Search Results (24)

For a long time, drought disasters have brought about a wide range of negative impacts on human socio-economics. Especially in large basins with many tributaries, once hydrological drought occurs synchronously in several tributaries, the hydrological drought condition in the mainstream will be aggravated, which will lead to more serious losses. However, there is still a lack of research on the probabilistic risk of simultaneous hydrologic droughts in various areas of large watersheds. In this study, the Standardized Runoff Index was used to characterize hydrological drought, and the Standardized Runoff Index (SRI) sequence characteristics of each region were analyzed. Subsequently, a multiregional hazard encounter probability distribution model with an R-vine structure was constructed with the help of the vine copula function to study the risk pattern of simultaneous hydrological drought in multiple tributaries under environmental changes. The model results showed that the probability of the four basins gradually decreased from 7.5% to 0.16% when the SRI changed from ≤−0.5 to ≤−2.0, indicating that the likelihood of the joint distribution of the compound disaster decreases with increase in the drought extremes. Meanwhile, the probability of hydrological drought in the three major basins showed significant spatial differences, and the risk ranking was Dongting Lake Basin > Poyang Lake Basin > Han River Basin. The model constructed in this study reveals the disaster risk law, provides theoretical support for the measurement of hydrological drought risk in multiple regions at the same time, and is of great significance for the prediction of compound drought disaster risk. Full article

Accurate preoperative prediction of biochemical recurrence (BCR) in prostate cancer (PCa) is essential for treatment optimization, and demands an explicit focus on tumor microenvironment (TME). To address this, we developed MRMS-CNNFormer, an innovative framework integrating 2D multi-region (intratumoral, peritumoral, and periprostatic) and multi-sequence magnetic resonance imaging (MRI) images (T2-weighted imaging with fat suppression (T2WI-FS) and diffusion-weighted imaging (DWI)) with clinical characteristics. The framework utilizes a CNN-based encoder for imaging feature extraction, followed by a transformer-based encoder for multi-modal feature integration, and ultimately employs a fully connected (FC) layer for final BCR prediction. In this multi-center study (46 BCR-positive cases, 186 BCR-negative cases), patients from centers A and B were allocated to training (n = 146) and validation (n = 36) sets, while center C patients (n = 50) formed the external test set. The multi-region MRI-based model demonstrated superior performance (AUC, 0.825; 95% CI, 0.808–0.852) compared to single-region models. The integration of clinical data further enhanced the model’s predictive capability (AUC 0.835; 95% CI, 0.818–0.869), significantly outperforming the clinical model alone (AUC 0.612; 95% CI, 0.574–0.646). MRMS-CNNFormer provides a robust, non-invasive approach for BCR prediction, offering valuable insights for personalized treatment planning and clinical decision making in PCa management. Full article

Background: Effective prevention and treatment of pelvic floor dysfunction (PFD) necessitates the identification of lesions within the complex pelvic floor muscle (PFM) groups associated with various symptoms. Here, we developed a multi-region pelvic floor muscle functional diagnosis system (MPDS) based on an inflatable stretchable electrode array, which aids in accurately locating areas related to PFD. Methods: Clinical diagnostic experiments were conducted on 56 patients with postpartum stress urinary incontinence (PSUI) and 73 postpartum asymptomatic controls. MPDS collects pelvic floor electromyography from all participants. By assessing EMG parameters such as activation time differences (ATD) and using Jensen–Shannon (JS) divergence to verify, with the aim of locating target muscle groups with functional abnormalities. Results: Clinical test results showed that by observing the AT sequence of the PSUI group and the control group, muscle groups with functional abnormalities in the Pubococcygeus muscle (PC) and Puborectalis muscle (PR) regions could be preliminarily diagnosed. In the assessment of regional muscle contribution values based on JS divergence, it was verified that the contribution values of rapid contraction in the PC and PR regions of the PSUI group were relatively lower compared to those of the control group, which correlated with urinary control dysfunction. Conclusions: These experiments demonstrate that the MPDS helps in accurately locating target muscle groups with functional abnormalities, showcasing its potential in precise assessment of complex muscle groups such as PFM, which may improve diagnostic precision and reliability. Full article

Since 2000, China’s energy intensity has shown a fluctuating downward trend. Most existing studies have attributed the decline to technological progress, and only a few studies have recognized the role of industrial structure change. In this paper, a multi-region and multi-sector CGE (computable general equilibrium) model and a numerical simulation method are used to study how technological progress and structural transformation affected the energy intensity of 30 provincial-level regions in China from 2000 to 2019. The results show the following points. (1) The contribution of technological progress to the decline in energy intensity was the highest in the central region, followed by the western region, and was the lowest in the eastern region. (2) The progress of energy technology in the agriculture and industry sectors promoted the transition of energy consumption to the service sector, thereby reducing the overall energy intensity. This effect was the strongest in the eastern region, followed by the central region, and was the weakest in the western region. (3) The progress of energy technology in the service industry promoted the transition of energy consumption to industry and agriculture, thereby enhancing the energy intensity, and this effect was the strongest in the eastern region, followed by the western region, and the weakest in the central region. The conclusion of this paper provides a theoretical basis for realizing regional carbon peaking in sequence in China. Full article

Spatial heterogeneity is a hallmark of cancer. Tumor heterogeneity can vary with time and location. The tumor microenvironment (TME) encompasses various cell types and their interactions that impart response to therapies. Therefore, a quantitative evaluation of tumor heterogeneity is crucial for the development of effective treatments. Different approaches, such as multiregional sequencing, spatial transcriptomics, analysis of autopsy samples, and longitudinal analysis of biopsy samples, can be used to analyze the intratumoral heterogeneity (ITH) and temporal evolution and to reveal the mechanisms of therapeutic response. However, because of the limitations of these data and the uncertainty associated with the time points of sample collection, having a complete understanding of intratumoral heterogeneity role is challenging. Here, we used a hybrid model that integrates a whole-patient compartmental quantitative-systems-pharmacology (QSP) model with a spatial agent-based model (ABM) describing the TME; we applied four spatial metrics to quantify model-simulated intratumoral heterogeneity and classified the TME immunoarchitecture for representative cases of effective and ineffective anti-PD-1 therapy. The four metrics, adopted from computational digital pathology, included mixing score, average neighbor frequency, Shannon’s entropy and area under the curve (AUC) of the G-cross function. A fifth non-spatial metric was used to supplement the analysis, which was the ratio of the number of cancer cells to immune cells. These metrics were utilized to classify the TME as “cold”, “compartmentalized” and “mixed”, which were related to treatment efficacy. The trends in these metrics for effective and ineffective treatments are in qualitative agreement with the clinical literature, indicating that compartmentalized immunoarchitecture is likely to result in more efficacious treatment outcomes. Full article

Neuroblastoma is the most common extra-cranial solid tumour in children. Despite multi-modal therapy, over half of the high-risk patients will succumb. One contributing factor is the one-size-fits-all nature of multi-modal therapy. For example, during the first step (induction chemotherapy), the standard regimen (rapid COJEC) administers fixed doses of chemotherapeutic agents in eight two-week cycles. Perhaps because of differences in resistance, this standard regimen results in highly heterogeneous outcomes in different tumours. In this study, we formulated a mathematical model comprising ordinary differential equations. The equations describe the clonal evolution within a neuroblastoma tumour being treated with vincristine and cyclophosphamide, which are used in the rapid COJEC regimen, including genetically conferred and phenotypic drug resistance. The equations also describe the agents’ pharmacokinetics. We devised an optimisation algorithm to find the best chemotherapy schedules for tumours with different pre-treatment clonal compositions. The optimised chemotherapy schedules exploit the cytotoxic difference between the two drugs and intra-tumoural clonal competition to shrink the tumours as much as possible during induction chemotherapy and before surgical removal. They indicate that induction chemotherapy can be improved by finding and using personalised schedules. More broadly, we propose that the overall multi-modal therapy can be enhanced by employing targeted therapies against the mutations and oncogenic pathways enriched and activated by the chemotherapeutic agents. To translate the proposed personalised multi-modal therapy into clinical use, patient-specific model calibration and treatment optimisation are necessary. This entails a decision support system informed by emerging medical technologies such as multi-region sequencing and liquid biopsies. The results and tools presented in this paper could be the foundation of this decision support system. Full article

Extensive intratumoral heterogeneity (ITH) is believed to contribute to therapeutic failure and tumor recurrence, as treatment-resistant cell clones can survive and expand. However, little is known about ITH in triple-negative breast cancer (TNBC) because of the limited number of single-cell sequencing studies on TNBC. In this study, we explored ITH in TNBC by evaluating gene expression-derived and imaging-derived multi-region differences within the same tumor. We obtained tissue specimens from 10 TNBC patients and conducted RNA sequencing analysis of 2–4 regions per tumor. We developed a novel analysis framework to dissect and characterize different types of variability: between-patients (inter-tumoral heterogeneity), between-patients across regions (inter-tumoral and region heterogeneity), and within-patient, between-regions (regional intratumoral heterogeneity). We performed a Bayesian changepoint analysis to assess and classify regional variability as low (convergent) versus high (divergent) within each patient feature (TNBC and PAM50 subtypes, immune, stroma, tumor counts and tumor infiltrating lymphocytes). Gene expression signatures were categorized into three types of variability: between-patients (108 genes), between-patients across regions (183 genes), and within-patients, between-regions (778 genes). Based on the between-patient gene signature, we identified two distinct patient clusters that differed in menopausal status. Significant intratumoral divergence was observed for PAM50 classification, tumor cell counts, and tumor-infiltrating T cell abundance. Other features examined showed a representation of both divergent and convergent results. Lymph node stage was significantly associated with divergent tumors. Our results show extensive intertumoral heterogeneity and regional ITH in gene expression and image-derived features in TNBC. Our findings also raise concerns regarding gene expression based TNBC subtyping. Future studies are warranted to elucidate the role of regional heterogeneity in TNBC as a driver of treatment resistance. Full article

For precise delineation of glioma extent, amino acid PET is superior to conventional MR imaging. Since metabolic MR sequences such as chemical exchange saturation transfer (CEST) imaging and MR spectroscopy (MRS) were developed, we aimed to evaluate the diagnostic accuracy of combined CEST and MRS to predict glioma infiltration. Eighteen glioma patients of different tumor grades were enrolled in this study; ¹⁸F-fluoroethyltyrosine (FET)-PET, amide proton transfer CEST at 7 Tesla(T), MRS and conventional MR at 3T were conducted preoperatively. Multi modalities and their association were evaluated using Pearson correlation analysis patient-wise and voxel-wise. Both CEST (R = 0.736, p < 0.001) and MRS (R = 0.495, p = 0.037) correlated with FET-PET, while the correlation between CEST and MRS was weaker. In subgroup analysis, APT values were significantly higher in high grade glioma (3.923 ± 1.239) and IDH wildtype group (3.932 ± 1.264) than low grade glioma (3.317 ± 0.868, p < 0.001) or IDH mutant group (3.358 ± 0.847, p < 0.001). Using high FET uptake as the standard, the CEST/MRS combination (AUC, 95% CI: 0.910, 0.907–0.913) predicted tumor infiltration better than CEST (0.812, 0.808–0.815) or MRS (0.888, 0.885–0.891) alone, consistent with contrast-enhancing and T2-hyperintense areas. Probability maps of tumor presence constructed from the CEST/MRS combination were preliminarily verified by multi-region biopsies. The combination of 7T CEST/MRS might serve as a promising non-radioactive alternative to delineate glioma infiltration, thus reshaping the guidance for tumor resection and irradiation. Full article

For lung cancers, cellular trajectories and fates are strongly pruned by cell intrinsic and extrinsic factors. Over the past couple of decades, the combination of comprehensive molecular and genomic approaches, as well as the use of relevant pre-clinical models, enhanced micro-dissection techniques, profiling of rare preneoplastic lesions and surrounding tissues, as well as multi-region tumor sequencing, have all provided in-depth insights into the early biology and evolution of lung cancers. The advent of single-cell sequencing technologies has revolutionized our ability to interrogate these same models, tissues, and cohorts at an unprecedented resolution. Single-cell tracking of lung cancer pathogenesis is now transforming our understanding of the roles and consequences of epithelial-microenvironmental cues and crosstalk during disease evolution. By focusing on non-small lung cancers, specifically lung adenocarcinoma subtype, this review aims to summarize our knowledge base of tumor cells-of-origin and tumor–immune dynamics that have been primarily fueled by single-cell analysis of lung adenocarcinoma specimens at various stages of disease pathogenesis and of relevant animal models. The review will provide an overview of how recent reports are rewriting the mechanistic details of lineage plasticity and intra-tumor heterogeneity at a magnified scale thanks to single-cell studies of early- to late-stage lung adenocarcinomas. Future advances in single-cell technologies, coupled with analysis of minute amounts of rare clinical tissues and novel animal models, are anticipated to help transform our understanding of how diverse micro-events elicit macro-scale consequences, and thus to significantly advance how basic genomic and molecular knowledge of lung cancer evolution can be translated into successful targets for early detection and prevention of this lethal disease. Full article

Human solid malignancies harbour a heterogeneous set of cells with distinct genotypes and phenotypes. This heterogeneity is installed at multiple levels. A biological diversity is commonly observed between tumours from different patients (inter-tumour heterogeneity) and cannot be fully captured by the current consensus molecular classifications for specific cancers. To extend the complexity in cancer, there are substantial differences from cell to cell within an individual tumour (intra-tumour heterogeneity, ITH) and the features of cancer cells evolve in space and time. Currently, treatment-decision making usually relies on the molecular characteristics of a limited tumour tissue sample at the time of diagnosis or disease progression but does not take into account the complexity of the bulk tumours and their constant evolution over time. In this review, we explore the extent of tumour heterogeneity with an emphasis on ITH and report the mechanisms that promote and sustain this diversity in cancers. We summarise the clinical strikes of ITH in the management of patients with cancer. Finally, we discuss the current material and technological approaches that are relevant to adequately appreciate ITH. Full article

Low geometric accuracy is one of the main limitations in double-sided incremental forming (DSIF) with a rough surface finish, long forming time, and excessive sheet thinning. The lost contact between the support tool and the sheet is considered the main reason for the geometric error. Researchers presented different solutions for geometric accuracy improvement, such as toolpath compensation, adaptation, material redistribution, and heat-assisted processes. Toolpath compensations strategies improve geometric precision without adding extra tooling to the setup. It relies on formulas, simulation, and algorithm-based studies to enhance the part accuracy. Toolpath adaptation improves the part accuracy by adding additional equipment such as pneumatically or spring-loaded support tools or changing the conventional toolpath sequence such as accumulative-DSIF (ADSIF) and its variants. It also includes forming multi-region parts with various arrangements. Toolpath adaptation mostly requires experimental trial-and-error experiments to adjust parameters to obtain the desired shape with precision. Material redistribution strategies are effective for high-wall-angle parts. It is the less studied area in the geometric precision context in the DSIF. The heat-assisted process mainly concentrates on hard-to-form material. It can align itself to any toolpath compensation or adaptation strategy. This work aims to provide DSIF variants and studies, which focus on improving geometric accuracy using various methodologies. It includes a brief survey of tool force requirements for different strategies, sheet thickness variation in DSIF, and support tool role on deformation and fracture mechanism. Finally, a brief discussion and future work are suggested based on the insights from several articles. Full article

Pulmonary enteric adenocarcinoma (PEAC) is a rare variant of lung adenocarcinoma first described in the early 1990s in a lung tumour with overlapping lung and small intestine features. It is a rare tumour with fewer than 300 cases described in the published literature and was only formally classified in 2011. Given these characteristics the diagnosis is challenging, but even more so in a patient with prior gastrointestinal malignancy. A 68-year-old Caucasian female presented with a cough and was found to have a right upper lobe mass. Her history was significant for a pT3N1 colon adenocarcinoma. The resected lung tumour showed invasive lung adenocarcinoma but also features of colorectal origin. Immuno-stains were strongly and diffusely positive for lung and enteric markers. Multi-region, whole-exome sequencing of the mass and archival tissue from the prior colorectal cancer showed distinct genomic signatures with higher mutational burden in the PEAC and very minimal overlap in mutations between the two tumours. This case highlights the challenge of diagnosing rare lung tumours, but more specifically PEAC in a patient with prior gastro-intestinal cancer. Our use of multi-region, next-generation sequencing revealed distinct genomic signatures between the two tumours further supporting our diagnosis, and evidence of PEAC intra-tumour heterogeneity. Full article

Classical molecular analyses of Mycobacterium bovis based on spoligotyping and Variable Number Tandem Repeat (MIRU-VNTR) brought the first insights into the epidemiology of animal tuberculosis (TB) in Portugal, showing high genotypic diversity of circulating strains that mostly cluster within the European 2 clonal complex. Previous surveillance provided valuable information on the prevalence and spatial occurrence of TB and highlighted prevalent genotypes in areas where livestock and wild ungulates are sympatric. However, links at the wildlife–livestock interfaces were established mainly via classical genotype associations. Here, we apply whole genome sequencing (WGS) to cattle, red deer and wild boar isolates to reconstruct the M. bovis population structure in a multi-host, multi-region disease system and to explore links at a fine genomic scale between M. bovis from wildlife hosts and cattle. Whole genome sequences of 44 representative M. bovis isolates, obtained between 2003 and 2015 from three TB hotspots, were compared through single nucleotide polymorphism (SNP) variant calling analyses. Consistent with previous results combining classical genotyping with Bayesian population admixture modelling, SNP-based phylogenies support the branching of this M. bovis population into five genetic clades, three with apparent geographic specificities, as well as the establishment of an SNP catalogue specific to each clade, which may be explored in the future as phylogenetic markers. The core genome alignment of SNPs was integrated within a spatiotemporal metadata framework to further structure this M. bovis population by host species and TB hotspots, providing a baseline for network analyses in different epidemiological and disease control contexts. WGS of M. bovis isolates from Portugal is reported for the first time in this pilot study, refining the spatiotemporal context of TB at the wildlife–livestock interface and providing further support to the key role of red deer and wild boar on disease maintenance. The SNP diversity observed within this dataset supports the natural circulation of M. bovis for a long time period, as well as multiple introduction events of the pathogen in this Iberian multi-host system. Full article

Intra-tumour heterogeneity is the molecular hallmark of renal cancer, and the molecular tumour composition determines the treatment outcome of renal cancer patients. In renal cancer tumourigenesis, in general, different tumour clones evolve over time. We analysed intra-tumour heterogeneity and subclonal mutation patterns in 178 tumour samples obtained from 89 clear cell renal cell carcinoma patients. In an initial discovery phase, whole-exome and transcriptome sequencing data from paired tumour biopsies from 16 ccRCC patients were used to design a gene panel for follow-up analysis. In this second phase, 826 selected genes were targeted at deep coverage in an extended cohort of 89 patients for a detailed analysis of tumour heterogeneity. On average, we found 22 mutations per patient. Pairwise comparison of the two biopsies from the same tumour revealed that on average, 62% of the mutations in a patient were detected in one of the two samples. In addition to commonly mutated genes (VHL, PBRM1, SETD2 and BAP1), frequent subclonal mutations with low variant allele frequency (<10%) were observed in TP53 and in mucin coding genes MUC6, MUC16, and MUC3A. Of the 89 ccRCC tumours, 87 (~98%) harboured private mutations, occurring in only one of the paired tumour samples. Clonally exclusive pathway pairs were identified using the WES data set from 16 ccRCC patients. Our findings imply that shared and private mutations significantly contribute to the complexity of differential gene expression and pathway interaction and might explain the clonal evolution of different molecular renal cancer subgroups. Multi-regional sequencing is central for the identification of subclones within ccRCC. Full article

Glioblastoma is one of the most common and lethal primary neoplasms of the brain. Patient survival has not improved significantly over the past three decades and the patient median survival is just over one year. Tumor heterogeneity is thought to be a major determinant of therapeutic failure and a major reason for poor overall survival. This work aims to comprehensively define intra- and inter-tumor heterogeneity by mapping the genomic and mutational landscape of multiple areas of three primary IDH wild-type (IDH-WT) glioblastomas. Using whole exome sequencing, we explored how copy number variation, chromosomal and single loci amplifications/deletions, and mutational burden are spatially distributed across nine different tumor regions. The results show that all tumors exhibit a different signature despite the same diagnosis. Above all, a high inter-tumor heterogeneity emerges. The evolutionary dynamics of all identified mutations within each region underline the questionable value of a single biopsy and thus the therapeutic approach for the patient. Multiregional collection and subsequent sequencing are essential to try to address the clinical challenge of precision medicine. Especially in glioblastoma, this approach could provide powerful support to pathologists and oncologists in evaluating the diagnosis and defining the best treatment option. Full article