Ultrafast learning of four-node hybridization cycles in phylogenetic networks using algebraic invariants.

Motivation: The abundance of gene flow in the Tree of Life challenges the notion that evolution can be represented with a fully bifurcating process which cannot capture important biological realities like hybridization, introgression, or horizontal gene transfer. Coalescent-based network methods are increasingly popular, yet not scalable for big data, because they need to perform a heuristic search in the space of networks as well as numerical optimization that can be NP-hard. Here, we introduce a novel method to reconstruct phylogenetic networks based on algebraic invariants. While there is a long tradition of using algebraic invariants in phylogenetics, our work is the first to define phylogenetic invariants on concordance factors (frequencies of four-taxon splits in the input gene trees) to identify level-1 phylogenetic networks under the multispecies coalescent model. Results: Our novel hybrid detection methodology is optimization-free as it only requires the evaluation of polynomial equations, and as such, it bypasses the traversal of network space, yielding a computational speed at least 10 times faster than the fastest-to-date network methods. We illustrate our method's performance on simulated and real data from the genus Canis. Availability and implementation: We present an open-source publicly available Julia package PhyloDiamond.jl available at https://github.com/solislemuslab/PhyloDiamond.jl with broad applicability within the evolutionary community.

An oral triple pill-based cocktail effectively controls acute myeloid leukemia with high translation.

Acute myeloid leukemia (AML) is a deadly hematological malignancy characterized by oncogenic translational addiction that results in over-proliferation and apoptosis evasion of leukemia cells. Various chemo- and targeted therapies aim to reverse this hallmark, but most show only modest efficacy. Here we report a single oral pill containing a low-dose triple small molecule-based cocktail, a highly active anti-cancer therapy (HAACT) with unique mechanisms that can effectively control AML. The cocktail comprises oncogenic translation inhibitor HHT, drug efflux pump P-gpi ENC and anti-apoptotic protein Bcl-2i VEN. Mechanistically, the cocktail can potently kill both leukemia stem cells (LSC) and bulk leukemic cells via co-targeting oncogenic translation, apoptosis machinery, and drug efflux pump, resulting in deep and durable remissions of AML in diverse model systems. We also identified EphB4/Bcl-xL as the cocktail response biomarkers. Collectively, our studies provide proof that a single pill containing a triple combination cocktail might be a promising avenue for AML therapy.

High-precision dynamic three-dimensional shape measurement of specular surfaces based on deep learning.

In order to solve the difficulty of traditional phase measuring deflectometry (PMD) in considering precision and speed, an orthogonal encoding PMD method based on deep learning is presented in this paper. We demonstrate for, what we believe to be, the first time that deep learning techniques can be combined with dynamic-PMD and can be used to reconstruct high-precision 3D shapes of specular surfaces from single-frame distorted orthogonal fringe patterns, enabling high-quality dynamic measurement of specular objects. The experimental results prove that the phase and shape information measured by the proposed method has high accuracy, almost reaching the results obtained by the ten-step phase-shifting method. And the proposed method also has excellent performance in dynamic experiments, which is of great significance to the development of optical measurement and fabrication areas.

Deep learning-based Phase Measuring Deflectometry for single-shot 3D shape measurement and defect detection of specular objects.

Phase Measuring Deflectometry (PMD) and Structured-Light Modulation Analysis Technique (SMAT) perform effectively in shape and defect measurements of specular objects, but the difficulty of giving consideration to accuracy and speed has also restricted the further development and application of them. Inspired by recent successes of deep learning techniques for computational imaging, we demonstrate for the first time that deep learning techniques can be used to recover high-precision modulation distributions of specular surfaces from a single-frame fringe pattern under SMAT, enabling fast and high-quality defect detection of specular surfaces. This method can also be applied to recover higher-precision phase distributions of specular surfaces from a single-frame fringe pattern under PMD, so as to realize the 3D shape measurement. In this paper, we combine depthwise separable convolution, residual structure and U-Net to build an improved U-Net network. The experimental results prove that the method has excellent performance in the phase and modulation retrieval of specular surfaces, which almost reach the accuracy of the results obtained by ten-step phase-shifting method.

Aberrantly Activated APOBEC3B Is Associated With Mutant p53-Driven Refractory/Relapsed Diffuse Large B-Cell Lymphoma.

Tumor protein 53 (TP53) mutation predicts an unfavorable prognosis in diffuse large B-cell lymphoma (DLBCL), but the molecular basis for this association remains unclear. In several malignancies, the cytidine deaminase apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) has been reported to be associated with the TP53 G/C-to-A/T mutation. Here, we show that the frequency of this mutation was significantly higher in relapsed/refractory (R/R) than in non-R/R DLBCL, which was positively associated with the APOBEC3B expression level. APOBEC3B overexpression induced the TP53 G/C-to-A/T mutation in vitro, resulting in a phenotype similar to that of DLBCL specimens. Additionally, APOBEC3B-induced p53 mutants promoted the growth of DLBCL cells and enhanced drug resistance. These results suggest that APOBEC3B is a critical factor in mutant p53-driven R/R DLBCL and is therefore a potential therapeutic target.

A Selective Small-Molecule c-Myc Degrader Potently Regresses Lethal c-Myc Overexpressing Tumors.

MYC oncogene is involved in the majority of human cancers and is often associated with poor outcomes, rendering it an extraordinarily desirable target, but therapeutic targeting of c-Myc protein has been a challenge for >30 years. Here, WBC100, a novel oral active molecule glue that selectively degrades c-Myc protein over other proteins and potently kills c-Myc overexpressing cancer cells is reported. WBC100 targets the nuclear localization signal 1 (NLS1)-Basic-nuclear localization signal 2 (NLS2) region of c-Myc and induces c-Myc protein degradation through ubiquitin E3 ligase CHIP mediated 26S proteasome pathway, leading to apoptosis of cancer cells. In vivo, WBC100 potently regresses multiple lethal c-Myc overexpressing tumors such as acute myeloid leukemia, pancreatic, and gastric cancers with good tolerability in multiple xenograft mouse models. Identification of the NLS1-Basic-NLS2 region as a druggable pocket for targeting the "undruggable" c-Myc protein and that single-agent WBC100 potently regresses c-Myc overexpressing tumors through selective c-Myc proteolysis opens new perspectives for pharmacologically intervening c-Myc in human cancers.

Natural small molecule triptonide inhibits lethal acute myeloid leukemia with FLT3-ITD mutation by targeting Hedgehog/FLT3 signaling.

Acute myeloid leukemia harboring internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD AML) is a subset of highly aggressive malignancies with poor clinical outcome. Despite some advances in the development of FLT3 tyrosine kinase inhibitors (FLT3 inhibitors), most of FLT3-ITD AML patients suffer from lethal disease relapse, suggesting the requirement of novel targets and agents. Here we describe a natural small molecule, triptonide that can efficiently inhibit FLT3-ITD-driven AML in vitro and in vivo. Mechanistically, triptonide targeted Hedgehog/FLT3 signaling by inhibiting its critical effectors, which are GLI2, c-Myc and FLT3 and induced apoptosis of FLT3-ITD-driven leukemia cells. In addition, we also observed that triptonide activated tumor suppressor p53. In vivo, triptonide treatment markedly suppressed lethal FLT3-ITD-driven AML with good tolerance and prolonged survival time in orthotopic mouse model. Our studies identify Hedgehog/FLT3 axis as a novel target for treating FLT3-ITD-driven leukemia and demonstrate that triptonide is an active lead compound that can kill FLT3-ITD-driven leukemia cells.

Identification of the novel Np17 oncogene in human leukemia.

We previously defined the HERV-K Np9 as a viral oncogene. Here we report the discovery of a novel oncogene, Np17, which is homologous to the viral Np9 gene and predominantly present in Hominoidea. Np17 is located on chromosome 8, consists of 7 exons, and encodes a 16.8kDa nuclear protein with149 amino-acid residue. Functionally, knockdown of Np17 induced growth inhibition of leukemia cells, whereas enforced expression of Np17 promoted growth of leukemia cells in vitro and in vivo. In human leukemia, Np17 was detected in 59.65% (34/57) of acute myeloid leukemia (AML) patients examined and associated with refractory/relapsed AML. Mechanistically, Np17 decreased p53 levels and its mechanism might be involved in recruiting nuclear MDM2 to p53 for ubiquitin-mediated degradation. These findings reveal that Np17 is a novel oncogene associated with refractory/relapsed leukemia.

Photothermal and fluorescent dual-mode assay based on the formation of polydopamine nanoparticles for accurate determination of organophosphate pesticides.

A photothermal and fluorescent dual-mode assay for sensitive organophosphate pesticides (Ops) determination is reported based on alkaline phosphatase (ALP)-inhibition-induced formation of polydopamine (PDA) nanoparticles. In the presence of ALP, ascorbic acid 2-phosphate (AAP) can be catalyzed to produce ascorbic acid (AA). AA can reduce MnO2 nanosheets, further inhibiting the oxidation of dopamine (DA). Ops as an inhibitor for ALP activity prevents the formation of AA and the reduction of MnO2 nanosheets. Eventually, the formation of PDA nanoparticles is promoted. The inhibitory effect of Ops on ALP activity causes obvious changes of photothermal signals and fluorescence signal at 495 nm. The detection limit (LOD) of dimethoate is 0.1 µM. The method displays excellent sensing capability for the dimethoate assay in real water with good recoveries of 99.4-107.6%. Graphical abstract A photothermal and fluorescent dual-mode biosensor for sensitive Ops detection was reported based on alkaline phosphatase (ALP)-inhibition-induced formation of polydopamine (PDA) nanoparticles. The dual-mode method significantly improved the accuracy and reliability of the results.

The diagnostic and prognostic value of cell division cycle associated gene family in Hepatocellular Carcinoma.

Cell division cycle associated (CDCA) gene family plays an important role in cells. However, some researchers revealed that overexpression of CDCAs might contribute to the tumor progression in several cancers. Here, we analyzed the role of this gene family in hepatocellular carcinoma (HCC). We used several web tools and found that most of CDCAs were highly expressed in tumor tissues compared to the paracancer tissues in HCC. We then used RT-qPCR to confirm our results. The results showed that CDCA2, CDCA3, CDCA5 and CDCA8 were up-regulated in HCC. We also found that these genes were associated with poor overall survival and relapse free survival except CDCA7. The functional analysis showed that this gene family might take part in many processes, including cell division, apoptosis, DNA damage and DNA repair, which might contribute to the tumor progression. The KEGG pathway analysis showed that these genes participated in several important pathways such as PI3K-Akt signaling pathway and hippo signaling pathway. In conclusion, our findings suggested that CDCA2, CDCA3, CDCA4, CDCA5, and CDCA8 might have potential diagnostic and prognostic values for hepatocellular carcinoma.

DNA Hydrogelation-Enhanced Imaging Ellipsometry for Sensing Exosomal microRNAs with a Tunable Detection Range.

Conventional imaging ellipsometry-based biosensing faces the challenges of poor sensitivity and narrow dynamic range, especially for some small molecules such as microRNA. Given that detection of various exosomal miRNAs with tunable range could provide high-precision disease information and improve the accuracy of diagnosis, a sensitive imaging ellipsometry sensor was introduced to improve sensitivity with a tunable detection range by terminus-regulated DNA hydrogelation. Tetrahedron DNA probes with complementary sequence to the target miRNA were used as biorecognition elements to form DNA hydrogelation. This DNA hydrogelation was formed by template-independent and isothermal amplification on the Au film. Due to its high dielectric constant, DNA hydrogelation structure could be used for improving the sensitivity of imaging ellipsometry significantly. Importantly, by changing the cycle of the DNA hydrogelation amplification, this strategy showed a tunable detection range from fM to nM for miRNA with a limit of detection of 0.2 fM for let-7a, 10 fM for miR-375, and 40 pM for miR-21. Furthermore, it also performed satisfactorily for the miRNA sensing in 50% human serum and 50% human plasma. This DNA hydrogelation-enhanced imaging ellipsometry could broaden the applications of conventional imaging ellipsometry in biosensing and provide a sensitive method for sensing miRNAs at different abundances.

CAMKIIγ is a targetable driver of multiple myeloma through CaMKIIγ/ Stat3 axis.

Aberrant activation of CAMKIIγ has been linked to leukemia and T-cell lymphoma, but not multiple myeloma (MM). The purpose of this study was to explore the role of CaMKIIγ in the pathogenesis and therapy of MM. In this study, we found that CaMKIIγ was aberrantly activated in human MM and its expression level was positively correlated with malignant progression and poor prognosis. Ectopic expression of CaMKIIγ promoted cell growth, colony formation, cell cycle progress and inhibited apoptosis of MM cell lines, whereas, knockdown of CAMKIIγ expression suppressed MM cell growth in vitro and in vivo. Mechanically, we observed that CaMKIIγ overexpression upregulated p-ERK and p-Stat3 levels and suppression of CaMKIIγ had opposite effects. CaMKIIγ is frequently dysregulated in MM and plays a critical role in maintaining MM cell growth through upregulating STAT3 signaling pathway. Furthermore, our preclinical studies suggest that CaMKIIγ is a potential therapeutic target in MM, and could be intervened pharmacologically by small-molecule berbamine analogues.

Aberrant activation of RPB1 is critical for cell overgrowth in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a group of highly aggressive malignancies with a 5-year overall survival of less than 40%. Cell overgrowth with defective apoptosis is a hallmark of AML, but little is known about how it occurs. Here, we show that aberrant activation of the largest subunit of RNA polymerase II (RPB1) encoded by POLR2A gene is critically involved in this hallmark. We retrospectively analyzed the expression profiles of POLR2A and RPB1 in a panel of AML cell lines, primary AML patients and peripheral blood samples. Meanwhile, correlation analysis was used to explore the correlation between the expression of RPB1 with tumor burden and overall survival time in untreated AML samples. RNA-Seq approach was performed to identify the differentially expressed genes between RPB1 silencing AML cells with control cells after knocking out RPB1. Furthermore, orthotopic AML models were established with RPB1 silencing and control cells to investigate the effects of RPB1 protein level on leukemia cell growth. In most AML patients, RPB1 was aberrantly activated and closely associated with poor prognosis, but not in normal hematopoietic cells. Global transcriptomic analysis revealed that POLR2A knockout strongly impaired growth of AML cells by selectively depleting a substantial set of AML-related oncogenic and anti-apoptosis genes such as MYC, RUNX2, MEIS1, CDC25A and BCL-2. Silencing RPB1 by genetic technology led to a potent regression of human refractory AML in mouse models. These findings reveal that dysregulated RPB1 is a central oncogenic hub that drives overgrowth by hijacking an array of oncogenic and anti-apoptosis factors. Targeting RPB1 is a potential therapeutic for treating AML.

Novel synthetic tosyl chloride-berbamine regresses lethal MYC-positive leukemia by targeting CaMKIIγ/Myc axis.

Proto-oncogene Myc, a key transcription factor, is frequently deregulated in human leukemia with aggressive and poor clinical outcome, but the development of MYC inhibitors remains challenging due to MYC helix-loop-helix topology lacking druggable domains. Here we describe a novel oral active small molecule analog of berbamine, tosyl chloride-berbamine (TCB), that efficiently eliminates MYC-positive leukemia in vitro and in vivo. Mechanistically, TCB potently reduced MYC protein by inhibiting CaMKIIγ, a critical enzyme that stabilizes MYC protein, and induces apoptosis of MYC-positive leukemia cells. In vivo, oral administration of TCB markedly eliminated lethal MYC-positive acute lymphoblastic leukemia (ALL) with well tolerability in orthotopic mouse model. Our studies identify CaMKIIγ/Myc axis as a valid target for developing small molecule-based new therapies for treating MYC-mediated leukemia and demonstrate that TCB is an orally active analog of berbamine that kills MYC-positive leukemia cells.

Clinical characteristics and outcomes of primary adrenal diffuse large B cell lymphoma in a large contemporary cohort: a SEER-based analysis.

Primary adrenal lymphoma (PAL) is an extremely rare lymphoma, and the most common histologic type is diffuse large B cell lymphoma (DLBCL). Primary adrenal DLBCL has a quite poor prognosis, but the prognostic determinants are rarely reported. With the Surveillance, Epidemiology, and End Results (SEER) program, we collected the demographic, clinical, therapeutic information of patients with primary adrenal DLBCL from 1983 to 2015. The Kaplan-Meier method was used to obtain overall survival (OS) and cause-specific survival (CSS) curves. The prognostic values of OS and CSS were assessed using Cox proportional hazards regression model with univariate and multivariate analyses. A total of 136 patients were included in our cohort. Adrenal DLBCL predominantly affected male and the aged, and there was a high rate of unilateral adrenal origin. The patients were more likely to present advanced stage disease. The OS rates of the entire cohort of patients with adrenal DLBCL at 5 and 10 years were respectively 19.17% and 3.33%, and the similar results were shown in 5-year and 10-year CSS rates. Age more than 70 years old and bilateral were identified as independent prognostic factors that were correlated with both adverse OS and CSS, and patients with chemotherapy had a superior OS and CSS to the patients without any treatment.

Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia.

As a heterogeneous group of clonal disorders, acute myeloid leukemia with internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) mutation usually shows an inferior prognosis. In the present study, we found that homoharringtonine (HHT), a protein translation inhibitor of plant alkaloid in China, exhibited potent cytotoxic effect against FLT3-ITD (+) cell lines and primary leukemia cells, and a remarkable synergistic anti-leukemia action was demonstrated in vitro and in vivo in xenograft mouse models when co-treated with the heat shock protein 90 inhibitor IPI504. Mechanistically, HHT combined with IPI504 synergistically inhibited the growth of leukemia cells by inducing apoptosis and G1 phase arrest. This synergistic action resulted in a prominent reduction of total and phosphorylated FLT3 (p-FLT3) as well as inhibition of its downstream signaling molecules such as STAT5, AKT, ERK and 4E-BP1. Furthermore, co-treatment of HHT and IPI504 led to a synergistic or additive effect on 55.56%(10/18) of acute myeloid leukemia cases tested, including three relapsed/refractory patients. In conclusion, our findings indicate that the combination of HHT and HSP90 inhibitor provides an alternative way for the treatment of FLT3-ITD positive acute myeloid leukemia, especially for relapsed/refractory AML.

BCL6 Rearrangement Indicates Poor Prognosis in Diffuse Large B-cell Lymphoma Patients: A Meta-analysis of Cohort Studies.

BCL6 (3q27) rearrangement is the most frequent chromosomal abnormality in diffuse large B-cell lymphoma (DLBCL). Previously, studies on the association between BCL6 rearrangement and DLBCL outcome remain controversial. Here we systematically reviewed literatures to identify the prognostic significance of BCL6 rearrangement in DLBCL. Meta-analytic methods are used to obtain pooled estimates of the association between BCL6 rearrangement and prognosis in DLBCL patients treated with different chemotherapy regimens. A total of 22 studies are enrolled in the cohort, involving 3037 patients. BCL6 rearrangement is verified to be negatively associated with overall survival (OS) (HR=1.36, p=0.000), but not with progression-free survival (PFS). Moreover, the subgroup analyses show that BCL6 rearrangement is prognostic only in DLBCLs treated with rituximab-containing regimens.

Identification of the UBA2-WTIP fusion gene in acute myeloid leukemia.

Identifying and targeting oncogenic fusion genes have revolutionized the treatment of leukemia, such as PML-RARα fusion gene in acute promyelocytic leukemia. Here we identified an intrachromosomal fusion gene located on chromosome 19q.13 between UBA2 and WTIP gene in a case of acute myeloid leukemia. The UBA2-WTIP fusion gene contains the N-terminal E1_enzyme_family, VAE_Ubl domains of UBA2, and the C-terminal LIM domains of WTIP. The UBA2-WTIP fusion was detected by reverse transcriptase polymerase chain reaction and Sanger sequencing in 19 of 56 acute myeloid leukemia samples (33.9%). Ectopic expression of the UBA2-WTIP fusion in human acute myeloid leukemia KG-1a cells showed enhanced cell proliferation both in vitro and in vivo. The UBA2-WTIP fusion induced phosphorylation of STAT3, STAT5 and ERK1/2, and abrogates WTIP-mediated mammalian processing body formation. Finally, triptolide displayed selective cytotoxicity against KG-1a cells harboring the UBA2-WTIP fusion. Collectively, our findings suggest that the UBA2-WTIP fusion is an oncogenic fusion gene, as well as a promising therapeutic target for the treatment of acute myeloid leukemia.

Activation of CaMKIIγ potentiates T-cell acute lymphoblastic leukemia leukemogenesis via phosphorylating FOXO3a.

Ca2+/calmodulin-dependent protein kinase II γ (CaMKIIγ) can regulate the proliferation and differentiation of myeloid leukemia cells and accelerate chronic myeloid leukemia blast crisis, but the role of CaMKIIγ in T-cell acute lymphoblastic leukemia (T-ALL) leukemogenesis remains poorly understood. We observed that activated (autophosphorylated) CaMKIIγ was invariably present in T-ALL cell lines and in the majority of primary T-ALL samples. Overexpression of CaMKIIγ enhanced the proliferation, colony formation, in vivo tumorigenesis and increased DNA damage of T-ALL leukemia cells. Furthermore, inhibition of CaMKIIγ activity with a pharmacologic inhibitor, gene knock-out, dominant-negative constructs or enhancement of CaMKIIγ activity by overexpression constructs revealed that the activated CaMKIIγ could phosphorylate FOXO3a. In Jurkat cells, the activated CaMKIIγ phosphorylated FOXO3a via directly or indirectly phosphorylating AKT, excluded FOXO3a from the nucleus and inhibited its transcriptional activity. These results indicate that the activated CaMKIIγ may play a key role in T-ALL leukemogenesis, and targeting CaMKIIγ might be a value approach in the treatment of T-ALL.