Determining how cells vary with their local signaling environment and organize into distinct cellular communities is critical for understanding processes as diverse as development, aging, and cancer. ...Here we introduce EcoTyper, a machine learning framework for large-scale identification and validation of cell states and multicellular communities from bulk, single-cell, and spatially resolved gene expression data. When applied to 12 major cell lineages across 16 types of human carcinoma, EcoTyper identified 69 transcriptionally defined cell states. Most states were specific to neoplastic tissue, ubiquitous across tumor types, and significantly prognostic. By analyzing cell-state co-occurrence patterns, we discovered ten clinically distinct multicellular communities with unexpectedly strong conservation, including three with myeloid and stromal elements linked to adverse survival, one enriched in normal tissue, and two associated with early cancer development. This study elucidates fundamental units of cellular organization in human carcinoma and provides a framework for large-scale profiling of cellular ecosystems in any tissue.
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•EcoTyper enables large-scale profiling of cell states and multicellular ecosystems•Applicable to bulk, single-cell, and spatially resolved gene expression data•A reference atlas of 69 cell states and 10 ecosystems across 16 types of carcinoma•Carcinoma ecosystems have distinct biology, clinical outcomes, and spatial topology
EcoTyper, a machine learning framework for identifying and characterizing cell states and ecosystems from gene expression data, yields insights into the cellular landscape and community structure of human carcinoma, the leading cause of cancer-related mortality.
Summary Background & aims Epidemiologic studies have revealed that early-life conditions influence later risk of chronic diseases. We aimed to explore whether exposure to Chinese famine between 1959 ...and 1962 during fetal and childhood period was related with metabolic syndrome (MS) in adulthood. Methods 6445 subjects from SPECT-China study were divided into fetal-exposed (1959–1962), childhood-exposed (1949–1958), adolescence/young adult-exposed (1921–1948), non-exposed (1963–1974) and non-exposed (after 1975). MS was defined by the International Diabetes Federation criteria. Results The prevalences of MS in the non-exposed (1963–1974), fetal and childhood-exposed were 16.4%, 20.1% and 19.1% in men and 13.5%, 23.7% and 33.5% in women, respectively. After adjustment for age, compared with non-exposed (1963–1974), fetal and childhood-exposed women had significantly higher prevalences of MS ( P < 0.05), but not in men. Famine exposure during the fetal period (OR 1.47, 95% CI 1.05, 2.07) and childhood (OR 1.80, 95% CI 1.22, 2.67) was associated with higher risk of MS in women after adjusting for age (both P < 0.05). Further adjustments for age, smoking, rural/urban residence and economic status did not significantly attenuate this association. Conclusions Exposure to famine in early life had sex-specific association with MS. It also suggests the adverse effects of malnutrition might extend beyond the 'first 1000 days' and last 9 years.
Context:
Epidemiologic studies have indicated that early life nutrition influences later risk of obesity, type 2 diabetes, and metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) is also ...considered a metabolic disease.
Objective:
The aim was to explore the association between adult NAFLD and fetal or childhood exposure to Great Chinese Famine between 1959 and 1962 during fetal and childhood period.
Design and setting:
In total, 5306 subjects from the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors study were divided into a fetal-exposed (1959–1962), childhood-exposed (1949–1958), adolescence/young adult-exposed (1921–1948), and nonexposed (1963–1974, reference) group.
Main outcome measure:
The degrees of steatosis of NAFLD were determined by ultrasonography.
Results:
The prevalences of NAFLD in the nonexposed (1963–1974), fetal-exposed, and childhood-exposed participants were 55.9%, 55.8%, and 55.4% in men and 33.0%, 46.3%, and 51.7% in women, respectively. Compared with those nonexposed, fetal- and childhood-exposed women but not men had a significantly higher prevalence of moderate-severe steatosis (P < .05). A significant association existed in women between increased alanine aminotransferase and both fetal and childhood exposure to famine, after adjusting for age, rural/urban residence, economic status, body mass index, diabetes, dyslipidemia, and hypertension (both P < .05). Famine exposure during the fetal period (odds ratio 1.77, 95% confidence interval 1.22, 2.57) and childhood (odds ratio 1.82, 95% confidence interval 1.35, 2.46) was associated with an increased prevalence of moderate-severe NAFLD in women in the above fully adjusted model.
Conclusions:
Exposure to the Great Famine in early life had sex-specific association with moderate-severe NAFLD. This indicates that malnutrition in early life may influence the development of adult NAFLD; thus pregnant women and their infants and children may require the highest priority in obtaining nutritional relief.
In 5306 subjects from SPECT-China study, exposure to Great Chinese Famine in early life had sex-specific association with NAFLD in adulthood.
Low surface energy coatings have gained considerable attention due to their superior surface hydrophobic properties. However, their abrasion resistance and sustainability of surface hydrophobicity ...are still not very satisfactory and need to be improved. In this work, a series of utraviolet (UV)-curable fluorosiloxane copolymers were synthesized and used as reactive additives to prepare polyurethane acrylate coatings with low surface energy. The effect of the addition of the fluorinated graft copolymers on the mechanical durability and surface hydrophobicity of the UV-cured hybrid films during the friction-annealing treatment cycles was investigated. The results show that introducing fluorosiloxane additives can greatly enhance surface hydrophobicity of the hybrid film. With addition of 2 wt.% fluorosiloxane copolymers, the water contact angle (WCA) value of the hybrid film was almost tripled compared to that of the pristine PU film, increasing from 58° to 144°. The hybrid film also showed enhanced abrasion resistance and could withstand up to about 60 times of friction under a pressure of 20 kPa. The microstructure formed in the annealed film was found to contribute much to achieve better surface hydrophobicity. The polyurethane acrylate/fluorinated siloxane resin hybrid film prepared in this study exhibits excellent potential for applications in the low surface energy field.
ObjectivesIn the past decade, China has been characterised by large-scale urbanisation as well as rapid economic growth. The aim of this study was to further investigate the prevalence of ...hyperuricaemia (HUA) in an Eastern Chinese population.DesignCross-sectional study.SettingSurvey of Prevalence in East China of Metabolic Diseases and Risk Factors China study.ParticipantsIn this study, 12 770 residents from 22 sites in Eastern China were recruited. Finally, 9225 subjects were included.Main outcome measuresThe serum levels of uric acid (UA), fasting plasma glucose (FPG), glycated haemoglobin and other metabolic parameters were tested. Waist circumference, weight, height and blood pressure were also measured. Questionnaires regarding smoking, drinking, education were collected from the subjects. HUA was defined as serum UA >420 µmol/L for men and >360 µmol/L for women.ResultsThe prevalence of HUA in this Eastern Chinese population was 11.3% (9.9, 12.7) overall, 20.7% (17.7, 23.7) in men and 5.6% (4.3, 6.7) in women. The prevalence of HUA in urban subjects was higher than that in rural subjects (12.9 vs 10.8%, p<0.01). The prevalence of HUA was negatively and positively associated with age in men and women, respectively. Residents with high body mass index levels had a higher prevalence of HUA. In the logistic regression analysis, male sex, urban residency, total cholesterol, triglyceride, overweight, obesity, systolic blood pressure and low economic status were independently correlated with HUA.ConclusionsThe estimated prevalence of HUA in this Eastern Chinese population was 11.3% (9.9, 12.7) overall and 20.7% (17.7, 23.7) and 5.6% (4.3, 6.7) in men and women, respectively. HUA has gradually become an important public health issue in China.Trial registration numberChiCTR-ECS-14005052.
The acquisition of oncogenic drivers is a critical feature of cancer progression. For some carcinomas, it is clear that certain genetic drivers occur early in neoplasia and others late. Why these ...drivers are selected and how these changes alter the neoplasia's fitness is less understood.
Here we use spatially oriented genomic approaches to identify transcriptomic and genetic changes at the single-duct level within precursor neoplasia associated with invasive breast cancer. We study HER2 amplification in ductal carcinoma in situ (DCIS) as an event that can be both quantified and spatially located via fluorescence in situ hybridization (FISH) and immunohistochemistry on fixed paraffin-embedded tissue.
By combining the HER2-FISH with the laser capture microdissection (LCM) Smart-3SEQ method, we found that HER2 amplification in DCIS alters the transcriptomic profiles and increases diversity of copy number variations (CNVs). Particularly, interferon signaling pathway is activated by HER2 amplification in DCIS, which may provide a prolonged interferon signaling activation in HER2-positive breast cancer. Multiple subclones of HER2-amplified DCIS with distinct CNV profiles are observed, suggesting that multiple events occurred for the acquisition of HER2 amplification. Notably, DCIS acquires key transcriptomic changes and CNV events prior to HER2 amplification, suggesting that pre-amplified DCIS may create a cellular state primed to gain HER2 amplification for growth advantage.
By using genomic methods that are spatially oriented, this study identifies several features that appear to generate insights into neoplastic progression in precancer lesions at a single-duct level.
Small cell lung cancer (SCLC) is a lethal form of lung cancer. Here, we develop a quantitative multiplexed approach on the basis of lentiviral barcoding with somatic CRISPR-Cas9-mediated genome ...editing to functionally investigate candidate regulators of tumor initiation and growth in genetically engineered mouse models of SCLC. We found that naphthalene pre-treatment enhances lentiviral vector-mediated SCLC initiation, enabling high multiplicity of tumor clones for analysis through high-throughput sequencing methods. Candidate drivers of SCLC identified from a meta-analysis across multiple human SCLC genomic datasets were tested using this approach, which defines both positive and detrimental impacts of inactivating 40 genes across candidate pathways on SCLC development. This analysis and subsequent validation in human SCLC cells establish TSC1 in the PI3K-AKT-mTOR pathway as a robust tumor suppressor in SCLC. This approach should illuminate drivers of SCLC, facilitate the development of precision therapies for defined SCLC genotypes, and identify therapeutic targets.
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•A meta-analysis identifies candidate drivers of SCLC, including mTOR signaling•Naphthalene enhances SCLC development upon lentiviral infection in mouse models•Implementation of Tuba-seq in a mouse model of SCLC validates cancer drivers•TSC1 is a tumor suppressor in mice and humans with SCLC
Lee et al. report a meta-analysis of published genomic studies to identify candidate drivers of SCLC development in patients. They implement a genetic screening approach in mouse models of SCLC to functionally validate mTOR signaling as a key driver of SCLC development, including the TSC1 tumor suppressor.
Few studies have investigated the association between serum uric acid (UA) and cadmium exposure. Our previous study revealed a significantly higher blood cadmium (CdB) level in the Chinese population ...compared to populations in other countries. To determine whether CdB in Chinese adults is associated with serum UA and hyperuricemia, 2996 participants from the cross-sectional SPECT-China study were recruited. CdB was measured by atomic absorption spectrometry. Hyperuricemia was defined as a serum UA concentration ≥416.4 μmol/L for men and ≥356.9 μmol/L for women. Regression analyses were used to analyze the association of CdB with serum UA and hyperuricemia. We found that the median CdB level was higher in men with hyperuricemia (2.40 μg/L) than in men without hyperuricemia (1.98 μg/L, P < 0.05). A positive relationship between serum UA and CdB was found in Chinese men after adjusting for the estimated glomerular filtration rate (eGFR), current smoking status, diabetes, dyslipidemia, hypertension and body mass index and in participants with eGFR > 60 mL/min per 1.73 m
. Further, the odds ratio of hyperuricemia increased with increasing CdB quartiles (P for trend < 0.05) in men. In conclusion, CdB was positively related to the serum UA level and to hyperuricemia in Chinese men but not in Chinese women.
Chinese population are experiencing remarkably changes of economic and cultural environments. The present study was to examine the prevalence of metabolic syndrome (MetS) by age between genders and ...to investigate the current characteristics of MetS and its components in China.
SPECT-China is a population-based cross-sectional survey on Chinese adults aged ≥18 years in East China. A total of 10,441 Chinese residents participated in anthropometric and laboratory measurements. Of these, 9969 subjects (females, 5868) were eligible for the data analysis reported here. Estimates of the prevalence of MetS and its components were calculated. Presence of MetS was defined based on the IDF/AHA harmonized criteria. MetS z-score was calculated to evaluate the degree of total metabolic disorder.
The age-standardized prevalence of the metabolic syndrome was 22.0% (21.9% in men and 22.0% in women). Unlike the continuous MetS rise with age in females, the MetS prevalence in males remained stable among 46-55, 56-65 and > 65 yrs. age groups (31.2%, 31.4%, 32.5%, p = 0.538). In the five components of MetS, contrary to the elevated BP and BG disorders, the frequency of TG disorders decreased with age in males (46.6%(46-55 yrs), 37.2% (56-65 yrs), 27.7%(> 65 yrs), p < 0.001). Multivariable logistic regression showed that in males, more TG disorders were associated with higher BMI, higher educational level and current nonsmoker. In the MetS subjects, the 3-factor combinations which included TG disorders decreased with age in both genders. The whole metabolic profile became better in older male MetS subjects, which was opposite to the female.
Our results showed a distinct age-related prevalence of MetS between genders in dramatically changed China, in which the TG disorders played an important role. More targeted measures need to be taken to meet the serious challenges of metabolic diseases.
ChiCTR-ECS- 14005052 , Survey on Prevalence in East China for Metabolic Diseases and Risk Factors (SPECT-China).
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