Search

Since the dawn of quantum mechanics, ways to visualize spins and their interactions have attracted the attention of researchers and philosophers of science. In this work we present a generalized measurement-based 3D-visualization approach for describing dynamics in strongly coupled spin ensembles. The approach brings together angular momentum probability surfaces (AMPS), Husimi Q functions, and DROPS (discrete representations of operators for spin systems) and finds particular utility when the total angular momentum basis is used for describing Hamiltonians. We show that, depending on the choice of a generalized measurement operator, the plotted surfaces either represent probabilities of finding the maximal projection of an angular momentum along any direction in space or represent measurable coherences between the states with different total angular momenta. Such effects are difficult to grasp by looking at (time-dependent) numerical values of density-matrix elements. The approach is complete in a sense that there is one-to-one correspondence between the plotted surfaces and the density matrix. Three examples of nuclear spin dynamics in two-spin systems are visualized: (i) a zero- to ultralow-field (ZULF) nuclear magnetic resonance (NMR) experiment in the presence of a magnetic field applied perpendicularly to the sensitive axis of the detector, (ii) interplay between chemical exchange and spin dynamics during high-field signal amplification by reversible exchange (SABRE), and (iii) a high-field spin-lock-induced crossing (SLIC) sequence, with the initial state being the singlet state between two spins. The presented visualization technique facilitates intuitive understanding of spin dynamics during complex experiments as exemplified here by the considered cases. Temporal sequences (“the movies”) of such surfaces show phenomena like interconversion of spin order between the coupled spins and are particularly relevant in ZULF NMR.

Central to homologous recombination (HR) is the assembly of Rad51 recombinase on single-strand DNA (ssDNA), forming the Rad51-ssDNA filament. How the Rad51 filament is efficiently established and sustained remains partially understood. Here, we find that the yeast ubiquitin ligase Bre1 and its human homolog RNF20, a tumor suppressor, function as recombination mediators, promoting Rad51 filament formation and subsequent reactions via multiple mechanisms independent of their ligase activities. We show that Bre1/RNF20 interacts with Rad51, directs Rad51 to ssDNA, and facilitates Rad51-ssDNA filament assembly and strand exchange in vitro. In parallel, Bre1/RNF20 interacts with the Srs2 or FBH1 helicase to counteract their disrupting effect on the Rad51 filament. We demonstrate that the above functions of Bre1/RNF20 contribute to HR repair in cells in a manner additive to the mediator protein Rad52 in yeast or BRCA2 in human. Thus, Bre1/RNF20 provides an additional layer of mechanism to directly control Rad51 filament dynamics.

The human tumor suppressor Ring finger protein 20 (RNF20)-mediated histone H2B monoubiquitination (H2Bub) is essential for proper chromosome segregation and DNA repair. However, what is the precise function and mechanism of RNF20–H2Bub in chromosome segregation and how this pathway is activated to preserve genome stability remain unknown. Here, we show that the single-strand DNA-binding factor Replication protein A (RPA) interacts with RNF20 mainly in the S and G2/M phases and recruits RNF20 to mitotic centromeres in a centromeric R-loop-dependent manner. In parallel, RPA recruits RNF20 to chromosomal breaks upon DNA damage. Disruption of the RPA–RNF20 interaction or depletion of RNF20 increases mitotic lagging chromosomes and chromosome bridges and impairs BRCA1 and RAD51 loading and homologous recombination repair, leading to elevated chromosome breaks, genome instability, and sensitivities to DNA-damaging agents. Mechanistically, the RPA–RNF20 pathway promotes local H2Bub, H3K4 dimethylation, and subsequent SNF2H recruitment, ensuring proper Aurora B kinase activation at centromeres and efficient loading of repair proteins at DNA breaks. Thus, the RPA–RNF20–SNF2H cascade plays a broad role in preserving genome stability by coupling H2Bub to chromosome segregation and DNA repair.

The single-stranded DNA (ssDNA) binding protein complex RPA plays a critical role in promoting DNA replication and multiple DNA repair pathways. However, how RPA is regulated to achieve its functions precisely in these processes remains elusive. Here, we found that proper acetylation and deacetylation of RPA are required to regulate RPA function in promoting high-fidelity DNA replication and repair. We show that yeast RPA is acetylated on multiple conserved lysines by the acetyltransferase NuA4 upon DNA damage. Mimicking constitutive RPA acetylation or blocking its acetylation causes spontaneous mutations with the signature of micro-homology-mediated large deletions or insertions. In parallel, improper RPA acetylation/deacetylation impairs DNA double-strand break (DSB) repair by the accurate gene conversion or break-induced replication while increasing the error-prone repair by single-strand annealing or alternative end joining. Mechanistically, we show that proper acetylation and deacetylation of RPA ensure its normal nuclear localization and ssDNA binding ability. Importantly, mutation of the equivalent residues in human RPA1 also impairs RPA binding on ssDNA, leading to attenuated RAD51 loading and homologous recombination repair. Thus, timely RPA acetylation and deacetylation likely represent a conserved mechanism promoting high-fidelity replication and repair while discriminating the error-prone repair mechanisms in eukaryotes.

Parahydrogen-based nuclear spin hyperpolarization allows various magnetic-resonance applications, and it is particularly attractive because of its technical simplicity, low cost, and ability to quickly (in seconds) produce large volumes of hyperpolarized material. Although many parahydrogen-based techniques have emerged, some of them remain unexplored due to the lack of careful optimization studies. In this work, we investigate and optimize a novel parahydrogen-induced polarization (PHIP) technique that relies on proton exchange referred to below as PHIP-relay. An INEPT (insensitive nuclei enhanced by polarization transfer) sequence is employed to transfer polarization from hyperpolarized protons to heteronuclei ($^{15}$N and $^{13}$C) and nuclear signals are detected using benchtop NMR spectrometers (1 T and 1.4 T, respectively). We demonstrate the applicability of the PHIP-relay technique for hyperpolarization of a wide range of biochemicals by examining such key metabolites as urea, ammonium, glucose, amino acid glycine, and a drug precursor benzamide. By optimizing chemical and NMR parameters of the PHIP-relay, we achieve a 17,100-fold enhancement of $^{15}$N signal of [$^{13}$C, $^{15}$N$_{2}$]-urea compared to the thermal signal measured at 1 T. We also show that repeated measurements with shorter exposure to parahydrogen provide a higher effective signal-to-noise ratio compared to longer parahydrogen bubbling.

To develop and externally validate models incorporating a PET radiomics signature (R-signature) obtained by the cross-combination method for predicting the survival of patients with diffuse large B-cell lymphoma (DLBCL).A total of 383 patients with DLBCL from two medical centres between 2011 and 2019 were included. The cross-combination method was used on three types of PET radiomics features from the training cohort to generate 49 feature selection-classification candidates based on 7 different machine learning models. The R-signature was then built by selecting the optimal candidates based on their progression-free survival (PFS) and overall survival (OS). Cox regression analysis was used to develop the survival prediction models. The calibration, discrimination, and clinical utility of the models were assessed and externally validated.The R-signatures determined by 12 and 31 radiomics features were significantly associated with PFS and OS, respectively (P0.05). The combined models that incorporated R-signatures, metabolic metrics, and clinical risk factors exhibited significant prognostic superiority over the clinical models, PET-based models, and the National Comprehensive Cancer Network International Prognostic Index in terms of both PFS (C-index: 0.801 vs. 0.732 vs. 0.785 vs. 0.720, respectively) and OS (C-index: 0.807 vs. 0.740 vs. 0.773 vs. 0.726, respectively). For external validation, the C-indices were 0.758 vs. 0.621 vs. 0.732 vs. 0.673 and 0.794 vs. 0.696 vs. 0.781 vs. 0.708 in the PFS and OS analyses, respectively. The calibration curves showed good consistency, and the decision curve analysis supported the clinical utility of the combined model.The R-signature could be used as a survival predictor for DLBCL, and its combination with clinical factors may allow for accurate risk stratification.

Acute myeloid leukemia (AML) is a disease of malignant proliferation of abnormally or poorly differentiated myeloid cells of the hematopoietic system. The clinical treatments of non-M3 AML are experiencing a lack of effective drugs. V8 is a newly synthesized derivative of the natural flavonoid wogonin, which belongs to the potential anticancer drug, and has shown significant antitumor activity in vitro and in vivo. In this study, we investigated the effects of V8 on AML cell lines and primary AML cells and the underlying mechanisms. The results showed that V8 inhibited the growth and induced the apoptosis of AML cell lines (ME-1, Kasumi-1, and U937) and primary AML cells in a concentration-dependent manner. Meanwhile, we revealed that V8-induced apoptosis was accompanied by mitochondrial injury, such as the reduction of mitochondrial membrane potential and ATP production, activation of endoplasmic reticulum stress (ERS) characterized by GRP78 and caspase-12 expression upregulation. Mechanism studies have shown that V8 induced mitochondrial injury and inhibited mitophagy via elevating the intracellular ROS level. In addition, V8 activated PERK-p-eIF2α-ATF4 and Ire1α-XBP1 pathways and induced apoptosis of AML cells via selectively activating CHOP. Correspondingly, the degree of apoptosis and expression of apoptosis-related proteins were alleviated after the elimination of cytoplasmic ROS with N-Acetyl-L-cysteine (NAC) and knocking out CHOP in the cells by transfection with CHOP shRNA, implicating that mitochondrial injury-triggered upregulation of ROS and CHOP played an important role in V8-induced apoptosis of AML cells. In primary AML cells-bearing NOD/SCID mice model and U937 cells-inoculating BALB/c nude mice xenografts transplantation tumor model, administration of V8 markedly prolonged survival time and inhibited the xenografts growth via CHOP-mediated ERS in vivo. In conclusion, our study provides a new insight into the mechanism of V8-induced apoptosis, suggesting the potential of V8 as a promising agent against AML.

Deep-learning (DL) based CT image generation methods are often evaluated using RMSE and SSIM. By contrast, conventional model-based image reconstruction (MBIR) methods are often evaluated using image properties such as resolution, noise, bias. Calculating such image properties requires time consuming Monte Carlo (MC) simulations. For MBIR, linearized analysis using first order Taylor expansion has been developed to characterize noise and resolution without MC simulations. This inspired us to investigate if linearization can be applied to DL networks to enable efficient characterization of resolution and noise. We used FBPConvNet as an example DL network and performed extensive numerical evaluations, including both computer simulations and real CT data. Our results showed that network linearization works well under normal exposure settings. For such applications, linearization can characterize image noise and resolutions without running MC simulations. We provide with this work the computational tools to implement network linearization. The efficiency and ease of implementation of network linearization can hopefully popularize the physics-related image quality measures for DL applications. Our methodology is general; it allows flexible compositions of DL nonlinear modules and linear operators such as filtered-backprojection (FBP). For the latter, we develop a generic method for computing the covariance images that is needed for network linearization.

While machine learning (ML) methods may significantly improve image quality for SPECT imaging for the diagnosis and monitoring of Parkinson’s disease (PD), they require a large amount of data for training. It is often difficult to collect a large population of patient data to support the ML research, and the ground truth of lesion is also unknown. This paper leverages a generative adversarial network (GAN) to generate digital brain phantoms for training ML-based PD SPECT algorithms. A total of 594 PET 3D brain models from 155 patients (113 male and 42 female) were reviewed and 1597 2D slices containing the full or a portion of the striatum were selected. Corresponding attenuation maps were also generated based on these images. The data were then used to develop a GAN for generating 2D brain phantoms, where each phantom consisted of a radioactivity image and the corresponding attenuation map. Statistical methods including histogram, Fréchet distance, and structural similarity were used to evaluate the generator based on 10,000 generated phantoms. When the generated phantoms and training dataset were both passed to the discriminator, similar normal distributions were obtained, which indicated the discriminator was unable to distinguish the generated phantoms from the training datasets. The generated digital phantoms can be used for 2D SPECT simulation and serve as the ground truth to develop ML-based reconstruction algorithms. The cumulated experience from this work also laid the foundation for building a 3D GAN for the same application.

PURPOSE Many interventional procedures aim at changing soft tissue perfusion or blood flow. One problem at present is that soft tissue perfusion and its changes cannot be assessed in an interventional suite because cone-beam computed tomography is too slow (it takes 4-10 s per volume scan). In order to address the problem, we propose a novel method called IPEN for Intra-operative four-dimensional soft tissue PErfusion using a standard x-ray system with No gantry rotation. METHODS IPEN uses two input datasets: (a) the contours and locations of three-dimensional regions-of-interest (ROIs) such as arteries and sub-sections of cancerous lesions, and (b) a series of x-ray projection data obtained from an intra-arterial contrast injection to contrast enhancement to wash-out. IPEN then estimates a time-enhancement curve (TEC) for each ROI directly from projections without reconstructing cross-sectional images by maximizing the agreement between synthesized and measured projections with a temporal roughness penalty. When path lengths through ROIs are known for each x-ray beam, the ROI-specific enhancement can be accurately estimated from projections. Computer simulations are performed to assess the performance of the IPEN algorithm. Intra-arterial contrast-enhanced liver scans over 25 s were simulated using XCAT phantom version 2.0 with heterogeneous tissue textures and cancerous lesions. The following four sub-studies were performed: (a) The accuracy of the estimated TECs with overlapped lesions was evaluated at various noise (dose) levels with either homogeneous or heterogeneous lesion enhancement patterns; (b) the accuracy of IPEN with inaccurate ROI contours was assessed; (c) we investigated how overlapping ROIs and noise in projections affected the accuracy of the IPEN algorithm; and (d) the accuracy of the perfusion indices was assessed. RESULTS The TECs estimated by IPEN were sufficiently accurate at a reference dose level with the root-mean-square deviation (RMSD) of 0.0027 ± 0.0001 cm-1 or 13 ± 1 Hounsfield unit (mean ± standard deviation) for the homogeneous lesion enhancement and 0.0032 ± 0.0005 cm-1 for the heterogeneous enhancement (N = 20 each). The accuracy was degraded with decreasing doses: The RMSD with homogeneous enhancement was 0.0220 ± 0.0003 cm-1 for 20% of the reference dose level. Performing 3 × 3 pixel averaging on projection data improved the RMSDs to 0.0051 ± 0.0002 cm-1 for 20% dose. When the ROI contours were inaccurate, smaller ROI contours resulted in positive biases in TECs, whereas larger ROI contours produced negative biases. The bias remained small, within ± 0.0070 cm-1 , when the Sorenson-Dice coefficients (SDCs) were larger than 0.81. The RMSD of the TEC estimation was strongly associated with the condition of the problem, which can be empirically quantified using the condition number of a matrix Az that maps a vector of ROI enhancement values z to projection data and a weighted variance of projection data: a linear correlation coefficient (R) was 0.794 (P

The prognostic value of 18F-FDG PET/CT for primary intestinal diffuse large B-cell lymphoma (PI-DLBCL) patients has not been determined. This prompted us to explore the value of 18F-FDG PET/CT for prognostic stratification in patients with PI-DLBCL treated with an R-CHOP-like regimen. Seventy-three PI-DLBCL patients who underwent baseline PET/CT between January 2010 and May 2019 were included in this retrospective study. Total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) were computed using the 41% SUVmax thresholding method. Progression-free survival (PFS) and overall survival (OS) were used as endpoints to evaluate prognosis. During the follow-up period of 3–117 months (29.0 ± 25.5 months), high TLG, non-germinal center B-cell-like (non-GCB) and high National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) were significantly associated with inferior PFS and OS. TLG, cell-of-origin and NCCN-IPI were independent predictors of PFS, and both TLG and NCCN-IPI were independent predictors of OS. The grading system was based on the number of risk factors (high TLG, non-GCB, high NCCN-IPI) and patients were divided into 4 risk groups (PFS: χ2 = 33.858, P

Cutaneous T-cell lymphoma (CTCL) is characterized by a heterogeneous group of extranodal non-Hodgkin lymphomas, in which monoclonal T lymphocytes infiltrate the skin. LW-213, a derivative of wogonin, was found to induce cell apoptosis in chronic myeloid leukemia (CML). In this study, we investigated the effects of LW-213 on CTCL cells and the underlying mechanisms. We showed that LW-213 (1–25 μM) dose-dependently inhibited human CTCL cell lines (Hut-102, Hut-78, MyLa, and HH) with IC(50) values of around 10 μM, meanwhile it potently inhibited primary leukemia cells derived from peripheral blood of T-cell lymphoma patients. We revealed that LW-213-induced apoptosis was accompanied by ROS formation and the release of calcium from endoplasmic reticulum (ER) through IP(3)R-1channel. LW-213 selectively activated CHOP and induced apoptosis in Hut-102 cells via activating PERK–eIF2α–ATF4 pathway. Interestingly, the degree of apoptosis and expression of ER stress-related proteins were alleviated in the presence of either N-acetyl cysteine (NAC), an ROS scavenger, or 2-aminoethyl diphenylborinate (2-APB), an IP(3)R-1 inhibitor, implicating ROS/calcium-dependent ER stress in LW-213-induced apoptosis. In NOD/SCID mice bearing Hut-102 cell line xenografts, administration of LW-213 (10 mg/kg, ip, every other day for 4 weeks) markedly inhibited the growth of Hut-102 derived xenografts and prolonged survival. In conclusion, our study provides a new insight into the mechanism of LW-213-induced apoptosis, suggesting the potential of LW-213 as a promising agent against CTCL.

Joint image reconstruction for multiphase CT can potentially improve image quality and reduce dose by leveraging the shared information among the phases. Multiphase CT scans are acquired sequentially. Inter-scan patient breathing causes small organ shifts and organ boundary misalignment among different phases. Existing multi-channel regularizers such as the joint total variation (TV) can introduce artifacts at misaligned organ boundaries. We propose a multi-channel regularizer using the infimal convolution (inf-conv) between a joint TV and a separable TV. It is robust against organ misalignment; it can work like a joint TV or a separable TV depending on a parameter setting. The effects of the parameter in the inf-conv regularizer are analyzed in detail. The properties of the inf-conv regularizer are then investigated numerically in a multi-channel image denoising setting. For algorithm implementation, the inf-conv regularizer is nonsmooth; inverse problems with the inf-conv regularizer can be solved using a number of primal-dual algorithms from nonsmooth convex minimization. Our numerical studies using synthesized 2-phase patient data and phantom data demonstrate that the inf-conv regularizer can largely maintain the advantages of the joint TV over the separable TV and reduce image artifacts of the joint TV due to organ misalignment.

Min Zhou,1,* Jing Wang,1,* Cui-Ping Li,2 Jing-Yan Xu,1 Bing Chen1 1Department of Hematology, The Affiliated DrumTower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, People’s Republic of China; 2Department of Transfusion, BenQ Medical Center, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bing Chen Tel/ Fax +86-25-83106666-61441Email chenbing2004@126.comPurpose: To evaluate whether autologous cytokine-induced killer (CIK) cell immunotherapy improves the prognosis of patients with high-risk diffuse large B cell lymphoma (DLBCL) after the first complete remission (CR).Patients and Methods: Peripheral blood mononuclear cells (PBMCs) were extracted from 20 patients with high-risk DLBCL (IPI≥ 3) after the first CR. Twenty CR patients who were age- and sex-matched during the same period were selected as controls. PBMCs were cultured with IFN-γ, IL-2 and anti-CD3 mAb to generate CIK cells. These obtained cells were then transfused back into the patients; the transfusion was repeated every 3 months up to a total of four courses. Changes in peripheral blood lymphocyte subgroups and survival were assessed.Results: Compared with the baseline proportions, the proportion of CD3+ T cells, CD3+CD8+ T cells, and NK cells in the peripheral blood were significantly higher after transfusions (p< 0.05). The 5-year DFS was improved from 45.0 ± 11.1% to 79.3 ± 9.2% in the CIK group (HR favoring CIK, 0.29; 95% CI, 0.09 to 0.92; p = 0.035), and the 5-year OS was estimated at 90 ± 6.7% for CIK versus 55 ± 11.1% for control (HR favoring CIK, 0.20; 95% CI, 0.04 to 0.93; p = 0.040). No severe side effects were observed related to CIK treatment.Conclusion: Autologous CIK cell immunotherapy has emerged as a safe and efficacious option to improve the prognosis of patients with high-risk DLBCL after the first CR.Keywords: diffuse large B cell lymphoma, high risk, cytokine-induced killer cells, immunotherapy

Since the dawn of quantum mechanics ways to visualize spins and their interactions attracted attention of researchers and philosophers of science. Angular momentum probability (AMP) surfaces are known for visualizing density matrices; a plotted surface represents probability of finding maximum projection of angular momentum along any direction in space. While AMP surfaces visually reveal symmetries of density matrices which directly translate to measured properties, they focus solely on one total-angular-momentum manifold, neglecting interaction between different manifolds often encountered in the NMR of multispin systems. In this work, we extend applicability of this visualization method and introduce its extension, angular momentum coherence (AMC) surface approach. Three examples of nuclear spin dynamics in two-spin systems are presented and visualized using the AMP/AMC surfaces: (I) spin-lock induced crossing (SLIC) sequence with initial state being the singlet state between two spins; (II) interplay between chemical exchange and spin dynamics during the high-field signal amplification by reversible exchange (SABRE) experiment; (III) zero- to ultralow-field (ZULF) NMR experiment in the presence of magnetic field applied perpendicular to the sensitive axis of the detector. The presented visualization technique extends applicability of AMP surfaces to coupled multispin systems and will facilitate intuitive understanding of spin dynamics during complex NMR experiments as exemplified here by the considered cases. The temporal sequences (“the movies”) of such surfaces show phenomena like interconversion of polarization moments (Auzinsh et al., 2010) and, as particularly relevant in NMR and demonstrated here, polarization transfer between different spins. Such effects are difficult to grasp by looking at (time-dependent) numerical values of density-matrix elements.

Context. Olivine responds to space weathering in the fastest and most profound way, which results in significant space weathering spectral alteration effects (SWSAEs) on airless silicate bodies. Although Mg-rich olivine (Fa10) has been subjected to extensive studies, SWSAEs of Fe-rich (Fa# > 20) or Fa-dominant (Fa# ⩾ 50) olivine are still poorly understood. Aims. We aim to systematically characterize the space weathering effects and the associated spectral alterations of Fe-rich olivine on the surface of Phobos and the Moon. Methods. We conducted nanosecond pulsed laser irradiation experiments on a set of synthetic Fe-rich olivine (Fa29, Fa50, Fa71, and Fa100) with energy levels simulated for Phobos and the Moon and analyzed the irradiated olivine for microscopic characteristics and near-infrared (NIR) and Raman spectroscopy. Results. Micron-level thick alteration layers are found in Fa100 compared to those hundreds of nanometers thick in Fa29, Fa50, and Fa71. With increasing irradiation energy levels and Fa# values, nanophase iron (np-Fe0) particles increase in size but decrease in quantity. The np-Fe0 formed via in situ decomposition are ubiquitously present, while those formed via vapor deposition are primarily found in Fa29 but rarely in Fa# ⩾ 50. The size fraction of intermediate (10–40 nm) and large (40–60 nm) np-Fe0 proportionally increases with Fa# values. The NIR spectra of weathered olivine show darkening over reddening in most cases, but Fa100 under the most irradiated condition shows brightening-reddening spectral effects. The Raman spectra of weathered olivine show a reduction in intensity without peak shifts. Conclusions. The Fa# values of olivine are a more critical factor in controlling the SWSAEs on Phobos than those on the Moon. If Phobos and Deimos contain substantial Fe-rich or Fa-dominant olivine, similar to Mars, thick alteration rims and large np-Fe0 formed via space weathering may cause darkening-reddening and potentially brightening-reddening spectral effects on the Martian moons.

To investigate the prognostic value of PET radiomics feature in the prognosis of patients with primary gastrointestinal diffuse large B cell lymphoma (PGI-DLBCL) treated with R-CHOP-like regimen.A total of 140 PGI-DLBCL patients who underwent pre-therapy [A total of 1421 PET radiomics features were extracted and reduced to 5 features to build a radiomics signature which was significantly associated with PFS and OS (p0.05). The combined model incorporating radiomics signatures, metabolic metrics, and clinical risk factors showed high C-indices in both the training (PFS: 0.825, OS: 0.834) and validation sets (PFS: 0.831, OS: 0.877). Decision curve analysis (DCA) demonstrated that the combined models achieved the most net benefit across a wider reasonable range of threshold probabilities for predicting PFS and OS.The newly developed radiomics signatures obtained by the ensemble strategy were independent predictors of PFS and OS for PGI-DLBCL patients. Moreover, the combined model with clinical and metabolic factors was able to predict patient prognosis and may enable personalized treatment decision-making.• Radiomics signatures generated from the optimal radiomics feature set from the [

Mitotic catastrophe of cancer cells induced by drugs is characterized by low dosage and low toxicity, representing a significant advantage in the cancer treatment. Effective therapeutic options are limited for T-cell malignancies patients who are still treated by high-dose multiagent chemotherapy, potentially followed by hematopoietic stem cell transplantation, highlighting the urgency for identification of more effective anti-T-cell malignancies drugs. The use of antineoplastic drugs which induced tumor cell mitotic catastrophe would be a new strategy for cancer therapy. Nevertheless, there is still no effective mitotic catastrophe agent in T-cell malignancies. Our study showed that nonlethal dosage (ND) of GL-V9 (5-hydroxy-8-methoxy-2-phenyl-7-(4-(pyrrolidin-1-yl) butoxy) 4 H-chromen-4-one) (2 µM), a potential anticancer drug, not only attenuated cell growth and survival, but also arrested the cell cycle in G2/M phase and induced multipolar spindles, nuclear alterations (micronucleation and multinucleation), which are the most prominent morphological characteristics of mitotic catastrophe, in T-cell malignancies cell lines including Jurkat, HuT-102, and HuT-78. Moreover, ND GL-V9 could trigger DNA damage, and significantly influence several mitosis-associated proteins. Besides, results showed that ND GL-V9 increased the activity of senescence-associated β-galactosidase (SA-β-Gal) following the induction of mitotic catastrophe in Jurkat and HuT-102 cells with intact p53, while causing apoptosis in p53-deficient HuT-78 cells. We concluded that the anti-T-cell malignancies effects of ND GL-V9 and clarified the precise regulation in the process of mitosis under the action of GL-V9 in T-cell malignancies. Our data provided new evidence for the study of T-cell malignancies treatment associated with mitotic catastrophe and cellular senescence induction.

Background Bortezomib in combination with thalidomide and dexamethasone (VTD) has been widely used for newly diagnosed multiple myeloma (MM). The aim of this study was to evaluate the efficacy and safety of a new high-dose bortezomib plus thalidomide and dexamethasone as an induction and consolidation therapy regimen for MM. Methods A total of 93 patients with previously untreated symptomatic MM were enrolled in this single-center study. In group-1, 40 patients received bortezomib 1.6 mg/m2 and dexamethasone 40 mg on days 1, 6 and 11, plus thalidomide 100 mg on days 1–21 (VTD-1). In group-2, 53 patients received bortezomib 1.3 mg/m2 and dexamethasone 40 mg on days 1, 4, 8 and 11 in combination with thalidomide 100 mg on days 1–21 (VTD-2). Results The odds ratio rates after 2 cycles of VTD and the best response during this study were 95% vs. 81.1% (P=0.044), and 95% vs. 90.6% (P=0.349) in group-1 and group-2, respectively. The best CR rate in group-1 was higher than that in group-2 [52.5% vs. 45.3% (P=0.316)]. In group-1, only 2 of 21 patients who achieved CR relapsed from the disease, as did 9 of 24 patients in group-2 (P=0.031). The median PFS in group-1 and group-2 were 34 and 28.8 months (P=0.969), and the median OS in group-1 and group-2 were 33.5 and 46.4 months (P=0.987). In group-1 and group-2, the median CD34+ cells of stem cell collection were 3.68×106 vs. 5.84×106 cells/kg (P=0.179). Patients in group-1 had a lower incidence of peripheral neuropathy than group-2 [32.5% vs. 41.5% (P=0.371)]. Conclusions High-dose bortezomib at a dose of 1.6 mg/m2 in combination with thalidomide and dexamethasone was well tolerated and highly efficient as an induction and consolidation therapy for MM.

Background Multiple myeloma (MM) is a heterogeneous disease characterized by chromosomal translocation, deletion, and amplification in plasma cells, resulting in a huge heterogeneity in its outcomes. In the era of novel agents such as bortezomib, thalidomide, and the cycles of treatment, risk stratification by chromosomal aberrations may enable a more rational risk-stratification selection of therapeutic approaches in patients with MM. Patients and Methods We performed a retrospective study in 63 patients with MM; 29 (46.03%) with 1q21 gain and 34 (53.97%) without gain. Result In all patients, we did not find that the patients with 1q21 gain had significantly better survival compared with patients without 1q21 gain (overall survival, P = .6916; progression-free survival, P = .8740). However, in 1q21 gain patients, we found that the bortezomib group had significantly better survival compared with the non-bortezomib group in terms of both the 3-year estimated overall survival (82.3% vs. 18.8%; P = .0154) and progression-free survival (62.8% vs. 8.75%; P = .0385). Conclusion 1q21 gain detected by fluorescence in situ hybridization is not as high risk for poor prognosis with regard to time for overall survival. And the clinical outcome of patients with 1q21 gain can be improved in those who received no less than 4 cycles of bortezomib-based therapy (bortezomib, thalidomide, and dexamethasone).

The impacts of driving capacity on single-event effect vulnerability of 40 nm standard cells were studied. The result shows that cells with high driving capacity are inclined to have stronger single-event effect tolerance. AND gate has smaller SET cross section and transient pulse width than OR gate and D flip-flop.

BackgroundThe positive transcription elongation factor b (P-TEFb) kinase activity is involved in the process of transcription. Cyclin-dependent kinase 9 (CDK9), a core component of P-TEFb, regulates the process of transcription elongation, which is associated with differentiation and apoptosis in many cancer types. Wogonin, a natural CDK9 inhibitor isolated fromScutellaria baicalensis.This study aimed to investigate the involved molecular mechanisms of wogonin on anti- chronic myeloid leukemia (CML) cells.Materials and methodsmRNA and protein levels were analysed by RT-qPCR and western blot. Flow cytometry was used to assess cell differentiation and apoptosis. Cell transfection, immunofluorescence analysis and co-immunoprecipitation (co-IP) assays were applied to address the potential regulatory mechanism of wogonin. KU-812 cells xenograftNOD/SCIDmice model was used to assess and verify the mechanism in vivo.ResultsWe reported that the anti-CML effects in K562, KU-812 and primary CML cells induced by wogonin were regulated by P-TEFb complex. We also confirmed the relationship between CDK9 and erythroid differentiation via knockdown the expression of CDK9. For further study the mechanism of erythroid differentiation induced by wogonin, co-IP experiments were used to demonstrate that wogonin increased the binding between GATA-1 and FOG-1 but decreased the binding between GATA-1 and RUNX1, which were depended on P-TEFb. Also, wogonin induced apoptosis and decreased the mRNA and protein levels of MCL-1 in KU-812 cells, which is the downstream of P-TEFb. In vivo studies showed wogonin had good anti-tumor effects in KU-812 xenograftsNOD/ SCIDmice model and decreased the proportion of human CD45+cells in spleens of mice. We also verified that wogonin exhibited anti-CML effects through modulating P-TEFb activity in vivo.ConclusionsOur study indicated a special mechanism involving the regulation of P-TEFb kinase activity in CML cells, providing evidences for further application of wogonin in CML clinical treatment.

Many interventional procedures aim at changing soft tissue perfusion or blood flow. One problem at present is that soft tissue perfusion and its changes cannot be assessed in an interventional suite because cone-beam computed tomography is too slow (it takes 4–10 s per volume scan). In order to address the problem, we propose a novel method called IPEN for Intra-operative 4-dimensional soft tissue PErfusion using a standard x-ray system with No gantry rotation. In this simulation study, we provide a proof-of-concept that the core ideas work.

Purpose The aim was to explore whether baseline total lesion glycolysis (TLG) can improve the prognostic value of the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) in primary gastric diffuse large B-cell lymphoma (PG-DLBCL) patients treated with an R-CHOP-like regimen. Materials and methods Ninety-four PG-DLBCL patients who underwent baseline PET/CT between July 2010 and May 2019 were included in this retrospective study. FDG-avid lesions in each patient were segmented to calculate the SUVmax, total metabolic tumor volume (TMTV), and TLG. Progression-free survival (PFS) and overall survival (OS) were used as end points to evaluate prognosis. Results During the follow-up period of 5 to 108 months (35.3 ± 23.5 months), high TLG and a high NCCN-IPI were significantly associated with poor PFS and OS. Total lesion glycolysis and the NCCN-IPI were independent predictors of PFS and OS. Patients were stratified into 3 groups according to the combination of TLG and the NCCN-IPI for PFS (P 1159.1 and NCCN-IPI 4-8) (PFS and OS, 57.7% and 61.5%, respectively, n = 42), intermediate-risk group (TLG > 1159.1 or NCCN-IPI 4-8) (PFS and OS, both 76.9%, n = 26), and low-risk group (TLG ≤ 1159.1 and NCCN-IPI 0-3) (PFS and OS, 97.6% and 100.0%, respectively, n = 26). Conclusions Both TLG and the NCCN-IPI are independent predictors of PG-DLBCL patient survival. Moreover, the combination of TLG and the NCCN-IPI improved patient risk stratification and might help personalize therapeutic regimens.

Purpose: The aim of the present study was to explore whether pretreatment total metabolic tumor volume (TMTV) combined with MYC/BCL-2 dual expression (DE) would improve the prognostic stratification of patients who were newly diagnosed with primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL).Materials and methods: Eighty-three patients between March 2011 and November 2019, diagnosed with PGI-DLBCL prior to treatment, were included in this retrospective study. Baseline TMTV on PET/CT scans were calculated automatically using the boundaries of voxels presenting a SUVmax≥2.5. Expression of MYC/BCL-2 were detected at protein levels via immunohistochemistry（IHC）. The distributions of Progression-free survival (PFS) and overall survival (OS) rates were estimated using the Kaplan-Meier method and differences were compared using a log-rank test followed by multivariate analysis using the Cox proportional hazards model.Results: TMTV and DE were significantly associated with a worse PFS and OS. Multivariate analysis revealed that TMTV (HR=6.090, P2=32.178, P2=23.091, PConclusions: TMTV and DE independently predicted survival outcomes in PGI-DLBCL patients. Furthermore, our findings suggest that combination of TMTV and DE may further improve the ability of clinicians to stratify patients in terms of differential prognoses.

Purpose The aim of this study was to explore the prognostic value of total metabolic tumor volume (TMTV) at baseline 18F-FDG PET/CT in patients diagnosed with peripheral T-cell lymphoma (PTCL). Materials and methods Eighty-four newly diagnosed PTCL patients who underwent baseline 18F-FDG PET/CT prior to treatment between March 2009 and January 2019 were enrolled in this retrospective study. The FDG-avid lesions in each patient were segmented using semiautomated software to calculate the maximum standardized uptake value (SUVmax), total metabolic tumor volume (TMTV), and total lesion glycolysis (TLG) values using the boundaries of voxels presenting with the 41% SUVmax threshold method. Progression-free survival (PFS) and overall survival (OS) were used as end points to evaluate patient prognosis. The log-rank test and Cox regression analyses were used to evaluate PFS and OS. Results ROC curve analysis indicated an ideal TMTV cut-off value of 228.8 cm3. During the 4–131 months (29.2 ± 28.5 months) follow-up period, high TMTV was significantly associated with worse PFS and OS. TMTV and the international peripheral T-cell lymphoma project score (IPTCLP) were independent predictors of PFS and OS with multivariate analysis. The combination of TMTV and the IPTCLP may provide significantly better risk substratification in PFS and OS of PTCL patients. Conclusions Both TMTV and IPTCLP are independent predictors of PTCL patient survival outcomes. Moreover, the combination of TMTV and IPTCLP improved patient risk stratification and may contribute to personalized therapeutic regimens.

Background: The aim of this study was to establish a precise prognostic model, based on significant clinical parameters, for predicting the overall survival (OS) of adult patients with primary gastrointestinal diffuse large B cell lymphoma (GI DLBCL). Materials and Methods: The data of 7,121 GI DLBCL patients, diagnosed between 1997 and 2015, were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. These patients were randomly divided into two sequential cohorts: training (n = 5,697) set and validation (n = 1,424) set. ROC methodology and calibration curves were explicitly used to evaluate the predictive performance of nomogram. Results: The median OS in the training cohort was 76 months (1–239 months), and 3, 5, and 10-year OS rates were 60.3, 53.9, and 39.5%, respectively. Age at diagnosis, Ann Arbor stage, and marital status were important clinical predictors of OS. These characteristics were used to build a nomogram. The AUC of the nomogram for predicting 3, 5, and 10-year OS were 0.669, 0.692, and 0.740, respectively. All RUC and calibration curves revealed good accuracy in predicting prognosis of GI DLBCL. Conclusion: In summary, the established nomogram was validated to predict OS for adult patients with GI DLBCL. This predictive model could help clinicians identify high-risk patients to improve their prognosis.

BackgroundThis study aimed to assess the role and mechanism of lncRNA NEAT1 in intervertebral disc degeneration (IVD).MethodsLncRNA profile (GSE56081) between IVD and healthy control was downloaded from the Gene Expression Omnibus (GEO) database and analyzes differential lncRNA expression. Expression of lncRNA NEAT1 in IVD tissue and TNF-α/IL-1β-stimulated nucleus pulposus cells were further measured by RT-PCR. The lncRNA NEAT1 overexpression plasmids (pcDNA-NEAT1) were constructed and transfected into nucleus pulposus cells. Catabolic biomarkers (MMP-3 and MMP-13), anabolic biomarkers (Col II and Aggrecan) and Nrf2 expression were further measured. To further investigate the function of Nrf2, nucleus pulposus cells were pretreated with or without 25 μM tert-Butylhydroquinone (TBHQ), a Nrf2 activator, for 18 h and subsequently cotreated with pcDNA-NEAT1.ResultsA total of 1432 lncRNAs were differentially expressed in GSE56081. Bioinformatic analysis found that these lncRNAs mainly enriched in Nrf2/ARE signaling pathway. LncRNA NEAT1 was highly expressed in IVD tissues than that of healthy control. Moreover, TNF-α/IL-1β induced a time- and dose-dependent increase in the mRNA expression of lncRNA NEAT1 in the nucleus pulposus cells. Overexpression of lncRNA NEAT1 abates promotes nucleus pulposus cells proliferation but induces matrix degradation. Meanwhile, nucleus and cytoplasm Nrf2 expression was significantly down-regulated by lncRNA NEAT1 upregulation. Nrf2 activator (TBHQ) could partially reverse the inhibitory effects of overexpression of lncRNA NEAT1 on matrix degradation.ConclusionCollectively, our data unveiled the lncRNA NEAT1 promotes matrix degradation by regulating Nrf2/ARE signaling pathway, suggesting a potential therapeutic for IVD in the future.

The past decade has seen the rapid growth of model based image reconstruction (MBIR) algorithms, which are often applications or adaptations of convex optimization algorithms from the optimization community. We review some state-of-the-art algorithms that have enjoyed wide popularity in medical image reconstruction, emphasize known connections between different algorithms, and discuss practical issues such as computation and memory cost. More recently, deep learning (DL) has forayed into medical imaging, where the latest development tries to exploit the synergy between DL and MBIR to elevate the MBIR's performance. We present existing approaches and emerging trends in DL-enhanced MBIR methods, with particular attention to the underlying role of convexity and convex algorithms on network architecture. We also discuss how convexity can be employed to improve the generalizability and representation power of DL networks in general.

We are interested in learning the hyperparameters in a convex objective function in a supervised setting. The complex relationship between the input data to the convex problem and the desirable hyperparameters can be modeled by a neural network; the hyperparameters and the data then drive the convex minimization problem, whose solution is then compared to training labels. In our previous work (Xu and Noo 2021 Phys. Med. Biol. 66 19NT01), we evaluated a prototype of this learning strategy in an optimization-based sinogram smoothing plus FBP reconstruction framework. A question arising in this setting is how to efficiently compute (backpropagate) the gradient from the solution of the optimization problem, to the hyperparameters to enable end-to-end training. In this work, we first develop general formulas for gradient backpropagation for a subset of convex problems, namely the proximal mapping. To illustrate the value of the general formulas and to demonstrate how to use them, we consider the specific instance of 1D quadratic smoothing (denoising) whose solution admits a dynamic programming (DP) algorithm. The general formulas lead to another DP algorithm for exact computation of the gradient of the hyperparameters. Our numerical studies demonstrate a 55%–65% computation time savings by providing a custom gradient instead of relying on automatic differentiation in deep learning libraries. While our discussion focuses on 1D quadratic smoothing, our initial results (not presented) support the statement that the general formulas and the computational strategy apply equally well to TV or Huber smoothing problems on simple graphs whose solutions can be computed exactly via DP.

Acute myeloid leukaemia (AML) comprises a range of disparate genetic subtypes, involving complex gene mutations and specific molecular alterations. Post‐translational modifications of specific proteins influence their translocation, stability, aggregation and even leading disease progression. Therapies that target to post‐translational modification of specific proteins in cancer cells represent a novel treatment strategy. Non‐homogenous subcellular distribution of PLSCR1 is involved in the primary AML cell differentiation. However, the nuclear translocation mechanism of PLSCR1 remains poorly understood. Here, we leveraged the observation that nuclear translocation of PLSCR1 could be induced during wogonoside treatment in some primary AML cells, despite their genetic heterogeneity that contributed to the depalmitoylation of PLSCR1 via acyl protein thioesterase 1 (APT‐1), an enzyme catalysing protein depalmitoylation. Besides, we found a similar phenomenon on another AML‐related protein, N‐RAS. Wogonoside inhibited the palmitoylation of small GTPase N‐RAS and enhanced its trafficking into Golgi complex, leading to the inactivation of N‐RAS/RAF1 pathway in some primary AML cells. Taken together, our findings provide new insight into the mechanism of wogonoside‐induced nuclear translocation of PLSCR1 and illuminate the influence of N‐RAS depalmitoylation on its Golgi trafficking and RAF1 signalling inactivation in AML.

Tumor necrosis factor alpha (TNFα) is a complicated cytokine which is involved in proliferation and differentiation of acute myelogenous leukemia (AML) cells through a poorly understood mechanism. Mechanistic studies indicate that TNFα induced binding of PI3K subunit p85α to N-terminal truncated nuclear receptor RXRα (tRXRα) proteins, and activated AKT. The activated PI3K/AKT pathway negatively regulated differentiation of AML cells through the upregulation of c-Myc. In addition, TNFα also induced activation of nuclear factor κB (NF-κB), a nuclear transcription factor which was shown to promote cell proliferation. The present study demonstrates that oroxylin A, a natural compound isolated from Scutellariae radix, sensitizes leukemia cells to TNFα and markedly enhances TNFα-induced growth inhibition and differentiation of AML cell including human leukemia cell lines and primary AML cells. Activation of PI3K/AKT pathway could be inhibited by oroxylin A through inhibiting expression of tRXRα in NB4 and HL-60-resistant cells. Furthermore, we found that oroxylin A inhibited the activation of NF-κB and the DNA binding activity by TNFα proved by EMSA in these two AML cell lines. Moreover, in vivo studies showed that treatment with oroxylin A in combination with TNFα decreased AML cell population and prolonged survival in NOD/SCID mice with xenografts of primary AML cells. Overall, our results indicate that oroxylin A is able to inhibit the negative effects of TNFα for AML therapy, suggesting that combination of oroxylin A and TNFα have the potential to delay growth or eliminate the abnormal leukemic cells, thus representing a promising strategy for AML treatment.

Background：Downregulation of CD20, a molecular target for monoclonal antibodies (mAbs), is a clinical problem leading to decreased efficacy of anti-CD20-based therapeutic regimens.Up to one-third of diffuse large B cell lymphoma (DLBCL) patients eventually develop resistance to R-CHOP regimen, since the remaining therapeutic options are limited. LW-213, a derivative of wogonin, is reported to possess antineoplastic properties in a variety of cancers, but whether it has effects on DLBCL is n-ot known. Studies have reported that upregulation of CD20 expression b-y either HDACi or silenced SOX2 expression showed sensitizing potential in Rituximab-induced cell death in malignant B cells. Our study was to explore whether LW-213 could sensitize DLBCL to Rixutimab thus improve therapeutic efficacy. Methods： Two DLBCL cell lines, RI-1 (ABC subtype) and Su-DHL -8 (GCB subtype), were used in our study. RI-1 and Su-DHL-8 cells were treated with LW-213 at different doses and for different times, and their proliferation and viability were detected by Cell counting kit-8 (CCK8).Flow cytometry was used to determine surface CD20 expression. Western blotting and q-PCR were applied to examine the protein and mRNA levels of CD20, SOX2, Ace-H3 and Ace-H3K27. CDC assay was used to evaluate the synergistic effects of LW-213 and Rixutimab. Results：We showed that LW-213 inhibited the proliferation of human DLBCL cell lines (Su-DHL-8、RI-1 ) in dose-and time-dependent manners with IC 50 values at the low μmol/L levels, meanwhile it potently inhibited primary lymphoma cells derived from peripheral blood of B-cel-l lymphoma patients. Furthermore, LW-213 significantly increased CD20 surface expression and the acetylation level of histone in DLBCL cell li-nes. Inversely，the SOX2 expression level remarkably decreased. Finally,Combination with LW-213 significantly synergized Rituximab-induced cell death in vitro. Conclusion： The results demonstrate that LW-213 sensitizes DLBCL cells to Rituximab in vitro by upregulating CD20 expression and the SOX2/ace-H3K27/ace-H3 axis may plays a critical role in CD20 upregulation processing. Even though this strategy is important in vitro models,the upregulating CD20 expression therapy against DLBCL proposed in this study warrants further study in vivo and clinical trials . Keywords：CD20 DLBCL Rituximab SOX2 Histone Deacetylation Disclosures No relevant conflicts of interest to declare.

Hepatitis B virus (HBV) is a hepatotropic and a lymphotropic virus. An association between HBV and hematologic malignancies has been determined previously; however, the association between HBV infection and multiple myeloma (MM) remains controversial. The present study aimed to assess the prevalence of HBV infection in patients with MM, and investigate their characteristics and prognostic significance. The clinical data of 165 patients with MM who had received at least four cycles of chemotherapy between April 2008 and February 2017 at Nanjing Drum Tower Hospital (Nanjing, China) were collected. HBV markers were determined using ELISA. The rates of acute or chronic HBV infection and resolved HBV infection in patients with MM were 12.12 and 26.06%, respectively. The gain of 1q21 was significantly more prevalent in the patients who were classified as HBV-positive compared with the patients who were classified as HBV-negative (54 vs. 38.2%; P=0.048), and the level of alanine transaminase in patients who were classified as HBV-positive was significantly increased compared with the non-infected group (63.29 vs. 24.66 U/l; P=0.043). Lactate dehydrogenase, serum creatinine and serum calcium levels were additionally determined to be significant risk factors of overall survival. The progression-free survival (PFS) of patients who were classified as HBV-positive was decreased compared with patients who were classified as HBV-negative (18.97 vs. 29.67 months; P=0.006), and being HBV-positive was determined to be an independent prognostic factor of PFS. HBV infection may contribute to MM progression through 1q21 amplification, and improved monitoring of HBV markers in patients with MM may be required.