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The article raised issues related to the design and execution of low-energy objects in Polish conditions. Based on the designed single-family house, adapted to the requirements of the National Fund for Environmental Protection and Water Management (“NF40” standard), the tools to assist investment decisions by investors were shown. An economic analysis and a multi-criteria analysis were performed using AHP method which had provided an answer to the question whether it is worthwhile to bear higher investment costs in order to adjust to the standards of energy-efficient buildings that fulfil a minimal energy consumption's requirements contained in Polish law. In addition, the variant of object that had optimal characteristics due to the different preferences of investors was indicated. This paper includes analysis and observations on the attempts to unify that part of the building sector, which so far is considered to be personalized, and objects in accordance with the corresponding idea are designed as “custom-made”.

We introduce certain modified Meyer-König and Zeller operators and we study their approximation properties. The similar results for modified Bernstein polynomials were given in [6]. [ABSTRACT FROM AUTHOR]

Steel structures for a conveyance guiding system are subjected to prolonged, intense corrosion during their operation leading to a considerable loss of material and structure capacity reduction. Shaft guides are made of closed profiles welded from hot-rolled channel sections. These profiles are categorized as class 1 cross-sections according to Eurocode 3, which means that they are resistant to local instability upon bending [1]. With an increase in the corrosion loss of the guides, the inertia moment of the cross-section is reduced. The resistance of profiles to local buckling is also reduced. However, calculations for local stability in guides upon bending are not required by the local Polish regulations on the operation of conveyance in shafts [2]. The question is whether this constitutes a shortcoming and risk for safe operation. Calculations according to steel construction standards [1] supported by numerical simulation were used to evaluate shaft steelwork guides resistance to buckling and their sensitivity to corrosion loss. It was shown that the guides of corrosion loss of 52–63%, depending on profile size, are prone to local buckling.

The presented dataset comes from an experimental study on the autogenous self-healing of high-strength concrete and the development of deep learning metasensor for crack width assessment and self-healing evaluation. Concrete specimens were prepared, matured, cracked, and exposed to self-healing. High-resolution scanning of the specimen surface and scale-invariant image processing were performed, multiple grid lines crossing cracks were established, and brightness degree profiles along grid lines were extracted. Then, reference measurements of the crack widths were obtained by an operator. The dataset comprises 19,098 records of brightness profiles, reference measurements, and benchmark measurements by deep learning and analytic models. The source images, stacked and marked with grid lines, are provided. The considerable number of brightness profiles coupled with manual reference measurements make the dataset well suited for developing an image-based deep CNN models or analytic algorithms for assessing crack widths in concrete. The technical validation study explored three factors that affect crack measurement: the specimen position in relation to the scanner, the surface moisture level, and the operator performing manual measurements., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Imaging-based spatial transcriptomics (ST) is evolving rapidly as a pivotal technology in studying the biology of tumors and their associated microenvironments. However, the strengths of the commercially available ST platforms in studying spatial biology have not been systematically evaluated using rigorously controlled experiments. In this study, we used serial 5-μm sections of formalin-fixed, paraffin-embedded surgically resected lung adenocarcinoma and pleural mesothelioma tumor samples in tissue microarrays to compare the performance of the single cell ST platforms CosMx, MERFISH, and Xenium (uni/multi-modal) platforms in reference to bulk RNA sequencing, multiplex immunofluorescence, GeoMx Digital Spatial Profiler, and hematoxylin and eosin staining data for the same samples. In addition to objective assessment of automatic cell segmentation and phenotyping, we performed pixel-resolution manual evaluation of phenotyping to carry out pathologically meaningful comparison between ST platforms. Our study detailed the intricate differences between the ST platforms, revealed the importance of parameters such as tissue age and probe design in determining the data quality, and suggested reliable workflows for accurate spatial profiling and molecular discovery., Competing Interests: Competing interests C.H. declares research funding to institution from Sanofi, BTG, Iovance, Obsidian, KSQ, EMD Serono, Takeda, Genentech, BMS, Summit Therapeutics, Artidis, Immunogenesis and Novartis; scientific advisory board member of Briacell with stock options; personal fees from Regeneron outside the scope of the submitted work. LS declares travel support for participation in 10x Genomic Pathology Day event and participation in NanoString Roadshow event, both unrelated to this work. M.A. declares research funding to institution from Genentech, Nektar Therapeutics, Merck, GlaxoSmithKline, Novartis, Jounce Therapeutics, Bristol Myers Squibb, Eli Lilly, Adaptimmune, Shattuck Lab, Gilead, Verismo therapeutics, Lyell; scientific advisory board member of GlaxoSmithKline, Shattuck Lab, Bristol Myers Squibb, AstraZeneca, Insightec, Regeneron, Genprex; personal fees from AstraZeneca, Nektar Therapeutics, SITC; participation of safety review committee for Nanobiotix-MDA Alliance, Henlius outside the scope of the submitted work. J.Z. declares research funding from Johnson and Johnson, Helius, Merck, Novartis and Summit, honoraria and consulting fees from AstraZeneca, BeiGene, Catalyst, GenePlus, Helius, Innovent, Johnson and Johnson, Novartis, Takeda and Varian outside the submitted work. D.L.G. has served on scientific advisory committees for Sanofi, Menarini Ricerche, Onconova, and Eli Lilly, and has received research support from Takeda, NGM Biopharmaceuticals, Boehringer Ingelheim and AstraZeneca. T.C. has received over the past 24 months speaker fees/honoraria (including travel/meeting expenses) from ASCO Post, AstraZeneca, Bio Ascend, Bristol Myers Squibb, Clinical Care Options, IDEOlogy Health, Medical Educator Consortium, Medscape, OncLive, PEAK Medicals, PeerView, Physicians’ Education Resource, Targeted Oncology; advisory role/consulting fees (including travel/meeting expenses) from AstraZeneca, Bristol Myers Squibb, Genentech, Merck, oNKo-innate, Pfizer, and RAPT Therapeutics; institutional research funding from AstraZeneca and Bristol Myers Squibb. All other authors declare no conflicts of interest related to the study.

With rising demand for wood products and reduced wood harvesting due to the European Green Deal, alternative lignocellulosic materials for insulation are necessary. In this work, we manufactured reference particleboard from industrial particles and fifteen different board variants from alternative lignocellulosic plants material, i.e., five types of perennial plant biomass in three substitutions: 30, 50 and 75% of their share in the board with a nominal density of 250 kg/m 3 . Within the analysis of manufactured boards, the mechanical, chemical and thermal properties were investigated-internal bond, formaldehyde emissions, thermal insulation, heat transfer coefficient and thermal conductivity. In the case of thermal conductivity, the most promising results from a practical point of view (W/mK < 0.07) were obtained with Sida hermaphrodita and Miscanthus , achieving the best results at 50% substitution. The lowest formaldehyde emissions were recorded for boards with Panicum virgatum and Miscanthus , highlighting their positive environmental performance. In terms of mechanical properties, the highest internal bond was noticed in particleboards with a 30% substitution of Spartina pectinata and Miscanthus . Research findings confirm the potential of perennial plants as a sustainable source of raw materials for insulation panel manufacturing. Despite needing improvements in mechanical properties, most notably internal bond strength, these plants offer an ecologically responsible solution aligned with global construction trends, thus lessening reliance on traditional wood products. Thus, long-term benefits may be realized through the strategic combination of diverse raw materials within a single particleboard.

Malignant peripheral nerve sheath tumor (MPNST) development is characterized by an altered DNA methylation landscape, which presents a promising area for developing MPNST-specific biomarkers for screening patients with NF1. Genome-wide DNA methylation profiling of a cohort of 13 patients with MPNST (29 samples of tumor and adjacent neurofibroma tissues) and of NF1-MPNST cell lines was performed to identify and validate candidate MPNST-specific CpG sites (CpGs). A logistic regression prediction model was constructed to select MPNST-specific CpGs distinct from adjacent neurofibromas and normal tissues. To test if hypermethylation at selected CpGs can also be detected in plasma from patients with MPNST, cfMBD-seq was applied to profile the cfDNA methylome of blood from patients with MPNST and NF1. Based on stringent feature-selection criteria and predictive modeling, we identified 73 candidate MPNST-specific CpGs (67 with unique CpG island locations) that reliably discriminated MPNSTs from neurofibromas. Validation of five candidate biomarkers confirmed successful MPNST detection (sensitivity: > 88%, specificity: > 91%) in tissues. In plasma samples, 63 of 67 selected genomic regions had greater than 1.2-fold higher methylation in patients with MPNST than those with NF1. Further, we identified 15 CpG islands that consistently separated plasma from patients with confirmed MPNST diagnosis from plasma of individuals with NF1 without a diagnosis of malignant transformation (FDR < 0.1). Our findings confirmed a unique hypermethylation pattern present during malignant transformation. This study highlights the potential to be investigated further as biomarkers in clinical settings for early MPNST detection in patients with NF1., (© 2024 The Author(s). Molecular Carcinogenesis published by Wiley Periodicals LLC.)

Imaging-based spatial transcriptomics (ST) is evolving rapidly as a pivotal technology in studying the biology of tumors and their associated microenvironments. However, the strengths of the commercially available ST platforms in studying spatial biology have not been systematically evaluated using rigorously controlled experiments. In this study, we used serial 5-m sections of formalin-fixed, paraffin-embedded surgically resected lung adenocarcinoma and pleural mesothelioma tumor samples in tissue microarrays to compare the performance of the single cell ST platforms CosMx, MERFISH, and Xenium (uni/multi-modal) platforms in reference to bulk RNA sequencing, multiplex immunofluorescence, GeoMx Digital Spatial Profiler, and hematoxylin and eosin staining data for the same samples. In addition to objective assessment of automatic cell segmentation and phenotyping, we performed pixel-resolution manual evaluation of phenotyping to carry out pathologically meaningful comparison between ST platforms. Our study detailed the intricate differences between the ST platforms, revealed the importance of parameters such as tissue age and probe design in determining the data quality, and suggested reliable workflows for accurate spatial profiling and molecular discovery.

Metal binding to β-sheets occurs in many metalloproteins and is also implicated in the pathology of Alzheimer's disease. De novo designed metallo-β-sheets have been pursued as models and mimics of these proteins. However, no crystal structures of canonical β-sheet metallopeptides have yet been obtained, in stark contrast to many examples for ɑ-helical metallopeptides, leading to a poor understanding for their chemistry. To address this, we have engineered tryptophan zippers, stable 12-residue β-sheet peptides, to bind Cu(II) ions and obtained crystal structures through single crystal X-ray diffraction (SC-XRD). We find that metal binding triggers several unexpected supramolecular assemblies that demonstrate the range of higher-order structures available to metallo-β-sheets. Overall, these findings underscore the importance of crystallography in elucidating the rich structural landscape of metallo-β-sheet peptides., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)

Multiple exciton physics in semiconductor nanocrystals play an important role in optoelectronic devices. This work investigates radially alloyed CdZnSe/CdS nanocrystals with suppressed Auger recombination due to the spatial separation of carriers, which also underpins their performance in optical gain and scintillation experiments. Due to suppressed Auger recombination, the biexciton lifetime is greater than 10 ns, much longer than most nanocrystals. The samples show optical gain, amplified spontaneous emission, and lasing at thresholds <2 excitons per particle. They also show broad gain bandwidth (>500 meV) encompassing 4 amplified spontaneous emission bands. Similarly enabled by slowed multiple exciton relaxation, the samples display strong performance in scintillating films under X-ray illumination. The CdZnSe/CdS samples have fast radioluminescence rise (<80 ps) and decay times (<5 ns), light yields up to 6700 photons·MeV -1 , and the demonstrated capacity for incorporation into large area films for scintillation imaging.

Purpose: Internationally, the COVID-19 pandemic impacted maternity services. In Australia, this included changes to antenatal appointments and the reduction of support people during labour and birth. For women pregnant during the pandemic there were increased stressors of infection in the community and in hospitals along with increased periods of isolation from friends and families during lockdown periods. The aim of this study was to explore the real-time experiences of women who were pregnant and had a baby during the first wave of the COVID-19 pandemic in Australia., Methods: This study followed seven women throughout their pregnancy and early parenthood. Women created audio or video recordings in real time using the Voqual app and were followed up by in-depth interviews after they gave birth., Results: Using narrative analysis their individual stories were compared and an overarching theme of 'feeling anxious' was found which was underpinned by the two themes 'model of care' and 'environment'., Conclusions: These findings highlight the protective impact midwifery continuity of care has on reducing anxiety in women during the pandemic, and that the home environment can either be secure and safe or a place of isolation., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Malignant pleural mesothelioma (MPM) is associated with poor prognosis despite advances in multimodal therapeutic strategies. While patients with resectable disease may benefit from added survival with oncologic resection, patient selection for mesothelioma operations often relies on both objective and subjective evaluation metrics. We sought to evaluate factors associated with improved overall survival (OS) in patients with mesothelioma who underwent macroscopic complete resection (MCR)., Methods: Patients with MPM who received neoadjuvant therapy and underwent MCR were identified in a prospectively maintained departmental database. Clinicopathologic, blood-based, and radiographic variables were collected and included in a Cox regression analysis (CRA). Response to neoadjuvant therapy was characterized by a change in tumor thickness from pretherapy to preoperative scans using the modified RECIST criteria., Results: In this study, 99 patients met the inclusion criteria. The median age of the included patients was 64.7 years, who were predominantly men, had smoking and asbestos exposure, and who received neoadjuvant therapy. The median change in tumor thickness following neoadjuvant therapy was -16.5% (interquartile range of -49.7% to +14.2%). CRA demonstrated reduced OS associated with non-epithelioid histology [hazard ratio (HR): 3.06, 95% confidence interval (CI): 1.62-5.78, p < 0.001] and a response to neoadjuvant therapy inferior to the median (HR: 2.70, CI: 1.55-4.72, p < 0.001). Patients who responded poorly (below median) to neoadjuvant therapy had lower median survival (15.8 months compared to 38.2 months, p < 0.001)., Conclusion: Poor response to neoadjuvant therapy in patients with MPM is associated with poor outcomes even following maximum surgical cytoreduction and should warrant a patient-centered discussion regarding goals of care and may therefore help guide further therapeutic decisions., Competing Interests: Author JZ reports grants from Merck, grants and personal fees from Johnson and Johnson and Novartis, personal fees from Bristol Myers Squibb, AstraZeneca, GenePlus, Innovent, and Hengrui outside the submitted work. Author PL reports support from AstraZeneca, as well as consulting fees from Varian, Viewray, Genentech, John & Johnson, payments for lectures from Varian, Viewray, and AstraZeneca, support for attending meetings from the Radiosurgery Society, and is an adviser for Genentech, Viewray, AstraZeneca. Author PL is on the board of directors of the Radiosurgery Society. Author CH declares research funding to institution from Sanofi, Dragonfly, BTG, Iovance, Obsidian, and Avenge; scientific advisory board member of Briacell with stock options; personal fees from Nanobiotix and speaker fees/honorarium from SWOG and SITC outside the scope of the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Deboever, Zhou, McGrail, Tomczak, Oliva, Feldman, Parra, Zhang, Lee, Antonoff, Hofstetter, Mehran, Rajaram, Rice, Roth, Swisher, Vaporciyan, Altan, Weissferdt, Tsao, Haymaker and Sepesi.)

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by high rate of therapy resistance. Since the cell of origin can impact response to therapy, it is crucial to understand the lineage composition of AML cells at time of therapy resistance. Here we leverage single-cell chromatin accessibility profiling of 22 AML bone marrow aspirates from eight patients at time of therapy resistance and following subsequent therapy to characterize their lineage landscape. Our findings reveal a complex lineage architecture of therapy-resistant AML cells that are primed for stem and progenitor lineages and spanning quiescent, activated and late stem cell/progenitor states. Remarkably, therapy-resistant AML cells are also composed of cells primed for differentiated myeloid, erythroid and even lymphoid lineages. The heterogeneous lineage composition persists following subsequent therapy, with early progenitor-driven features marking unfavorable prognosis in The Cancer Genome Atlas AML cohort. Pseudotime analysis further confirms the vast degree of heterogeneity driven by the dynamic changes in chromatin accessibility. Our findings suggest that therapy-resistant AML cells are characterized not only by stem and progenitor states, but also by a continuum of differentiated cellular lineages. The heterogeneity in lineages likely contributes to their therapy resistance by harboring different degrees of lineage-specific susceptibilities to therapy., (© 2023. The Author(s).)

Purpose: Cisplatin (CDDP)-based chemotherapy is a first-line treatment for patients with advanced head and neck squamous cell carcinomas (HNSCC), despite a high rate of treatment failures, acquired resistance, and subsequent aggressive behavior. The purpose of this study was to study the mechanism of CDDP resistance and metastasis in HNSCC. We investigated the role of NRF2 pathway activation as a driven event for tumor progression and metastasis of HNSCC., Experimental Design: Human HNSCC cell lines that are highly resistant to CDDP were generated. Clonogenic survival assays and a mouse model of oral cancer were used to examine the impact of NRF2 activation in vitro and in vivo on CDDP sensitivity and development of metastasis. Western blotting, immunostaining, whole-exome sequencing, single-cell transcriptomic and epigenomic profiling platforms were performed to dissect clonal evolution and molecular mechanisms., Results: Implantation of CDDP-resistant HNSCC cells into the tongues of nude mice resulted in a very high rate of distant metastases. The CDDP-resistant cells had significantly higher expression of NRF2 pathway genes in the presence of newly acquired KEAP1 mutations, or via epigenomic activation of target genes. Knockdown of NRF2 or restoration of the wild-type KEAP1 genes resensitized resistant cells to CDDP and decreased distant metastasis (DM). Finally, treatment with inhibitor of glutaminase-1, a NRF2 target gene, alleviated CDDP resistance., Conclusions: CDDP resistance and development of DM are associated with dysregulated and epigenetically reprogrammed KEAP1-NRF2 signaling pathway. A strategy targeting KEAP1/NRF2 pathway or glutamine metabolism deserves further clinical investigation in patients with CDDP-resistant head and neck tumors., (©2023 The Authors; Published by the American Association for Cancer Research.)

The research on Paulownia cultivation and wood properties is up to date in many countries. However, there are no data on the properties of this wood defined on a microscale, on microtome samples. The main aim of this study was to find the best valorization path for the wood of Paulownia Shang Tong Hybrid F1 from an extensively cultivated plantation established in April 2017 in Poland by determining the tensile strength, the wood density, the strength-to-density ratio, and the modulus of elasticity on a cross-section of the trunk. The wood was collected from extensive plantation, where production is based on the natural resources of the habitat and ambient weather conditions, which is the opposite to the intensive cultivation model, which is the recommended model of Paulownia cultivation. The results of this study show that the mean density of the analyzed samples was approximately 210 kg/m 3 when the mean value of the modulus of elasticity (MOE) was approximately 2400 MPa. The mean result for the tensile strength ratio to density was 11.25 km. In the case of anatomical structure, the increasing trend with age was noticed both in fiber and vessel characteristics. The study results provide unique data worldwide about Paulownia wood's properties based on a cross-section of the trunk, from plantations cultivated in conditions which are not recommended by seedlings producers. The obtained data indicate that the Paulownia wood (examined) from the cultivation in this study has a technical quality similar to that of model-intensive agricultural plantations.

Materials for studying biological interactions and for alternative energy applications are continuously under development. Semiconductor quantum dots are a major part of this landscape due to their tunable optoelectronic properties. Size-dependent quantum confinement effects have been utilized to create materials with tunable bandgaps and Auger recombination rates. Other mechanisms of electronic structural control are under investigation as not all of a material's characteristics are affected by quantum confinement. Demonstrated here is a new structure-property concept that imparts the ability to spatially localize electrons or holes within a core/shell heterostructure by tuning the charge carrier's kinetic energy on a parabolic potential energy surface. This charge carrier separation results in extended radiative lifetimes and in continuous emission at the single-nanoparticle level. These properties enable new applications for optics, facilitate novel approaches such as time-gated single-particle imaging, and create inroads for the development of other new advanced materials.

Novel therapeutic strategies targeting glioblastoma (GBM) often fail in the clinic, partly because preclinical models in which hypotheses are being tested do not recapitulate human disease. To address this challenge, we took advantage of our previously developed spontaneous Qk/Trp53/Pten (QPP) triple-knockout model of human GBM, comparing the immune microenvironment of QPP mice with that of patient-derived tumors to determine whether this model provides opportunity for gaining insights into tumor physiopathology and preclinical evaluation of therapeutic agents. Immune profiling analyses and single-cell sequencing of implanted and spontaneous tumors from QPP mice and from patients with glioma revealed intratumoral immune components that were predominantly myeloid cells (e.g., monocytes, macrophages, and microglia), with minor populations of T, B, and NK cells. When comparing spontaneous and implanted mouse samples, we found more neutrophils and T and NK cells in the implanted model. Neutrophils and T and NK cells were increased in abundance in samples derived from human high-grade glioma compared with those derived from low-grade glioma. Overall, our data demonstrate that our implanted and spontaneous QPP models recapitulate the immunosuppressive myeloid-dominant nature of the tumor microenvironment of human gliomas. Our model provides a suitable tool for investigating the complex immune compartment of gliomas.

T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with inducible knock-down of glutaminase, the key glutamine enzyme, confers synthetic lethality in mice harboring NOTCH1-mutated T-ALL. We leverage on this synthetic lethal interaction to demonstrate that IACS-010759 in combination with chemotherapy containing L-asparaginase, an enzyme that uncovers the glutamine dependency of leukemic cells, causes reduced glutaminolysis and profound tumor reduction in pre-clinical models of human T-ALL. In summary, this metabolic dependency of T-ALL on OxPhos provides a rational therapeutic target., (© 2022. The Author(s).)

Purpose: Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL) historically yields a 40%-50% response rate in metastatic melanoma. However, the determinants of outcome are largely unknown., Experimental Design: We investigated tumor-based genomic correlates of overall survival (OS), progression-free survival (PFS), and response to therapy by interrogating tumor samples initially collected to generate TIL infusion products., Results: Whole-exome sequencing (WES) data from 64 samples indicated a positive correlation between neoantigen load and OS, but not PFS or response to therapy. RNA sequencing analysis of 34 samples showed that expression of PDE1C, RTKN2, and NGFR was enriched in responders who had improved PFS and OS. In contrast, the expression of ELFN1 was enriched in patients with unfavorable response, poor PFS and OS, whereas enhanced methylation of ELFN1 was observed in patients with favorable outcomes. Expression of ELFN1, NGFR, and PDE1C was mainly found in cancer-associated fibroblasts and endothelial cells in tumor tissues across different cancer types in publicly available single-cell RNA sequencing datasets, suggesting a role for elements of the tumor microenvironment in defining the outcome of TIL therapy., Conclusions: Our findings suggest that transcriptional features of melanomas correlate with outcomes after TIL therapy and may provide candidates to guide patient selection., (©2022 American Association for Cancer Research.)

Objective: Enhancer aberrations are beginning to emerge as a key epigenetic feature of colorectal cancers (CRC), however, a comprehensive knowledge of chromatin state patterns in tumour progression, heterogeneity of these patterns and imparted therapeutic opportunities remain poorly described., Design: We performed comprehensive epigenomic characterisation by mapping 222 chromatin profiles from 69 samples (33 colorectal adenocarcinomas, 4 adenomas, 21 matched normal tissues and 11 colon cancer cell lines) for six histone modification marks: H3K4me3 for Pol II-bound and CpG-rich promoters, H3K4me1 for poised enhancers, H3K27ac for enhancers and transcriptionally active promoters, H3K79me2 for transcribed regions, H3K27me3 for polycomb repressed regions and H3K9me3 for heterochromatin., Results: We demonstrate that H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumour-specific enhancers for crucial oncogenes, such as ASCL2 and FZD10, was required for excessive proliferation. Consistently, combination of MEK plus bromodomain inhibition was found to have synergistic effects in CRC patient-derived xenograft models. Probing intertumour heterogeneity, we identified four distinct enhancer subtypes (EPIgenome-based Classification, EpiC), three of which correlate well with previously defined transcriptomic subtypes (consensus molecular subtypes, CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, TGFβi, mTORi and SRCi) for EpiC groups., Conclusion: Our data suggest that the dynamics of active enhancer underlies CRC progression and the patient-specific enhancer patterns can be leveraged for precision combination therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

In contrast to the curative effect of allogenic stem cell transplantation in acute myeloid leukemia via T cell activity, only modest responses are achieved with checkpoint-blockade therapy, which might be explained by T cell phenotypes and T cell receptor (TCR) repertoires. Here, we show by paired single-cell RNA analysis and TCR repertoire profiling of bone marrow cells in relapsed/refractory acute myeloid leukemia patients pre/post azacytidine+nivolumab treatment that the disease-related T cell subsets are highly heterogeneous, and their abundance changes following PD-1 blockade-based treatment. TCR repertoires expand and primarily emerge from CD8 + cells in patients responding to treatment or having a stable disease, while TCR repertoires contract in therapy - resistant patients. Trajectory analysis reveals a continuum of CD8 + T cell phenotypes, characterized by differential expression of granzyme B and a bone marrow-residing memory CD8 + T cell subset, in which a population with stem-like properties expressing granzyme K is enriched in responders. Chromosome 7/7q loss, on the other hand, is a cancer-intrinsic genomic marker of PD-1 blockade resistance in AML. In summary, our study reveals that adaptive T cell plasticity and genomic alterations determine responses to PD-1 blockade in acute myeloid leukemia., (© 2021. The Author(s).)

This paper reveals the relationships between key factors that determine the ability of cementitious composites to self-heal autogenously and specific measures for quantifying the effects of this process. The following material factors: water-to-binder ratio (w/b), uniaxial compressive strength and age of the composite at the time of defect formation were considered, as well as the method and degree of damage to the tested material. The subjects of this study were mortars and concretes in which Portland cement was partially replaced, to varying degrees, with mechanically activated fluidized bed combustion fly ash (MAFBC fly ash) and siliceous fly ash. The samples were subjected to three-point bending or cyclic compression tests after 14 or 28 days of aging, in order to induce defects and then cured in water for 122 days. Microscopic (MO) and high-resolution scanning (HRS) observations along with computer image processing techniques were used to visualize and quantify the changes occurring in the macro-crack region near the outer surface of the material during the self-sealing process. Techniques based on the measurement of the ultrasonic pulse velocity (UPV) allowed the quantification of the changes occurring inside the damaged materials. Mechanical testing of the composites allowed quantification of the effects of the activity of the binder-supplementary cementitious materials (SCMs) systems. The analysis of the results indicates a significant influence of the initial crack width on the ability to completely close the cracks; however, there are repeated deviations from this rule and local variability of the self-sealing process. It has been shown that the compressive strength of a material is an important indicator of binder activity concerning crack width reduction due to self-sealing. Regardless of the crack induction method, the internal material changes caused by self-sealing are dependent on the degree of material damage.