Targeting DNMT3A-mediated oxidative phosphorylation to overcome ibrutinib resistance in mantle cell lymphoma.

The use of Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib achieves a remarkable clinical response in mantle cell lymphoma (MCL). Acquired drug resistance, however, is significant and affects long-term survival of MCL patients. Here, we demonstrate that DNA methyltransferase 3A (DNMT3A) is involved in ibrutinib resistance. We find that DNMT3A expression is upregulated upon ibrutinib treatment in ibrutinib-resistant MCL cells. Genetic and pharmacological analyses reveal that DNMT3A mediates ibrutinib resistance independent of its DNA-methylation function. Mechanistically, DNMT3A induces the expression of MYC target genes through interaction with the transcription factors MEF2B and MYC, thus mediating metabolic reprogramming to oxidative phosphorylation (OXPHOS). Targeting DNMT3A with low-dose decitabine inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting DNMT3A-mediated metabolic reprogramming to OXPHOS with decitabine provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory MCL.

A Non-Flammable and Flexible Aluminum Derived Lithium-Ion Storage Device with a Wide Temperature Range of Operation.

With the rapid development and increasing popularity of electric vehicles and wearables, battery safety has become a leading focus in the field of energy storage research. Specifically, aluminum-ion batteries are gaining increasing attention as low-cost energy-storage systems with high safety levels and theoretical energy density. However, the dense alumina passivation layer on the aluminum anode surface and slow kinetic performance of commonly used ionic liquid electrolytes still render poor performance. This report presents a new type of aluminum-derived lithium-ion battery (ALIB) that maintains a certain discharge performance under damaging conditions, including continuous bending, high- and low-temperature environments, and shearing. This new ALIB effectively meets the current demand for flexible and wearable batteries. The prepared ALIB achieves a stable cycle of 130 mAh g-1 specific capacity and ≈260 Wh kg-1 theoretical energy density at a wide voltage platform of 2 V and a test temperature of 25 °C without undergoing combustion. Additionally, the study analyzes the reaction mechanism of this ALIB based on density functional theory and conducts ex situ XRD and XPS analyses to elucidate the underlying storage mechanism.

EGR1-mediated metabolic reprogramming to oxidative phosphorylation contributes to ibrutinib resistance in B-cell lymphoma.

The use of Bruton tyrosine kinase inhibitors, such as ibrutinib, to block B-cell receptor signaling has achieved a remarkable clinical response in several B-cell malignancies, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). Acquired drug resistance, however, is significant and affects the long-term survival of these patients. Here, we demonstrate that the transcription factor early growth response gene 1 (EGR1) is involved in ibrutinib resistance. We found that EGR1 expression is elevated in ibrutinib-resistant activated B-cell-like subtype DLBCL and MCL cells and can be further upregulated upon ibrutinib treatment. Genetic and pharmacological analyses revealed that overexpressed EGR1 mediates ibrutinib resistance. Mechanistically, TCF4 and EGR1 self-regulation induce EGR1 overexpression that mediates metabolic reprogramming to oxidative phosphorylation (OXPHOS) through the transcriptional activation of PDP1, a phosphatase that dephosphorylates and activates the E1 component of the large pyruvate dehydrogenase complex. Therefore, EGR1-mediated PDP1 activation increases intracellular adenosine triphosphate production, leading to sufficient energy to enhance the proliferation and survival of ibrutinib-resistant lymphoma cells. Finally, we demonstrate that targeting OXPHOS with metformin or IM156, a newly developed OXPHOS inhibitor, inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting EGR1-mediated metabolic reprogramming to OXPHOS with metformin or IM156 provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory DLBCL or MCL.

Self-supervised deep clustering of single-cell RNA-seq data to hierarchically detect rare cell populations.

Single-cell RNA sequencing (scRNA-seq) is a widely used technique for characterizing individual cells and studying gene expression at the single-cell level. Clustering plays a vital role in grouping similar cells together for various downstream analyses. However, the high sparsity and dimensionality of large scRNA-seq data pose challenges to clustering performance. Although several deep learning-based clustering algorithms have been proposed, most existing clustering methods have limitations in capturing the precise distribution types of the data or fully utilizing the relationships between cells, leaving a considerable scope for improving the clustering performance, particularly in detecting rare cell populations from large scRNA-seq data. We introduce DeepScena, a novel single-cell hierarchical clustering tool that fully incorporates nonlinear dimension reduction, negative binomial-based convolutional autoencoder for data fitting, and a self-supervision model for cell similarity enhancement. In comprehensive evaluation using multiple large-scale scRNA-seq datasets, DeepScena consistently outperformed seven popular clustering tools in terms of accuracy. Notably, DeepScena exhibits high proficiency in identifying rare cell populations within large datasets that contain large numbers of clusters. When applied to scRNA-seq data of multiple myeloma cells, DeepScena successfully identified not only previously labeled large cell types but also subpopulations in CD14 monocytes, T cells and natural killer cells, respectively.

Polyphosphate as an antithrombotic target and hemostatic agent.

Polyphosphate (PolyP) is a polymer comprised of linear phosphate units connected by phosphate anhydride bonds. PolyP exists in a diverse range of eukaryotes and prokaryotes with varied chain lengths ranging from six to thousands of phosphate units. Upon activation, human platelets and neutrophils release short-chain PolyP, along with other components, to initiate the coagulation pathway. Long-chain PolyP derived from cellular or bacterial organelles exhibits higher proinflammatory and procoagulant effects compared to short-chain PolyP. Notably, PolyP has been identified as a low-hemorrhagic antithrombotic target since neutralizing plasma PolyP suppresses the thrombotic process without impairing the hemostatic functions. As an inorganic polymer without uniform steric configuration, PolyP is typically targeted by cationic polymers or recombinant polyphosphatases rather than conventional antibodies, small-molecule compounds, or peptides. Additionally, because of its procoagulant property, PolyP has been incorporated in wound-dressing materials to facilitate blood hemostasis. This review summarizes current studies on PolyP as a low-hemorrhagic antithrombotic target and the development of hemostatic materials based on PolyP.

In Vivo Surface-Enhanced Transmission Raman Spectroscopy under Maximum Permissible Exposure: Toward Photosafe Detection of Deep-Seated Tumors.

The detection of deep-seated lesions is of great significance for biomedical applications. However, due to the strong photon absorption and scattering of biological tissues, it is challenging to realize in vivo deep optical detections, particularly for those using the safe laser irradiance below clinical maximum permissible exposure (MPE). In this work, the combination of ultra-bright surface-enhanced Raman scattering (SERS) nanotags and transmission Raman spectroscopy (TRS) is reported to achieve the non-invasive and photosafe detection of "phantom" lesions deeply hidden in biological tissues, under the guidance of theoretical calculations showing the importance of SERS nanotags' brightness and the expansion of laser beam size. Using a home-built TRS system with a laser power density of 0.264 W cm-2 (below the MPE criteria), we successfully demonstrated the detection of SERS nanotags through up to 14-cm-thick ex vivo porcine tissues, as well as in vivo imaging of "phantom" lesions labeled by SERS nanotags in a 1.5-cm-thick unshaved mouse under MPE. This work highlights the potential of transmission Raman-guided identification and non-invasive imaging toward clinically photosafe cancer diagnoses.

NEIL3 promotes hepatoma epithelial-mesenchymal transition by activating the BRAF/MEK/ERK/TWIST signaling pathway.

Hepatocellular carcinoma (HCC) is among the most prevalent visceral neoplasms. So far, reliable biomarkers for predicting HCC recurrence in patients undergoing surgery are far from adequate. In the aim of searching for genetic biomarkers involved in HCC development, we performed analyses of cDNA microarrays and found that the DNA repair gene NEIL3 was remarkably overexpressed in tumors. NEIL3 belongs to the Fpg/Nei protein superfamily, which contains DNA glycosylase activity required for the base excision repair for DNA lesions. Notably, the other Fpg/Nei family proteins NEIL1 and NEIL2, which have the same glycosylase activity as NEIL3, were not elevated in HCC; NEIL3 was specifically induced to participate in HCC development independently of its glycosylase activity. Using RNA-seq and invasion/migration assays, we found that NEIL3 elevated the expression of epithelial-mesenchymal transition (EMT) factors, including the E/N-cadherin switch and the transcription of MMP genes, and promoted the invasion, migration, and stemness phenotypes of HCC cells. Moreover, NEIL3 directly interacted with the key EMT player TWIST1 to enhance invasion and migration activities. In mouse orthotopic HCC studies, NEIL3 overexpression also caused a prominent E-cadherin decrease, tumor volume increase, and lung metastasis, indicating that NEIL3 led to EMT and tumor metastasis in mice. We further found that NEIL3 induced the transcription of MDR1 (ABCB1) and BRAF genes through the canonical E-box (CANNTG) promoter region, which the TWIST1 transcription factor recognizes and binds to, leading to the BRAF/MEK/ERK pathway-mediated cell proliferation as well as anti-cancer drug resistance, respectively. In the HCC cohort, the tumor NEIL3 level demonstrated a high positive correlation with disease-free and overall survival after surgery. In conclusion, NEIL3 activated the BRAF/MEK/ERK/TWIST pathway-mediated EMT and therapeutic resistances, leading to HCC progression. Targeted inhibition of NEIL3 in HCC individuals with NEIL3 induction is a promising therapeutic approach. © 2022 The Pathological Society of Great Britain and Ireland.

Spatiotemporal gating of Stat nuclear influx by Drosophila Npas4 in collective cell migration.

Collective migration is important to embryonic development and cancer metastasis, but migratory and nonmigratory cell fate discrimination by differential activity of signal pathways remains elusive. In Drosophila oogenesis, Jak/Stat signaling patterns the epithelial cell fates in early egg chambers but later renders motility to clustered border cells. How Jak/Stat signal spatiotemporally switches static epithelia to motile cells is largely unknown. We report that a nuclear protein, Dysfusion, resides on the inner nuclear membrane and interacts with importin α/ß and Nup153 to modulate Jak/Stat signal by attenuating Stat nuclear import. Dysfusion is ubiquitously expressed in oogenesis but specifically down-regulated in border cells when migrating. Increase of nuclear Stat by Dysfusion down-regulation triggers invasive cell behavior and maintains persistent motility. Mammalian homolog of Dysfusion (NPAS4) also negatively regulates the nuclear accumulation of STAT3 and cancer cell migration. Thus, our finding demonstrates that Dysfusion-dependent gating mechanism is conserved and may serve as a therapeutic target for Stat-mediated cancer metastasis.

The promising novel therapies for familial hypercholesterolemia.

BACKGROUND: The incidence of premature atherosclerotic cardiovascular disease in familial hypercholesterolemia (FH) is high. In recent years, novel therapeutic modalities have shown significant lipid-lowering ability. In this paper, we summarize the recent developments in novel therapies for FH via the treatment of different targets and discuss the characteristics of each targeted therapy. Based on the process of protein synthesis, we attempt to summarize the direct-effect targets including protein, RNA, and DNA. METHODS: For this systematic review, relevant studies are assessed by searching in several databases including PubMed, Web of Science, Scopus, and Google Scholar. The publications of original researches are considered for screening. RESULTS: Most drugs are protein-targeted such as molecule-based and monoclonal antibodies, including statins, ezetimibe, alirocumab, evolocumab, and evinacumab. Both antisense oligonucleotide (ASO) and small interfering RNA (siRNA) approaches, such as mipomersen, vupanorsen, inclisiran, and ARO-ANG3, are designed to reduce the number of mRNA transcripts and then degrade proteins. DNA-targeted therapies such as adeno-associated virus or CRISPR-Cas9 modification could be used to deliver or edit genes to address a genetic deficiency and improve the related phenotype. CONCLUSION: While the therapies based on different targets including protein, RNA, and DNA are on different stages of development, the mechanisms of these novel therapies may provide new ideas for precision medicine.

Fluorescein Leakage and Optical Coherence Tomography Angiography Features of Microaneurysms in Diabetic Retinopathy.

RESULTS: Thirty-six, fifty-two, and seventy-nine MAs showed no, mild, and severe leakage on FA, respectively. Most MAs (61.7%) were centered in the inner nuclear layer. Cystoid spaces were observed adjacent to 60 (35.9%) MAs. MAs with severe leakage had a statistically higher flow proportion compared to MAs with no or mild leakage (both P < 0.001). Only 112 MAs (67.1%) were visualized in the OCTA en face images, while 165 MAs (98.8%) could be visualized in the OCT en face images. The location of MAs did not associate significantly with FA leakage status. The presence of nearby cystoid spaces and higher flow proportion by OCT B-scan with flow overlay correlated significantly with FA leakage status. CONCLUSION: The flow proportion of MAs observed on OCT B-scans with flow overlay might be a potential biomarker to identify leaking MAs. A combination of OCT B-scan, OCT en face, and OCTA en face images increased the detection rate of diabetic MAs in a noninvasive way.

Fluorescence turn-on immunosensing of HE4 biomarker and ovarian cancer cells based on target-triggered metal-enhanced fluorescence of carbon dots.

Rapid and sensitive detection of tumor biomarkers and cancer cells is of crucial importance for the early diagnosis and prognosis prediction of cancer. The present report describes a target-induced fluorescence enhancement immunosensor that utilizes the optical property of carbon dots (CDs) and the metal-enhanced fluorescence effect (MEF) property of silver nanoparticles (AgNPs) for the sensitive detection of the cancer biomarker human epididymis protein 4 (HE4) and ovarian cancer cells. Nitrogen and sulfur co-doped CDs with a quantum yield of 85.6% were prepared and served as the fluorophore in MEF. The HE4 antibody (Ab) specific to the HE4 antigen was linked covalently to the surface of the synthesized CDs as the capture. The HE4 Ab-conjugated AgNPs (AgNPs-Ab) were prepared and utilized as signal amplification elements. In the presence of the target HE4, composite sandwich structures were formed between the labeled CDs-Ab and AgNPs-Ab, which brought the CDs and AgNPs into proximity, resulting in the fluorescence of CDs enhancement owing to MEF. The intensity of fluorescence enhancement was positively correlated with the HE4 concentration in the clinically important range of 0.01-200 nM with a limit detection of 2.3 pM. Moreover, the immunosensor was also successfully applied to specific fluorescence labeling and quantitative determination of HE4-positive ovarian cancer cells. The proposed target-triggered MEF sensor platform demonstrated high sensitivity, excellent anti-interference ability, along with successful validation in complex biological matrices, providing a new approach for HE4 detection in early diagnosis and therapeutic monitoring.

CPAP enhances and maintains chronic inflammation in hepatocytes to promote hepatocarcinogenesis.

Chronic and persistent inflammation is a well-known carcinogenesis promoter. Hepatocellular carcinoma (HCC) is one of the most common inflammation-associated cancers; most HCCs arise in the setting of chronic inflammation and hepatic injury. Both NF-κB and STAT3 are important regulators of inflammation. Centrosomal P4.1-associated protein (CPAP), a centrosomal protein that participates primarily in centrosome functions, is overexpressed in HCC and can increase TNF-α-mediated NF-κB activation and IL-6-induced STAT3 activation. A transgenic (Tg) mouse model with hepatocyte-specific CPAP expression was established to investigate the physiological role of CPAP in hepatocarcinogenesis. Obvious inflammatory cell accumulation and fatty change were observed in the livers of CPAP Tg mice. The alanine aminotransferase (ALT) level and the expression levels of inflammatory genes, such as IL-6, IL-1ß and TNF-α, were higher in CPAP Tg mice than in wild type (WT) mice. High-dose/short-term treatment with diethylnitrosamine (DEN) increased the ALT level, proinflammatory gene expression levels, and STAT3 and NF-κB activation in CPAP Tg mice; low-dose/long-term DEN treatment induced more severe liver tumor formation in CPAP Tg mice than in WT mice. CPAP can increase the expression of chemokine (C-C motif) ligand 16 (CCL-16), an important chemotactic cytokine, in human hepatocytes. CCL-16 expression is positively correlated with CPAP and TNF-α mRNA expression in the peritumoral part of HCC. In summary, these results suggest that CPAP may promote hepatocarcinogenesis through enhancing the inflammation pathway via increasing the expression of CCL-16.

The LDLR c.501C>A is a disease-causing variant in familial hypercholesterolemia.

BACKGROUND: As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly attributed to disease-causing variants in the low-density lipoprotein receptor (LDLR) gene. The aim of this study was to explore the molecular mechanism of LDLR c.501C>A variant in FH and assess the efficacy of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor treatment for FH patients. METHODS: The whole-exome sequencing was performed on two families to identify disease-causing variants, which were verified by Sanger sequencing. The function of LDLR variant was further explored in HEK293 cells by Western Blot and confocal microscopy. Besides, the therapeutic effects of PCSK9 inhibitor treatment for two probands were assessed for 3 months. RESULTS: All members of the two families with the LDLR c.501C>A variant showed high levels of LDLC. The relationship between the clinical phenotype and LDLR variants was confirmed in the current study. Both in silico and in vitro analyses showed that LDLR c.501C>A variant decreased LDLR expression and LDL uptake. PCSK9 inhibitor treatment lowered the lipid level in proband 1 by 24.91%. However, the treatment was ineffective for proband 2. A follow-up study revealed that the PCSK9 inhibitor treatment had low ability of lipid-lowering effect in the patients. CONCLUSIONS: LDLR c.501C>A variant might be pathogenic for FH. The PCSK9 inhibitor therapy is not a highly effective option for treatment of FH patients with LDLR c.501C>A variant.

Downregulation of METTL7B Inhibits Proliferation of Human Clear Cell Renal Cancer Cells In Vivo and In Vitro.

Clear cell renal cell carcinoma (ccRCC) is the most aggressive urologic tumor, and its incidence and diagonosis have been continuously increasing. Identifying novel molecular biomarker for inhibiting the progression of ccRCC will facilitate developing new treatment strategies. Although methyltransferase-like 7B (METTL7B) was identified as a Golgi-associated methyltransferase, the function and mechanism of METTL7B in ccRCC development and progression has not been explored. METTL7B expression were significantly upregulated in ccRCC tissues (n = 60), which significantly associated with TNM classification, tumor size, lymph node metastasis, and poor prognosis for ccRCC patients. Functional studies showed downregulation of METTL7B inhibited cell proliferation, migration in vitro, and xenograft tumor formation in vivo. In addition, METTL7B knockdown promoted cell cycle arrest at G0/G1phase and induced cellular apoptosis. Taken together, downregulation of METTL7B inhibits ccRCC cell proliferation and tumorigenesis in vivo and in vitro. These findings provide a rationale for using METTL7B as a potential therapeutic target in ccRCC patients.

Epstein-Barr virus latent membrane protein-1 upregulates autophagy and promotes viability in Hodgkin lymphoma: Implications for targeted therapy.

Hodgkin lymphoma (HL) is composed of neoplastic Hodgkin and Reed-Sternberg cells in an inflammatory background. The neoplastic cells are derived from germinal center B cells that, in most cases, are infected by Epstein-Barr virus (EBV), which may play a role in tumorigenesis. Given that EBV-latent membrane protein 1 (LMP1) regulates autophagy in B cells, we explored the role of autophagy mediated by EBV or LMP1 in HL. We found that EBV-LMP1 transfection in HL cells induced a modest increase in autophagy signals, attenuated starvation-induced autophagic stress, and alleviated autophagy inhibition- or doxorubicin-induced cell death. LMP1 knockdown leads to decreased autophagy LC3 signals. A xenograft mouse model further showed that EBV infection significantly increased expression of the autophagy marker LC3 in HL cells. Clinically, LC3 was expressed in 15% (19/127) of HL samples, but was absent in all cases of nodular lymphocyte-predominant and lymphocyte-rich classic HL cases. Although expression of LC3 was not correlated with EBV status or clinical outcome, autophagic blockade effectively eradicated LMP1-positive HL xenografts with better efficacy than LMP1-negative HL xenografts. Collectively, these results suggest that EBV-LMP1 enhances autophagy and promotes the viability of HL cells. Autophagic inhibition may be a potential therapeutic strategy for treating patients with HL, especially EBV-positive cases.

Crystal structure of the yeast heterodimeric ADAT2/3 deaminase.

BACKGROUND: The adenosine-to-inosine (A-to-I) editing in anticodons of tRNAs is critical for wobble base-pairing during translation. This modification is produced via deamination on A34 and catalyzed by the adenosine deaminase acting on tRNA (ADAT) enzyme. Eukaryotic ADATs are heterodimers composed of the catalytic subunit ADAT2 and the structural subunit ADAT3, but their molecular assemblies and catalytic mechanisms are largely unclear. RESULTS: Here, we report a 2.8-Å crystal structure of Saccharomyces cerevisiae ADAT2/3 (ScADAT2/3), revealing its heterodimeric assembly and substrate recognition mechanism. While each subunit clearly contains a domain resembling their prokaryotic homolog TadA, suggesting an evolutionary gene duplication event, they also display accessory domains for additional structural or functional purposes. The N-lobe of ScADAT3 exhibits a positively charged region with a potential role in the recognition and binding of tRNA, supported by our biochemical analysis. Interestingly, ScADAT3 employs its C-terminus to block tRNA's entry into its pseudo-active site and thus inactivates itself for deamination despite the preservation of a zinc-binding site, a mechanism possibly shared only among yeasts. CONCLUSIONS: Combining the structural with biochemical, bioinformatic, and in vivo functional studies, we propose a stepwise model for the pathway of deamination by ADAT2/3. Our work provides insight into the molecular mechanism of the A-to-I editing by the eukaryotic ADAT heterodimer, especially the role of ADAT3 in catalysis.

Stem cell characteristics promote aggressiveness of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) may present initially in bone marrow, liver and spleen without any lymphadenopathy (referred to as BLS-type DLBCL), which is aggressive and frequently associated with hemophagocytic syndrome. Its tumorigenesis and molecular mechanisms warrant clarification. By gene microarray profiling with bioinformatics analysis, we found higher expression of the stem cell markers HOXA9 and NANOG, as well as BMP8B, CCR6 and S100A8 in BLS-type than conventional DLBCL. We further validated expression of these markers in a large cohort of DLBCL including BLS-type cases and found that expression of HOXA9 and NANOG correlated with inferior outcome and poor prognostic parameters. Functional studies with gene-overexpressed and gene-silenced DLBCL cell lines showed that expression of NANOG and HOXA9 promoted cell viability and inhibited apoptosis through suppression of G2 arrest in vitro and enhanced tumor formation and hepatosplenic infiltration in a tail-vein-injected mouse model. Additionally, HOXA9-transfected tumor cells showed significantly increased soft-agar clonogenic ability and tumor sphere formation. Interestingly, B cells with higher CCR6 expression revealed a higher chemotactic migration for CCL20. Taken together, our findings support the concept that tumor or precursor cells of BLS-type DLBCL are attracted by chemotaxis and home to the bone marrow, where the microenvironment promotes the expression of stem cell characteristics and aggressiveness of tumor cells.

CPAP promotes angiogenesis and metastasis by enhancing STAT3 activity.

Centrosomal P4.1-associated protein (CPAP) is overexpressed in hepatocellular carcinoma (HCC) and positively correlated with recurrence and vascular invasion. Here, we found that CPAP plays an important role in HCC malignancies. Functional characterization indicated that CPAP overexpression increases tumor growth, angiogenesis, and metastasis ex vivo and in vivo. In addition, overexpressed CPAP contributes to sorafenib resistance. Mechanical investigation showed that the expression level of CPAP is positively correlated with activated STAT3 in HCC. CPAP acts as a transcriptional coactivator of STAT3 by directly binding with STAT3. Interrupting the interaction between CPAP and STAT3 attenuates STAT3-mediated tumor growth and angiogenesis. Overexpression of CPAP upregulates several STAT3 target genes such as IL-8 and CD44 that are involved in angiogenesis, and CPAP mRNA expression is positively correlated with the levels of both mRNAs in HCC. Knocked-down expression of CPAP impairs IL-6-mediated STAT3 activation, target gene expression, cell migration, and invasion abilities. IL-6/STAT3-mediated angiogenesis is significantly increased by CPAP overexpression and can be blocked by decreased expression of IL-8. Our findings not only shed light on the importance of CPAP in HCC malignancies, but also provide potential therapeutic strategies for inhibiting the angiogenesis pathway and treating metastatic HCC.

A selective Aurora-A 5'-UTR siRNA inhibits tumor growth and metastasis.

Many Aurora-A inhibitors have been developed for cancer therapy; however, the specificity and safety of Aurora-A inhibitors remain uncertain. The Aurora-A mRNA yields nine different 5'-UTR isoforms, which result from mRNA alternative splicing. Interestingly, we found that the exon 2-containing Aurora-A mRNA isoforms are predominantly expressed in cancer cell lines as well as human colorectal cancer tissues, making the Aurora-A mRNA exon 2 a promising treatment target in Aurora-A-overexpressing cancers. In this study, a selective siRNA, siRNA-2, which targets Aurora-A mRNA exon 2, was designed to translationally inhibit the expression of Aurora-A in cancer cells but not normal cells; locked nucleic acid (LNA)-modified siRNA-2 showed improved efficacy in inhibiting Aurora-A mRNA translation and tumor growth. Xenograft animal models combined with noninvasion in vivo imaging system (IVIS) analysis further confirmed the anticancer effect of LNA-siRNA-2 with improved efficiency and safety and reduced side effects. Mice orthotopically injected with colorectal cancer cells, LNA-siRNA-2 treatment not only inhibited the tumor growth but also blocked liver and lung metastasis. The results of our study suggest that LNA-siRNA-2 has the potential to be a novel therapeutic agent for cancer treatment.

Angioimmunoblastic T-cell lymphoma in Taiwan reveals worse progression-free survival for RHOA G17V mutated subtype.

Angioimmunoblastic T-cell lymphoma (AITL) carries genetic mutations of TET2, RHOA, and IDH2, but the prognostic impact of these mutations is not widely investigated. Although one study shows no difference in overall survival between patients with or without RHOA G17V mutation, a poor performance status is associated with RHOA G17V-mutated AITL, which is an independent adverse factor. We retrospectively investigated the prognostic impact of RHOA G17V mutation in AITL patients. A total of 31 cases were enrolled (male-to-female, 2.1; mean age: 62.8 years). RHOA G17V mutation was analyzed by deep sequencing. We found that in contrast to RHOA-wild type, patients with RHOA G17V-mutated AITL more frequently had B symptoms (p = .035), stronger PD1 expression (p = .045), ≥3 TFH markers (p = .011), higher blood vessel density (p<.001), and poorer progression-free survival (p = .046). These results support a role for RHOA genetic testing in AITL patients as ROHA G17V mutation carries a worse prognosis, probably associated with B symptoms and stage IV disease.