CD7-positive leukemic blasts with DNMT3A mutations predict poor prognosis in patients with acute myeloid leukemia.

Background: DNMT3A mutations can be detected in premalignant hematopoietic stem cells and are primarily associated with clonal hematopoiesis of indeterminate potential; however, current evidence does not support assigning them to a distinct European Leukemia Net (ELN) prognostic risk stratification. CD7 is a lymphoid antigen expressed on blasts in approximately 30% of acute myeloid leukemia (AML), and its role in AML remains unclear and depends on subgroup evaluation. This study investigated the prognostic value of DNMT3A mutation combined with CD7 expression in AML. Methods: We retrospectively analyzed the clinical data of 297 newly diagnosed non-M3 AML patients. According to the DNMT3A mutation and CD7 expression in AML cells, patients were divided into the DNMT3A-mutated/CD7-positive (CD7+), DNMT3A-mutated/CD7-negative (CD7-), DNMT3A-wild-type/CD7+, and DNMT3A-wild-type/CD7- groups. Results: The DNMT3A-mutated/CD7+ group had lower complete remission rates and higher relapse rates. Importantly, these patients had significantly shorter overall survival (OS) and relapse-free survival (RFS). Furthermore, multivariate analysis showed that CD7+ with DNMT3A mutation was an independent risk factor for OS and RFS. Conclusion: CD7+ with DNMT3A mutation predicts a poor prognosis in AML patients, and the immunophenotype combined with molecular genetic markers can help to further refine the current risk stratification of AML.

High Red Blood Cell Distribution Width to Platelet Ratio is an Independent Poor Prognostic Factor in Patients with Newly Diagnosed Multiple Myeloma.

BACKGROUND: The red blood cell distribution width to platelet ratio (RPR) is an inflammatory marker that is a convenient and reliable prognostic indicator for several solid malignancies. However, the correlation between RPR and myeloma prognosis has not been reported. Therefore, this study aims to explore the correlation between RPR level and the prognosis of multiple myeloma (MM) patients. METHODS: We retrospectively analyzed 145 newly diagnosed patients with MM. The receiver operating characteristic curve (ROC) method was used to determine the RPR cut-off value. In addition, we studied the correlation between pre-treatment RPR levels and clinical characteristics, immunophenotype, cytogenetics, and its impact on the disease prognosis. RESULTS: The optimal cut-off value for RPR was 0.12 and was divided into high RPR and low RPR groups. Patients in the high RPR group are more likely to have anemia, thrombocytopenia, high ß2-macroglobulinemia, a high percentage of bone marrow plasma cells, late-stage status by Dury-Salmon (DS) and international staging system (ISS) (p < 0.05). More notably, between the high RPR and low RPR groups, the incidence rates of CD56-positive, D13S319-positive, RB1-positive, and 1q21 amplification were statistically significant (p < 0.05). Additionally, survival analysis revealed that compared with patients in the low RPR group, the median progression-free survival (PFS) and overall survival (OS) of patients in the high RPR group were substantially shortened (p < 0.05). Multivariate analysis confirmed that RPR ≥0.12, D13S319-positive, and 1q21 amplification were independent risk factors for poor PFS and OS. CONCLUSIONS: RPR is a practical and effective prognostic marker in newly diagnosed patients with MM, and a high RPR is an independent poor prognostic factor.

Differential effects of recombinant human thrombopoietin on clinical outcomes in CD7-positive and CD7-negative acute myeloid leukaemia.

To investigate the effect of recombinant human thrombopoietin (rhTPO) application on the clinical outcomes of CD7-positive acute myeloid leukaemia (CD7 + AML) patients following chemotherapy, we retrospectively studied 159 newly diagnosed non-M3 AML patients. Patients were divided into the following four groups according to the expression of CD7 in AML blasts and the use of rhTPO after chemotherapy: the CD7 + rhTPO group (n = 41), the CD7 + non-rhTPO group (n = 42), the CD7 negative (CD7-) rhTPO group (n = 37), and the CD7- non-rhTPO group (n = 39). The complete remission rate was higher in the CD7 + rhTPO group than in the CD7 + non-rhTPO group. Importantly, patients in the CD7 + rhTPO group had significantly higher 3-year overall survival (OS) rates and event-free survival (EFS) rates than those in the CD7 + non-rhTPO group, whereas they did not differ statistically between the CD7- rhTPO and CD7- non-rhTPO groups. In addition, multivariate analysis showed that rhTPO was an independent prognostic factor for OS and EFS in CD7 + AML. In conclusion, rhTPO led to better clinical outcomes for patients with CD7 + AML, while it had no significant effect on those with CD7- AML.

AXL upregulates c­Myc expression through AKT and ERK signaling pathways in breast cancers.

Breast cancer (BC) is common worldwide. c-Myc and AXL are both overexpressed in BC, promoting its progression. The present study aimed to investigate the role of AXL in c-Myc expression in BC. Overexpression of AXL increased c-Myc expression while knockdown of AXL decreased c-Myc expression as determined by western blot analysis. Pharmaceutical inhibition of AXL also suppressed c-Myc expression. AKT and ERK inhibitor LY294002 and U0126 suppressed c-Myc expression, respectively. AXL overexpression which activates AKT and ERK signaling, upregulates c-Myc expression, while kinase-dead AXL which cannot activate AKT and ERK signaling, does not upregulate c-Myc expression, emphasizing the important role of these two signaling pathways in c-Myc upregulation. Finally, expression data of BC tissues from The Cancer Proteome Atlas displayed an association between AXL and c-Myc. Taken together, the present study revealed that AXL upregulates c-Myc expression through AKT and ERK signaling pathways in BC.

Roles of PADI4 in the expression of cytokines involved in inflammation and adhesion in differentiated NB4 cells treated with ATRA.

Differentiation syndrome (DS) is a common complication in patients with acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA). However, the target of ATRA during DS in patients with APL remains to be elucidated. Therefore, the current study aimed to investigate the role of peptidylarginine deiminase 4 (PADI4) in the differentiation of ATRA-induced NB4 APL cells. The results showed that PADI4 was significantly upregulated in peripheral blood samples derived from patients with APL DS compared with patients with APL only. In addition, whether ATRA could enhance the expression levels of PADI4 in NB4 cells in vitro was subsequently investigated. The results also showed that PADI4 overexpression promoted the differentiation of NB4 cells treated with ATRA, which was reversed after PADI4 silencing. To uncover the potential mechanisms underlying the above process, PADI4 overexpression induced the secretion of inflammation-related cytokines, such as TNF-α, IL-1ß, IL-8, C-C motif chemokine (CCL)2, CCL4, CCR1 and intercellular adhesion molecule-1 in ATRA-treated NB4 cells. However, PADI4 knockdown in the same cells had the opposite effect. The above findings indicated that PADI4 could be involved in the differentiation of ATRA-induced NB4 cells and upregulation of cytokines.

SHP2 Inhibitors Show Anti-Myeloma Activity and Synergize With Bortezomib in the Treatment of Multiple Myeloma.

Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. The protein tyrosine phosphatase SHP2 is a central node regulating RAS/mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) signaling pathway which plays a crucial role in the pathogenesis and proteasome inhibitor (PI) resistance of MM. Several preclinical studies have demonstrated that SHP2 inhibitors exerted antitumor activity in cancer-harboring diverse mutations in the RAS pathway, offering the potential for targeting myeloma. In this study, we showed that pharmacological inhibition of SHP2 activity using SHP099 and RMC-4550 efficiently inhibited the proliferation of MM cells by inducing apoptosis and cell cycle arrest. As per the mechanism, SHP2 inhibitors activated the level of cleaved caspase3, BAK, and P21 and downregulated ERK phosphorylation in MM cells. Moreover, the blockade of SHP2 exhibited anti-myeloma effect in vivo in a mouse xenograft model. In addition, SHP2 inhibitors synergized the antineoplastic effect of bortezomib in bortezomib-sensitive MM cells and showed identical efficacy in targeting bortezomib-resistant MM cells. Overall, our findings suggest that SHP2-specific inhibitors trigger anti-myeloma activity in vitro and in vivo by regulating the ERK pathway and enhancing cytotoxicity of bortezomib, providing therapeutic benefits for both bortezomib naïve and resistant MM.

Corrections to "iPhantom: A Framework for Automated Creation of Individualized Computational Phantoms and its Application to CT Organ Dosimetry".

In [1], the dose estimation accuracy using the alternative baseline method under modulated tube current was not correctly calculated due to an unintentional simulation error.

iPhantom: A Framework for Automated Creation of Individualized Computational Phantoms and Its Application to CT Organ Dosimetry.

OBJECTIVE: This study aims to develop and validate a novel framework, iPhantom, for automated creation of patient-specific phantoms or "digital-twins (DT)" using patient medical images. The framework is applied to assess radiation dose to radiosensitive organs in CT imaging of individual patients. METHOD: Given a volume of patient CT images, iPhantom segments selected anchor organs and structures (e.g., liver, bones, pancreas) using a learning-based model developed for multi-organ CT segmentation. Organs which are challenging to segment (e.g., intestines) are incorporated from a matched phantom template, using a diffeomorphic registration model developed for multi-organ phantom-voxels. The resulting digital-twin phantoms are used to assess organ doses during routine CT exams. RESULT: iPhantom was validated on both with a set of XCAT digital phantoms (n = 50) and an independent clinical dataset (n = 10) with similar accuracy. iPhantom precisely predicted all organ locations yielding Dice Similarity Coefficients (DSC) 0.6 - 1 for anchor organs and DSC of 0.3-0.9 for all other organs. iPhantom showed <10% errors in estimated radiation dose for the majority of organs, which was notably superior to the state-of-the-art baseline method (20-35% dose errors). CONCLUSION: iPhantom enables automated and accurate creation of patient-specific phantoms and, for the first time, provides sufficient and automated patient-specific dose estimates for CT dosimetry. SIGNIFICANCE: The new framework brings the creation and application of CHPs (computational human phantoms) to the level of individual CHPs through automation, achieving wide and precise organ localization, paving the way for clinical monitoring, personalized optimization, and large-scale research.

Using Graphlet Spectrograms for Temporal Pattern Analysis of Virus-Research Collaboration Networks.

We introduce a new method for temporal pattern analysis of scientific collaboration networks. We investigate in particular virus research activities through five epidemic or pandemic outbreaks in the recent two decades and in the ongoing pandemic with COVID-19. Our method embodies two innovative components. The first is a simple model of temporal collaboration networks with time segmented in publication time and convolved in citation history, to effectively capture and accommodate collaboration activities at mixed time scales. The second component is the novel use of graphlets to encode topological structures and to detect change and persistence in collaboration activities over time. We discover in particular two unique and universal roles of bi-fork graphlet in (1) identifying bridges among triangle clusters and (2) quantifying grassroots as the backbone of every collaboration network. We present a number of intriguing patterns and findings about the virus-research activities.

Iterative inversion of deformation vector fields with feedback control.

PURPOSE: Often, the inverse deformation vector field (DVF) is needed together with the corresponding forward DVF in four-dimesional (4D) reconstruction and dose calculation, adaptive radiation therapy, and simultaneous deformable registration. This study aims at improving both accuracy and efficiency of iterative algorithms for DVF inversion, and advancing our understanding of divergence and latency conditions. METHOD: We introduce a framework of fixed-point iteration algorithms with active feedback control for DVF inversion. Based on rigorous convergence analysis, we design control mechanisms for modulating the inverse consistency (IC) residual of the current iterate, to be used as feedback into the next iterate. The control is designed adaptively to the input DVF with the objective to enlarge the convergence area and expedite convergence. Three particular settings of feedback control are introduced: constant value over the domain throughout the iteration; alternating values between iteration steps; and spatially variant values. We also introduce three spectral measures of the displacement Jacobian for characterizing a DVF. These measures reveal the critical role of what we term the nontranslational displacement component (NTDC) of the DVF. We carry out inversion experiments with an analytical DVF pair, and with DVFs associated with thoracic CT images of six patients at end of expiration and end of inspiration. RESULTS: The NTDC-adaptive iterations are shown to attain a larger convergence region at a faster pace compared to previous nonadaptive DVF inversion iteration algorithms. By our numerical experiments, alternating control yields smaller IC residuals and inversion errors than constant control. Spatially variant control renders smaller residuals and errors by at least an order of magnitude, compared to other schemes, in no more than 10 steps. Inversion results also show remarkable quantitative agreement with analysis-based predictions. CONCLUSION: Our analysis captures properties of DVF data associated with clinical CT images, and provides new understanding of iterative DVF inversion algorithms with a simple residual feedback control. Adaptive control is necessary and highly effective in the presence of nonsmall NTDCs. The adaptive iterations or the spectral measures, or both, may potentially be incorporated into deformable image registration methods.

Effect of Rta protein of Epstein-Barr virus on the cell cycle in HeLa cells.

Epstein-Barr virus (EBV) replication and transcription activator (Rta) is an immediate-early transcription factor that mediates the switch from latent to lytic infection. DNA viruses often modulate the function of critical cell cycle proteins to maximize the efficiency of virus replication. Here we have examined the effect of Rta on cell cycle progression. Cell cycle analysis revealed that Rta induced HeLa cells in G0/G1-phase to reenter the S-phase. Analysis of the expression pattern of a key set of cell cycle regulators revealed that expression of Rta inhibited the expression of Rb and p53 and induced the expression of E2F1. These findings suggest that Rta plays an active role in redirecting HeLa cell physiology through an Rta-mediated cell cycle transformation.

Cisplatin-enhanced sensitivity of glioblastoma multiforme U251 cells to adenovirus-delivered TRAIL in vitro.

TRAIL is a novel therapeutic agent for potential use in glioblastoma multiforme therapy; however, glioblastoma multiforme cells exhibit resistance to TRAIL-induced apoptosis. To evaluate the effects of cisplatin on sensitivity of human glioma cell line U251 to Ad-TRAIL and to investigate the potential mechanism, U251 cells were transfected with Ad-TRAIL and then exposed to cisplatin. The proliferation inhibition of the treated cells was studied by the method of MTT. The cell apoptosis was analyzed by Hoechst33342 staining and by flow cytometry with propidium iodide staining. Semi-quantitative RT-PCR was introduced to detect the mRNA expression of TRAIL, DR4, DR5, Caspase 3, and survivin. Protein expression of DR5 and cleaved Caspase 3 was detected by Western blot assay. The results showed that the combination treatment of cisplatin and Ad-TRAIL could inhibit the proliferation of U251 cells significantly compared with the alone treatment (P < 0.01), which was chiefly attributed to the induction of obvious apoptosis. The enhancement of Ad-TRAIL by cisplatin was due to the up-regulation of DR5 but not DR4 expression, and followed by the down-regulation of survivin and activation of Caspase 3. In conclusion, cisplatin could enhance the apoptosis induction of U251 cells to adenovirous vector carried TRAIL.

Video rate spectral imaging using a coded aperture snapshot spectral imager.

We have previously reported on coded aperture snapshot spectral imagers (CASSI) that can capture a full frame spectral image in a snapshot. Here we describe the use of CASSI for spectral imaging of a dynamic scene at video rate. We describe significant advances in the design of the optical system, system calibration procedures and reconstruction method. The new optical system uses a double Amici prism to achieve an in-line, direct view configuration, resulting in a substantial improvement in image quality. We describe NeAREst, an algorithm for estimating the instantaneous three-dimensional spatio-spectral data cube from CASSI's two-dimensional array of encoded and compressed measurements. We utilize CASSI's snapshot ability to demonstrate a spectral image video of multi-colored candles with live flames captured at 30 frames per second.

Multichannel sampling schemes for optical imaging systems.

We introduce a framework of focal-plane coding schemes for multichannel sampling in optical systems. A particular objective is to develop an ultrathin imager without compromising image resolution. We present a complete f/2.1 optical system with a thickness of 2.2 mm. The resolution is maintained in the thin optical system by an integrated design of the encoding scheme, the process of making the coding elements, and the decoding algorithms.

Antibacterial constituents from Pedicularis armata.

A new neolignan glycoside named armaoside (1), together with six known compounds (2-7), have been isolated from the whole plant of Pedicularis armata Maxim. The structure of 1 was elucidated as erythro-(7S,8R)-1-(4-O-beta-D-glucopyranosyl-3-methoxyphenyl)-2-[3,5-dimethoxyl-4-oxo-cinnamic aldehyde]propane-1, 3-diol by spectroscopic and chemical methods. All compounds were assayed against Bacillus subtilis, Escherichia coli, and Staphylococcus aureus.

Reference structure tomography.

Reference structure tomography (RST) uses multidimensional modulations to encode mappings between radiating objects and measurements. RST may be used to image source-density distributions, estimate source parameters, or classify sources. The RST paradigm permits scan-free multidimensional imaging, data-efficient and computation-efficient source analysis, and direct abstraction of physical features. We introduce the basic concepts of RST and illustrate the use of RST for multidimensional imaging based on a geometric radiation model.