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Lineage plasticity has long been documented in both small cell lung cancer (SCLC) and neuroblastoma, two clinically distinct neuroendocrine (NE) cancers. In this study, we quantified the NE features of cancer as NE scores and performed a systematic comparison of SCLC and neuroblastoma. We found neuroblastoma and SCLC cell lines have highly similar molecular profiles and shared therapeutic sensitivity. In addition, NE heterogeneity was observed at both the inter- and intra-cell line levels. Surprisingly, we did not find a significant association between NE scores and overall survival in SCLC or neuroblastoma. We described many shared and unique NE score–associated features between SCLC and neuroblastoma, including dysregulation of Myc oncogenes, alterations in protein expression, metabolism, drug resistance, and selective gene dependencies. Implications: Our work establishes a reference for molecular changes and vulnerabilities associated with NE to non-NE transdifferentiation through mutual validation of SCLC and neuroblastoma samples.

This study aimed to determine the effectiveness of brachytherapy in post-operative cervical cancer patients with risk factors other than positive stump, and to identify the candidates most likely to benefit.Newly diagnosed, non-metastatic cervical cancer patients treated in our hospital between January 2012 and November 2015 were retrospectively reviewed. Early stage patients receiving radical surgery and needing adjuvant external radiotherapy were included, but those with positive stump were excluded. All patients received external radiotherapy. They were divided into two groups: one group received vaginal brachytherapy and the other did not. The 5-year local-regional recurrence free survival (LRRFS) and overall survival (OS) rates in the two groups were compared.Two hundred and twenty-five patients were included in this study; while 99 received brachytherapy, 126 did not. The brachytherapy group had significantly superior 5-year LRRFS (87.7% vs. 72.5%, p = 0.004), but did not show a significant overall survival benefit (78.4% vs. 75.3%, p = 0.055). In multivariate analysis, brachytherapy, pathological type, high-risk factors, duration of radiotherapy, and transfusion were independent prognostic factors for 5-year LRRFS. In stratified analysis, the brachytherapy group showed superior LRRFS in those meeting Sedlis criteria (p = 0.017).The combination of external beam radiation therapy and brachytherapy can improve LRRFS in post-operative cervical cancer patients with risk factors other than positive stump. Therefore, brachytherapy should be considered for these patients.

We compared the immunologic characteristics of mycoplasma pneumoniae-triggered Kawasaki disease (MP-KD) with Kawasaki disease (KD) not associated with mycoplasma pneumoniae (MP), with mycoplasma pneumoniae-triggered Henoch-Schönlein purpura (MP-HSP), and with healthy controls.Complement levels, cellular and humoral immunity were assessed in KD, in MP-KD, in MP-HSP, and in healthy children.Of 622 children with KD, 74 had MP-KD. Complement C3 and CD4/CD8 ratio were significantly increased in MP-KD compared to KD. C3, C4, and the ratio of CD4/CD8 in the MP-KD group were higher than those in the MP-HSP group. IgA and CD56 were lower in the MP-KD group than the MP-HSP group.Both C3 and polyclonal CD4

Qualitative spatial/temporal reasoning (QSR/QTR) plays a key role in research on human cognition, e.g., as it relates to navigation, as well as in work on robotics and artificial intelligence. Although previous work has mainly focused on various spatial and temporal calculi, more recently representation learning techniques such as embedding have been applied to reasoning and inference tasks such as query answering and knowledge base completion. These subsymbolic and learnable representations are well suited for handling noise and efficiency problems that plagued prior work. However, applying embedding techniques to spatial and temporal reasoning has received little attention to date. In this paper, we explore two research questions: (1) How do embedding-based methods perform empirically compared to traditional reasoning methods on QSR/QTR problems? (2) If the embedding-based methods are better, what causes this superiority? In order to answer these questions, we first propose a hyperbolic embedding model, called HyperQuaternionE, to capture varying properties of relations (such as symmetry and anti-symmetry), to learn inversion relations and relation compositions (i.e., composition tables), and to model hierarchical structures over entities induced by transitive relations. We conduct various experiments on two synthetic datasets to demonstrate the advantages of our proposed embedding-based method against existing embedding models as well as traditional reasoners with respect to entity inference and relation inference. Additionally, our qualitative analysis reveals that our method is able to learn conceptual neighborhoods implicitly. We conclude that the success of our method is attributed to its ability to model composition tables and learn conceptual neighbors, which are among the core building blocks of QSR/QTR.

Controlling for MYCN amplification status increases the statistical significance of NE score vs. MYCN expression association.

Examples of different and similar compound sensitivity dynamic ranges in SCLC and NBL.

Intratumoral NE heterogeneity in SCLC patient tumors and intra-cell line NE heterogeneity in SCLC and NBL cell lines.

Comparing NE score-associated features between SCLC and other cancer types.

A meta-analysis example that summarizes the association between MEK inhibitor resistance and NE scores.

Lineage plasticity has long been documented in both small cell lung cancer (SCLC) and neuroblastoma, two clinically distinct neuroendocrine (NE) cancers. In this study, we quantified the NE features of cancer as NE scores and performed a systematic comparison of SCLC and neuroblastoma. We found neuroblastoma and SCLC cell lines have highly similar molecular profiles and shared therapeutic sensitivity. In addition, NE heterogeneity was observed at both the inter- and intra-cell line levels. Surprisingly, we did not find a significant association between NE scores and overall survival in SCLC or neuroblastoma. We described many shared and unique NE score–associated features between SCLC and neuroblastoma, including dysregulation of Myc oncogenes, alterations in protein expression, metabolism, drug resistance, and selective gene dependencies.Implications:Our work establishes a reference for molecular changes and vulnerabilities associated with NE to non-NE transdifferentiation through mutual validation of SCLC and neuroblastoma samples.

Known NBL prognostic factors consistently associate with outcome across different NBL studies but not NE scores.

SCLC vs. NBL concordance of NE score association with omics, drug sensitivity, and dependency data.

SUMMARYCancer cells reprogram their metabolism to support cell growth and proliferation in harsh environments. While many studies have documented the importance of mitochondrial oxidative phosphorylation (OXPHOS) in tumor growth, some cancer cells experience conditions of reduced OXPHOS in vivo and induce alternative metabolic pathways to compensate. To assess how human cells respond to mitochondrial dysfunction, we performed metabolomics in fibroblasts and plasma from patients with inborn errors of mitochondrial metabolism, and in cancer cells subjected to inhibition of the electron transport chain (ETC). All these analyses revealed extensive perturbations in purine-related metabolites; in non-small cell lung cancer (NSCLC) cells, ETC blockade led to purine metabolite accumulation arising from a reduced cytosolic NAD+/NADH ratio (NADH reductive stress). Stable isotope tracing demonstrated that ETC deficiency suppressed de novo purine nucleotide synthesis while enhancing purine salvage. Analysis of NSCLC patients infused with [U-13C]glucose revealed that tumors with markers of low oxidative mitochondrial metabolism exhibited high expression of the purine salvage enzyme HPRT1 and abundant levels of the HPRT1 product inosine monophosphate (IMP). ETC blockade also induced production of ribose-5’ phosphate (R5P) by the pentose phosphate pathway (PPP) and import of purine nucleobases. Blocking either HPRT1 or nucleoside transporters sensitized cancer cells to ETC inhibition, and overexpressing nucleoside transporters was sufficient to drive growth of NSCLC xenografts. Collectively, this study mechanistically delineates how cells compensate for suppressed purine metabolism in response to ETC blockade, and uncovers a new metabolic vulnerability in tumors experiencing NADH excess.

Epibacteria of seaweeds play an important role for the development of hosts and are influenced by the planktonic surrounding seawater bacteria. However, to date, the knowledges related to both epiphytic and surrounding seawater bacterial communities associated with northern farmed Saccharina japonica are very limited. In this study, using 16S rRNA gene amplicon sequencing, the shifts of epiphytic and surrounding seawater bacterial communities of the northern farmed S. japonica from mature sporophytes, sporelings (3 time points) to juvenile sporophytes (2 time points) were investigated. The dominant genera of epibacterial communities were Alcanivorax (mature sporophytes and 4-week-old sporelings), Bacillus (7-week-old sporelings and 9-week-old sporelings), Halomonas (4-week-old juvenile sporophytes) and Cobetia (9-week-old juvenile sporophytes). Meanwhile, the Chao1 indexes and beta diversity of epibacterial communities were significantly different with the development of S. japonica (p < 0.05). Furthermore, Alcanivorax, Bacillus and Halomonas were both dominant and core genera, indicating that these taxa may be beneficial to the development of S. japonica. The alpha diversity indexes of both epiphytic and surrounding seawater bacterial communities were significantly different for 9-week-old juvenile sporophytes. Therefore, the epibacterial communities were influenced by both development of S. japonica and the surrounding seawater bacterial communities. This study not only extends the understanding of the bacterial communities associated with the northern farmed S. japonica, but also help to make production management by monitoring the variations in both epiphytic and surrounding seawater bacterial communities.

Supplementary Figure S1 - PDF file 1194K, Gamma-H2AX foci and Comet assay normalized of LNCaP plus or minus androgen normalized to time 0

Supplementary Table S2 - PDF file 250K, Defining AR-regulated DNA repair genes in LNCaP

Supplementary Figure S2 - PDF file 1705K, LNCaP cell cycle distribution by PI and BrdU analyses plus or minus androgen

Supplementary Figure S4 - PDF file 793K, Immunoblot of LNCaP demonstrating LIG4 knockdown

Supplementary Figure S3 - PDF file 1337K, LNCaP cell cycle distribution by PI and BrdU analyses plus or minus ARN-509

Supplementary Table S1 - PDF file 170K, Gene set enrichment analysis of ARN-509-treated LNCaP-AR xenografts

Using 1-min data, we explore the dynamic variation of the intraday lead-lag relations between stock indices and their derivatives through a comprehensive study with broader coverage of research objectives and methodologies. This paper provides explicit evidence that the futures and options exhibit price leadership over the spot market, and the options is ahead of the futures on most trading days in all three markets. This paper also reports a new finding that the relation between the derivative and its underlying index reverses when the index return has a significantly larger mean value, and the reversal phenomenon is also observed in the relations between the futures and the options, which enriches the empirical results of intraday lead-lag relations. Moreover, these conclusions still hold under the impact of extreme events, e.g., the outbreak of the Covid-19. Finally, we construct a pair trading strategy based on the intraday lead-lag relationships, which can get better performance than the corresponding spot index. Our findings can potentially help regulators understand the price discovery process between the index and its derivatives, and also be of great value for timely adjustment of investors intraday trading strategies.

WD repeat domain 5 (WDR5), an integral component of the MLL/KMT2A lysine methyltransferase complex, is critically involved in oncogenesis and represents an attractive onco-target. Inhibitors targeting protein-protein interactions (PPIs) between WDR5 and its binding partners, however, do not inhibit all of WDR5-mediated oncogenic functions and exert rather limited antitumor effects. Here, we report a cereblon (CRBN)-recruiting proteolysis targeting chimera (PROTAC) of WDR5, MS40, which selectively degrades WDR5 and the well-established neo-substrates of immunomodulatory drugs (IMiDs):CRBN, the Ikaros zinc finger (IKZF) transcription factors IKZF1 and IKZF3. MS40-induced WDR5 degradation caused disassociation of the MLL/KMT2A complex off chromatin, resulting in decreased H3K4me2. Transcriptomic profiling revealed that targets of both WDR5 and IMiDs:CRBN were significantly repressed by treatment of MS40. In MLL-rearranged leukemias, which exhibit IKZF1 high expression and dependency, co-suppression of WDR5 and Ikaros by MS40 is superior in suppressing oncogenesis to the WDR5 PPI inhibitor, to MS40's non-PROTAC analog controls (MS40N1 and MS40N2, which do not bind CRBN and WDR5, respectively), and to a matched VHL-based WDR5 PROTAC (MS169, which degrades WDR5 but not Ikaros). MS40 suppressed the growth of primary leukemia patient cells in vitro and patient-derived xenografts in vivo. Thus, dual degradation of WDR5 and Ikaros is a promising anti-cancer strategy.

Cardiac troponins are highly sensitive and specific biomarkers for cardiac injury. Previous studies evaluating the effect of positive airway pressure (PAP) on cardiac troponins in patients with sleep-disordered breathing (SDB) have yielded conflicting results. The meta-analysis was performed to examine the effect of PAP on cardiac troponins in SDB patients.PubMed, Web of Science, and EMBASE before September 2021 on original English language studies were searched. The data on cardiac troponins in both baseline and post-PAP treatment were extracted from all studies. The data on the change of cardiac troponins in both PAP and control group were extracted from randomized controlled trials. Standardized mean difference (SMD) was used to synthesize quantitative results.A total of 11 studies were included. PAP treatment was not associated with a significant change in cardiac troponin T between the baseline and post-PAP treatment (SMD = -0.163, 95% confidence interval [CI] = -0.652 to 0.326, z = 0.65, p = .514). The pooled estimate of SMD of cardiac troponin I between the pre- and post-PAP treatment was 0.287, and the 95% CI was -0.586 to 1.160 (z = 0.64, p = .519). The pooled SMD of change of cardiac troponin T between the PAP group and control group was -0.473 (95% CI = -1.198 to 0.252, z = 1.28, p = .201).This meta-analysis revealed that PAP treatment was not associated with any change of cardiac troponin in SDB patients.

Knowledge graphs (KGs) are a novel paradigm for the representation, retrieval, and integration of data from highly heterogeneous sources. Within just a few years, KGs and their supporting technologies have become a core component of modern search engines, intelligent personal assistants, business intelligence, and so on. Interestingly, despite large-scale data availability, they have yet to be as successful in the realm of environmental data and environmental intelligence. In this paper, we will explain why spatial data require special treatment, and how and when to semantically lift environmental data to a KG. We will present our KnowWhereGraph that contains a wide range of integrated datasets at the human–environment interface, introduce our application areas, and discuss geospatial enrichment services on top of our graph. Jointly, the graph and services will provide answers to questions such as “what is here,” “what happened here before,” and “how does this region compare to …” for any region on earth within seconds.

Canonically, EZH2 serves as the catalytic subunit of PRC2, which mediates H3K27me3 deposition and transcriptional repression. Here, we report that in acute leukaemias, EZH2 has additional noncanonical functions by binding cMyc at non-PRC2 targets and uses a hidden transactivation domain (TAD) for (co)activator recruitment and gene activation. Both canonical (EZH2-PRC2) and noncanonical (EZH2-TAD-cMyc-coactivators) activities of EZH2 promote oncogenesis, which explains the slow and ineffective antitumour effect of inhibitors of the catalytic function of EZH2. To suppress the multifaceted activities of EZH2, we used proteolysis-targeting chimera (PROTAC) to develop a degrader, MS177, which achieved effective, on-target depletion of EZH2 and interacting partners (that is, both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes). Compared with inhibitors of the enzymatic function of EZH2, MS177 is fast-acting and more potent in suppressing cancer growth. This study reveals noncanonical oncogenic roles of EZH2, reports a PROTAC for targeting the multifaceted tumorigenic functions of EZH2 and presents an attractive strategy for treating EZH2-dependent cancers.

Joint replacement surgery is one of the orthopedic surgeries with high successful rates; however, wear debris generated from prostheses can ultimately lead to periprosthetic osteolysis and failure of the implant. The implant-derived particulate debris such as ultrahigh molecular weight polyethylene (UHMWPE) can initiate the local immune response and recruit monocytic cells to phagocytose particles for generating reactive oxygen species (ROS). ROS induces osteoclastogenesis and macrophages to secrete cytokines which ultimately promote the development of osteolysis. In this work, we develop the few-layered Nb2C (FNC) as an antioxidant which possesses the feature of decreasing the production of cytokines and inhibiting osteoclastogenesis by its ROS adsorption. Moreover, local injection of FNC attenuates the UHMWPE-induced osteolysis in a mouse calvarial model. In sum, our results suggest that FNC can be used for treating osteolytic bone disease caused by excessive osteoclastogenesis., Graphical abstract Image 1, Highlights • Few-layered Nb2C (FNC) was synthesized by chemical exfoliation from bulk Nb2C (BNC) and showed an outstanding elimination of ROS on the basis of density functional theory (DFT) and inhibition effect of oxidative stress in vitro. • Osteoxlastogenesis was driven by reactive oxygen species (ROS), controlling osteoclasts differentiation in the early stage. • FNC inhibited osteoclastogenesis via scavenging ROS and dampening related signal pathway. • UHMWPE-induced osteolysis was attenuated by FNC therapy.

By the photopolymerization 3D printing of photopolymerizable deep eutectic solvents, a stable and sensitive solid-state capacitive ionic skin is reported.

The λ-shape dielectric anomaly follows the Curie–Weiss law with a 105.8-fold change at a frequency of 500 Hz. The spontaneous polarization of TATC can reach 1.4 μC cm−2. The TATC crystal has a 4.03 eV indirect bandgap.

This Supplementary Figure S4 shows that DNMT3A hotspot mutation does not prefer flanking sequences for CpG methylation and that a heterodimerization interface is critical for the R882 mutant to induce transformation and CpG hypomethylation.

This contains Supplementary Figure S2, which reveals CpG hypomethylation included by DNMT3A hotspot mutations.

Supplemental Table S1 Patient characteristics for the National Lung Screening Trial (NLST) and The Cancer Genome Atlas (TCGA) datasets.

PDF file - 1065KB, Supplemental Data for Figure 4.

This contains Supplementary Figure S3, which shows dose-dependent effect by DNMT3A hotspot mutation on transformation and CpG hypomethylation.

Supplemental Figure S8 Volcano plots of gene set enrichment analysis results correlating mRNA expression level with stroma nuclei density and karyorrhexis density, respectively.

PDF file - 48KB

Supplemental Figure S7 Illustration of Delaunay triangle construction.

Supplemental Figure S6. Validation of macrophage detection results in whole-slide image nuclei segmentation and classification by HD-Staining model.

Supplemental Figure S4 Whole-slide image nuclei segmentation and classification by HD-Staining model.