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This article examines the use of tyrosine kinase inhibitor (TKI) therapy as a maintenance treatment after chimeric antigen receptor (CAR) T-cell therapy in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who cannot undergo allogeneic hematopoietic cell transplantation (alloHCT). The study presents a case series of seven patients who received CAR-T cells for relapsed/refractory Ph+ ALL and subsequently received TKI maintenance. The article discusses the patients' characteristics and outcomes, emphasizing the need for further research and data on this approach. The study suggests that TKI maintenance therapy after CAR-T may be beneficial, particularly in patients who achieve complete molecular remission (CMR) and have no evidence of minimal residual disease (MRD). The authors recommend larger prospective trials to confirm the effectiveness and safety of TKI maintenance therapy post-CAR-T, and to explore its potential application to other subtypes of ALL. [Extracted from the article]

All freely available plane‐of‐array (POA) transposition models and photovoltaic (PV) temperature and performance models in pvlib‐python and pvpltools‐python were examined against multiyear field data from Albuquerque, New Mexico. The data include different PV systems composed of crystalline silicon modules that vary in cell type, module construction, and materials. These systems have been characterized via IEC 61853‐1 and 61853‐2 testing, and the input data for each model were sourced from these system‐specific test results, rather than considering any generic input data (e.g., manufacturer's specification [spec] sheets or generic Panneau Solaire [PAN] files). Six POA transposition models, 7 temperature models, and 12 performance models are included in this comparative analysis. These freely available models were proven effective across many different types of technologies. The POA transposition models exhibited average normalized mean bias errors (NMBEs) within ±3%. Most PV temperature models underestimated temperature exhibiting mean and median residuals ranging from −6.5°C to 2.7°C; all temperature models saw a reduction in root mean square error when using transient assumptions over steady state. The performance models demonstrated similar behavior with a first and third interquartile NMBEs within ±4.2% and an overall average NMBE within ±2.3%. Although differences among models were observed at different times of the day/year, this study shows that the availability of system‐specific input data is more important than model selection. For example, using spec sheet or generic PAN file data with a complex PV performance model does not guarantee a better accuracy than a simpler PV performance model that uses system‐specific data. [ABSTRACT FROM AUTHOR]

P2‐type cobalt‐free MnNi‐based layered oxides are promising cathode materials for sodium‐ion batteries (SIBs) due to their high reversible capacity and well chemical stability. However, the phase transformations during repeated (dis)charge steps lead to rapid capacity decay and deteriorated Na+ diffusion kinetics. Moreover, the electrode manufacturing based on polyvinylidene difluoride (PVDF) binder system has been reported with severely defluorination issue as well as the energy intensive and expensive process due to the use of toxic and volatile N‐methyl‐2‐pyrrolidone (NMP) solvent. It calls for designing a sustainable, better performing, and cost‐effective binder for positive electrode manufacturing. In this work, we investigated inorganic sodium metasilicate (SMS) as a viable binder in conjunction with P2‐Na0.67Mn0.55Ni0.25Fe0.1Ti0.1O2 (NMNFT) cathode material for SIBs. The NMNFT‐SMS electrode delivered a superior electrochemical performance compared to carboxy methylcellulose (CMC) and PVDF based electrodes with a reversible capacity of ~161 mAh/g and retaining ~83 % after 200 cycles. Lower cell impedance and faster Na+ diffusion was also observed in this binder system. Meanwhile, with the assistance of TEM technique, SMS is suggested to form a uniform and stable nanoscale layer over the cathode particle surface, protecting the particle from exfoliation/cracking due to electrolyte attack. It effectively maintained the electrode connectivity and suppressed early phase transitions during cycling as confirmed by operando XRD study. With these findings, SMS binder can be proposed as a powerful multifunctional binder to enable positive electrode manufacturing of SIBs and to overall reduce battery manufacturing costs. [ABSTRACT FROM AUTHOR]

Amorphous Al2O3 film that naturally exists on any Al substrate is a critical bottleneck for the cyclic performance of metallic Al in rechargeable Al batteries. The so‐called electron/ion insulator Al oxide slows down the anode's activation and hinders Al plating/stripping. The Al2O3 film induces different surface properties (roughness and microstructure) on the metal. Al foils present two optically different sides (shiny and non‐shiny), but their surface properties and influence on plating and stripping have not been studied so far. Compared to the shiny side, the non‐shiny one has a higher (~28 %) surface roughness, and its greater concentration of active sites (for Al plating and stripping) yields higher current densities. Immersion pretreatments in Ionic‐Liquid/AlCl3‐based electrolyte with various durations modify the surface properties of each side, forming an electrode‐electrolyte interphase layer rich in Al, Cl, and N. The created interphase layer provides more tunneling paths for better Al diffusion upon plating and stripping. After 500 cycles, dendritic Al deposition, generated active sites, and the continuous removal of the Al metal and oxide cause accelerated local corrosion and electrode pulverization. We highlight the mechanical surface properties of cycled Al foil, considering the role of immersion pretreatment and the differences between the two sides. [ABSTRACT FROM AUTHOR]

The formation of the solid electrolyte interphase (SEI) on HC composite electrodes plays a crucial role in enhancing the performance and operational stability of sodium (Na+) ion batteries. It has been demonstrated that for HC anodes improved electrochemical performance, e. g., increase in coulombic efficiency (CE) and improved rate performance have been achieved in ether‐based electrolytes. Here, we investigate spray‐coated HC composite electrodes charged at low and high current rates in 1 M sodium hexafluorophosphate (NaPF6) in diglyme using half‐cell experiments. The pristine and cycled HC anodes were examined in terms of conductivity and their electrochemical properties after cycling. In 1 M NaPF6 ether‐based electrolyte, the spray‐coated HC composite electrodes (film thickness approx. 22.0 μm with an active mass loading of approx. 2.0 mg cm−2) reached a discharge capacity of 431 mA h g−1 at 0.1 C that stays constant for 40 cycles, which is substantially higher than that obtained in carbonate‐based electrolytes. We investigated the formed interphase using conductive atomic force microscopy (c‐AFM), scanning electrochemical microscopy (SECM), X‐ray photoelectron spectroscopy (XPS) and time‐of‐flight secondary‐ion mass spectrometry (ToF‐SIMS), revealing distinct differences for longer cycling and at varying current rates which indicates that the properties of the formed SEI layers are influenced by the formation conditions. [ABSTRACT FROM AUTHOR]

Different data pipelines and statistical methods are applied to photovoltaic (PV) performance datasets to quantify the performance loss rate (PLR). Since the real values of PLR are unknown, a variety of unvalidated values are reported. As such, the PV industry commonly assumes PLR based on statistically extracted ranges from the literature. However, the accuracy and uncertainty of PLR depend on several parameters including seasonality, local climatic conditions, and the response of a particular PV technology. In addition, the specific data pipeline and statistical method used affect the accuracy and uncertainty. To provide insights, a framework of (≈ 200 million) synthetic simulations of PV performance datasets using data from different climates is developed. Time series with known PLR and data quality are synthesized, and large parametric studies are conducted to examine the accuracy and uncertainty of different statistical approaches over the contiguous US, with an emphasis on the publicly available and "standardized" library, RdTools. In the results, it is confirmed that PLRs from RdTools are unbiased on average, but the accuracy and uncertainty of individual PLR estimates vary with climate zone, data quality, PV technology, and choice of analysis workflow. Best practices and improvement recommendations based on the findings of this study are provided. [ABSTRACT FROM AUTHOR]

The Photovoltaic (PV) Performance Modeling Collaborative (PVPMC) organized a blind PV performance modeling intercomparison to allow PV modelers to blindly test their models and modeling ability against real system data. Measured weather and irradiance data were provided along with detailed descriptions of PV systems from two locations (Albuquerque, New Mexico, USA, and Roskilde, Denmark). Participants were asked to simulate the plane‐of‐array irradiance, module temperature, and DC power output from six systems and submit their results to Sandia for processing. The results showed overall median mean bias (i.e., the average error per participant) of 0.6% in annual irradiation and −3.3% in annual energy yield. While most PV performance modeling results seem to exhibit higher precision and accuracy as compared to an earlier blind PV modeling study in 2010, human errors, modeling skills, and derates were found to still cause significant errors in the estimates. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined the effects of carbamylation induced by potassium cyanates (KOCN), a well-established carbamylating agent used in vitro models, and urea on prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen measured in pooled normal human plasma. Topics include how a normal plasma pool (NPP) used in the study was prepared, PT, aPTT, and fibrinogen values after the KOCN, and factor that may affect the results of coagulation tests.

Perovskite photovoltaics (PVs) are an emerging solar energy generation technology that is nearing commercialization. Despite the unprecedented progress in increasing power conversion efficiency (PCE) for perovskite solar cells (PSCs), up‐scaling lab‐made cells to solar modules remains a challenge. In this work, the recent progress of making perovskite mini‐modules is reviewed. In particular, a database summarizing the module size, performance, hysteresis, and operational lifetimes reported in the literature is built. After analyzing the performance losses from scaling PSCs to mini‐modules based on the data collected from the literature, the current key to high‐performance perovskite mini‐modules is found to be the coating method optimization. If the perovskite layer quality is well reserved, a >24% mini‐module efficiency is projected by only considering the losses from lateral resistivity and laser scribing area. Next, performance characteristics are explored including hysteresis and meta‐stable power outputs that must be overcome to correctly characterize perovskite modules. Finally, current challenges associated with the long‐term stability of perovskite modules are examined and the importance of such durability for commercialization is discussed. It is hoped that the findings in this review provide a bridge for the development of perovskite modules that will lead to commercialization in the near future. [ABSTRACT FROM AUTHOR]

Background: A lower baseline bone marrow blast percentage (bBMB%) is associated with better outcomes in patients with B‐cell acute lymphoblastic leukemia (B‐ALL) receiving blinatumomab. The objective of this analysis was to investigate the association between bBMB% and treatment outcomes in relapsed/refractory (R/R) B‐ALL. Methods: Data from five trials of blinatumomab for R/R B‐ALL were pooled for analyses. Patients were placed in one of three groups: group 1, ≥50% bBMBs; group 2, ≥25% to <50% bBMBs; group 3, ≥5% to <25% bBMBs. Response and survival outcomes were compared between groups. Results: Data from 683 patients (166 pediatric, 517 adult) were analyzed. Collectively, patients in groups 2 and 3 had significantly higher odds of achieving a complete remission (CR) (odds ratio [OR], 3.50 [95% confidence interval (CI), 2.23–5.48] and 3.93 [95% CI, 2.50–6.18], respectively; p <.001) and minimal/measurable residual disease response (OR, 2.61 and 3.37, respectively; p <.001) when compared with group 1 (reference). Groups 2 and 3 had a 37% and 46% reduction in the risk of death (hazard ratio [HR], 0.63 and 0.54, respectively; p <.001) and a 41% and 43% reduction in the risk of an event (relapse or death) (HR, 0.59 and 0.57, respectively; p <.001) compared with group 1. No significant differences in response or survival outcomes were observed between groups 2 and 3. Seven of nine patients whose bBMB% was lowered to <50% with dexamethasone achieved CR with blinatumomab. Conclusion: Any bBMB% <50% was associated with improved efficacy following blinatumomab treatment for R/R B‐ALL. Patients with a baseline leukemia burden of <50% bone marrow blasts achieved better outcomes with blinatumomab compared with those who had ≥50% blasts. There was no statistical difference in clinical outcomes with blinatumomab in patients who had ≥5% to <50% bone marrow blasts at baseline. [ABSTRACT FROM AUTHOR]

Background and Aims: Limited information exists regarding individual subgroups of recovery from opioid use disorder (OUD) following treatment and how these subgroups may relate to recovery trajectories. We used multi‐dimensional criteria to identify OUD recovery subgroups and longitudinal transitions across subgroups. Design, Setting and Participants: In a national longitudinal observational study in the United States, individuals who previously participated in a clinical trial for subcutaneous buprenorphine injections for treatment of OUD were enrolled and followed for an average of 4.2 years after participation in the clinical trial. Measurements: We identified recovery subgroups based on psychosocial outcomes including depression, opioid withdrawal and pain. We compared opioid use, treatment utilization and quality of life among these subgroups. Findings Three dimensions of the recovery process were identified: depression, opioid withdrawal and pain. Using these three dimensions, participants were classified into four recovery subgroups: high‐functioning (minimal depression, mild withdrawal and no/mild pain), pain/physical health (minimal depression, mild withdrawal and moderate pain), depression (moderate depression, mild withdrawal and mild/moderate pain) and low‐functioning (moderate/severe withdrawal, moderate depression and moderate/severe pain). Significant differences among subgroups were observed for DSM‐5 criteria (P < 0.001) and remission status (P < 0.001), as well as with opioid use (P < 0.001), treatment utilization (P < 0.001) and quality of life domains (physical health, psychological, environment and social relationships; Ps < 0.001, Cohen's fs ≥ 0.62). Recovery subgroup assignments were dynamic, with individuals transitioning across subgroups during the observational period. Moreover, the initial recovery subgroup assignment was minimally predictive of long‐term outcomes. Conclusions: There appear to be four distinct subgroups among individuals in recovery from OUD. Recovery subgroup assignments are dynamic and predictive of contemporaneous, but not long‐term, substance use, substance use treatment utilization or quality of life outcomes. [ABSTRACT FROM AUTHOR]

The cost of photovoltaic (PV) modules has declined by 85% since 2010. To achieve this reduction, manufacturers altered module designs and bill of materials; changes that could affect module durability and reliability. To determine if these changes have affected module durability, we measured the performance degradation of 834 fielded PV modules representing 13 module types from 7 manufacturers in 3 climates over 5 years. Degradation rates (Rd) are highly nonlinear over time, and seasonal variations are present in some module types. Mean and median degradation rate values of −0.62%/year and −0.58%/year, respectively, are consistent with rates measured for older modules. Of the 23 systems studied, 6 have degradation rates that will exceed the warranty limits in the future, whereas 13 systems demonstrate the potential of achieving lifetimes beyond 30 years, assuming Rd trends have stabilized. [ABSTRACT FROM AUTHOR]

The increasing global demand for high‐quality and low‐cost battery electrodes poses major challenges for battery cell production. As mechanical defects on the electrode sheets have an impact on the cell performance and their lifetime, inline quality control during electrode production is of high importance. Correlation of detected defects with process parameters provides the basis for optimization of the production process and thus enables long‐term reduction of reject rates, shortening of the production ramp‐up phase, and maximization of equipment availability. To enable automatic detection of visually detectable defects on electrode sheets passing through the process steps at a speed of 9 m s−1, a You‐Only‐Look‐Once architecture (YOLO architecture) for the identification of visual detectable defects on coated electrode sheets is demonstrated within this work. The ability of the quality assurance (QA) system developed herein to detect mechanical defects in real time is validated by an exemplary integration of the architecture into the electrode manufacturing process chain at the Battery Lab Factory Braunschweig. [ABSTRACT FROM AUTHOR]

Non‐aqueous aprotic battery electrolytes need to perform well over a wide range of temperatures in practical applications. Herein we present a one‐shot active learning study to find all conductivity optima, confidence bounds, and relating formulation trends in the temperature range from −30 °C to 60 °C. This optimization is enabled by a high‐throughput formulation and characterization setup guided by one‐shot active learning utilizing robust and heavily regularized polynomial regression. Whilst there is an initially good agreement for intermediate and low temperatures, there is a need for the active learning step to improve the model for high temperatures. Optimized electrolyte formulations likely correspond to the highest physically possible conductivities within this formulation system when compared to literature data. A thorough error propagation analysis yields a fidelity assessment of conductivity measurements and electrolyte formulation. [ABSTRACT FROM AUTHOR]

Fault detection and classification in photovoltaic (PV) systems through real‐time monitoring is a fundamental task that ensures quality of operation and significantly improves the performance and reliability of operating systems. Different statistical and comparative approaches have already been proposed in the literature for fault detection; however, accurate classification of fault and loss incidents based on PV performance time series remains a key challenge. Failure diagnosis and trend‐based performance loss routines were developed in this work for detecting PV underperformance and accurately identifying the different fault types and loss mechanisms. The proposed routines focus mainly on the differentiation of failures (e.g., inverter faults) from irreversible (e.g., degradation) and reversible (e.g., snow and soiling) performance loss factors based on statistical analysis. The proposed routines were benchmarked using historical inverter data obtained from a 1.8 MWp PV power plant. The results demonstrated the effectiveness of the routines for detecting failures and loss mechanisms and the capability of the pipeline for distinguishing underperformance issues using anomaly detection and change‐point (CP) models. Finally, a CP model was used to extract significant changes in time series data, to detect soiling and cleaning events and to estimate both the performance loss and degradation rates of fielded PV systems. [ABSTRACT FROM AUTHOR]

Spatially resolved characterization of electrode surfaces or electrode–electrolyte interfaces is of fundamental interest in battery research to unravel the complex underlying physicochemical processes. Scanning probe microscopy (SPM) techniques and derived methods have recently gained importance in in situ or operando studies of battery electrodes. This minireview provides an overview on well‐established and advanced SPM methods such as scanning electrochemical cell microscopy (SECCM) and hybrid atomic force microscopy–scanning electrochemical microscopy (AFM‐SECM) and their future potential for in situ/operando studies providing correlated structure/reactivity information. Although, most studies so far are focusing on lithium (Li)‐ion batteries, the potential for post‐Li battery chemistries is clearly evident. Future approaches for rapid performance assessment using scanning droplet cell electrochemistry in combination with advanced scanning probe microscopy are proposed and contrasted with the emerging challenges in the characterization of novel battery chemistries, as SPM methods have not yet been much used in this research area. [ABSTRACT FROM AUTHOR]

BATTERY 2030+ targets the development of a chemistry neutral platform for accelerating the development of new sustainable high‐performance batteries. Here, a description is given of how the AI‐assisted toolkits and methodologies developed in BATTERY 2030+ can be transferred and applied to representative examples of future battery chemistries, materials, and concepts. This perspective highlights some of the main scientific and technological challenges facing emerging low‐technology readiness level (TRL) battery chemistries and concepts, and specifically how the AI‐assisted toolkit developed within BIG‐MAP and other BATTERY 2030+ projects can be applied to resolve these. The methodological perspectives and challenges in areas like predictive long time‐ and length‐scale simulations of multi‐species systems, dynamic processes at battery interfaces, deep learned multi‐scaling and explainable AI, as well as AI‐assisted materials characterization, self‐driving labs, closed‐loop optimization, and AI for advanced sensing and self‐healing are introduced. A description is given of tools and modules can be transferred to be applied to a select set of emerging low‐TRL battery chemistries and concepts covering multivalent anodes, metal‐sulfur/oxygen systems, non‐crystalline, nano‐structured and disordered systems, organic battery materials, and bulk vs. interface‐limited batteries. [ABSTRACT FROM AUTHOR]

Materials acceleration platforms (MAPs) operate on the paradigm of integrating combinatorial synthesis, high‐throughput characterization, automatic analysis, and machine learning. Within a MAP, one or multiple autonomous feedback loops may aim to optimize materials for certain functional properties or to generate new insights. The scope of a given experiment campaign is defined by the range of experiment and analysis actions that are integrated into the experiment framework. Herein, the authors present a method for integrating many actions within a hierarchical experimental laboratory automation and orchestration (HELAO) framework. They demonstrate the capability of orchestrating distributed research instruments that can incorporate data from experiments, simulations, and databases. HELAO interfaces laboratory hardware and software distributed across several computers and operating systems for executing experiments, data analysis, provenance tracking, and autonomous planning. Parallelization is an effective approach for accelerating knowledge generation provided that multiple instruments can be effectively coordinated, which the authors demonstrate with parallel electrochemistry experiments orchestrated by HELAO. Efficient implementation of autonomous research strategies requires device sharing, asynchronous multithreading, and full integration of data management in experimental orchestration, which to the best of the authors' knowledge, is demonstrated for the first time herein. [ABSTRACT FROM AUTHOR]

Background: Myelodysplastic syndrome (MDS) arises from a rare population of aberrant hematopoietic stem and progenitor cells (HSPCs). These cells are relatively quiescent and therefore treatment resistant. Understanding mechanisms underlying their maintenance is critical for effective MDS treatment. Methods: We evaluated microRNA‐126 (miR‐126) levels in MDS patients' sample and in a NUP98‐HOXD13 (NHD13) murine MDS model along with their normal controls and defined its role in MDS HSPCs' maintenance by inhibiting miR‐126 expression in vitro and in vivo. Identification of miR‐126 effectors was conducted using biotinylated miR‐126 pulldown coupled with transcriptome analysis. We also tested the therapeutic activity of our anti‐miR‐126 oligodeoxynucleotide (miRisten) in human MDS xenografts and murine MDS models. Results: miR‐126 levels were higher in bone marrow mononuclear cells from MDS patients and NHD13 mice relative to their respective normal controls (P < 0.001). Genetic deletion of miR‐126 in NHD13 mice decreased quiescence and self‐renewal capacity of MDS HSPCs, and alleviated MDS symptoms of NHD13 mice. Ex vivo exposure to miRisten increased cell cycling, reduced colony‐forming capacity, and enhanced apoptosis in human MDS HSPCs, but spared normal human HSPCs. In vivo miRisten administration partially reversed pancytopenia in NHD13 mice and blocked the leukemic transformation (combination group vs DAC group, P < 0.0001). Mechanistically, we identified the non‐coding RNA PTTG3P as a novel miR‐126 target. Lower PTTG3P levels were associated with a shorter overall survival in MDS patients. Conclusions: MiR‐126 plays crucial roles in MDS HSPC maintenance. Therapeutic targeting of miR‐126 is a potentially novel approach in MDS. [ABSTRACT FROM AUTHOR]

Hypoxic environment is essential for chondrocyte maturation and longitudinal bone growth. Although hypoxia‐inducible factor 1 alpha (Hif‐1α) has been known as a key player for chondrocyte survival and function, the function of Hif‐2α in cartilage is mechanistically and clinically relevant but remains unknown. Here we demonstrated that Hif‐2α was a novel inhibitor of chondrocyte maturation through downregulation of Runx2 stability. Mechanistically, Hif‐2α binding to Runx2 inhibited chondrocyte maturation by Runx2 degradation through disrupting Runx2/Cbfβ complex formation. The Hif‐2α‐mediated‐Runx2 degradation could be rescued by Cbfβ transfection due to the increase of Runx2/Cbfβ complex formation. Consistently, mesenchymal cells derived from Hif‐2α heterozygous mice were more rapidly differentiated into hypertrophic chondrocytes than those of wild‐type mice in a micromass culture system. Collectively, these findings demonstrate that Hif‐2α is a novel inhibitor for chondrocyte maturation by disrupting Runx2/Cbfβ complex formation and consequential regulatory activity. [ABSTRACT FROM AUTHOR]

The IEA PVPS Task 13 group, experts who focus on photovoltaic performance, operation, and reliability from several leading R&D centers, universities, and industrial companies, is developing a framework for the calculation of performance loss rates of a large number of commercial and research photovoltaic (PV) power plants and their related weather data coming across various climatic zones. The general steps to calculate the performance loss rate are (i) input data cleaning and grading; (ii) data filtering; (iii) performance metric selection, corrections, and aggregation; and finally, (iv) application of a statistical modeling method to determine the performance loss rate value. In this study, several high‐quality power and irradiance datasets have been shared, and the participants of the study were asked to calculate the performance loss rate of each individual system using their preferred methodologies. The data are used for benchmarking activities and to define capabilities and uncertainties of all the various methods. The combination of data filtering, metrics (performance ratio or power based), and statistical modeling methods are benchmarked in terms of (i) their deviation from the average value and (ii) their uncertainty, standard error, and confidence intervals. It was observed that careful data filtering is an essential foundation for reliable performance loss rate calculations. Furthermore, the selection of the calculation steps filter/metric/statistical method is highly dependent on one another, and the steps should not be assessed individually. [ABSTRACT FROM AUTHOR]

Blinatumomab is a bispecific T cell‐engaging antibody approved for treatment of relapsed/refractory (r/r) ALL, with 40%‐50% complete response (CR)/CR with incomplete count recovery (CRi). Cytokine release syndrome (CRS) as a major adverse effect after blinatumomab therapy. Here, we evaluated the possible association between single‐nucleotide polymorphisms (SNPs) in cytokine genes, disease response, and CRS in r/r ALL patients who received blinatumomab between 2012 and 2017 at our center (n = 66), using patients' archived DNA samples. With a median duration of 9.5 months (range: 1‐37), 37 patients (56.1%) achieved CR/CRi, 54 (81.8%) experienced CRS (G1: n = 35, G2: n = 14, G3: n = 5), and 9 (13.6%) developed neurotoxicity. By multivariable analysis, after adjusting for high disease burden, one SNP on IL2 (rs2069762), odds ratio (OR) = 0.074 (95% CI: NE‐0.43, P =.01) and one SNP on IL17A (rs4711998), OR = 0.28 (95% CI: 0.078‐0.92, P =.034) were independently associated with CR/CRi. None of the analyzed SNPs were associated with CRS. To our knowledge, this is the first study demonstrating a possible association between treatment response to blinatumomab and SNPs. Our hypothesis‐generated data suggest a potential role for IL‐17 and IL‐2 in blinatumomab response and justify a larger confirmatory study, which may lead to personalized blinatumomab immunotherapy for B‐ALL. [ABSTRACT FROM AUTHOR]

Background: Blinatumomab is a BiTE® immuno‐oncology therapy indicated for the treatment of patients with relapsed or refractory (r/r) B‐cell precursor (BCP) acute lymphoblastic leukemia (ALL). Aims: To assess the efficacy and safety of blinatumomab as first salvage versus second or later salvage in patients with r/r BCP ALL. Materials & Methods: Patient‐level pooled data were used for this analysis. In total, 532 adults with r/r BCP ALL treated with blinatumomab were included (first salvage, n = 165; second or later salvage, n = 367). Results: Compared with patients who received blinatumomab as second or later salvage, those who received blinatumomab as first salvage had a longer median overall survival (OS; 10.4 vs. 5.7 months; HR, 1.58; 95% CI, 1.26–1.97; P <.001) and relapse‐free survival (10.1 vs. 7.3 months; HR, 1.38; 95% CI, 0.98–1.93; P =.061), and higher rates of remission (n = 89 [54%] vs. n = 150 [41%]; odds ratio, 0.59; 95% CI, 0.41–0.85; P =.005), minimal residual disease response (n = 68 [41%] vs. n = 118 [32%]), and allogeneic hematopoietic stem cell transplant (alloHSCT) realization (n = 60 [36%] vs. n = 88 [24%]), and alloHSCT in continuous remission (n = 33 [20%] vs. n = 52 (14%]). In a subgroup analysis, there was no apparent effect of prior alloHSCT on median OS in either salvage group. The safety profile of blinatumomab was generally similar between the groups; however, cytokine release syndrome, febrile neutropenia, and infection were more frequent with second or later salvage than with first salvage. Discussion: In this pooled analysis, the logistic regression analyses indicated greater benefit with blinatumomab as first salvage than as second or later salvage, as evident by the longer median OS, longer median RFS, and higher rates of remission. Conclusion: Overall, blinatumomab was beneficial as first salvage and as second or later salvage, but the effects were favorable as first salvage. [ABSTRACT FROM AUTHOR]

Background: Blinatumomab is a CD19 BiTE (bispecific T‐cell engager) immuno‐oncology therapy that mediates the lysis of cells expressing CD19. Methods: A pooled analysis of long‐term follow‐up data from 2 phase 2 studies that evaluated blinatumomab in heavily pretreated adults with Philadelphia chromosome–negative, relapsed/refractory B‐cell precursor acute lymphoblastic leukemia was conducted. Results: A total of 259 patients were included in the analysis. The median overall survival (OS) among all patients, regardless of response, was 7.5 months (95% confidence interval [CI], 5.5‐8.5 months); the median follow‐up time for OS was 36.0 months (range, 0.3‐60.8 months). The median relapse‐free survival (RFS) among patients who achieved a complete remission (CR) or complete remission with partial hematologic recovery (CRh) in the first 2 cycles (n = 123) was 7.7 months (95% CI, 6.2‐10.0 months); the median follow‐up time for RFS was 35.0 months (range, 9.5‐59.5 months). OS and RFS plateaued with 3‐year rates of 17.7% and 23.4%, respectively. The cumulative incidence function of the time to relapse, with death not due to relapse considered a competing risk, for patients who achieved a CR/CRh within 2 cycles of treatment also plateaued with a 3‐year relapse rate of 59.3%. For patients who achieved a CR/CRh with blinatumomab followed by allogeneic hematopoietic stem cell transplantation while in continuous CR, the median OS was 18.1 months (95% CI, 10.3‐30.0 months) with a 3‐year survival rate of 37.2%. Conclusions: These data suggest that long‐term survival is possible after blinatumomab therapy. Lay Summary: Immuno‐oncology therapies such as blinatumomab activate the patient's own immune system to kill cancer cells.This study combined follow‐up data from 2 blinatumomab‐related clinical trials to evaluate long‐term survival in patients with relapsed and/or refractory B‐cell precursor acute lymphoblastic leukemia at high risk for unfavorable outcomes.Among patients who achieved a deep response with blinatumomab, one‐third lived 3 years or longer. These findings suggest that long‐term survival is possible after treatment with blinatumomab. Patients achieving remission after blinatumomab can have a durable response. The survival plateau indicates a high probability of a cure in those patients responding to blinatumomab and alive after 3 years. [ABSTRACT FROM AUTHOR]

Data integrity is crucial for the performance and reliability analysis of photovoltaic (PV) systems, since actual in‐field measurements commonly exhibit invalid data caused by outages and component failures. The scope of this paper is to present a complete methodology for PV data processing and quality verification in order to ensure improved PV performance and reliability analyses. Data quality routines (DQRs) were developed to ensure data fidelity by detecting and reconstructing invalid data through a sequence of filtering stages and inference techniques. The obtained results verified that PV performance and reliability analyses are sensitive to the fidelity of data and, therefore, time series reconstruction should be handled appropriately. To mitigate the bias effects of 10% or less invalid data, the listwise deletion technique provided accurate results for performance analytics (exhibited a maximum absolute percentage error of 0.92%). When missing data rates exceed 10%, data inference techniques yield more accurate results. The evaluation of missing power measurements demonstrated that time series reconstruction by applying the Sandia PV Array Performance Model yielded the lowest error among the investigated data inference techniques for PV performance analysis, with an absolute percentage error less than 0.71%, even at 40% missing data rate levels. The verification of the routines was performed on historical datasets from two different locations (desert and steppe climates). The proposed methodology provides a set of standardized analytical procedures to ensure the validity of performance and reliability evaluations that are performed over the lifetime of PV systems. [ABSTRACT FROM AUTHOR]

Breast cancer stem cells (BCSCs) are competent to initiate tumor formation and growth and refractory to conventional therapies. Consequently BCSCs are implicated in tumor recurrence. Many signaling cascades associated with BCSCs are critical for epithelial‐to‐mesenchymal transition (EMT). We developed a model system to mechanistically examine BCSCs in basal‐like breast cancer using MCF10AT1 FACS sorted for CD24 (negative/low in BCSCs) and CD44 (positive/high in BCSCs). Ingenuity Pathway Analysis comparing RNA‐seq on the CD24−/low versus CD24+/high MCF10AT1 indicates that the top activated upstream regulators include TWIST1, TGFβ1, OCT4, and other factors known to be increased in BCSCs and during EMT. The top inhibited upstream regulators include ESR1, TP63, and FAS. Consistent with our results, many genes previously demonstrated to be regulated by RUNX factors are altered in BCSCs. The RUNX2 interaction network is the top significant pathway altered between CD24−/low and CD24+/high MCF10AT1. RUNX1 is higher in expression at the RNA level than RUNX2. RUNX3 is not expressed. While, human‐specific quantitative polymerase chain reaction primers demonstrate that RUNX1 and CDH1 decrease in human MCF10CA1a cells that have grown tumors within the murine mammary fat pad microenvironment, RUNX2 and VIM increase. Treatment with an inhibitor of RUNX binding to CBFβ for 5 days followed by a 7‐day recovery period results in EMT suggesting that loss of RUNX1, rather than increase in RUNX2, is a driver of EMT in early stage breast cancer. Increased understanding of RUNX regulation on BCSCs and EMT will provide novel insight into therapeutic strategies to prevent recurrence. [ABSTRACT FROM AUTHOR]

In bone cells vitamin D dependent regulation of gene expression principally occurs through modulation of gene transcription. Binding of the active vitamin D metabolite, 1,25‐dihydroxy vitamin D3 (1,25(OH)2D3) to the vitamin D receptor (VDR) induces conformational changes in its C‐terminal domain enabling competency for interaction with physiologically relevant coactivators, including SRC‐1. Consequently, regulatory complexes can be assembled that support intrinsic enzymatic activities with competency to posttranslationally modify chromatin histones at target genomic sequences to epigenetically alter transcription. Here we examine specific transitions in representation and/or enrichment of epigenetic histone marks during 1,25(OH)2D3 mediated upregulation of CYP24A1 gene expression in osteoblastic cells. This gene encodes the 24‐hydroxylase enzyme, essential for biological control of vitamin D levels. We demonstrate that as the CYP24A1 gene promoter remains transcriptionally silent, there is enrichment of H4R3me2s together with its "writing" enzyme PRMT5 and decreased abundance of the istone H3 and H4 acetylation, H3R17me2a, and H4R3me2a marks as well as of their corresponding "writers." Exposure of osteoblastic cells to 1,25(OH)2D3 stimulates the recruitment of a VDR/SRC‐1 containing complex to the CYP24A1 promoter to mediate increased H3/H4 acetylation. VDR/SRC‐1 binding occurs concomitant with the release of PRMT5 and the recruitment of the arginine methyltransferases CARM1 and PRMT1 to catalyze the deposition of the H3R17me2a and H4R3me2a marks, respectively. Our results indicate that these dynamic transitions of histone marks at the CYP24A1 promoter, provide a "chromatin context" that is transcriptionally competent for activation of the CYP24A1 gene in osteoblastic cells in response to 1,25(OH)2D3. [ABSTRACT FROM AUTHOR]

Despite recent advances in targeted therapies, the molecular mechanisms driving breast cancer initiation, progression, and metastasis are minimally understood. Growing evidence indicate that transfer RNA (tRNA)‐derived small RNAs (tsRNA) contribute to biological control and aberrations associated with cancer development and progression. The runt‐related transcription factor 1 (RUNX1) transcription factor is a tumor suppressor in the mammary epithelium whereas RUNX1 downregulation is functionally associated with breast cancer initiation and progression. We identified four tsRNA (ts‐19, ts‐29, ts‐46, and ts‐112) that are selectively responsive to expression of the RUNX1 tumor suppressor. Our finding that ts‐112 and RUNX1 anticorrelate in normal‐like mammary epithelial and breast cancer lines is consistent with tumor‐related activity of ts‐112 and tumor suppressor activity of RUNX1. Inhibition of ts‐112 in MCF10CA1a aggressive breast cancer cells significantly reduced proliferation. Ectopic expression of a ts‐112 mimic in normal‐like mammary epithelial MCF10A cells significantly increased proliferation. These findings support an oncogenic potential for ts‐112. Moreover, RUNX1 may repress ts‐112 to prevent overactive proliferation in breast epithelial cells to augment its established roles in maintaining the mammary epithelium. [ABSTRACT FROM AUTHOR]

Transcription networks and epigenetic mechanisms including DNA methylation, histone modifications, and noncoding RNAs control lineage commitment of multipotent mesenchymal progenitor cells. Proteins that read, write, and erase histone tail modifications curate and interpret the highly intricate histone code. Epigenetic reader proteins that recognize and bind histone marks provide a crucial link between histone modifications and their downstream biological effects. Here, we investigate the role of bromodomain‐containing (BRD) proteins, which recognize acetylated histones, during osteogenic differentiation. Using RNA‐sequencing (RNA‐seq) analysis, we screened for BRD proteins (n = 40) that are robustly expressed in MC3T3 osteoblasts. We focused functional follow‐up studies on Brd2 and Brd4 which are highly expressed in MC3T3 preosteoblasts and represent "bromodomain and extra terminal domain" (BET) proteins that are sensitive to pharmacological agents (BET inhibitors). We show that small interfering RNA depletion of Brd4 has stronger inhibitory effects on osteoblast differentiation than Brd2 loss as measured by osteoblast‐related gene expression, extracellular matrix deposition, and alkaline phosphatase activity. Similar effects on osteoblast differentiation are seen with the BET inhibitor +JQ1, and this effect is reversible upon its removal indicating that this small molecule has no lasting effects on the differentiation capacity of MC3T3 cells. Mechanistically, we find that Brd4 binds at known Runx2 binding sites in promoters of bone‐related genes. Collectively, these findings suggest that Brd4 is recruited to osteoblast‐specific genes and may cooperate with bone‐related transcription factors to promote osteoblast lineage commitment and maturation. [ABSTRACT FROM AUTHOR]

Local microvascular dysfunction and consequent tissue ischemia/hypoxia contribute to the symptoms of complex regional pain syndrome (CRPS) and peripheral neuropathic pain. As nitric oxide (NO) is a key regulator of microvascular blood flow, compounds that increase it are potentially therapeutic for these pain conditions. This led us to hypothesize that the topical administration of drugs that modulate local tissue NO levels can alleviate the pain of CRPS and peripheral neuropathic pain. We investigated the anti‐allodynic effect of a combination of two NO‐modulating drugs: meldonium and N‐acetylcysteine (NAC). An equimolar topical formulation of the two drugs was tested on chronic post‐ischemic pain (CPIP), a rat model of CRPS, as well as chronic constriction injury (CCI) of the sciatic nerve and chemotherapy‐induced painful neuropathy (CIPN), rat models of peripheral neuropathic pain. Topical meldonium‐NAC produced significant anti‐allodynia in CPIP, CCI, and CIPN rats. Moreover repeated application of topical meldonium‐NAC produced an increase in the duration of anti‐allodynia in the CPIP and CCI rats. While pre‐treatment with an NO synthase inhibitor attenuated the anti‐allodynic effects of meldonium‐NAC, 30‐min hyperbaric oxygen treatment combined with a non‐effective dose of meldonium‐NAC produced significant anti‐allodynic effects in CPIP rats. Both experiments implicated NO in the drug combination's anti‐allodynic effects. To ascertain the role played by changes in local tissue NO, we performed a quantification of plantar muscle NO in CPIP rats after hind paw topical treatment with meldonium‐NAC and revealed significantly increased plantar muscle NO levels in drug‐treated rats. The drug combination also reversed the reduction in tissue oxygenation normally observed in CPIP hind paws. In addition to introducing a novel topical treatment for mechanical allodynia in CRPS and peripheral neuropathic pain, this work showcases the analgesic potential of locally targeting microvascular dysfunction and tissue ischemia/hypoxia in these conditions, with emphasis on the role of NO. [ABSTRACT FROM AUTHOR]

The "disappearing polymorph" phenomenon is well established in organic solids, and has had a profound effect in pharmaceutical materials science. The first example of this effect in metal‐containing systems in general, and in coordination‐network solids in particular, is here reported. Specifically, attempts to mechanochemically synthesize a known interpenetrated diamondoid (dia) mercury(II) imidazolate metal–organic framework (MOF) yielded a novel, more stable polymorph based on square‐grid (sql) layers. Simultaneously, the dia‐form was found to be highly elusive, observed only as a short‐lived intermediate in monitoring solvent‐free synthesis and not at all from solution. The destabilization of a dense dia‐framework relative to a lower dimensionality one is in contrast to the behavior of other imidazolate MOFs, with periodic density functional theory (DFT) calculations showing that it arises from weak interactions, including structure‐stabilizing agostic C−H⋅⋅⋅Hg contacts. While providing a new link between MOFs and crystal engineering of organic solids, these findings highlight a possible role for agostic interactions in directing topology and stability of MOF polymorphs. [ABSTRACT FROM AUTHOR]

Background: A single-arm, phase 2 trial demonstrated the efficacy and safety of blinatumomab, a bispecific T-cell-engaging antibody construct, in patients with relapsed/refractory (r/r) Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), a rare hematologic malignancy with limited treatment options. This study compared outcomes with blinatumomab with those of a historical control treated with the standard of care (SOC).Methods: The blinatumomab trial enrolled adult patients with Ph+ ALL who were r/r to at least 1 second-generation tyrosine kinase inhibitor (n = 45). Propensity score analysis (PSA) was used to compare outcomes with blinatumomab with those of an external cohort of similar patients receiving SOC chemotherapy (n = 55). The PSA mitigated confounding variables between studies by adjusting for imbalances in the age at diagnosis and start of treatment, sex, duration from diagnosis to most recent treatment, prior allogeneic hematopoietic stem cell transplantation, prior salvage therapy, and number of salvage therapies. Bayesian data augmentation was applied to improve power to 80% with data from a phase 3 blinatumomab study in r/r Philadelphia chromosome-negative ALL.Results: In the PSA, the rate of complete remission or complete remission with partial hematologic recovery was 36% for blinatumomab and 25% for SOC, and this resulted in an odds ratio of 1.54 (95% confidence interval [CI], 0.61-3.89) or 1.70 (95% credible interval [CrI], 0.94-2.94) with Bayesian data augmentation. Overall survival favored blinatumomab over SOC, with a hazard ratio of 0.81 (95% CI, 0.57-1.14) or 0.77 (95% CrI, 0.61-0.96) with Bayesian data augmentation.Conclusions: These results further support blinatumomab as a treatment option for patients with r/r Ph+ ALL. [ABSTRACT FROM AUTHOR]

Background: Blinatumomab, a bispecific T-cell-engaging (BiTE®) immuno-oncology therapy, demonstrated superior overall survival versus standard-of-care chemotherapy (SOC) in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R ALL) in the phase 3 TOWER study. Herein, the authors reported clinical features and outcomes for those patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after treatment with blinatumomab.Methods: In the TOWER study, adults with R/R ALL were randomized 2:1 to receive blinatumomab or SOC. Study treatment consisted of 2 cycles of induction with blinatumomab or SOC followed by consolidation and maintenance therapy. At any time after the first cycle, patients who were eligible for HSCT could proceed to HSCT.Results: Of the 97 patients who underwent HSCT during the study, baseline characteristics generally were comparable and donor types were similar between the patients treated with blinatumomab (65 patients) and those receiving SOC (32 patients). There was no evidence to suggest that the survival benefit of HSCT differed between the patients treated with blinatumomab and those receiving SOC (P = .68). On the basis of descriptive statistics, a survival benefit of HSCT versus no HSCT was not observed in patients who achieved complete remission with full, partial, or incomplete hematologic recovery with blinatumomab (odds ratio, 1.17; 95% CI, 0.54-2.53). The best outcomes were achieved in patients with no prior salvage therapy and with minimal residual disease response to blinatumomab regardless of on-study HSCT status.Conclusions: Survival was found to be driven by response to study treatment and by salvage status regardless of on-study HSCT status. These data should be interpreted with caution because the current study was not designed to prospectively assess survival outcomes associated with HSCT after blinatumomab.Lay Summary: Evidence before this study: Blinatumomab is associated with superior morphologic and molecular response rates and superior overall outcome when compared with standard of care chemotherapy in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Added value of this study: The best outcomes with blinatumomab were observed in patients who achieved minimal residual disease remission in first salvage treatment regardless of subsequent allogeneic stem cell transplantation (HSCT). Implications of all the available evidence: Patients achieving CR/CRh/CRi following blinatumomab can have a durable response with or without HSCT. [ABSTRACT FROM AUTHOR]

In continuation of the investigation of osteogenic potential of solvent fractions of ethanolic extract of Cissus quadrangularis (CQ), an ancient medicinal plant, most notably known for its bone‐healing properties, to isolate and identify antiosteoporotic compounds. In the current study, we report the effect of hexane fraction (CQ‐H) and dichloromethane fraction (CQ‐D) of CQ on the differentiation and mineralization of mouse preosteoblast cell line MC3T3‐E1 (subclone 4). Growth, viability, and proliferation assays revealed that low concentrations (0.1, 1, and 100 ng/ml) of both solvent fractions were nontoxic, whereas higher concentrations were toxic to the cells. Differentiation and mineralization of MC3T3‐E1 with nontoxic concentrations of CQ‐D and CQ‐H revealed that CQ‐D delayed the mineralization of MC3T3‐E1 cells. However, early and enhanced mineralization was observed in cultures treated with nontoxic concentrations of CQ‐H, as indicated by Von Kossa staining and expression profile of osteoblast marker genes such as osterix, Runx2, alkaline phosphatase (ALP), collagen (Col1a1), integrin‐related bone sialoprotein (IBSP), osteopontin (OPN), and osteocalcin (OCN). These findings suggest CQ‐H as the most efficacious solvent fraction for further investigation to isolate and identify the active compounds in CQ‐H. [ABSTRACT FROM AUTHOR]

The cells of the bone marrow microenvironment are emerging as important contributors and regulators of normal hematopoiesis. This microenvironment is perturbed during leukemogenesis, and evidence points toward a bidirectional communication between leukemia cells and the normal cells of the bone marrow, mediated by direct cell–cell contact as well as soluble factors. These interactions are increasingly appreciated to play a role in leukemogenesis and possibly in resistance to chemotherapy. In fact, several compounds that specifically target the bone marrow microenvironment, including inhibitors of cell adhesion, are being tested as adjuncts to leukemia therapy. [ABSTRACT FROM AUTHOR]

We conducted a retrospective analysis of AML patients treated with the combination of VEN/HMA at our institution between June 2016 and April 2019. Furthermore, we also show a promising CR/CRi rate (38%) in patients with r/r I TP53 i m AML, which includes some patients relapsing after prior alloHCT. Most patients in our cohort received decitabine as their HMA, and this preference may have been influenced by results of a study utilising 10-day courses of decitabine in I TP53 i m myeloid neoplasms and yielding a 100% response rate (Welch I et al i , [10]). Although our preliminary results with VEN/HMA appear favourable compared to the dismal outcomes reported in I TP53 i m AML patients when treated with conventional combination chemotherapy (Grossmann I et al i , [5]; Rucker I et al i , [7]), the median LFS was relatively short, and relapses occurred frequently. [Extracted from the article]

Background and Aims: Government regulations of nicotine vaping products (NVP) have evolved rapidly during the past decade. The impact of NVP regulatory environment and vaping on cigarette demand is unknown. The current study aims to investigate whether or not respondents' reported cigarette demand, as measured by a hypothetical cigarette purchase task, varies with (1) smoking status, (2) vaping status or (3) NVP regulatory environment (country used as proxy). Design Cross‐sectional survey data from wave 1 of the International Tobacco Control (ITC) Four Country Smoking and Vaping (4CV) Survey (2016). Setting: Australia, Canada, England and the United States. Participants: A total of 10 316 adult smokers. Measurements A hypothetical purchase task asked smokers to estimate how many cigarettes they would purchase for consumption in a single day across multiple cigarette prices. Responses were used to derive measures of cigarette demand. Overall sensitivity of cigarette consumption to price increases was quantified to index cigarette demand elasticity, whereas estimated consumption when cigarettes are free was used to index cigarette demand intensity. Findings A majority of the non‐daily smokers had previously smoked daily (72.3%); daily vapers were more likely to be former daily smokers (89.9%) compared to non‐daily vapers (70.1%) and non‐vapers (69.2%) (P < 0.001). The smoking status × vaping status interaction was significant for cigarette demand intensity (F = 4.93; P = 0.007) and elasticity (F = 7.30; P = 0.001): among non‐daily smokers, vapers reported greater intensity but lower elasticity (i.e. greater demand) relative to non‐vapers (Ps < 0.05). Among daily smokers, daily vapers reported greater intensity relative to non‐vapers (P = 0.005), but vaping status did not impact elasticity (Ps > 0.38). Intensity was higher in Australia compared with all other countries (Ps < 0.001), but elasticity did not vary by country (F = 2.15; P = 0.09). Conclusions: In a hypothetical purchase task, non‐daily smokers showed lower price elasticity if they used e‐cigarettes than if they did not, while there was no clear difference in elasticity between e‐cigarette users and non‐users among daily smokers or according to regulatory environment of their country with regard to e‐cigarettes. [ABSTRACT FROM AUTHOR]

Osteosarcomas are bone tumors that frequently metastasize to the lung. Aberrant expression of the transcription factor, runt‐related transcription factor 2 (RUNX2), is a key pathological feature in osteosarcoma and associated with loss of p53 and miR‐34 expression. Elevated RUNX2 may transcriptionally activate genes mediating tumor progression and metastasis, including the RUNX2 target gene osteopontin (OPN/SPP1). This gene encodes a secreted matricellular protein produced by osteoblasts to regulate bone matrix remodeling and tissue calcification. Here we investigated whether and how the RUNX2/OPN axis regulates lung metastasis of osteosarcoma. Importantly, RUNX2 depletion attenuates lung metastasis of osteosarcoma cells in vivo. Using next‐generation RNA‐sequencing, protein‐based assays, as well as the loss‐ and gain‐of‐function approaches in selected osteosarcoma cell lines, we show that osteopontin messenger RNA levels closely correlate with RUNX2 expression and that RUNX2 controls the levels of secreted osteopontin. Elevated osteopontin levels promote heterotypic cell–cell adhesion of osteosarcoma cells to human pulmonary microvascular endothelial cells, but not in the presence of neutralizing antibodies. Collectively, these findings indicate that the RUNX2/OPN axis regulates the ability of osteosarcoma cells to attach to pulmonary endothelial cells as a key step in metastasis of osteosarcoma cells to the lung. [ABSTRACT FROM AUTHOR]

In a sequel to investigate osteogenic potential of ethanolic extract of Cissus quadrangularis (CQ), the present study reports the osteoblast differentiation and mineralization potential of ethyl acetate (CQ‐EA) and butanol (CQ‐B) extracts of CQ on mouse pre‐osteoblast cell line MC3T3‐E1 (sub‐clone 4) with an objective to isolate an antiosteoporotic compound. Growth curve, proliferation, and viability assays showed that both the extracts were nontoxic to the cells even at high concentration (100 µg/ml). The cell proliferation was enhanced at low concentrations (0.1 µg/ml and 1 µg/ml) of both the extracts. They also upregulated the osteoblast differentiation and mineralization processes in MC3T3‐E1 cells as reflected by expression profile of osteoblast marker genes such as RUNX2, Osterix, Collagen (COL1A1), Alkaline Phosphatase (ALP), Integrin‐related Bone Sialoprotein (IBSP), Osteopontin (OPN), and Osteocalcin (OCN). CQ‐EA treatment resulted in early differentiation and mineralization as compared with the CQ‐B treatment. These findings suggest that low concentrations of CQ‐EA and CQ‐B have proliferative and osteogenic properties. CQ‐EA, however, is more potent osteogenic than CQ‐B. The present study reports the osteoblast differentiation and mineralization potential of ethyl acetate (CQ‐EA) and butanol (CQ‐B) extracts of Cissus quadrangularis (CQ) on mouse pre‐osteoblast cell line MC3T3‐E1 (sub‐clone 4) with an objective to isolate an antiosteoporotic compound. We have concluded in this part of the study that the CQ‐EA treatment resulted in early differentiation and mineralization as compared with the CQ‐B treatment. These findings suggest that low concentrations of CQ‐EA and CQ‐B have proliferative and osteogenic properties. CQ‐EA, however, is more potent osteogenic than CQ‐B. [ABSTRACT FROM AUTHOR]

The major role of integrins is to mediate cell adhesion but some of them are involved in the osteoblasts–titanium (Ti) interactions. In this study, we investigated the participation of integrins in osteoblast differentiation induced by Ti with nanotopography (Ti‐Nano) and with microtopography (Ti‐Micro). By using a PCR array, we observed that, compared with Ti‐Micro, Ti‐Nano upregulated the expression of five integrins in mesenchymal stem cells, including integrin β3, which increases osteoblast differentiation. Silencing integrin β3, using CRISPR‐Cas9, in MC3T3‐E1 cells significantly reduced the osteoblast differentiation induced by Ti‐Nano in contrast to the effect on T‐Micro. Concomitantly, integrin β3 silencing downregulated the expression of integrin αv, the parent chain that combines with other integrins and several components of the Wnt/β‐catenin and BMP/Smad signaling pathways, all involved in osteoblast differentiation, only in cells cultured on Ti‐Nano. Taken together, our results showed the key role of integrin β3 in the osteogenic potential of Ti‐Nano but not of Ti‐Micro. Additionally, we propose a novel mechanism to explain the higher osteoblast differentiation induced by Ti‐Nano that involves an intricate regulatory network triggered by integrin β3 upregulation, which activates the Wnt and BMP signal transductions. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1303–1313, 2019. [ABSTRACT FROM AUTHOR]

The RUNX1 transcription factor has recently been shown to be obligatory for normal development. RUNX1 controls the expression of genes essential for proper development in many cell lineages and tissues including blood, bone, cartilage, hair follicles, and mammary glands. Compromised RUNX1 regulation is associated with many cancers. In this review, we highlight evidence for RUNX1 control in both invertebrate and mammalian development and recent novel findings of perturbed RUNX1 control in breast cancer that has implications for other solid tumors. As RUNX1 is essential for definitive hematopoiesis, RUNX1 mutations in hematopoietic lineage cells have been implicated in the etiology of several leukemias. Studies of solid tumors have revealed a context‐dependent function for RUNX1 either as an oncogene or a tumor suppressor. These RUNX1 functions have been reported for breast, prostate, lung, and skin cancers that are related to cancer subtypes and different stages of tumor development. Growing evidence suggests that RUNX1 suppresses aggressiveness in most breast cancer subtypes particularly in the early stage of tumorigenesis. Several studies have identified RUNX1 suppression of the breast cancer epithelial‐to‐mesenchymal transition. Most recently, RUNX1 repression of cancer stem cells and tumorsphere formation was reported for breast cancer. It is anticipated that these new discoveries of the context‐dependent diversity of RUNX1 functions will lead to innovative therapeutic strategies for the intervention of cancer and other abnormalities of normal tissues. Growing evidence suggests that RUNX1 suppresses aggressiveness in most breast cancer subtypes and particularly in the early stage of tumorigenesis. In this review, we present the diverse regulatory roles of RUNX1 in the development of normal tissue and the consequences of RUNX1 dysregulation in cancer development. [ABSTRACT FROM AUTHOR]