mFOLFOX-HAIC+lenvatinib+PD-1 inhibitors versus GC/GS/GEMOX chemotherapy as a first line therapy for advanced biliary tract cancer: A single-center retrospective cohort study.

Biliary tract tumors (BTC) account for about 3% of all digestive system tumors, with rising incidence and limited treatment options, particularly for advanced stages, underscoring the need for innovative therapies. This retrospective cohort study evaluated the safety and efficacy of a novel regimen combining hepatic artery infusion chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX-HAIC) alongside lenvatinib and programmed cell death protein-1 (PD-1) inhibitors (mFOLFOX-HAIC+lenvatinib+PD-1i) compared to standard regimens of gemcitabine plus cisplatin, gemcitabine plus S1, or gemcitabine plus oxaliplatin (GC/GS/GEMOX) in advanced BTC patients treated from March 2019 to November 2023. A total of 89 patients were analyzed, with 55 receiving hepatic arterial infusion chemotherapy and 34 receiving the GC/GS/GEMOX regimens. Among these, 23 patients were in the mFOLFOX-HAIC+lenvatinib+PD-1i group, while 24 were in the GC/GS/GEMOX group. The median progression-free survival (mPFS) for the mFOLFOX-HAIC+lenvatinib+PD-1i group was 15 months compared to 6 months for the GC/GS/GEMOX group. Similarly, the median overall survival (mOS) was 20 months for the mFOLFOXHAIC+lenvatinib+PD-1i group versus 13 months for the GC/GS/GEMOX group. The objective response rate (ORR) and disease control rate (DCR) for the mFOLFOX-HAIC+lenvatinib+PD-1i group were 48.5% and 87.0%, respectively, both significantly higher than those observed in the GC/GS/GEMOX group at three months of treatment. The incidence of adverse events (AEs) was similar between the mFOLFOX-HAIC+lenvatinib+PD-1i group and the GC/GS/GEMOX group, at 86.5% and 84.2%, respectively, with no statistically significant difference in complication rates. Overall, mFOLFOX-HAIC+lenvatinib+PD-1i appears to be a safe and well-tolerated treatment for advanced BTC, demonstrating superior mPFS and mOS compared to standard regimens.

Impact of Microparticle Transarterial Chemoembolization (mTACE) on myeloid-derived suppressor cell subtypes in hepatocellular carcinoma: Clinical correlations and therapeutic implications.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) play a pivotal role in immunosuppression and tumor progression in hepatocellular carcinoma (HCC). While various treatments like surgical resection, ablation, and radiotherapy have been studied for their effects on circulating MDSC frequencies in HCC patients, the findings remain inconclusive. Transarterial Chemoembolization (TACE) stands as the standard care for unresectable HCC, with Microparticle TACE (mTACE) gaining prominence for its capacity to induce significant tumor necrosis. However, the immunological ramifications of such pathological outcomes are scarcely reported. METHODS AND RESULTS: This study aims to elucidate the alterations in MDSC subtypes, specifically monocytic MDSCs (mMDSCs) and early-stage MDSCs (eMDSCs), post-mTACE and to investigate their clinical correlations in HCC patients. A cohort comprising 75 HCC patients, 16 liver cirrhosis patients, and 20 healthy controls (HC) was studied. Peripheral blood samples were collected and analyzed for MDSC subtypes. The study also explored the associations between MDSC frequencies and various clinical parameters in HCC patients. The frequency of mMDSCs was significantly elevated in the HCC group compared to liver cirrhosis and HC. Importantly, mMDSC levels were strongly correlated with aggressive clinical features of HCC, including tumor size, vascular invasion, and distant metastasis. Post-mTACE, a marked reduction in mMDSC frequencies was observed, while eMDSC levels remained stable. CONCLUSIONS: Our findings underscore the critical role of mMDSCs in HCC pathogenesis and their potential as a therapeutic target. The study also highlights the efficacy of mTACE in modulating the immunosuppressive tumor microenvironment, thereby opening new avenues for combinatorial immunotherapeutic strategies in HCC management.

Comparing iodized oil with polyvinyl alcohol for portal vein embolization in promoting liver remnant increase before partial hepatectomy.

BACKGROUND: To compare the efficacy and safety of iodized oil versus polyvinyl alcohol (PVA) particles in portal vein embolization (PVE) before partial hepatectomy. METHODS: From October 2016 to December 2021, 86 patients who planned to undergo hepatectomy after PVE were enrolled, including 61 patients post-PVE with PVA particles + coils and 25 patients post-PVE with iodized oil + coils. All patients underwent CT examination before and 2-3 weeks after PVE to evaluate the future liver remnant (FLR). The intercohort comparison included the degree of liver volume growth, changes in laboratory data, and adverse events. RESULTS: There was no significant difference in the resection rate between the iodized oil group and the PVA particle group (68 % vs. 70 %, p = 0.822). In terms of the degree of hypertrophy (9.52 % ± 13.47 vs. 4.03 % ± 10.55, p = 0.047) and kinetic growth rate (4.07 % ± 5.4 vs. 1.55 % ± 4.63, p = 0.032), the iodized oil group was superior to the PVA group. The PVE operation time in the PVA particle group was shorter than that in the iodized oil group (121. 72 min ± 34.45 vs. 156. 2 min ± 71.58, p = 0.029). There was no significant difference in the degree of hypertrophy between the high bilirubin group and the control group (5.32 % ± 9.21 vs. 6.1 % ± 14.79, p = 0.764). Only 1 patient had a major complication. CONCLUSIONS: Compared with PVA particles, iodized oil PVE can significantly increase liver volume and the degree of hypertrophy without any significant difference in safety.

Hepatic arterial infusion chemotherapy plus lenvatinib with or without programmed cell death protein-1 inhibitors for advanced cholangiocarcinoma.

Background: New treatment strategies are needed to improve outcomes for patients with advanced cholangiocarcinoma (CCA) due to the limited efficacy of current first-line chemotherapy regimens. Although the combination of hepatic arterial infusion chemotherapy (HAIC), lenvatinib, and programmed cell death protein-1 (PD-1) inhibitors has been extensively evaluated in the treatment of advanced hepatocellular carcinoma, their roles in advanced CCA remain poorly understood. The purpose of this study is to compare the efficacy and safety of HAIC plus lenvatinib with or without PD-1 inhibitors in patients with advanced CCA. Methods: Between March 2019 to June 2022, patients diagnosed with advanced CAA who received HAIC plus lenvatinib with or without PD-1 inhibitors treatment were reviewed for eligibility. Efficacy was evaluated according to survival and tumor response, and safety was evaluated according to the incidence of adverse events (AEs). Results: Fifty-five patients with advanced CCA were included in the study, and they were divided into the HAIC+lenvatinib (LEN)+PD-1 inhibitors (PD-1i) group (n = 35) and HAIC+LEN group (n = 20). The median follow-up time was 14.0 (5-42) months. Patients in the HAIC+LEN+PD-1i group had significantly better PFS (HR = 0.390; 95% CI 0.189-0.806; p = 0.001) and OS (HR = 0.461; 95% CI 0.229-0.927; p = 0.01) than those in the HAIC+LEN group. The HAIC+LEN+PD-1i group showed a higher objective response rate and disease control rate than the HAIC+LEN group but did not find a significant difference. The incidence of grade 1-2 and grade 3-4 AEs was not significantly higher in the HAIC+LEN+PD-1i group compared to the HAIC+LEN group, whereas two patients (5.7%) in the HAIC+LEN+PD-1i group experienced grade 5 immune-mediated pneumonia. Conclusion: HAIC plus lenvatinib with PD-1 inhibitors is safe and well-tolerated, and has the potential to prolong the survival of patients with advanced CCA. The addition of PD-1 inhibitors may enhance the efficacy of HAIC and lenvatinib. Therefore, the combined therapy has the potential to become a treatment option for advanced CCA.

KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors. While activating NOTCH1 mutations are the dominant genetic drivers of T-ALL, epigenetic dysfunction plays a central role in the pathology of T-ALL and can provide alternative mechanisms to oncogenesis in lieu of or in combination with genetic mutations. The histone demethylase enzyme KDM6A (UTX) is also recurrently mutated in T-ALL patients and functions as a tumor suppressor. However, its gene paralog, KDM6B (JMJD3), is never mutated and can be significantly overexpressed, suggesting it may be necessary for sustaining the disease. Here, we used mouse and human T-ALL models to show that KDM6B is required for T-ALL development and maintenance. Using NOTCH1 gain-of-function retroviral models, mouse cells genetically deficient for Kdm6b were unable to propagate T-ALL. Inactivating KDM6B in human T-ALL patient cells by CRISPR/Cas9 showed KDM6B-targeted cells were significantly outcompeted over time. The dependence of T-ALL cells on KDM6B was proportional to the oncogenic strength of NOTCH1 mutation, with KDM6B required to prevent stress-induced apoptosis from strong NOTCH1 signaling. These studies identify a crucial role for KDM6B in sustaining NOTCH1-driven T-ALL and implicate KDM6B as a novel therapeutic target in these patients.

Intrahepatic portal venous systems in adult patients with cavernous transformation of portal vein: Imaging features and a new classification.

BACKGROUND: Cavernous transformation of the portal vein (CTPV) due to portal vein obstruction is a rare vascular anomaly defined as the formation of multiple collateral vessels in the hepatic hilum. This study aimed to investigate the imaging features of intrahepatic portal vein in adult patients with CTPV and establish the relationship between the manifestations of intrahepatic portal vein and the progression of CTPV. METHODS: We retrospectively analyzed 14 CTPV patients in Beijing Tsinghua Changgung Hospital. All patients underwent both direct portal venography (DPV) and computed tomography angiography (CTA) to reveal the manifestations of the portal venous system. The vessels measured included the left portal vein (LPV), right portal vein (RPV), main portal vein (MPV) and the portal vein bifurcation (PVB). RESULTS: Nine males and 5 females, with a median age of 40.5 years, were included in the study. No significant difference was found in the diameters of the LPV or RPV measured by DPV and CTA. The visualization in terms of LPV, RPV and PVB measured by DPV was higher than that by CTA. There was a significant association between LPV/RPV and PVB/MPV in term of visibility revealed with DPV (P = 0.01), while this association was not observed with CTA. According to the imaging features of the portal vein measured by DPV, CTPV was classified into three categories to facilitate the diagnosis and treatment. CONCLUSIONS: DPV was more accurate than CTA for revealing the course of the intrahepatic portal vein in patients with CTPV. The classification of CTPV, that originated from the imaging features of the portal vein revealed by DPV, may provide a new perspective for the diagnosis and treatment of CTPV.

Insight into Viral Hijacking of CRL4 Ubiquitin Ligase through Structural Analysis of the pUL145-DDB1 Complex.

Viruses evolve mechanisms to exploit cellular pathways that increase viral fitness, e.g., enhance viral replication or evade the host cell immune response. The ubiquitin-proteosome system, a fundamental pathway-regulating protein fate in eukaryotes, is hijacked by all seven classes of viruses. Members of the Cullin-RING family of ubiquitin (Ub) ligases are frequently co-opted by divergent viruses because they can target a broad array of substrates by forming multisubunit assemblies comprised of a variety of adapters and substrate receptors. For example, the linker subunit DDB1 in the cullin 4-RING (CRL4)-DDB1 Ub ligase (CRL4DDB1) interacts with an H-box motif found in several unrelated viral proteins, including the V protein of simian virus 5 (SV5-V), the HBx protein of hepatitis B virus (HBV), and the recently identified pUL145 protein of human cytomegalovirus (HCMV). In HCMV-infected cells, pUL145 repurposes CRL4DDB1 to target STAT2, a protein vital to the antiviral immune response. However, the details of how these divergent viral sequences hijack DDB1 is not well understood. Here, we use a combination of binding assays, X-ray crystallography, alanine scanning, cell-based assays, and computational analysis to reveal that viral H-box motifs appear to bind to DDB1 with a higher affinity than the H-box motifs from host proteins DCAF1 and DDB2. This analysis reveals that viruses maintain native hot-spot residues in the H-box motif of host DCAFs and also acquire favorable interactions at neighboring residues within the H-box. Overall, these studies reveal how viruses evolve strategies to produce high-affinity binding and quality interactions with DDB1 to repurpose its Ub ligase machinery. IMPORTANCE Many different viruses modulate the protein machinery required for ubiquitination to enhance viral fitness. Specifically, several viruses hijack the cullin-RING ligase CRL4DDB1 to degrade host resistance factors. Human cytomegalovirus (HCMV) encodes pUL145 that redirects CRL4DDB1 to evade the immune system through the targeted degradation of the antiviral immune response protein STAT2. However, it is unclear why several viruses bind specific surfaces on ubiquitin ligases to repurpose their activity. We demonstrate that viruses have optimized H-box motifs that bind DDB1 with higher affinity than the H-box of native binders. For viral H-boxes, native interactions are maintained, but additional interactions that are absent in host cell H-boxes are formed, indicating that rewiring CRL4DDB1 creates a selective advantage for the virus. The DDB1-pUL145 peptide structure reveals that water-mediated interactions are critical to the higher affinity. Together, our data present an interesting example of how viral evolution can exploit a weakness in the ubiquitination machinery.

Efficacy and safety of hepatic artery infusion chemotherapy with mFOLFOX in primary liver cancer patients with hyperbilirubinemia and ineffective drainage: a retrospective cohort study.

Background: Hyperbilirubinemia is a major barrier to anti-tumor treatment in patients with end-stage primary liver cancer. However, no research has demonstrated the efficacy and safety of hepatic artery infusion chemotherapy (HAIC) in primary liver cancer patients with hyperbilirubinemia. This study investigated HAIC with a modified oxaliplatin, fluorouracil, and leucovorin (mFOLFOX) regimen. The efficacy and safety of the treatment regimen was evaluated and the optimal conditions for further anti-tumor treatments were identified. Methods: A total of 34 patients with hyperbilirubinemia (with an elevation of more than three times the upper limit of normal range in total bilirubin) who were not candidates for surgery, transplantation, tyrosine kinase inhibitor therapy, nor immune checkpoint inhibitor (ICI) therapy, and who received HAIC with the mFOLFOX regimen were enrolled in this study. The laboratory indexes (total bilirubin, tumor markers, and blood count), quality of life [World Health Organization Quality of Life (WHOQOL)-100 score], adverse reactions [Common Terminology Criteria for Adverse Events (CTCAE)-5.0], and overall survival were analyzed. Results: Between June 2017 and January 2021, 34 patients received a total of 81 cycles of HAIC after percutaneous transhepatic biliary drainage (PTBD). The total bilirubin (TBIL) decreased significantly at 1 month after the last cycle of HAIC (127.8 vs. 68.3 µmol/L; P<0.01). There was no significant decrease in platelet, white blood cell, nor red blood cell counts, suggesting that HAIC had limited toxicity on the hematopoietic system. The WHOQOL-100 score significantly increased at 3 months after HAIC (78.16 vs. 69.26; P<0.05). The median overall survival was 9.5 months (range, 2-24 months), the objective response rate was 14.7%, and the disease control rate was 61.8% in HAIC-treated patients. A total of 14 patients received targeted or immunological therapy after HAIC, and 2 of these patients achieved complete remission. Conclusions: HAIC improved the liver function and the quality of life in patients with liver cancer and hyperbilirubinemia, which provided options for further anti-tumor treatments in such patients.

Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses.

As one of the most induced genes in activated macrophages, immune-responsive gene 1 (IRG1) encodes a mitochondrial metabolic enzyme catalysing the production of itaconic acid (ITA). Although ITA has an anti-inflammatory property, the underlying mechanisms are not fully understood. Here we show that ITA is a potent inhibitor of the TET-family DNA dioxygenases. ITA binds to the same site on TET2 as the co-substrate α-ketoglutarate, inhibiting TET2 catalytic activity. Lipopolysaccharide treatment, which induces Irg1 expression and ITA accumulation, inhibits Tet activity in macrophages. Transcriptome analysis reveals that TET2 is a major target of ITA in suppressing lipopolysaccharide-induced genes, including those regulated by the NF-κB and STAT signalling pathways. In vivo, ITA decreases the levels of 5-hydroxymethylcytosine, reduces lipopolysaccharide-induced acute pulmonary oedema as well as lung and liver injury, and protects mice against lethal endotoxaemia, depending on the catalytic activity of Tet2. Our study thus identifies ITA as an immune modulatory metabolite that selectively inhibits TET enzymes to dampen the inflammatory responses.

Assessment of efficacy and safety by CalliSpheres versus HepaSpheres for drug-eluting bead transarterial chemoembolization in unresectable large hepatocellular carcinoma patients.

This study aimed to compare efficacy and safety of HepaSpheres and CalliSpheres in unresectable large hepatocellular carcinoma (HCC) patients. One hundred and twenty-seven unresectable large HCC patients receiving drug-eluting bead transarterial chemoembolization (DEB-TACE) treatment with CalliSpheres or HepaSpheres microspheres were analyzed. Treatment response, Karnofsky performance status (KPS) score, adverse events, main liver function indexes, time to progression (TTP), and overall survival (OS) were analyzed. Objective response rate (82.7% vs. 63.8%, p=.030) and disease control rate (100.0% vs. 91.5%, p=.030) were increased in CalliSpheres group compared to HepaSpheres group at 1 month after treatment, while no difference was found between the two groups regarding treatment response at 3 or 6 months post treatment (all p>.05). The KPS score at 1, 3, and 6 months was similar between the two groups (all p>.05). As for the liver function, the ALT, AST, ALB, and TBIL levels at 7 and 30 days were of no difference between the two groups (all p>.05). In addition, the adverse events including nausea/vomiting, pain, fever, myelosuppression, biloma, and abscess were of no difference between the two groups, either (all p>.05). In terms of survival profile, there was no difference regarding TTP (6.3 months (95%CI: 5.9-6.6 months) vs. 6.0 months (95%CI: 5.6-6.4 months), p=.082) or OS (23.0 months (95%CI: 20.1-25.9 months) vs. 22.0 months (95%CI: 20.2-23.8 months), p=.571) between the two groups. In conclusion, CalliSpheres seems to be superior in short-term efficacy and equal in long-term efficacy as well as safety compared to HepaSpheres for DEB-TACE treatment in unresectable large HCC patients.

Changes in the Peripheral Blood Treg Cell Proportion in Hepatocellular Carcinoma Patients After Transarterial Chemoembolization With Microparticles.

Objective: Transarterial chemoembolization (TACE) stands for an ideal therapy for patients with intermediate stage HCC. This study was carried out to observe the effect of microparticles-transarterial chemoembolization (microparticles-TACE, m-TACE) on the immune function of hepatocellular carcinoma (HCC) patients by detecting the proportion of regulatory (Treg) cells in the peripheral blood of HCC patients before and after m-TACE, and to determine whether m-TACE has a positive regulatory effect on the immune function of HCC patients. Methods: 33 HCC patients treated with Gelatn Sponge Microparticles (GSMs-TACE) were enrolled. Flow cytometry was used to determine the proportion of Treg cells and CD4+/CD8+ T cells in peripheral blood of HCC patients 1 day before GSMs-TACE, 1 to 2 weeks and 3 to 5 weeks after GSMs-TACE, respectively. Results: The Tregs cell proportion of HCC patients was significantly higher than that of the healthy and cirrhosis controls and was associated with various clinical indicators of HCC patients. The Treg cell proportion in HCC patients with BCLC stage C was higher than that of stage B patients; The Treg cell proportion at 1 to 2 weeks postoperatively was 8.54 ± 1.27%, which was significantly lower than that before the GSMs-TACE. The Treg cell proportion at 3 to 5 weeks postoperatively was 7.59 ± 1.27%, which continued to decline. The ratio of CD4+/CD8+ T cells was 1.31 ± 0.56, 1.86 ± 0.73, 1.76 ± 0.58% (P<0.01) respectively. Conclusion: These results indicated that m-TACE could exert a positive regulatory effect on the anticancer immune function of HCC patients, which may be used in combination with immune adjuvant therapies to enhance the efficacy of HCC.

Genome-wide distribution and functions of the AAE complex in epigenetic regulation in Arabidopsis.

Heterochromatin is widespread in eukaryotic genomes and has diverse impacts depending on its genomic context. Previous studies have shown that a protein complex, the ASI1-AIPP1-EDM2 (AAE) complex, participates in polyadenylation regulation of several intronic heterochromatin-containing genes. However, the genome-wide functions of AAE are still unknown. Here, we show that the ASI1 and EDM2 mostly target the common genomic regions on a genome-wide level and preferentially interacts with genetic heterochromatin. Polyadenylation (poly(A) sequencing reveals that AAE complex has a substantial influence on poly(A) site usage of heterochromatin-containing genes, including not only intronic heterochromatin-containing genes but also the genes showing overlap with heterochromatin. Intriguingly, AAE is also involved in the alternative splicing regulation of a number of heterochromatin-overlapping genes, such as the disease resistance gene RPP4. We provided evidence that genic heterochromatin is indispensable for the recruitment of AAE in polyadenylation and splicing regulation. In addition to conferring RNA processing regulation at genic heterochromatin-containing genes, AAE also targets some transposable elements (TEs) outside of genes (including TEs sandwiched by genes and island TEs) for epigenetic silencing. Our results reveal new functions of AAE in RNA processing and epigenetic silencing, and thus represent important advances in epigenetic regulation.

AI-assisted CT imaging analysis for COVID-19 screening: Building and deploying a medical AI system.

The sudden outbreak of novel coronavirus 2019 (COVID-19) increased the diagnostic burden of radiologists. In the time of an epidemic crisis, we hope artificial intelligence (AI) to reduce physician workload in regions with the outbreak, and improve the diagnosis accuracy for physicians before they could acquire enough experience with the new disease. In this paper, we present our experience in building and deploying an AI system that automatically analyzes CT images and provides the probability of infection to rapidly detect COVID-19 pneumonia. The proposed system which consists of classification and segmentation will save about 30%-40% of the detection time for physicians and promote the performance of COVID-19 detection. Specifically, working in an interdisciplinary team of over 30 people with medical and/or AI background, geographically distributed in Beijing and Wuhan, we are able to overcome a series of challenges (e.g. data discrepancy, testing time-effectiveness of model, data security, etc.) in this particular situation and deploy the system in four weeks. In addition, since the proposed AI system provides the priority of each CT image with probability of infection, the physicians can confirm and segregate the infected patients in time. Using 1,136 training cases (723 positives for COVID-19) from five hospitals, we are able to achieve a sensitivity of 0.974 and specificity of 0.922 on the test dataset, which included a variety of pulmonary diseases.

A Role for PICKLE in the Regulation of Cold and Salt Stress Tolerance in Arabidopsis.

Arabidopsis PICKLE (PKL) is a putative CHD3-type chromatin remodeling factor with important roles in regulating plant growth and development as well as RNA-directed DNA methylation (RdDM). The role of PKL protein in plant abiotic stress response is still poorly understood. Here, we report that PKL is important for cold stress response in Arabidopsis. Loss-of-function mutations in the PKL gene lead to a chlorotic phenotype in seedlings under cold stress, which is caused by the alterations in the transcript levels of some chlorophyll metabolism-related genes. The pkl mutant also exhibits increased electrolyte leakage after freezing treatment. These results suggest that PKL is required for proper chilling and freezing tolerance in plants. Gene expression analysis shows that CBF3, encoding a key transcription factor involved in the regulation of cold-responsive genes, exhibits an altered transcript level in the pkl mutant under cold stress. Transcriptome data also show that PKL regulates the expression of a number of cold-responsive genes, including RD29A, COR15A, and COR15B, possibly through its effect on the expression of CBF3 gene. Mutation in PKL gene also results in decreased cotyledon greening rate and reduced primary root elongation under high salinity. Together, our results suggest that PKL regulates plant responses to cold and salt stress.

Changes in the frequency of myeloid-derived suppressor cells after transarterial chemoembolization with gelatin sponge microparticles for hepatocellular carcinoma.

PURPOSE: A series of clinical studies have established the safety and efficacy of transcatheter arterial chemoembolization (TACE) with gelatin sponge microparticles (GSMs) in treating hepatocellular carcinoma (HCC). HCC can lead to obvious necrosis inside tumors, especially larger ones, although it is unclear whether such necrotic tumor tissue can induce favorable immune reactions against the tumor. Myeloid-derived suppressor cells (MDSCs) have immunosuppressive functions and are currently considered a very important cell type affecting tumor immunity. This study observed changes in MDSC frequency in peripheral blood before and after GSM-TACE to evaluate the effect on the immune function of HCC patients. METHODS: Eight patients diagnosed with HCC underwent GSM-TACE treatment in the Hepatobiliary Interventional Department of Beijing Tsinghua Chang Gung Hospital, Beijing, China; we followed up with the patients over a period of 30 days post-surgery. We used flow cytometry (FCM) to quantify the frequency of MDSCs in peripheral blood before TACE, 10 days after surgery and 30 days after surgery. RESULTS: MDSC frequency after GSM-TACE had a significant downward trend. Pre-TACE, it was 30.73% ±â€¯11.93%, decreasing to 18.60% ±â€¯11.37% at 10 days after operation. This decrease was not statistically significant (P > 0.05). MDSC frequency was even lower 30 days after TACE (7.63% ±â€¯7.32%) than at 10 days after TACE (P < 0.05), and there was a significant difference compared with pre-TACE (P < 0.001). We evaluated tumor response at 30 days after GSM-TACE according to the Modified Response Evaluation Criteria in Solid Tumors (mRECIST), and all eight patients showed partial response (PR). CONCLUSION: Our results confirmed that GSM-TACE was beneficial for improving anti-tumor immunity in the treatment of HCC.

Corrigendum to "Changes in the frequency of myeloid-derived suppressor cells after transarterial chemoembolization with gelatin sponge microparticles for hepatocellular carcinoma" [J. Interv. Med. 2 (2019) 21-26].

[This corrects the article DOI: 10.1016/j.jimed.2019.05.006.].

Transarterial chemoembolization with gelatin sponge microparticles for barcelona clinic liver cancer Stage C and large hepatocellular carcinoma: Initial clinical experience.

OBJECTIVE: The purpose of this investigation is to present a preliminary clinical experience in transarterial chemoembolization (TACE) with gelatin sponge microparticles (GSMs) for barcelona clinic liver cancer (BCLC) Stage C and large hepatocellular carcinoma (HCC) patients in China. MATERIALS AND METHODS: Between August 2009 and August 2012, 20 BCLC Stage C HCC patients with tumor size ≥5 cm undergoing GSMs-TACE were retrospectively analyzed. Tumor response was evaluated using modified response evaluation criteria in solid tumors (mRECIST) with enhanced magnetic resonance/computed tomography imaging performed 4-6 weeks after each GSMs-TACE procedure. Kaplan-Meier curves were used to assess overall survival (OS). Complications postprocedure was also analyzed. RESULTS: In this cohort of 20 HCC patients, vascular invasion was present in 8 patients (40%), extrahepatic metastases in 6 patients (30%), and both in 6 individuals (30%). Median tumor size was 9.9 ± 3.2 cm. All procedures were successfully performed with minimal complications. The mean number of TACE per patient was 2.6 sessions (range 1-5). Median OS (mOS) was 14 months for the entire study population. Survival rates at 6 and 12 months were 85% and 73.7%, respectively. According to mRECIST criteria, follow-up images were obtained 6 months after initial GSMs-TACE. Five patients (25.0%) achieved complete response, 8 patients (40.0%) had partial response, 4 (20.0%) had stable disease, and 3 (15.0%) had progressive disease. The objective response rate for TACE was 65%. CONCLUSIONS: From our preliminary clinical experience, GSMs-TACE in the treatment of BCLC Stage C and large HCC appears to offer favorable survival and tumor response with low morbidity. However, further prospective studies are required to assess its safety and efficacy.

Structure determination and activity manipulation of the turfgrass ABA receptor FePYR1.

Turfgrass are widely cultivated ornamental plants that have important ecological, societal and economical values. However, many turfgrass species are susceptible to drought and demand frequent irrigation thus consuming large amounts of water. With the ultimate goal of improving drought resistance in turfgrass, we identified several ABA receptors in turfgrass that are important to mediate ABA signaling and drought stress response. The ABA receptor FePYR1 from turfgrass Festuca elata was demonstrated to bind ABA as a monomer. Crystal structure analysis revealed that FePYR1 recognizes and binds ABA by the common gate-latch-lock mechanism resembling the Arabidopsis ABA receptors, but the ABA binding pocket in FePYR1 shows discrepant residues resulting in different binding affinity to ABA. Structure-guided alterations of amino acid residues in FePYR1 generated ABA receptor variants with significantly increased ABA binding affinity. Expression of FePYR1 in Arabidopsis conferred enhanced drought resistance in the transgenic plants. These findings provided detailed information about FePYR1 and demonstrated that structure-assisted engineering could create superior ABA receptors for improving plant drought resistance. The detailed structural information of FePYR1 would also assist future rational design of small molecules targeting specific ABA receptors in economically important plant species.

Arabidopsis EDM2 promotes IBM1 distal polyadenylation and regulates genome DNA methylation patterns.

DNA methylation is important for the silencing of transposons and other repetitive elements in many higher eukaryotes. However, plant and mammalian genomes have evolved to contain repetitive elements near or inside their genes. How these genes are kept from being silenced by DNA methylation is not well understood. A forward genetics screen led to the identification of the putative chromatin regulator Enhanced Downy Mildew 2 (EDM2) as a cellular antisilencing factor and regulator of genome DNA methylation patterns. EDM2 contains a composite Plant Homeo Domain that recognizes both active and repressive histone methylation marks at the intronic repeat elements in genes such as the Histone 3 lysine 9 demethylase gene Increase in BONSAI Methylation 1 (IBM1) and is necessary for maintaining the expression of these genes by promoting mRNA distal polyadenylation. Because of its role in maintaining IBM1 expression, EDM2 is required for preventing CHG methylation in the bodies of thousands of genes. Our results thus increase the understanding of antisilencing, genome methylation patterns, and regulation of alternative RNA processing by intronic heterochromatin.

Graft-union development: a delicate process that involves cell-cell communication between scion and stock for local auxin accumulation.

Grafting is an ancient cloning method that has been used widely for thousands of years in agricultural practices. Graft-union development is also an intricate process that involves substantial changes such as organ regeneration and genetic material exchange. However, the molecular mechanisms for graft-union development are still largely unknown. Here, a micrografting method that has been used widely in Arabidopsis was improved to adapt it a smooth procedure to facilitate sample analysis and to allow it to easily be applied to various dicotyledonous plants. The developmental stage of the graft union was characterized based on this method. Histological analysis suggested that the transport activities of vasculature were recovered at 3 days after grafting (dag) and that auxin modulated the vascular reconnection at 2 dag. Microarray data revealed a signal-exchange process between cells of the scion and stock at 1 dag, which re-established the communication network in the graft union. This process was concomitant with the clearing of cell debris, and both processes were initiated by a wound-induced programme. The results demonstrate the feasibility and potential power of investigating various plant developmental processes by this method, and represent a primary and significant step in interpretation of the molecular mechanisms underlying graft-union development.