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γδ T cells are a distinct subgroup of T cells that bridge the innate and adaptive immune system and can attack cancer cells in an MHC-unrestricted manner. Trials of adoptive γδ T cell transfer in solid tumors have had limited success. Here, we show that DNA methyltransferase inhibitors (DNMTis) upregulate surface molecules on cancer cells related to γδ T cell activation using quantitative surface proteomics. DNMTi treatment of human lung cancer potentiates tumor lysis by ex vivo-expanded Vδ1-enriched γδ T cells. Mechanistically, DNMTi enhances immune synapse formation and mediates cytoskeletal reorganization via coordinated alterations of DNA methylation and chromatin accessibility. Genetic depletion of adhesion molecules or pharmacological inhibition of actin polymerization abolishes the potentiating effect of DNMTi. Clinically, the DNMTi-associated cytoskeleton signature stratifies lung cancer patients prognostically. These results support a combinatorial strategy of DNMTis and γδ T cell-based immunotherapy in lung cancer management., Gamma delta (γδ) T cells have potential for use in immunotherapy against tumours. Here, the authors demonstrate that treatment of tumours with DNA methyltransferase inhibitors modulates cytoskeleton arrangements, upregulates adhesion molecules and increases tumour killing by γδ T cells.

The coincident downregulation of NR4A1 and NR4A3 has been implicated in myeloid leukemogenesis, but it remains unknown how these two genes function in myeloid cells and how their combined downregulation promotes myeloid leukemogenesis. Since NR4A1 abrogation is thought to confer a survival and proliferation advantage to myeloid cells, we hypothesized that downregulation of NR4A3 may have a complementary effect on myeloid cell differentiation. First, we tested the association between differentiation status of leukemic cells and NR4A3 expression using two large clinical datasets from patients with different acute myeloid leukemia (AML) subtypes. The analysis revealed a close association between differentiation status and different subtypes of AML Then, we probed the effects of differentiation-inducing treatments on NR4A3 expression and NR4A3 knockdown on cell differentiation using two myeloid leukemia cell lines. Differentiation-inducing treatments caused upregulation of NR4A3, while NR4A3 knockdown prevented differentiation in both cell lines. The cell culture findings were validated using samples from chronic myeloid leukemia (CML) patients at chronic, accelerated and blastic phases, and in acute promyelocytic leukemia (APL) patients before and after all trans-retinoic acid (ATRA)-based differentiation therapy. Progressive NR4A3 downregulation was coincident with impairments in differentiation in patients during progression to blastic phase of CML, and NR4A3 expression was increased in APL patients treated with ATRA-based differentiating therapy. Together, our findings demonstrate a tight association between impaired differentiation status and NR4A3 downregulation in myeloid leukemias, providing a plausible mechanistic explanation of how myeloid leukemogenesis might occur upon concurrent downregulation of NR4A1 and NR4A3.

Reactivation of hepatitis B virus (HBV) by reverse seroconversion (HBV-RS) after allogeneic haematopoietic stem cell transplantation (allo-HSCT) can occur in patients with resolved HBV infection (rHBV, defined as negative HBV surface antigen [HBsAg] and positive HBV core antibody), and may cause fatal hepatitis. To explore the risk factors, we retrospectively identified 817 consecutive patients who underwent allo-HSCT from 2005 to 2016 in this largest single centre cohort from National Taiwan Univerisity Hospital. Transplants using donors or recipients positive for HBsAg or HBV DNA were excluded, leaving 445 rHBV patients for analysis. The 3- and 5-year cumulative incidence of HBV-RS after allo-HSCT was 8·7% and 10·5%, respectively, at a median 16 months after allo-HSCT. All had concurrent HBV reactivation. HBV flares developed in 19% of HBV-RS cases, but none experienced hepatic failure. Neither did it impact non-relapse mortality or overall survival. Multivariate analysis revealed that patients with donor lacking hepatitis B surface antibody and extensive chronic graft-versus-host disease (cGVHD) have the highest risk for HBV-RS, with 5-year incidence of 24·2%. In conclusion, adoptive immunity transfer from the donor seems to have protective effects against HBV-RS, which may alter future donor selection algorithms, and combined with extensive cGVHD provides a good target for risk-adaptive HBV prophylaxis.

In this paper, we present a descriptive analysis of a performance index, ΔVDIBLSS/(Ion/Ioff), used for performance monitoring. Scaled nand p-channel metal-oxide-semiconductor field-effect transistors (MOSFETs) (planar and FinFET devices) are included for comparison of performance trends. Also, the simplified ΔVDIBL/(Ion/Ioff) for monitoring the electrical characteristics of MOSFET devices is proposed due to the “quick measurements” required in the last step of the semiconductor manufacturing process. ΔVDIBL/(Ion/Ioff) only accounts for drain-induced barrier lowering in its numerator and on/off current ratio in its denominator. The calculation process for ΔVDIBL/(Ion/Ioff) is much quicker than for ΔVDIBLSS/(Ion/Ioff), where we need to make an extra measurement of the value of the subthreshold swing. Performance metrics, such as Ion/Ioff and intrinsic gain, gm × ro, are reported using ΔVDIBLSS/(Ion/Ioff) and ΔVDIBL/(Ion/Ioff). ΔVDIBLSS of about 100 mV in scaled MOSFETs is required to ensure that the gate control is strong. Since Ion/Ioff is a sensitive function of threshold voltage, the estimates of the ΔVDIBLSS/(Ion/Ioff) and ΔVDIBL/(Ion/Ioff) are therefore dependent on the design of threshold voltage. In planar MOSFETs, small values of ΔVDIBLSS/(Ion/Ioff) and ΔVDIBL/(Ion/Ioff) are hard to achieve. However, in FinFETs, it is easy to achieve the performance requirements due to its tri-gate structure.

The genus Agrobacterium contains a group of plant-pathogenic bacteria that have been developed into an important tool for genetic transformation of eukaryotes. To further improve this biotechnology application, a better understanding of the natural genetic variation is critical. During the process of isolation and characterization of wild-type strains, we found a novel strain (i.e., NCHU2750) that resembles Agrobacterium phenotypically but exhibits high sequence divergence in several marker genes. For more comprehensive characterization of this strain, we determined its complete genome sequence for comparative analysis and performed pathogenicity assays on plants. The results demonstrated that this strain is closely related to Neorhizobium in chromosomal organization, gene content, and molecular phylogeny. However, unlike the characterized species within Neorhizobium, which all form root nodules with legume hosts and are potentially nitrogen-fixing mutualists, NCHU2750 is a gall-forming pathogen capable of infecting plant hosts across multiple families. Intriguingly, this pathogenicity phenotype could be attributed to the presence of an Agrobacterium-type tumor-inducing plasmid in the genome of NCHU2750. These findings suggest that these different lineages within the family Rhizobiaceae are capable of transitioning between ecological niches by having novel combinations of replicons. In summary, this work expanded the genomic resources available within Rhizobiaceae and provided a strong foundation for future studies of this novel lineage. With an infectivity profile that is different from several representative Agrobacterium strains, this strain may be useful for comparative analysis to better investigate the genetic determinants of host range among these bacteria.

Background: Multicolor flow cytometry (MFC) analysis is widely used to identify minimal residual disease (MRD) after treatment for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, current manual interpretation suffers from drawbacks of time consuming and interpreter idiosyncrasy. Artificial intelligence (AI), with the expertise in assisting repetitive or complex analysis, represents a potential solution for these drawbacks. Methods: From 2009 to 2016, 5333 MFC data from 1742 AML or MDS patients were collected. The 287 MFC data at post-induction were selected as the outcome set for clinical outcome validation. The rest were 4:1 randomized into the training set (n = 4039) and the validation set (n = 1007). AI algorithm learned a multi-dimensional MFC phenotype from the training set and input it to support vector machine (SVM) classifier after Gaussian mixture model (GMM) modeling, and the performance was evaluated in The validation set. Findings: Promising accuracies (84·6% to 92·4%) and AUCs (0·921–0·950) were achieved by the developed algorithms. Interestingly, the algorithm from even one testing tube achieved similar performance. The clinical significance was validated in the outcome set, and normal MFC interpreted by the AI predicted better progression-free survival (10·9 vs 4·9 months, p

As our mediated and interconnected everyday life has been deeply implicated in the global changes related to the COVID-19 pandemic, I look at the residual world-system coloniality in disease preven...

γδ T cells are a distinct subgroup of T cells that bridge the innate and adaptive immune systems and can attack cancer or virus-infected cells in an MHC-unrestricted manner. Despite its antitumor ability in both autologous and allogeneic settings, earlier trials of adoptive γδ T cell transfer in solid tumors had limited success due to limitations in cell expansion and the lack of a strategy to modulate tumor lytic interactions between γδ T and cancer cells. Here, we show through quantitative surface proteomics and gene enrichment analyses that DNA methyltransferase inhibitors (DNMTis) upregulate multiple surface molecules related to γδ T cell activation in cancer cells. DNMTi treatment of human lung cancer potentiates tumor lysis by ex vivo-expanded γδ T cells using a clinical-grade expansion protocol developed by our team to enrich for the Vδ1 subset while preserving their antitumor effector functions. Mechanistically, DNMTis enhance immune synapse formation and stabilize the synaptic cleft to facilitate γδ T-mediated tumor lysis. Through integrated analysis of RNA-seq, DNA methylation, and ATAC-seq, we demonstrate that depletion of DNMTs induces coordinated pattern alterations of immune synaptic-cytoskeletal networks at the cancer side of the immune synapse. In addition, single-cell mass cytometry reveals enrichment of polyfunctional γδ T subsets by DNMTis. Combined DNMTi and adoptive γδ T transfer in a mouse lung cancer model offers a significant survival benefit. Consistently, the DNMTi-associated cytoskeleton signature identifies a subset of lung cancer patients with improved survival. Our results demonstrate that epigenetic mechanisms are crucial for cytoskeletal remodeling in cancer to potentiate immune attack and support a combinatorial strategy of DNMTis and γδ T cell-based immunotherapy in lung cancer management.One Sentence SummaryDNA methyltransferase inhibitors potentiate the killing of lung cancer by γδ T cells through remodeling cytoskeletal-immune synaptic networks.

Mutations of the GATA binding protein 2 (GATA2) gene in myeloid malignancies usually cluster in the zinc finger 1 (ZF1) and the ZF2 domains. Mutations in different locations of GATA2 may have distinct impact on clinico-biological features and outcomes in AML patients, but little is known in this aspect. In this study, we explored GATA2 mutations in 693 de novo non-M3 AML patients and identified 44 GATA2 mutations in 43 (6.2%) patients, including 31 in ZF1, 10 in ZF2, and three outside the two domains. Different from GATA2 ZF2 mutations, ZF1 mutations were closely associated with French-American-British (FAB) M1 subtype, CEBPA double mutations (CEBPAdouble-mut), but inversely correlated with FAB M4 subtype, NPM1 mutations, and FLT3-ITD. ZF1-mutated AML patients had a significantly longer overall survival (OS) than GATA2-wild patients and ZF2-mutated patients in total cohort as well as in those with intermediate-risk cytogenetics and normal karyotype. ZF1 mutations also predicted better disease-free survival and a trend of better OS in CEBPAdouble-mut patients. Sequential analysis showed GATA2 mutations could be acquired at relapse. In conclusion, GATA2 ZF1 mutations are associated with distinct clinico-biological features and predict better prognosis, different from ZF2 mutations, in AML patients.

Venetoclax, a selective B cell leukemia/lymphoma-2 (BCL2) inhibitor, has recently shown activity in relapsed or refractory (R/R) acute myeloid leukemia (AML). Effective biomarkers for identifying patients most likely to respond to venetoclax-based treatment are of clinical utility. In this study, we aimed to evaluate the efficacy and safety profiles of venetoclax-based therapy in a total 40 R/R AML patients and identify the potentially predictive factors for response. Overall response rate was 50%, including 9 (22.5%) complete response (CR) or CR with incomplete hematologic recovery of either neutrophil or platelet counts (CRi). Median time to best response was 1.4 months and the median overall survival (OS) was 6.6 months. Presence of intermediate-risk cytogenetics predicted better OS compared to unfavorable-risk cytogenetics. Patients harboring NPM1, RUNX1, or SRSF2 mutations seemed to have higher CR/CRi rates and median OS was significantly longer in RUNX1-mutated patients. On the contrary, patients with FLT3-ITD, TP53, or DNMT3A mutations did not reach any objective response and had worse OS. No laboratory or clinical tumor lysis syndrome was observed and the most common adverse events were prolonged cytopenias which resulted in 67.5% of febrile neutropenia. Patients with concurrent use of azole antifungals had similar incidence of cytopenias compared with those without azole antifungals. In summary, we demonstrate that venetoclax is an effective and well-tolerated salvage option for R/R AML patients. Survival benefits were particularly remarkable in patients with intermediate-risk cytogenetics or RUNX1 mutations. In contrast, TP53, NRAS, and DNMT3A mutations as well as FLT3-ITD conferred negative impact on survival.

OBJECTIVES Acute myeloid leukemia (AML) with hyperleukocytosis (HL) is intuitively thought as a unique group with dismal prognosis. However, comprehensive studies regarding the genetic landscape and clinical outcome in this group of patients are limited. METHODS A total of 693 newly diagnosed de novo non-M3 AML patients were consecutively enrolled. We compared relevant mutations in 20 genes between AML patients with or without HL and exposed their prognostic implications. RESULTS Hyperleukocytosis, defined as initial white blood cell counts above 50 000/μL, occurred in 28.9% of AML patients. HL patients had higher incidences of FLT3-ITD, NPM1, DNMT3A, CEBPA, and TET2 mutations. Multivariate analysis demonstrated that HL was an independent poor prognostic factor for overall survival and disease-free survival in total patients, those with intermediate-risk cytogenetics and normal karyotype irrespective of genetic alterations. Intriguingly, HL predicted poor survival in CEBPA double mutated, NPM1 + /FLT3-ITD- and NPM1-/FLT3-ITD- patients. Further, HL patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR) had a significantly longer overall survival and disease-free survival than those without allo-HSCT. CONCLUSIONS Hyperleukocytosis is an independent poor prognostic factor irrespective of cytogenetics and mutation status. Allo-HSCT in first CR seems to ameliorate the poor prognostic impact of HL.

Background DNMT3A gene mutation has been associated with poor prognosis in acute myeloid leukemia, but its clinical implications in myelodysplastic syndrome (MDS) and dynamic changes during disease progression remain controversial. Results In this study, DNMT3A mutation was identified in 7.9% of 469 de novo MDS patients. DNMT3A-mutated patients had higher platelet counts at diagnosis, and patients with ring sideroblasts had the highest incidence of DNMT3A mutations, whereas those with multilineage dysplasia had the lowest incidence. Thirty-one (83.8%) of 37 DNMT3A-mutated patients had additional molecular abnormalities at diagnosis, and DNMT3A mutation was highly associated with mutations of IDH2 and SF3B1. Patients with DNMT3A mutations had a higher risk of leukemia transformation and shorter overall survival. Further, DNMT3A mutation was an independent poor prognostic factor irrespective of age, IPSS-R, and genetic alterations. The sequential study demonstrated that the original DNMT3A mutations were retained during follow-ups unless allogeneic hematopoietic stem cell transplantation was performed, while DNMT3A mutation was rarely acquired during disease progression. Conclusions DNMT3A mutation predicts unfavorable outcomes in MDS and was stable during disease evolutions. It may thus be a potential biomarker to predict prognosis and monitor the treatment response. Electronic supplementary material The online version of this article (10.1186/s13148-018-0476-1) contains supplementary material, which is available to authorized users.

This paper aims to investigate the device parameters, including drain-induced barrier lowering (DIBL), subthreshold swing (SS), and saturation drive current, $I_{\rm d,{\mathrm{ sat}}} $ , of bulk-Si n-channel FinFET devices (bulk n-FinFETs). The impact of lightly doped drain (LDD) process on the performance of bulk n-FinFETs is also examined in this paper. According to our measured data, excluding LDD in bulk n-FinFETs not only reduces mask costs but it also enables slightly better short-channel control compared to the inclusion of LDD. A new figure of merit, $\Delta V_{\mathrm{ DIBLSS}} /(I_{\rm d,{\mathrm{ sat}}} /I_{\rm sd,{\mathrm{ leak}}} )$ , is introduced for monitoring short-channel performance of bulk n-FinFETs, where $\Delta V_{\mathrm{ DIBLSS}} $ accounts for the DIBL and SS, and $I_{\rm sd,{\mathrm{ leak}}} $ is the source/drain subthreshold off-state leakage current.

Motivated by the increasing thermal load in urban environment, this work established Urban Climatic map (UCmap) focusing on thermal environment issues based on urban development factors, e.g., land cover and building characteristics, representing thermal load of human body and ventilation path in the urban structures. In the established process of UCmap in this work, Tainan city, which is a highly developed city in southern Taiwan, is selected as the research area. A 50-m resolution grid is used to capture urban development factors and the climate data based on 1 year of mobile and fix-point measurements, from which the thermal load and the wind environment map are constructed. The results herein reveal that a higher urban development level is associated with a higher thermal load, and similar areas are more likely than others to suffer from an extreme thermal load and low wind pass conditions. Open and sparse low-rise buildings constitute the most appropriate urban characteristics for urban built environment in Tainan. By the simple approach of establishing UCmap, the microclimate condition and development intensity of regions can be easily detected and linked, for example the compact high-rise areas should be limited by floor area ratio in order to prevent the formation of hot spots. The government, urban planners, and architects without a meteorological background can efficiently obtain climate information by way of mapping the certain area, and making regulations to mitigate the growing problem of thermal stress and urban heat island.

We examine the interrelationships among liquidity creation, regulatory capital, and bank profitability of US banks. We find that regulatory capital and liquidity creation affect each other positively after controlling for bank profitability. However, this relationship is largely driven by small banks and primarily during non-crisis periods. It is also sensitive to the level of banks' regulatory capital and how it is measured. Furthermore, we find that banks which create more liquidity and exhibit higher illiquidity risk have lower profitability. Finally, the relationship between regulatory capital and bank performance is not linear and depends on the level of capitalization. Regulatory capital is negatively related to bank profitability for higher capitalized banks but positively related to profitability for lower capitalized banks. Therefore, a change in regulatory capital has differential impacts on bank performance. Our findings have various implications for policymakers and bank regulators.

Table S1. Correlation of HOXB-AS3 expression with clinical characteristics and frequent somatic gene mutations in de novo AML patients. Table S2. Correlation of HOXB-AS3 expression with clinical characteristics in MDS patients. Table S3. Correlation of HOXB-AS3 expression with frequent gene mutations in MDS patients. Figure S1. Overview of Hoxb5os in mouse HOXB cluster. Figure S2. Alignment of mouse Hoxb5os and human HOXB-AS3. Figure S3. HOXB-AS3 promotes S phase entering in the cell cycle regulation. Figure S4. GSEA pathway analysis of the differentially expressed genes in HOXB-AS3 knockdown cells compared to the control cells. Figure S5. Cell cycle pathway from Wikipathway analysis of downstream pathways affected by downregulation of HOXB-AS3 in the myeloid cell lines. Figure S6. DNA replication pathway from Wikipathway analysis of downstream pathways affected by downregulation of HOXB-AS3 in the myeloid cell lines. Figure S7. RB pathway from Wikipathway analysis of downstream pathways affected by downregulation of HOXB-AS3 in the myeloid cell lines. Figure S8. G1-S pathway from Wikipathway analysis of downstream pathways affected by downregulation of HOXB-AS3 in the myeloid cell lines. Figure S9. Quantitative PCR analysis of the expressions of indicated genes in TF-1 cells infected with lentivirus carrying pAS5.1w-Pbsd (control), or pAS5.1w-Pbsd-HOXB-AS3 (HOXB-AS3 overexpression). Figure S10. HOXB-AS3 expressions of AML patients and health donors. Figure S11. Survival analysis of AML patients stratified by the expressions of HOXB-AS3. Figure S12. HOXB-AS3 expression of non-APL AML patients and health donors. Figure S13. Survival analysis of non-APL AML patients stratified by the expressions of HOXB-AS3 in the NTUH AML cohort. Figure S14. HOXB-AS3 expressions of MDS patients and health donors. Figure S15. Overall survival of MDS patients stratified by the expressions of HOXB-AS3. Figure S16. Quantitative PCR analysis of the expressions of different variants in TF-1 and OCI/AML3 cell lines. (PDF 2900 kb)

We empirically compare the reliability of the dividend (DIV) model, the residual income valuation (CT, GLS) model, and the abnormal earnings growth (OJ) model. We find that valuation estimates from the OJ model are generally more reliable than those from the other three models, because the residual income valuation model anchored by book value gets off to a poor start when compared with the OJ model led by capitalized next-year earnings. We adopt a 34-year sample covering from 1985 to 2013 to compare the reliability of valuation estimates via their means of absolute pricing errors ( MAPE) and corresponding t statistics. We further use the switching regression of Barrios and Blanco to show that the average probability of OJ valuation estimates is greater in explaining stock prices than the DIV, CT, and GLS models. In addition, our finding that the OJ model yields more reliable estimates is robust to analysts-based and model-based earnings measures.

We examine the effect of herding behaviour on the credit quality of bank loans in Australia. We find that bank herding varies with different types of loans. It tends to be more prevalent in owner-occupied housing loans and credit cards than other types of loans. During the global financial crisis period, herding in owner-occupied housing loans was most pronounced due to the flight-to-quality phenomenon in the housing sector. Furthermore, we find that the big four banks tend to herd more than smaller and regional banks. Bank herding behaviour is countercyclical, as it is negatively related to real GDP growth and the cost of funding but is positively related to market risk. Regulatory capital requirements may also encourage herding as banks are required to hold less risk-weighted capital for residential loans. Most importantly, bank herding is related to higher impaired assets and therefore lower loan quality. Our findings may have implications for policymakers and bank regulators.

This study examines how heterogeneous institutional ownership affects stock price delay. Our result shows higher total institutional ownership and the number of institutions reduce price delay. We further classify institution types from stock’s perspective (top 5 and year-long) and institution’s perspective (low churn rate, high churn rate, concentrated, skilled, and independent). After controlling the total institutional ownership, investor attention, and firm characteristic variables, we find ownership from top 5 and low churn rate, and ownership increase from independent institutions help lower price delay while high churn rate, concentrated, and skilled institutional ownerships increase the delay. Moreover, the price delay components related to year-long, high churn rate, concentrated, and skilled institutions are positively associated with expected stock returns. Our results suggest while top 5 and low churn rate institutions actively monitor firms and reduce price delay, high churn rate, concentrated, and skilled institutions may utilize their information advantage and hinder uninformed investors’ trading, resulting in delayed price adjustment to information.

Based on the macro-financial risk framework of Gray et al. (2006) that links the balance sheets of the financial sector and public sector together through government guarantees, we propose an indicator, sovereign distance-to-default (SDD), for implementing the countercyclical capital buffer schemes of Basel III. Using a sample of 29 European countries from 1975 to 2011, we find that SDD outperforms credit-to-GDP ratio, the primary indicator recommended by the Basel Committee for Banking Supervision. More specifically, SDD generates more reliable signals for the build-up of capital buffers three years prior to a crisis and the release of capital buffers in the same year that the crisis occurs. Our findings suggest that SDD can be used as a leading indicator for the build-up phase and an anchor for the release phase of the countercyclical capital buffer schemes.

We examine the impact of information asymmetry on a firm's capital structure decisions with a unique information rating scheme that draws from 114 measures over five dimensions of information disclosures on each firm from 2006 to 2012. We find that a firm with high (low) information rating is related to low (high) debt financing and leverage. In particular, a firm that moves from the lowest to the highest information rating experiences a 7.8% reduction in firm leverage on average. This relationship is robust to firm characteristics, incentive conflicts, and the agreement theory of Dittmar and Thakor (2007). Our results suggest that information asymmetry is influential on a firm's pecking order behavior independent of these effects.