Hyper-Interferon Sensitive influenza induces adaptive immune responses and overcomes resistance to anti-PD-1 in murine non-small cell lung cancer.

Despite recent advances in immunotherapy with immune checkpoint inhibitors (ICI), many patients with non-small cell lung cancer (NSCLC) fail to respond or develop resistance after an initial response. In situ vaccination (ISV) with engineered viruses has emerged as a promising antigen-agnostic strategy that can both condition the tumor microenvironment (TME) and augment anti-tumor T cell responses to overcome immune resistance. We engineered a live attenuated viral vaccine, Hyper-Interferon Sensitive virus (HIS), by conducting a genome-wide functional screening and introducing eight interferon (IFN)-sensitive mutations in the influenza genome. Compared to wild-type (WT) influenza, HIS replication was attenuated in immunocompetent hosts, enhancing its potential as a safe option for cancer therapy. HIS ISV elicited robust yet transient type I IFN responses in murine NSCLCs, leading to an enrichment of polyfunctional effector Th1 CD4 and cytotoxic CD8 T cells into the tumor. HIS ISV demonstrated enhanced anti-tumor efficacy compared to WT in multiple syngeneic murine models of NSCLC with distinct driver mutations and varying mutational burden. This efficacy was dependent on host type 1 IFN responses and T lymphocytes. HIS ISV overcame resistance to anti-PD-1 in LKB-1 deficient murine NSCLC, resulting in improved overall survival and enduring systemic tumor-specific immunity. These studies provide compelling evidence to support further clinical evaluation of HIS as a novel 'off-the-shelf' ISV strategy for patients with NSCLC refractory to ICI.

Why does HER2-positive breast cancer metastasize to the brain and what can we do about it?

Breast cancer is the most frequent malignancy in women. However, in the middle and late stages, some people develop distant metastases, which considerably lower the quality of life and life expectancy. The brain is one of the sites where metastasis frequently happens. According to epidemiological research, brain metastases occur at a late stage in 30-50% of patients with HER2-positive breast cancer, resulting in a poor prognosis. Additionally, few treatments are available for HER2-positive brain metastatic breast cancer, and the mortality rate is remarkable owing to the complexity of the brain's anatomical structure and physiological function. In this review, we described the stages of the brain metastasis of breast cancer, the relationship between the microenvironment and metastatic cancer cells, and the unique molecular and cellular mechanisms. It involves cancer cells migrating, invading, and adhering to the brain; penetrating the blood-brain barrier; interacting with brain cells; and activating signal pathways once inside the brain. Finally, we reviewed current clinically used treatment approaches for brain metastasis in HER2-positive breast cancer; summarized the traditional treatment, targeted treatment, immunotherapy, and other treatment modalities; compared the benefits and drawbacks of each approach; discussed treatment challenges; and emphasized the importance of identifying potential targets to improve patient survival rates and comprehend brain metastasis in breast cancer.

Integrative proteomics and metabolomics of Guizhou Miao Sour Soup affecting simple obese rats.

Miao Sour Soup (MSS) is a fermented product from the Qiandongnan region of Guizhou Province, which enrich many beneficial ingredients and is widely consumed in the whole China. Fermented food is beneficial to physical health with the potential positive regulating affection on simple obesity. In this study, we analyzed the mechanism of action of MSS to prevent simple obesity induced by high-fat diet by proteomics and metabolomics. Quantitative proteomics with tandem mass tagging labeling and liquid chromatography-mass spectrometry was used to analyze the changes of liver proteins and metabolites after the MSS intervention. MSS intervention upregulated 33 proteins and 9 metabolites and downregulated 19 proteins and 10 metabolites. Bioinformatics analysis showed that MSS could prevent simple obesity by acting on the PPAR signaling pathway, retinol metabolism, fatty acid ß-oxidation, fatty acid degradation, fatty acid biosynthesis, glycine, serine and threonine metabolism, pyruvate metabolism, citrate cycle (TCA cycle) and other signaling pathways. This study provides new insights into the use of MSS to prevent simple obesity caused by high-fat diets and the search for healthy eating patterns with MSS.

Road runoff as a significant nonpoint source of parabens and their metabolites in urban rivers.

Parabens are widely added to food, cosmetics, and medicines as preservatives and are typical contaminants of pharmaceuticals and personal care products (PPCPs). However, their fate and transport in urban watersheds remain largely unexplored. This study investigated the role of road runoff as a critical nonpoint source of parabens and their metabolites in urban rivers based on 73 multimedia (road runoff and dust in different urban land uses, wastewater, stormwater discharge and river water) samples collected from a highly urbanized drainage area. Seven parabens and five metabolites were detected in the road runoff, with mean concentrations of ∑parabens and ∑metabolites equal to 47.5 ng/L and 4710 ng/L, respectively. The concentrations in road runoff were comparable to those in treated wastewater and river water and showed a land use pattern of residential > industrial > commercial. A first flush effect of the contaminants was observed in a heavy rainfall event with an antecedent dry period. In general, the population-based and area-based emission intensities of ∑parabens and ∑metabolites in road runoff were one order of magnitude higher than those in wastewater effluent during the rainfall events. This study provides quantitative evidence that road runoff can be a major pollution source of parabens and their metabolites in rapidly growing cities during the wet season and calls for the integrated management of nonpoint sources to prevent urban river contamination by typical PPCPs.

Role of Organic and Conservation Agriculture in Ammonia Emissions and Crop Productivity in China.

There is an increasing food demand with growing population and limited land for agriculture. Conventional agriculture with nitrogen (N) fertilizer applications, however, is a key source of ammonia (NH3) emissions that cause severe haze pollution and impair human health. Organic and conservation agricultural (OCA) practices are thereby recommended to address these dual challenges; however, whether OCA provides cobenefits for both air quality and crop productivity is controversial. Here, we perform a meta-analysis and machine learning algorithm with data from China, a global hotspot for agricultural NH3 emissions, to quantify the effects of OCA on NH3 emissions, crop yields and nitrogen use efficiency (NUE). We find that the effects of OCA depend on soil and climate conditions, and the 40-60% substitution of synthetic fertilizers with livestock manure achieves the maximum cobenefits of enhanced crop production and reduced NH3 emissions. Model forecasts further suggest that the appropriate application of livestock manure, straw return, and no-till could increase grain production up to 59.7 million metric tons (100% of straw return) and reduce maximum US$2.7 billion (60% substitution with livestock manure) in damage costs to human health from NH3 emissions by 2030. Our findings provide data-driven pathways and options for achieving multiple sustainable development goals and improving food systems and air quality in China.

Policy-enabled stabilization of nitrous oxide emissions from livestock production in China over 1978-2017.

Mitigating livestock-related nitrous oxide (N2O) emissions is key for China to meet its 2060 carbon neutrality target. Here we present a comprehensive analysis of the magnitude, spatiotemporal variation and drivers of Chinese livestock N2O emissions from 1978 to 2017. We developed scenarios to explore emissions mitigation potential and associated marginal abatement costs and social benefits. The average growth rate of China's livestock N2O emissions increased by 4.6% per year through 2006, falling sharply over 2007-2015 and gradually declining in 2017 due to a slowdown in population and meat-consumption growth rates. We estimate the technical mitigation potential of livestock N2O emissions in 2030 to be 7-21% (or 23.1-70.9 Gg N2O), with implementation costs of US$5.5 billion to US$6.0 billion. Priority regions for intervention were identified in the North China Plain, Northeast Plain and Lianghu Plain. Among mitigation opportunities, anaerobic digestion offers the greatest social benefit, while low crude protein feed is the most cost-effective option.

Crosstalk Between Tumor-Associated Microglia/Macrophages and CD8-Positive T Cells Plays a Key Role in Glioblastoma.

Glioblastoma is considered to be the most malignant disease of the central nervous system, and it is often associated with poor survival. The immune microenvironment plays a key role in the development and treatment of glioblastoma. Among the different types of immune cells, tumor-associated microglia/macrophages (TAM/Ms) and CD8-positive (CD8+) T cells are the predominant immune cells, as well as the most active ones. Current studies have suggested that interaction between TAM/Ms and CD8+ T cells have numerous potential targets that will allow them to overcome malignancy in glioblastoma. In this review, we summarize the mechanism and function of TAM/Ms and CD8+ T cells involved in glioblastoma, as well as update on the relationship and crosstalk between these two cell types, to determine whether this association alters the immune status during glioblastoma development and affects optimal treatment. We focus on the molecular factors that are crucial to this interaction, and the role that this crosstalk plays in the biological processes underlying glioblastoma treatment, particularly with regard to immune therapy. We also discuss novel therapeutic targets that can aid in resolving reticular connections between TAM/Ms and CD8+ T cells, including depletion and reprogramming TAM/Ms and novel TAM/Ms-CD8+ T cell cofactors with potential translational usage. In addition, we highlight the challenges and discuss future perspectives of this crosstalk between TAM/Ms and CD8+ T cells.

Update on Nanoparticle-Based Drug Delivery System for Anti-inflammatory Treatment.

Nanobiotechnology plays an important role in drug delivery, and various kinds of nanoparticles have demonstrated new properties, which may provide opportunities in clinical treatment. Nanoparticle-mediated drug delivery systems have been used in anti-inflammatory therapies. Diseases, such as inflammatory bowel disease, rheumatoid arthritis, and osteoarthritis have been widely impacted by the pathogenesis of inflammation. Efficient delivery of anti-inflammatory drugs can reduce medical dosage and improve therapeutic effect. In this review, we discuss nanoparticles with potential anti-inflammatory activity, and we present a future perspective regarding the application of nanomedicine in inflammatory diseases.

Oxidative Stress, Endocrine Disturbance, and Immune Interference in Humans Showed Relationships to Serum Bisphenol Concentrations in a Dense Industrial Area.

Bisphenol A (BPA) analogues, used in a range of products due to health concerns regarding BPA, have emerged as ubiquitous environmental contaminants worldwide. This study aims to evaluate the levels of nine bisphenols (BPs) and eight biomarkers (malondialdehyde, MDA; 8-hydroxy-2'-deoxyguanosine, 8-OHdG; estradiol, E2; follicle-stimulating hormone, FSH; luteinizing hormone, LH; complement compound 3, C3; immunoglobulin M, IgM and c-reaction protein, CRP) in human serum (n = 353) to explore their potential relationships. The detection rates (DRs) of eight BPs in serum samples taken from people working in a dense industrial area of Shenzhen (Guangdong Province, China) were over 72% except for bisphenol B (BPB) (DR = 27.5%). The mean concentrations of BPA, bisphenol P (BPP), BPB, bisphenol F (BPF), bisphenol FL (BPFL), 4,4'-dihydroxy-benzophenone (DHBP), bisphenol AF (BPAF), 4,4'-thiodiphenol (TDP) and bisphenol S (BPS) were 42.062, 2.083, 0.765, 0.578, 0.423, 0.402, 0.191, 0.120, and 0.071 ng/mL, respectively. BPA and BPFL were significantly correlated with the level of oxidative stress indices MDA and 8-OHdG; BPAF, BPB, and DHBP were strongly correlated with the level of endocrine disturbance indices E2, FSH, and LH; and BPF, DHBP, and BPAF were apparently related to the level of immune interference indices C3 and IgM. This study also suggests multiple impacts (oxidative stress, endocrine disturbance, and immune interference) mediated by BPs contaminants in vivo. To our knowledge, this is the first study to report the correlations among these nine serum BPs and oxidative stress and endocrine and immune system indices in human serum samples collected from dense industrial areas.

Improving urban drainage systems to mitigate PPCPs pollution in surface water: A watershed perspective.

Parabens are preservatives widely used in pharmaceutical and personal care products (PPCPs). This study investigated urban water pollution by parabens from a watershed perspective. Water and sediment samples were collected from one of the most polluted urban streams in China. Six parabens and five paraben metabolites were frequently detected in the samples, whereas the overall pollution level was intermediate according to a global comparison. The spatial distributions of the chemical concentrations along the river are influenced by multiple factors, and WWTPs appear to be a major factor. In general, the target pollutants were detected at higher concentrations in the dry season than in the wet season, but extraordinary concentration peaks in water were observed downstream of wastewater treatment plants (WWTPs), indicating a dominant contribution from combined sewage overflows (CSOs) during rainfall events. In a representative WWTP-influenced reach, CSOs account for its 97.3% of ∑parabens input and 96.9% of ∑metabolites input in a typical rainfall event. Converting the existing combined sewer systems to separate stormwater drainage systems could reduce the inputs of ∑parabens and ∑metabolites by 86.9-84.5%, respectively. This study highlights the role of urban drainage systems in preventing surface water pollution by PPCPs. CAPSULE: Urban drainage systems play a critical role in controlling pollution by parabens and their metabolites in urban surface water.

Occurrence, distribution, bioaccumulation, and ecological risk of bisphenol analogues, parabens and their metabolites in the Pearl River Estuary, South China.

Bisphenol analogues and alkyl esters of p-hydroxybenzoic (parabens) can be defined as emerging endocrine-disrupting compounds (EDCs) due to their similar characteristics. This study analyzed eight bisphenol analogues, six parabens, and five paraben metabolites in seawater (including aqueous and suspended particle matter (SPM)), as well as organism samples from the Pearl River Estuary, in order to determine their occurrence, distribution, bioaccumulation, and ecological and human health risk in South China's marine environment. The aggregation concentrations of bisphenol analogues, parabens, and paraben metabolites were 106 ng/L, 4.53 ng/L, and 231 ng/L in aqueous samples, 868 ng/g, 173 ng/g, and 9320 ng/g in SPM samples, 41.6 ng/g, 6.46 ng/g, and 460 ng/g in marine organisms, respectively. This study identified significantly higher concentrations of paraben metabolites than their parent parabens in the marine environment, which has not yet been reported in previous studies. These findings call for greater attention on the contamination of paraben metabolites in marine environments. Moreover, the median values of the logarithm of bioaccumulation factors (BAF) for the detected 20 target compounds ranged from 0.11 to 5.07. Bisphenol analogues including bisphenol A (BPA), bisphenol S (BPS), bisphenol F (BPF), bisphenol B (BPB), bisphenol P (BPP), and Fluornen-9-bisphenol (BPFL) (3.3 < lg BAF < 3.7), and three paraben metabolites including 4-hydroxybenzoic acid (4-HB) (3.3 < lg BAF < 3.7), methyl protocatechuate (OH-MeP), and ethyl protocatechuate (OH-EtP) (Log BAF > 3.7), exhibited varying degrees of potential bioaccumulation effect in the majority of organism samples. Furthermore, all tested chemicals in this study were at low risk quotient (RQ) levels for acute and chronic toxicity in seawater. However, the target hazard quotient (THQ) values of two paraben metabolites, 4-HB and benzoic acid (BA), were higher than 1, which indicates that paraben metabolites have the potential to adsorb into organisms, and their associated human health risks should be of great concern. Overall, the study results suggest that the occurrence and risks of emerging EDCs in coastal waters are deserving of further studies, especially in densely populated regions of the world.

[Relationship between risk of childhood acute leukemia and children's and parents' lifestyles and household environment exposure].

OBJECTIVE: To investigate the association between children's and their parents' lifestyles, household environmental exposures and risk of childhood acute leukemia (AL). METHODS: A 1:2 matched case-control study of childhood AL was conducted in Shanghai between April 2011 and January 2014. The study enrolled 66 cases aged < 15, diagnosed with AL and 132 controls matched by age, gender and residence. All of the controls had no hematological diseases or previous history of malignancy. Children who had been adopted and had congenital genetic syndromes such as Down's syndrome or a positive HIV test result were not eligible as either cases or controls. Information was obtained from standardized face-to-face interviews of their parents/guardians with detailed questions on demographic characteristics, lifestyle, and household environment. Conditional logistic regression models were used to analyze effecting factors of childhood AL, odds ratios (OR) and their 95% confidence intervals (CI) were calculated. RESULTS: Among 198 cases, 66 cases were aged (5.0 ± 3.7) years old, and 132 controls were aged (6.0 ± 3.8) years old (t = 0.48, P = 0.523). The paternal drink frequencies of cases and controls were 57.6% (38/66), and 31.1% (41/132), respectively (χ² = 4.91, P = 0.027). And the frequencies of household insecticides usage in the last year in the two groups were 78.8% (52/66), and 65.2% (86/132) (χ² = 3.87, P = 0.049). Chemical exposure during childhood (OR = 4.76, 95% CI: 1.34-16.89), maternal exposure to chemicals (OR = 4.51, 95% CI: 1.65-12.33), household insecticides use during 0-3 years of child (OR = 2.90, 95% CI: 1.31-6.39), and renovating after their children's birth (OR = 3.12, 95% CI: 1.26-7.74) were associated with an increased risk of childhood AL and these differences between the cases and the controls have statistical significance. Besides, we found that frequent contaction with other children during 0-3 years old (OR = 0.32, 95% CI: 0.15-0.69) and ventilation during sleeping in summer (OR = 0.43, 95% CI: 0.18-0.98) were associated with a decreased risk of childhood AL. CONCLUSION: Our results support the association between children's and their parents' lifestyles, household environmental exposures and childhood AL.