Heterogeneous Development Research Articles

In Situ Tracking of Water Oxidation Generated Nanoscale Dynamics in Layered Double Hydroxides Nanosheets.

Layered double hydroxides (LDHs) are potential catalysts for water oxidation, and it is recognized that they undergo dynamic evolution during the operation. However, little is known about the interfacial behaviors at the nanoscale under working conditions nor the underlying effects on electrocatalytic performance. Herein, using electrochemical atomic force microscopy, we in situ visualize the heterogeneous evolution of LDH nanosheets during oxygen evolution reaction (OER). By further combining density functional theory calculations, we elucidate the origin of the heterogeneous dynamics and their impact on the OER efficiency. Our findings demonstrate that NiCo LDHs transform to the catalytically active NiCoOx(OH)2-x phase during OER, and the redox transition between is accompanied by compressive and tensile strain, leading to in-plane contraction and reversible expansion of the nanosheets. Nonisotropic strain and out-of-plane strain relaxation due to defects and interparticle interactions result in cracking and wrinkling in the nanostructure, which is responsible for the partial activation and long-term deterioration of LDH electrocatalysts toward the OER. With this knowledge, we suggest and validate that engineering defects can precisely tune these dynamic behaviors, improving the OER activity and stability among LDH-based electrocatalysts.

Non-Debye to Debye spectral shift in solid solutions of orientationally disordered crystals.

Debye relaxation is a simple and unique physical mechanism by which a macroscopic orientational polarization decays monoexponentially with time. However, the very existence of the Debye process in complex systems such as water, aqueous solutions, and monohydroxyl alcohols, among others, is puzzling to date and their microscopic origin is still ambiguously explained. In order to shed light on some of these aspects, orientational dynamics of an orientationally disordered dipolar crystal with an identically structured nonpolar matrix has been studied in the form of solid solutions. A crossover from non-Debye to Debye-type spectral behavior has been observed with increasing concentration of the nonpolar matrix in the solid solutions. Analysis of the dynamic response shows that the evolution of cooperativity and spatial heterogeneity with concentration of nonpolar matrix is responsible for the observed trends. The results not only authenticate a possible mechanism of the Debye process as originating from localized orientational fluctuations due to molecular dipoles but also shed light on the evolution of non-Debye characteristics in these systems.

Laboratory Earthquakes Simulations—Emergence, Structure, and Evolution of Fault Heterogeneity

AbstractSeismic faults are known to exhibit a high level of spatial and temporal complexity, and the causes and consequences of this complexity have been the topic of numerous research works in the past decade. In this paper, we investigate the origins and the structure of this complexity by considering a numerical model of laboratory earthquake experiment, where we introduce a fault with homogeneous mechanical properties but allow it to evolve spontaneously to its natural level of complexity. This is achieved by coupling the elastic deformability of the off‐fault medium (and therefore allowing for heterogeneous stress fields to develop) and the discrete degradation and gouge formation at the fault plane (and therefore allowing for structural heterogeneity to develop). Numerical results show the development of persistent stress, damage, and gouge thickness heterogeneities, with a much larger variability in space than in time. Strong positive correlations are found between these quantities, which suggest a positive feedback between local normal stress and damage rate, only mildly mitigated by the mobility of the granular gouge in the interface. For a wide range of confining stresses, after a sufficient number of seismic cycles, the fault reaches a state of established disorder with a constant roughness, a certain amount of periodicity at the millimetric scale, and a power law decay of the Power Spectral Density at smaller spatial scales. The typical height‐to‐wavelength ratio of geometrical asperities and the correlations between stress and damage profiles are in good agreement with previous field or lab estimates.

A phase I/II, first-in-human study of VLS-1488, an oral KIF18A inhibitor, in patients with advanced cancer.

TPS3181 Background: Chromosomal instability (CIN) is a hallmark of cancer characterized by high rates of chromosomal segregation errors during mitosis. This creates structural and numerical changes to chromosomes, driving genetic heterogeneity and cancer evolution. KIF18A is a mitotic kinesin protein shown to be important for successful division of cancer cells with CIN but not required for mitosis in normal diploid cells. Pre-clinical studies demonstrated that treatment of chromosomally unstable cancer cells in vitro and in xenograft models (HCC15 and OVCAR-3) with a KIF18A inhibitor resulted in failure of chromosomal congression, mitotic arrest, cell death and dose-dependent inhibition of tumor growth. VLS-1488 is an oral small molecule inhibitor of KIF18A that is being examined in an open-label, phase I/II, first-in-human study evaluating the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity in advanced solid tumors with high prevalence of CIN. Methods: Key eligibility criteria include specific histologically confirmed metastatic or advanced tumor types with at least one site of measurable disease per RECIST 1.1, adequate organ function, and mismatch repair proficient/microsatellite stable.Eligible tumor types include high grade serous ovarian/fallopian tube/primary peritoneal cancer, squamous non-small cell lung cancer, triple negative breast cancer, gastric adenocarcinoma, gastroesophageal cancer, esophageal cancer, colorectal adenocarcinoma, transitional cell carcinoma of bladder, head and neck squamous cell carcinoma, ovarian or uterine carcinosarcoma, and uterine serous carcinoma. Subjects will receive VLS-1488 monotherapy continuously for 28-day cycles once daily. The study consists of two parts, Dose Escalation and Dose Expansion. Utilizing a Bayesian Optimal Interval (BOIN) design, Dose Escalation will examine the safety and tolerability of VLS-1488 at various dose levels (DLs) to identify the Maximum Tolerated Dose (MTD) and to select DLs for Dose Expansion. Dose Expansion may commence after the MTD or DLs of interest are identified. Dose Expansion will examine the safety, tolerability, preliminary efficacy and preliminary drug-drug interaction (DDI) and food effect risk of VLS-1488 in selected tumor types. Subjects enrolled to specific tumor type cohorts may be randomized to DLs of interest. Enrollment to Dose Escalation began in September 2023 and is ongoing. Clinical trial information: NCT05902988 .

An oxo‐acetato‐bridged trinuclear cobalt(III) cluster‐persuaded cobalt oxide active electrocatalyst for efficient hydrogen evolution activity

This study presents the synthesis and electrocatalytic performance of the cobalt(III) complex [Co3(μ1,1,1‐O)(μ1,3‐CH3CO2)(L)3]2(DMF)3 (Cotri), featuring a double deprotonated (N,O)‐donor ligand (L2‐), where the protonated form of it (H2L) is 2,2′‐(hydrazine‐1,2‐diylidenebis(ethan‐1‐yl‐1‐ylidene))diphenol. The X‐ray structure reveals a trinuclear cobalt cluster formed with three cobalt(III) centers interlinking through oxido (μ1,1,1‐O) and acetato (μ1,3‐O2CCH3) bridges in coupling with bis‐congregator‐type chelating ligands. Cotri adopts cobalt centers of octahedral and trigonal bipyramidal coordination geometries and bears a dominant Co(2)…H(DMF) agostic interactions appraised by lattice dimethyl formamide (DMF) molecules. Further, Cotri shows promising heterogeneous electrocatalytic hydrogen evolution activity in 1 M KOH, with an overpotential of 441 mV to achieve 10 mA/cm2 current density. Tafel slope analysis suggests the Volmer–Heyrovsky step as the rate‐determining step. The number of active sites and TOF for Cotri were estimated at 4.010 × 10−8 mol and 0.2467 s−1, respectively, ensuring its excellent hydrogen generation activity. Stability assessments through controlled potential electrolysis (CPE) and cyclic voltammetry (CV) for multiple cycles addressed the transformation of Cotri to Co2O3 nanoparticles, which turned out to be a more active Co2O3 electrocatalyst. The morphology and particle size of the in situ developed Co2O3 active catalyst under the electrochemical conditions attributes to the superior hydrogen evolution activity.

Circulating tumour DNA analysis and new uses of anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer

Currently, tumour tissue biopsy to determine RAS/BRAF gene alterations, assess microsatellite instability status, and determine HER‑2/neu gene amplification/hyperexpression is the gold standard of diagnosis and allows the selection of optimal molecularly targeted therapy when considering treatment strategies for patients with metastatic colorectal cancer. However, biopsy does not fully reflect the existing intratumoural heterogeneity and clonal evolution of tumour cells, which can often be the cause of therapeutic failures. In recent years, liquid biopsy has attracted increasing attention as an additional and potentially alternative non-invasive tool for molecular tumour profiling. Assessment of circulating tumour DNA allows changes in the genetic status of the tumour to be monitored and the «burden» of disease to be measured dynamically in real time. Advances in liquid biopsy technology have led to promising new strategies for the management of patients with metastatic colorectal cancer in late-line therapy. The standard drug arsenal in this group of patients is limited to either repeat administration of previously effective therapy or regorafenib and the combination of trifluridine/tipiracil with bevacizumab, which are characterized by limited clinical activity. However, thanks to the discovery of the NeoRAS wild-type phenomenon and the rechallenge strategy of anti-EGFR monoclonal antibodies based on the study of clonal selection and evolution of tumour cells, the administration of epidermal growth factor inhibitors in a molecularly selected by liquid biopsy population is accompanied by good tolerability and efficacy. Numerous clinical studies are ongoing to further understand the mechanisms of tumour resistance and to develop new evidence-based treatment approaches in order to realise the concept of personalised medicine.

Short-term evolution pattern in salt marsh landscapes: the importance of physical constraints

ContextSalt marsh landscapes at the land-sea interfaces exhibit contrasting spatiotemporal dynamics, resulting from varying physical constraints that limit new marsh establishment. The expansion of salt marsh landscapes towards the sea or their retreat towards the land is determined by patch-level changes, relying on the balance of power between the intrinsic biota traits and external physical disturbances.ObjectivesExamine how marsh dynamics respond to physical constraints, and clarify the pathway from coupled physical processes involving hydrodynamic forces, sediment transport, and morphological changes to rapid patch evolution and landscape changes.MethodsWe defined and distinguished four types of marsh changes based on patch proximities from five-month drone images in two typical marsh pioneer zones of the Yangtze Estuary, China: outlying expansion, edge expansion, infilling expansion, and retreat. Hydrodynamics and sediment transport were synchronously measured and compared near the two marsh edges, and morphological changes were generated by drone-derived digital elevation models (DEMs).ResultsWe identified distinct seasonal patterns of net marsh expansion at the accretion-prone site, that is: Net marsh expansion started from the outlying expansion in spring, followed by edge expansion in summer and infilling expansion in autumn. However, at the erosion-prone site that experienced high bed shear stress, low sediment availability and high seaward sediment transport, we only observed limited infilling and edge expansion in spring. This suggests that the potential for long-distance patch formation beyond the initial marsh edges is diminished in areas subjected to intensive physical disturbances.ConclusionsPatch evolution dynamics in response to site-specific physical constraints drive state differentiation of salt marsh landscape changes. Consequently, the heterogeneous evolution in salt marsh landscapes should be taken into account in restoration practice.

Abstract PO3-23-08: Cancer and immune cells evolutionary trajectories under treatment with the aromatase inhibitor letrozole and the CDK4/6 inhibitor ribociclib

Abstract Cancer and immune cells evolutionary trajectories under treatment with the aromatase inhibitor letrozole and the CDK4/6 inhibitor ribociclib. Marie Fongaard1, Leonard Schmiester2, Salim Ghannoum1, Pål Marius Bjørnstad1, Tatjana Bosnjak3, Signe Meltzer Kleivbo3, Knut Selsås4, Stephanie Beate Geisler5, Kamilla Fjermeros5, Sameer Bhargava5, Manouchehr Seyedzadeh6, Unn-Cathrin Buvarp5, Aino Katri Rosenskiold5, Nam Thi Nguyen5, Torben Lüders7, Diether Lambrechts8, Marianne Lyngra9, Arnoldo Frigessi2, Vessela Kristensen1,10, Jürgen Geisler5,10,*, Xavier Tekpli1,* 1) Department of Medical Genetics, Oslo University Hospital, Oslo, Norway 2) University of Oslo, Oslo Centre for Biostatistics and Epidemiology (OCBE), University of Oslo, Norway 3) Novartis, Medical Affairs, Oslo, Norway 4) Department of Breast and Endocrine Surgery, Akershus University Hospital, Oslo, Norway 5) Department of Oncology, Akershus University Hospital, Oslo, Norway 6) Department of Radiology, Akershus University Hospital, Oslo, Norway 7) Department of Clinical Molecular Biology (EPIGEN), Akershus University Hospital, Oslo, Norway 8) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium 9) Department of Pathology, Akershus University Hospital, Oslo, Norway 10) University of Oslo, Institute of Clinical Medicine, Faculty of Medicine, Oslo, Norway< * Jointly supervised the work, shared corresponding authors Background The recent introduction of CDK4/6 inhibitors is regarded as a major improvement in the field of breast cancer therapy. A growing body of evidence suggests that CDK4/6 inhibitors may impact on the recruitment of immune cells within the tumor microenvironment during therapy. Further, CDK4/6 inhibitors may potentially contribute to the extinction or survival of specific cancer cell clones through evolutionary pressure exerted on breast tumors. Clinical trial The NEOLETRIB-study is a multicenter, single-arm, open-label phase II clinical trial. Patients with locally advanced, LUM-A/LUM-B breast cancer, characterized by cT3-cT4 tumors and/or cN2-3 lymph node involvement, receive ribociclib (600 mg daily, 21 days on and 7 days off) in combination with letrozole (2.5 mg daily) for a duration of 6 months in the neoadjuvant setting. Patients with large cT2 tumors are also allowed to participate. Aim of the study Using single-cell analyses at different time points of treatment, we aim at studying the evolutionary trajectories of cancer and immune cells in 30 patients participating in the NEOLETRIB-trial. Methods Tumor biopsies taken before treatment (baseline) and during treatment (day 21 of ribociclib cycles 1 and 6, respectively), underwent single-cell RNA (scRNA), T cell receptor (TCR), and B cell receptor (BCR) sequencing. The sequencing data was first processed using cellRanger and Seurat . Results Initial clustering of the scRNA enabled the identification of the main cell types in breast tumors, which included T/NK cells, B cells, epithelial cells, cancer-associated fibroblasts, myeloid cells and endothelial cells. Focusing on epithelial cells, we were distinguished cancer cells from normal epithelial cells using the InferCNV algorithm. Further, by estimating the copy number events, we determined the genetic background of clones resistant or sensitive to combination therapies for each patient, revealing the dynamics of tumor heterogeneity evolution during treatment. Additionally, we examined CD4, CD8 and NK cell types, identified different cell states within these cell types and inferred pseudotime and immune cell type differentiation trajectories. ConclusionsWe identified the cell types present in tumor biopsies from the NEOLETRIB trial. We characterized the effects of therapies on the evolution of cancer and immune cells and gain insights into the factors influencing sensitivity and resistance to the combination of letrozole and ribociclib. Citation Format: Marie Fongård, Leonard Schmiester, Salim Ghannoum, Marius Bjørnstad, Tatjana Bosnjak, Signe Kleivbo, Knut Selsås, Stephanie Geisler, Kamilla Fjermeros, Sameer Bhargava, Manouchehr Seyedzadeh, Unn-Cathrin Buvarp, Aino Vuoriluoto, Nam Thi Nguyen, Torben Lüders, Diether Lambrechts, Marianne Lyngra, Arnoldo Frigessi, Vessela Kristensen, Jürgen Geisler, Xavier Tekpli. Cancer and immune cells evolutionary trajectories under treatment with the aromatase inhibitor letrozole and the CDK4/6 inhibitor ribociclib [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-23-08.

PDRs4All

Context. Interstellar dust particles, in particular carbonaceous nano-grains (like polycyclic aromatic hydrocarbons, fullerenes, and amorphous hydrogenated carbon), are critical players for the composition, energy budget, and dynamics of the interstellar medium (ISM). The dust properties, specifically the composition and size of dust grains are not static; instead, they exhibit considerable evolution triggered by variations in local physical conditions such as the density and gas temperature within the ISM, as is the case in photon-dominated regions (PDRs). The evolution of dust and its impact on the local physical and chemical conditions is thus a key question for understanding the first stages of star formation. Aims. From the extensive spectral and imaging data of the JWST PDRs4All program, we study the emission of dust grains within the Orion Bar – a well-known, highly far-UV (FUV)-irradiated PDR situated at the intersection between cold, dense molecular clouds, and warm ionized regions. The Orion Bar because of its edge-on geometry provides an exceptional benchmark for characterizing dust evolution and the associated driving processes under varying physical conditions. Our goal is to constrain the local properties of dust by comparing its emission to models. Taking advantage of the recent JWST data, in particular the spectroscopy of dust emission, we identify new constraints on dust and further previous works of dust modelling. Methods. To characterize interstellar dust across the Orion Bar, we follow its emission as traced by JWST NIRCam (at 3.35 and 4.8 μm) and MIRI (at 7.7, 11.3, 15.0, and 25.5 μm) broad band images, along with NIRSpec and MRS spectroscopic observations. First, we constrain the minimum size and hydrogen content of carbon nano-grains from a comparison between the observed dust emission spectra and the predictions of the Heterogeneous dust Evolution Model for Interstellar Solids (THEMIS) coupled to the numerical code DustEM. Using this dust model, we then perform 3D radiative transfer simulations of dust emission with the SOC code (Scattering with OpenCL) and compare to data obtained along well chosen profiles across the Orion Bar. Results. The JWST data allows us, for the first time, to spatially resolve the steep variation of dust emission at the illuminated edge of the Orion Bar PDR. By considering a dust model with carbonaceous nano-grains and submicronic coated silicate grains, we derive unprecedented constraints on the properties of across the Orion Bar. To explain the observed emission profiles with our simulations, we find that the nano-grains must be strongly depleted with an abundance (relative to the gas) 15 times less than in the diffuse ISM. The NIRSpec and MRS spectroscopic observations reveal variations in the hydrogenation of the carbon nano-grains. The lowest hydrogenation levels are found in the vicinity of the illuminating stars suggesting photo-processing while more hydrogenated nano-grains are found in the cold and dense molecular region, potentially indicative of larger grains.

In-situ deformation inhomogeneity and damage evolution of mixed-grain structure with tempered sorbite/bainite in Fe–Cr–Mo–Mn steel

The inhomogeneous tempered sorbite/bainite (TS/B) with various morphologies and orientations play a significant role in deformation coordination and damage evolution. In this paper, the influence of distinct morphologies and orientations of the mixed-grain structure with TS/B on the deformation heterogeneity were extensively investigated by in-situ tensile testing. Furthermore, a multi-scale model of dislocation density-based crystal plasticity (CP) coupled with the phase field method (PFM) was developed to illustrate the damage nucleation and its evolution via the representative volume element (RVE) modelling. The results shows that mixed-grain structure with TS/B exhibits non-homogeneous deformation during the tensile process, and the coarse grains bear the main plastic deformation, resulting in cross-slip traces and the wrinkling phenomenon at the grain boundary and the interior of coarse grains. Furthermore, the activation of slip systems was determined through slip trace analysis, and the slip transfer behavior between adjacent microstructure was analyzed. According to the critical resolved shear stress (CRSS), the {123}<111> slip system was determined to be the most activated slip system during the in-situ deformation. Hard-orientated lath-shaped B (M1) is more prone to accumulate low angle grain boundaries (LAGBs) than hard-orientated TS (M2) and soft-orientated granular B (M3), resulting in higher orientation rotation degree and geometrically necessary dislocations (GNDs) density of M1 than M2 and M3. The M1 exhibits the nucleation of damage during the initial deformation stage. In addition, compared with the M2 and M3, the Schmid factor (SF) of M1 dominates the transformation from hard orientation to soft orientation and the higher value of damage factor (φ) of M1 results in the more activated slip systems and local damage at high strain levels. This study provides new insights into elucidate the effects of TS/B morphologies and orientations on deformation heterogeneity and damage evolution in large-scale forged spindles for offshore wind power.

How does rapid urban construction land expansion affect the spatial inequalities of ecosystem health in China? Evidence from the country, economic regions and urban agglomerations

Identifying the adaptation mechanisms between urban construction land expansion (UCE) and ecosystem health (EHI) is a crucial aspect of sustainable management. However, there is still progress room for existing studies in distinguishing the impact mechanisms of UCE on the EHI of China's cities, different economic subregions and urban agglomerations. These gaps hinder the development of differentiated supportive frameworks for urban land management policies and ecosystem restoration initiatives across various scales in China. This study integrated multivariate satellite remote sensing data to monitor the heterogeneous evolution patterns of EHI and UCE in Chinese cities, economic subregions and urban agglomerations. A set of spatial measure models are utilized to distinguish the variability impact of UCE on China's EHI from a multi-dimensional perspective, including global and local, whole-area and sub-area, and direct and indirect influences. The results indicate that as UCE continues to grow, EHI steadily declined, reaching 0.512 with an average annual decrease of 1.507% from 2000 to 2020. A diminishing cluster pattern of EHI was observed, primarily concentrated in urban agglomerations such as BTH, GBA, and YRD. UCE exhibited a significant negative spatial dependence on EHI, and both global and local perspectives, UCE had a gradually weakening negative effect on the EHI of Chinese cities and economic subregions. However, the impacts of UCE on EHI in mature urban agglomerations (e.g., GBA, BTH, and YRD) were dominated by spatial spillovers, whereas growing urban agglomerations (e.g., MRYRU and CCU) were more affected by direct shocks from UCE. Our investigation informs site-specific ecologically sustainable management strategies in China based on cross-scale analyses, providing new perspectives into establishing cooperative mechanisms for cross-regional ecological management while emphasizing ecological risks management under the integration of urban agglomerations.

Insights into chloroplast genome evolution in Rutaceae through population genomics

Chloroplast genomes, pivotal for understanding plant evolution, remain unexplored in Rutaceae, a family with key perennial crops like citrus. Leveraging next-generation sequencing data from 509 Rutaceae accessions across 15 species, we conducted a de novo assembly of 343 chloroplast genomes, unveiling a chloroplast variation map highlighting the heterogeneous evolution rates across genome regions. Notably, differences in chloroplast genome size primarily originate from large single-copy and small single-copy regions. Structural variants predominantly occurred in the single-copy region, with two insertions located at the single-copy and inverted repeat region boundary. Phylogenetic analysis, principal component analysis, and population genetic statistics confirmed the cohesive clustering of different Citrus species, reflecting evolutionary dynamics in Citrus diversification. Furthermore, a close chloroplast genetic affinity was revealed among Atalantia (previously regarded as primitive citrus), Clausena, and Murraya. Zanthoxylum formed a distinct group with heightened genetic diversity. Through expanding our analysis to include 34 published chloroplast genomes, we explored chloroplast gene selection, revealing divergent evolutionary trends in photosynthetic pathways. While Photosystem I and Photosystem II exhibited robust negative selection, indicating stability, the Nicotinamide adenine dinucleotide (NADH) dehydrogenase pathway demonstrated rapid evolution, which was indicative of environmental adaptation. Finally, we discussed the effects of gene length and GC content on chloroplast gene evolution. In conclusion, our study reveals the genetic characterization of chloroplast genomes during Rutaceae diversification, providing insights into the evolutionary history of this family.

Navigating HER2-Low Testing in Invasive Breast Cancer: Update Recommendations for Pathologists.

The article discusses the importance of accurately distinguishing HER2-low from HER2-negative breast cancer, as novel ADCs have demonstrated activity in a large population of patients with HER2-low-expressing BC. While current guidelines recommend a dichotomous classification of HER2 as either positive or negative, the emergence of the HER2-low concept calls for standardization of HER2 testing in breast cancer, using currently available assays to better discriminate HER2 levels. This review covers the evolution and latest updates of the ASCO/CAP guidelines relevant to this important biomarker in breast cancer, including still-evolving concepts such as HER2 low, HER2 heterogeneity, and HER2 evolution. Our group presents the latest Mexican recommendations for HER2 status evaluation in breast cancer, considering the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, accurate HER2 status assessment remains one of the most important biomarkers in breast cancer, and the commitment of Mexican pathologists to theragnostic biomarker quality is crucial for providing the most efficient care in oncology.

Molecular Heterogeneity in Leiomyosarcoma and Implications for Personalised Medicine.

Leiomyosarcoma (LMS) is one of the more common subtypes of soft tissue sarcomas (STS), accounting for about 20% of cases. Differences in anatomical location, risk of recurrence and histomorphological variants contribute to the substantial clinical heterogeneity in survival outcomes and therapy responses observed in patients. There is therefore a need to move away from the current one-size-fits-all treatment approach towards a personalised strategy tailored for individual patients. Over the past decade, tissue profiling studies have revealed key genomic features and an additional layer of molecular heterogeneity among patients, with potential utility for optimal risk stratification and biomarker-matched therapies. Furthermore, recent studies investigating intratumour heterogeneity and tumour evolution patterns in LMS suggest some key features that may need to be taken into consideration when designing treatment strategies and clinical trials. Moving forward, national and international collaborative efforts to aggregate expertise, data, resources and tools are needed to achieve a step change in improving patient survival outcomes in this disease of unmet need.

The role of compaction in the diagenetic evolution of Pre-Salt Aptian deposits of Santos Basin, Brazil

The discovery of huge oil accumulations in the South Atlantic Pre-Salt carbonate lacustrine deposits has attracted much exploration and research interest on these challenging reservoirs, but no work has focused on the compaction processes. A petrological and geochemical study was therefore performed on two cored wells in Santos Basin to identify the main syngenetic and diagenetic constituents, and to identify the compaction features that affected these deposits. They are mainly composed of Mg-clays, calcite spherulites and fascicular shrubs, which have undergone a heterogeneous diagenetic evolution. Mechanical compaction occurred during shallow burial, promoting a closer packing of the constituents, reorientation and fracturing of calcite spherulites and bioclasts, and deformation of the clay matrix. Pressure dissolution occurred under increasing pressure and temperature during burial, developing inter-aggregate sutured contacts, dissolution seams and stylolites, as consequence of overburden. Macrocrystalline quartz and calcite, drusy quartz, and saddle dolomite precipitated during burial diagenesis, related to basinal fluids and probably to pressure dissolution, as source for the late carbonate phases. Understanding the role of compaction is essential to evaluate trends of porosity destruction, thickness modification and mass transfer, which directly impacted the quality and the dynamic evolution of fluids in the deep Pre-Salt reservoirs.

Concept and feasibility of the Augsburg Longitudinal Plasma Study (ALPS) – a prospective trial for comprehensive liquid biopsy-based longitudinal monitoring of solid cancer patients

Abstract Objectives Liquid biopsy (LBx) provides diagnostic, prognostic and predictive insights for malignant diseases and offers promising applications regarding tumor burden, tumor heterogeneity and clonal evolution. Methods The Augsburg Longitudinal Plasma Study (ALPS) is a prospective trial for patients with metastatic cancer that comprises sequential collection of LBx samples, tumor tissue, radiological imaging data, clinical information and patient-reported outcomes. Peripheral blood plasma is collected based on the individual patient’s staging intervals and LBx-derived ctDNA analyses are performed using CAncer Personalized Profiling sequencing (CAPP-seq). Results From April 2021 to October 2023, 419 patients have been enrolled. A total of 1,293 LBx samples were collected, 419 samples (100 %) at the beginning of the study and an average of 3 (range 1–12) during the 30-month follow-up period of the current interim analysis. 380 tissue biopsy (TBx) samples (90.7 %) were available at baseline and 39.6 % had ≥1 TBx samples at follow-up. Lung cancer patients are most prevalent in ALPS (n=147), followed by colorectal (n=38), prostate (n=31) and gastroesophageal cancer (n=28). On average, 12.0 ng/mL plasma cell-free DNA (cfDNA) could be isolated. First CAPP-seq analyses in 60 patients comprised 110 samples and demonstrated a detection sensitivity of 0.1 %. Conclusions The first interim analysis of ALPS confirms feasibility for comprehensive longitudinal evaluation of LBx and demonstrates suitability for ctDNA evaluation.

Categorizing Extrachromosomal Circular DNA as Biomarkers in Serum of Cancer.

Extrachromosomal circular DNA (eccDNA), a double-stranded circular DNA molecule found in multiple organisms, has garnered an increasing amount of attention in recent years due to its close association with the initiation, malignant progression, and heterogeneous evolution of cancer. The presence of eccDNA in serum assists in non-invasive tumor diagnosis as a biomarker that can be assessed via liquid biopsies. Furthermore, the specific expression patterns of eccDNA provide new insights into personalized cancer therapy. EccDNA plays a pivotal role in tumorigenesis, development, diagnosis, and treatment. In this review, we comprehensively outline the research trajectory of eccDNA, discuss its role as a diagnostic and prognostic biomarker, and elucidate its regulatory mechanisms in cancer. In particular, we emphasize the potential application value of eccDNA in cancer diagnosis and treatment and anticipate the development of novel tumor diagnosis strategies based on serum eccDNA in the future.

Genetic intratumour heterogeneity and clonal evolution in extramammary Paget's disease.

All tumour cells in a patient have shared and non-shared genetic alterations, and the diversity of mutations is described as intratumoural heterogeneity (ITH). Multiregion sequencing is a genome sequencing analytical technique used for multiple, spatially-separated biopsy tissues that may further our understanding of ITH and tumour evolution. Although genetic mutations in extramammary Paget's disease (EMPD) have recently been detected by next-generation sequencing analysis, there have been no reports of ITH based on multiregion sequencing in EMPD. Thus, we clarified the landscape of ITH and tumour evolution in EMPD. We performed whole-exome sequencing on 35 tissues (30 tumour tissues and five normal skin samples as a paired control), collected from five patients with EMPD. The rate of private mutations was significantly higher than that of ubiquitous and shared mutations. Ubiquitous mutations were not present in driver genes, and most driver genes exhibited private and shared mutations. The most frequent base substitution was C>T in almost all lesions, and most mutational signatures corresponded to signature 1, 2, 3, and 8. The types of proposed aetiology in most lesions were based on age and AID/APOBEC family and BRCA1/BRCA2 mutations. Evolutionary trees were characterized by short trunks and long branches due to the extremely high ratio of private mutations. In contrast, pathogenic factors, such as base substitutions, mutational signatures, and proposed aetiology, were shared. Tumour evolution in EMPD appears to be characterized by a high level of genetic ITH with shared background factors.

THEMIS 2.0: A self-consistent model for dust extinction, emission, and polarisation

Context. Recent observational constraints in emission, extinction, and polarisation have at least partially invalidated most of the astronomical standard grain models for the diffuse interstellar medium. Moreover, laboratory measurements on interstellar silicate analogues have shown quite significant differences with the optical properties used in these standard models. Aims. To address these issues, our objective is twofold: (i) to update the optical properties of silicates and (ii) to develop The Heterogeneous dust Evolution Model for Interstellar Solids (THEMIS) to allow the calculation of polarised extinction and emission. Methods. Based on optical constants measured in the laboratory from 5 µm to 1 mm for amorphous silicates and on observational constraints in mid-IR extinction and X-ray scattering, we defined new optical constants for the THEMIS silicates. Absorption and scattering efficiencies for spheroidal grains using these properties were subsequently derived with the discrete dipole approximation. Results. These new optical properties make it possible to explain the dust emission and extinction, both total and polarised. It is noteworthy that the model is not yet pushed to its limits since it does not require the perfect alignment of all grains to explain the observations and it therefore has the potential to accommodate the highest polarisation levels inferred from extinction measurements. Moreover, the dispersion of the optical properties of the different silicates measured in the laboratory naturally explain the variations in both the total and polarised emission and extinction observed in the diffuse interstellar medium. Conclusions. A single, invariant model calibrated on one single set of observations is obsolete for explaining contemporary observations. We are proposing a completely flexible dust model based entirely on laboratory measurements that has the potential to make major advances in understanding the exact nature of interstellar grains and how they evolve as a function of their radiative and dynamic environment. Even if challenging, this is also relevant for future cosmic microwave background (CMB) missions that will aim to perform precise measurements of the CMB spectral distortions and polarisation.

The impact of interfacial characteristics on the interfacial properties of 316 L/CuSn10 multi-material manufactured by laser powder bed fusion

Multi-material additive manufacturing (MMAM) enables the simultaneous creation of multi-material components in a single process, accomplishing customized different performances in specific regions of the same components. In particular, the copper-steel multi-material structure can provide considerable strength and high thermal conductivity, thus playing a crucial role in electronic components, heat exchangers and injection molds. However, few studies have explored the relationship between the microstructure and properties of the copper-steel fusion zone. Therefore, this study aims to reveal the heterogeneous evolution of the microstructure in the copper/steel fusion zone and its impact on the interfacial properties of 316 L/CuSn10 multi-material structure fabricated by laser powder bed fusion (L-PBF). We characterized the multi-layer specimens using laser confocal microscopy and SEM to obtain the macroscopic and microscopic microstructure, liquid metal embrittlement (LME) microcrack characteristics and precipitation evolution of the copper-steel fusion zone. The generation of liquid phase separation (LPS) was explored based on block specimens, and the textural characteristics of the fusion zone were analyzed using EBSD. As a result, because of multiple element precipitation and the high thermal conductivity of copper alloy, abrupt grain size changes occur in the fusion zone, affecting the fusion zone's corrosion resistance and nano-hardness. In tensile tests analyzing the anisotropy, the results show that LME microcracks have little impact on the interfacial bonding properties of the copper-steel bimetallic structure, among which the ultimate tensile strength of the specimens formed at 30° to the substrate reached a maximum of 562.9 MPa. These findings add substantially to our understanding of the relationship between the microstructure and properties of copper-steel bimetallic interface, and provide a theoretical reference for additive manufacturing copper-steel multi-material components.