damage mechanism of fatigue fractures, it is concluded that the cleavage step is formed by the intersection of cleavage planes formed by branch cracks, with the main crack of the confluence extending forward to form a cleavage fracture. The crack propagation path was also analyzed, and under the action of cyclic load and tip passivation, the crack shows Z-shaped propagation.

MiR-137 knockdown promotes the osteogenic differentiation of human adipose-derived stem cells via the LSD1/BMP2/SMAD4 signaling network.

MicroRNAs are a group of endogenous regulators that participate in several cellular physiological processes. However, the role of miR-137 in the osteogenic differentiation of human adipose-derived stem cells (hASCs) has not been reported. This study verified a general downward trend in miR-137 expression during the osteogenic differentiation of hASCs. MiR-137 knockdown promoted the osteogenesis of hASCs in vitro and in vivo. Mechanistically, inhibition of miR-137 activated the bone morphogenetic protein 2 (BMP2)-mothers against the decapentaplegic homolog 4 (SMAD4) pathway, whereas repressed lysine-specific histone demethylase 1 (LSD1), which was confirmed as a negative regulator of osteogenesis in our previous studies. Furthermore, LSD1 knockdown enhanced the expression of BMP2 and SMAD4, suggesting the coordination of LSD1 in the osteogenic regulation of miR-137. This study indicated that miR-137 negatively regulated the osteogenic differentiation of hASCs via the LSD1/BMP2/SMAD4 signaling network, revealing a new potential therapeutic target of hASC-based bone tissue engineering.

An Improved Protocol for the Virtual Screening Discovery of Novel Histone Deacetylase Inhibitors.

Histone deacetylases (HDACs) are enzymes that play a key role in structural modification and gene expression. The overexpression of HDAC is associated with cancer, and thus inhibiting the enzyme could be an efficient cancer therapy. To discover new HDAC inhibitors (HDACis), we proposed an improved protocol combining a hierarchical pharmacophore search, molecular docking, and molecular dynamic simulations. The test results showed that the improved screening protocol effectively reduced the false-positive rates of drug-like chemicals. Based on the protocol, we obtained 16 hit compounds as potential HDACis from the Life Chemicals database. Enzyme inhibition experiments showed that two of the hit chemical compounds had HDAC-inhibitory effects. In vitro assays showed that Z165155756 could selectively inhibit the proliferation of cancer cells and specifically promoted apoptosis and induced G1/S phase arrest in A2780 cells. It may have potential therapeutic effects in ovarian cancer and is worthy of further investigation.

[Clinical Characteristics of Liver Dysfunction in Patients with Hemophagocytic Syndrome].

OBJECTIVE: To explore the clinical feature of liver injury in patients with hemophagocytic syndrome (HPS). METHODS: The clinical data of 92 patients with HPS in our hospital were analyzed retrospectively, and the characteristics of hepatic lesion and its relationship with prognosis in HPS patients were explored. RESULT: 92 cases of HPS showed different degrees of liver dysfunction from mild to moderate. The clinical parameters of liver dysfunction included the increased level of LDH (89.13%), AST (64.13%), TBIL (59.78%) and decreased level of ALB (90.22%). Moreover, 76.09% and 67.39% of the patients had the prolonging of APTT and PT respectively. The ALB level of patients in rheumatoid immune group were higher than that in infection, maglinancy and unexplained groups, all with statistically and significant difference (P＜0.05, P＜0.05 and P＜0.01), the ALB level of patients in infection group were statistically and significantly higher than that in unexplained group (P＜0.01). The Fbg level of patients in infection group were lower than that in maglinancy group, unexplained group and rheumatoid immune group, all the differences were statistically significant (P＜0.05, P＜0.01 and P＜0.05). Child-Pugh grading was further carried out in HPS patients with liver disfunction. Survival time of the patients grade A was significantly higher than that of grade B and C of patients. Univariate analysis showed that the patients with LDH≥2000 U/L, ALB＜30 g/L and PT≥15.1 s had a survival time inferior to control patients (P＜0.05, P＜0.01 and P＜0.01, respectively). Multivariate analysis showed that ALB＜30 g/L was an independent adverse prognostic factor for these patients (P＜0.01). CONCLUSION: Patients with HPS generally have impaired liver function mainly manifested with elevated LDH and AST levels, and declined ALB level, which may correlate with the disease cause and prognosis. Patients with LDH≥2000 U/L, ALB＜30 g/L and PT≥15.1 s have a poorer prognosis and should be treated as soon as possible.

A novel benzamine lead compound of histone deacetylase inhibitor ZINC24469384 can suppresses HepG2 cells proliferation by upregulating NR1H4.

Histone deacetylases (HDACs) can enzymatically transferred acetyl functional group from protein or lysine residues of histone, so they can regulate the expression of lots of genes. Now HDACs are used as drug targets and many HDAC inhibitors (HDACis) were approved for cancer therapy or in clinical trials. However, the physiological mechanisms and regulatory processes of HDACi anti-cancer effects are largely unexplored and uncompleted. Here we use the virtual screening workflow obtained 25 hit compounds and ZINC24469384 can significantly inhibit HDAC activity while arrest cell cycle at G1/S phase and significantly induced HepG2 cell apoptosis, time-course RNA-seq demonstrate that HepG2 cells transcriptionally respond to ZINC24469384. Pathway analysis of DEGs and DASGs reveal that NR1H4 may play an important role in ZINC24469384-induced anti-proliferation effect and is dramatically alleviated by down-regulating the SOCS2 expression and promoting STAT3 phosphorylation in knockdown NR1H4 HepG2 cells. Analysis based on TCGA database indicated that NR1H4 and SOCS2 were downregulated in liver cancer, this suggest NR1H4 and SOCS2 may play an important role in tumorigenesis. These results indicated that ZINC24469384 is a novel benzamine lead compound of HDACi and provides a novel mechanism for HDACi to inhibit cancer.

Effect of phosphate on amorphous iron mineral generation and arsenic behavior in paddy soils.

Arsenic (As) contamination was detected in paddy soils of Guangdong, China due to mining and weathering processes. Furthermore, As may be released into the soil and irrigation water during the application of phosphate (P). In this study, As behavior was assessed in three paddy soils (S6, S8 and TR) along the Hengshi river using batch and circular flow experiments with different phosphate application doses (0, 1, 5, 10, 50, 100 mg/L). The results indicate that pH variation (3-7) and higher phosphate concentrations in solution, can induce the release of As, with total As release ranked in the order: S6 > S8 > TR. In addition, AsV was the main state affected by phosphate in the circular soil solution. In particular, after 7 days of P10 application, the highest As concentration in S6, S8 and TR soil solutions reached 2298.4, 829.9 and 153.9 µg/L respectively, with the AsV state accounting for 93%, 97% and 18% of As. Some minerals were found to be generated in the middle container, most of which were amorphous iron or aluminum oxides and hydroxides, as confirmed by XRD. With mineral generation, the As concentration in soil solutions decreased to 314.2, 98.1 and 34.1 µg/L. The SEM results indicate that the minerals became more fine (<100 nm) when more P was applied. In addition, XPS, SEM-eds and elemental analysis results also revealed that As distribution was closely associated with iron minerals. Along with soil depth, P influenced the state and distribution of iron minerals and As in the topsoil, while phosphate increased the available As and reduced the amorphous iron mineral content in the soil. Therefore, it is essential to evaluate As behavior in paddy soils, to monitor and avoid potential food security risks.