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Mevalonate metabolism plays an important role in regulating tumor growth and progression; however, its role in immune evasion and immune checkpoint modulation remains unclear. Here, we found that non-small cell lung cancer (NSCLC) patients with higher plasma mevalonate response better to anti-PD-(L)1 therapy, as indicated by prolonged progression-free survival and overall survival. Plasma mevalonate levels were positively correlated with programmed death ligand-1 (PD-L1) expression in tumor tissues. In NSCLC cell lines and patient-derived cells, supplementation of mevalonate significantly up-regulated the expression of PD-L1, whereas deprivation of mevalonate reduced PD-L1 expression. Mevalonate increased CD274 mRNA level but did not affect CD274 transcription. Further, we confirmed that mevalonate improved CD274 mRNA stability. Mevalonate promoted the affinity of the AU-rich element-binding protein HuR to the 3′-UTR regions of CD274 mRNA and thereby stabilized CD274 mRNA. By in vivo study, we further confirmed that mevalonate addition enhanced the anti-tumor effect of anti-PD-L1, increased the infiltration of CD8+ T cells, and improved cytotoxic function of T cells. Collectively, our findings discovered plasma mevalonate levels positively correlated with the therapeutic efficacy of anti-PD-(L)1 antibody, and provided the evidence that mevalonate supplementation could be an immunosensitizer in NSCLC.

Lipids have been found to modulate tumor biology, including proliferation, survival, and metastasis. With the new understanding of tumor immune escape that has developed in recent years, the influence of lipids on the cancer–immunity cycle has also been gradually discovered. First, regarding antigen presentation, cholesterol prevents tumor antigens from being identified by antigen presenting cells. Fatty acids reduce the expression of major histocompatibility complex class I and costimulatory factors in dendritic cells, impairing antigen presentation to T cells. Prostaglandin E2 (PGE2) reduce the accumulation of tumor-infiltrating dendritic cells. Regarding T-cell priming and activation, cholesterol destroys the structure of the T-cell receptor and reduces immunodetection. In contrast, cholesterol also promotes T-cell receptor clustering and relative signal transduction. PGE2 represses T-cell proliferation. Finally, regarding T-cell killing of cancer cells, PGE2 and cholesterol weaken granule-dependent cytotoxicity. Moreover, fatty acids, cholesterol, and PGE2 can improve the activity of immunosuppressive cells, increase the expression of immune checkpoints and promote the secretion of immunosuppressive cytokines. Given the regulatory role of lipids in the cancer–immunity cycle, drugs that modulate fatty acids, cholesterol and PGE2 have been envisioned as effective way in restoring antitumor immunity and synergizing with immunotherapy. These strategies have been studied in both preclinical and clinical studies.

Cancer is a highly heterogeneous disease, and different individuals of the same cancer type can display different therapeutic effects and prognosis. Genetic variation of long non-coding RNA is the key factor driving tumor development, and plays an important role in genetic and biological heterogeneity. Therefore, it is of great significance to identify lncRNA as a driving factor in the non-coding region and explain its function in tumors for revealing the pathogenesis of cancer. In this study, we developed an integrated method to identify Personalized Functional Driver lncRNAs (PFD-lncRNAs) by integrating the DNA copy number data, gene expression data, and the biological subpathways information. Then, we applied the method to identify 2695 PFD-lncRNAs in 5334 samples across 19 cancer types. We performed an analysis of the association between PFD-lncRNAs and drug sensitivity, which provides medication guidance in disease therapy and drug discovery in the individual. Our research is of great significance for elucidating the biological roles of lncRNA genetic variation in cancer, revealing the related mechanism of cancer, and providing novel insights for individualized medicine.

Although studies have estimated the associations of PM2.5 with total mortality or cardiopulmonary mortality, few have comprehensively examined cause-specific mortality risk and burden caused by ambient PM2.5. Thus, this study investigated the association of short-term exposure to PM2.5 with cause-specific mortality using a death-spectrum wide association study (DWAS). Individual information of 5,450,764 deaths during 2013–2018 were collected from six provinces in China. Daily PM2.5 concentration in the case and control days were estimated by a random forest model. A time-stratified case-crossover study design was applied to estimate the associations (access risk, ER) of PM2.5 with cause-specific mortality, which was then used to calculate the population-attributable fraction (PAF) of mortality and the corresponding mortality burden caused by PM2.5. Each 10 μg/m3 increase in PM2.5 concentration (lag03) was associated with a 0.80 % [95 % confidence interval (CI): 0.73 %, 0.86 %] rise in total mortality. We found greater mortality effect at PM2.5 concentrations

Histological transformation is one of the mechanisms of resistance to targeted therapy, chemotherapy and immunotherapy in non-small cell lung cancer (NSCLC). The histological transformation from adenocarcinoma (ADC) to squamous cell carcinoma (SCC) after tyrosine kinase inhibitor (TKI) treatment is rare in epidermal growth factor receptor (EGFR)-mutated NSCLC. However, few effective strategies have been previously reported for these patients. Here, we report a lung ADC patient with EGFR 19del who showed a poor response to EGFR-TKI therapy and acquired histological transformation to SCC with high expression of programmed cell death-ligand 1 (PD-L1) after developing EGFR-TKI resistance and undergoing sequential radiotherapy and chemotherapy. The patient then received combination treatment with the immune checkpoint inhibitor (ICI) sintilimab plus anlotinib followed by sintilimab maintenance therapy, which achieved long-term survival. This case report discusses the potential mechanisms of SCC transformation in EGFR-mutated NSCLC and speculates that immunotherapy plus anti-angiogenic therapy may be a good choice for EGFR-mutated lung ADC patients with SCC transformation and high expression of PD-L1 after TKI resistance development.

Cancer is a highly heterogeneous disease with different functional disorders among individuals. The initiation and progression of cancer is usually related to dysregulation of local regions within pathways. Identification of individualized risk pathways is crucial for revealing the mechanisms of tumorigenesis and heterogeneity. However, approach that focused on mining patient-specific risk subpathway regions is still lacking. Here, we developed an individualized cancer risk subpathway identification method that was referred as InCRiS by integrating multi-omics data. Then, the method was applied to nearly 3000 samples across 9 TCGA cancer types and its robustness and reliability were evaluated. Dissecting dysregulated subpathways in these tumor samples revealed several key regions which may play oncogenic roles in cancer. The construction of risk subpathway dysregulation profile of pan-cancers revealed 11 pan-cancer molecular classification (InCRiS subtypes) with significantly different clinical outcomes. Moreover, subpathway regions that tend to be disordered in individuals of specific subtypes were examined for understanding the pathogenesis of tumor and some key genes such as CTNNB1, EP300 and PRKDC were nominated in different subtypes. In summary, the proposed method and resulting data presented useful resources to study the mechanism of tumor heterogeneity and to discovery novel therapeutic targets for precise treatment of cancer.

Background: Short-term exposure to fine particulate matter (PM2.5) increases the excess risk (ER) of deaths. The metals are important constituents that are responsible for health risks of PM2.5. However, the short-term mortality risks that are associated with individual PM2.5-bound metals are not comprehensively understood. Objective: Estimate the short-term mortality risks and corresponding thresholds of PM2.5-bound metals, with the purpose of advancing our understanding of the health risks of PM2.5 exposure, meanwhile, guiding the policy making of PM2.5 pollution prevention and early warning. Methods: Daily PM2.5 samples, which were collected in the urban region of Guangzhou from 2015 to 2016, were analyzed for metals. Air pollutants, meteorological and mortality data were collected during the same period. A distributed lag non-linear model was used to associate the ER of mortality with individual PM2.5-bound metals. A cluster analysis was processed to classify the cumulative ER of different metals into groups. Results: 11 PM2.5-bound metals were statistically significantly associated with non-accidental death; the highest cumulative ER of mortality was 2.22%, 1.85%, 1.42%, 2.04%, 1.41%, 1.26%, 0.65%, 2.24%, 1.23%, 2.86%, and 1.84% for an interquartile range (IQR) increase in concentrations of lead (Pb), cadmium (Cd), arsenic (As), selenium (Se), antimony (Sb), manganese (Mn), nickel (Ni), thallium (Tl), barium (Ba), aluminum (Al), and iron (Fe), respectively. The metals were classified into high (Pb, Cd, Se, Tl, and Al), middle (As, Sb, Mn, Ba, and Fe), and low (Ni, copper, and zinc) ER groups according to their highest cumulative ER values. No threshold was found for concentration-response relationships between all the metals and mortality. Conclusion: Pb, Cd, Se, Tl, and Al had more contributions to PM2.5-related mortality risk than the other metals. Specific emission source-control measures were needed to reduce the mortality risk of PM2.5 exposure. The mortality risks, which were associated with low-level exposure of PM2.5-bound metals, deserve attention in the design of early warning and self-prevention. Comprehensive exposure assessment of PM2.5-bound metals is required to understand and reduce the PM2.5-related health risks.

Although studies have investigated the associations between PM2.5 and mortality risk, evidence from rural areas is scarce. We aimed to compare the PM2.5-mortality associations between urban cities and rural areas in China. Daily mortality and air pollution data were collected from 215 locations during 2014–2017 in China. A two-stage approach was employed to estimate the location-specific and combined cumulative associations between short-term exposure to PM2.5 (lag 0–3 days) and mortality risks. The excess risks (ER) of all-cause, respiratory disease (RESP), cardiovascular disease (CVD), and cerebrovascular disease (CED) mortality for each 10 μg/m3 increment in PM2.5 across all locations were 0.54% (95% confidence interval [CI]: 0.38%, 0.70%), 0.51% (0.10%, 0.93%), 0.74% (0.50%, 0.97%), and 0.52% (0.20%, 0.83%), respectively. Slightly stronger associations for CVD (0.80% versus 0.60%) and CED (0.61% versus 0.26%) mortality were observed in urban cities than in rural areas, and slightly greater associations for RESP mortality (0.51% versus 0.43%) were found in rural areas than in urban cities. A mean of 2.11% (attributable fraction [AF], 95% CI: 1.48%, 2.76%) of all-cause mortality was attributable to PM2.5 exposure in China, with a larger AF in urban cities (2.89% [2.12%, 3.67%]) than in rural areas (0.61% [−0.60%, 1.84%]). Disparities in PM2.5-mortality associations between urban cities and rural areas were also found in some subgroups classified by sex and age. This study provided robust evidence on the associations of PM2.5 with mortality risks in China and demonstrated urban-rural disparities of PM2.5-mortality associations for various causes of death.

Summary: Although numerous studies have investigated premature deaths attributable to temperature, effects of temperature on years of life lost (YLL) remain unclear. We estimated the relationship between temperatures and YLL, and quantified the YLL per death caused by temperature in China. We collected daily meteorological and mortality data, and calculated the daily YLL values for 364 locations (2013–2017 in Yunnan, Guangdong, Hunan, Zhejiang, and Jilin provinces, and 2006–2011 in other locations) in China. A time-series design with a distributed lag nonlinear model was first employed to estimate the location-specific associations between temperature and YLL rates (YLL/100,000 population), and a multivariate meta-analysis model was used to pool location-specific associations. Then, YLL per death caused by temperatures was calculated. The temperature and YLL rates consistently showed U-shaped associations. A mean of 1.02 (95% confidence interval: 0.67, 1.37) YLL per death was attributable to temperature. Cold temperature caused 0.98 YLL per death with most from moderate cold (0.84). The mean YLL per death was higher in those with cardiovascular diseases (1.14), males (1.15), younger age categories (1.31 in people aged 65–74 years), and in central China (1.34) than in those with respiratory diseases (0.47), females (0.87), older people (0.85 in people ≥75 years old), and northern China (0.64) or southern China (1.19). The mortality burden was modified by annual temperature and temperature variability, relative humidity, latitude, longitude, altitude, education attainment, and central heating use. Temperatures caused substantial YLL per death in China, which was modified by demographic and regional characteristics.

Non–small cell lung cancer (NSCLC) with activating EGFR mutations in exon 19 and 21 typically responds to EGFR tyrosine kinase inhibitors (TKI); however, for some patients, responses last only a few months. The underlying mechanisms of such short responses have not been fully elucidated. Here, we sequenced the genomes of 16 short-term responders (SR) that had progression-free survival (PFS) of less than 6 months on the first-generation EGFR TKI and compared them to 12 long-term responders (LR) that had more than 24 months of PFS. All patients were diagnosed with advanced lung adenocarcinoma and harbored EGFR 19del or L858R mutations before treatment. Paired tumor samples collected before treatment and after relapse (or at the last follow-up) were subjected to targeted next-generation sequencing of 416 cancer-related genes. SR patients were significantly younger than LR patients (P < .001). Collectively, 88% of SR patients had TP53 variations compared to 13% of LR patients (P < .001). Additionally, 37.5% of SR patients carried EGFR amplifications compared to 8% of LR patients. Other potential primary resistance factors were also identified in the pretreatment samples of 12 SR patients (75%), including PTEN loss; BIM deletion polymorphism; and amplifications of EGFR, ERBB2, MET, HRAS, and AKT2. Comparatively, only three LR patients (25%) were detected with EGFR or AKT1 amplifications that could possibly exert resistance. The diverse preexisting resistance mechanisms in SR patients revealed the complexity of defining treatment strategies even for EGFR-sensitive mutations.

Background: Experimental studies have indicated that alterations in the gut microbiota might play a role in the pathway of diabetes induction resulting from particulate matter pollution with aerodynamic diameters

Summary: Background: From 2003 to 2005, standardised 5-year cancer survival in China was much lower than in developed countries and varied substantially by geographical area. Monitoring population-level cancer survival is crucial to the understanding of the overall effectiveness of cancer care. We therefore aimed to investigate survival statistics for people with cancer in China between 2003 and 2015. Methods: We used population-based data from 17 cancer registries in China. Data for the study population was submitted by the end of July 31, 2016, with follow-up data on vital status obtained on Dec 31, 2015. We used anonymised, individual cancer registration records of patients (aged 0–99 years) diagnosed with primary, invasive cancers from 2003 to 2013. Patients eligible for inclusion had data for demographic characteristics, date of diagnosis, anatomical site, morphology, behaviour code, vital status, and last date of contact. We analysed 5-year relative survival by sex, age, and geographical area, for all cancers combined and 26 different cancer types, between 2003 and 2015. We stratified survival estimates by calendar period (2003–05, 2006–08, 2009–11, and 2012–15). Findings: There were 678 842 records of patients with invasive cancer who were diagnosed between 2003 and 2013. Of these records, 659 732 (97·2%) were eligible for inclusion in the final analyses. From 2003–05 to 2012–15, age-standardised 5-year relative survival increased substantially for all cancers combined, for both male and female patients, from 30·9% (95% CI 30·6–31·2) to 40·5% (40·3–40·7). Age-standardised 5-year relative survival also increased for most cancer types, including cancers of the uterus (average change per calendar period 5·5% [95% CI 2·5–8·5]), thyroid (5·4% [3·2–7·6]), cervix (4·5% [2·9–6·2]), and bone (3·2% [2·1–4·4]). In 2012–15, age-standardised 5-year survival for all patients with cancer was higher in urban areas (46·7%, 95% CI 46·5–47·0) than in rural areas (33·6%, 33·3–33·9), except for patients with oesophageal or cervical cancer; but improvements in survival were greater for patients residing in rural areas than in urban areas. Relative survival decreased with increasing age. The increasing trends in survival were consistent with the upward trends of medical expenditure of the country during the period studied. Interpretation: There was a marked overall increase in cancer survival from 2003 to 2015 in the population covered by these cancer registries in China, possibly reflecting advances in the quality of cancer care in these areas. The survival gap between urban and rural areas narrowed over time, although geographical differences in cancer survival remained. Insight into these trends will help prioritise areas that need increased cancer care. Funding: National Key R&D Program of China, PUMC Youth Fund and the Fundamental Research Funds for the Central Universities, and Major State Basic Innovation Program of the Chinese Academy of Medical Sciences.

The porous few-layer g-C3N4 (PFL-g-C3N4) is prepared by a simple molecular self-assembly method. Compared with pure g-C3N4, the as-prepared PFL-g-C3N4 is ultrathin, the surface is rich in pores, and the photocatalytic nitrogen fixation activity is greatly increased to 8.20 mM h−1 gCat−1. Few-layer and ultrathin nature of PFL-g-C3N4 can provide a larger specific surface area, expose more active sites, and reduce the diffusion path of charges and protons from the inside to the surface. In addition, the porous structure can narrow the band gap, thereby increasing the light absorption range and enhancing the light absorption capability. Meanwhile, the presence of nitrogen vacancies causes PFL-g-C3N4 to move to a more negative conductive band value. More importantly, the isotopic experiments using 15N2 as nitrogen source confirm the ammonia production originating from N2 rather than the decomposition of g-C3N4. Therefore, PFL-g-C3N4 can greatly improve the efficiency of visible light photocatalytic nitrogen fixation. Keywords: Molecular self-assembly, g-C3N4, Porous structure, Nitrogen vacancies, Photocatalytic nitrogen fixation