Integrated spatial metabolomics and transcriptomics decipher the hepatoprotection mechanisms of wedelolactone and demethylwedelolactone on non-alcoholic fatty liver disease.

Eclipta prostrata L. has been used in traditional medicine and known for its liver-protective properties for centuries. Wedelolactone (WEL) and demethylwedelolactone (DWEL) are the major coumarins found in E. prostrata L. However, the comprehensive characterization of these two compounds on non-alcoholic fatty liver disease (NAFLD) still remains to be explored. Utilizing a well-established zebrafish model of thioacetamide (TAA)-induced liver injury, the present study sought to investigate the impacts and mechanisms of WEL and DWEL on NAFLD through integrative spatial metabolomics with liver-specific transcriptomics analysis. Our results showed that WEL and DWEL significantly improved liver function and reduced the accumulation of fat in the liver. The biodistributions and metabolism of these two compounds in whole-body zebrafish were successfully mapped, and the discriminatory endogenous metabolites reversely regulated by WEL and DWEL treatments were also characterized. Based on spatial metabolomics and transcriptomics, we identified that steroid biosynthesis and fatty acid metabolism are mainly involved in the hepatoprotective effects of WEL instead of DWEL. Our study unveils the distinct mechanism of WEL and DWEL in ameliorating NAFLD, and presents a "multi-omics" platform of spatial metabolomics and liver-specific transcriptomics to develop highly effective compounds for further improved therapy.

Exploring variations in IPC competencies: a cross-sectional study among healthcare professionals in Northwest China.

BACKGROUND: This cross-sectional study investigates infection prevention and control (IPC) competencies among healthcare professionals in northwest China, examining the influence of demographic factors, job titles, education, work experience, and hospital levels. METHODS: Data from 874 respondents across 47 hospitals were collected through surveys assessing 16 major IPC domains. Statistical analyses, including Mann-Whitney tests, were employed to compare competencies across variables. RESULTS: Significant differences were identified based on gender, job titles, education, work experience, and hospital levels. Females demonstrated higher IPC competencies, while senior positions exhibited superior performance. Higher educational attainment and prolonged work experience positively correlated with enhanced competencies. Variances across hospital levels underscored context-specific competencies. CONCLUSION: Demographic factors and professional variables significantly shape IPC competencies. Tailored training, considering gender differences and job roles, is crucial. Higher education and prolonged work experience positively impact proficiency. Context-specific interventions are essential for diverse hospital settings, informing strategies to enhance IPC skills and mitigate healthcare-associated infections effectively.

Directed differentiation of human embryonic stem cells into parathyroid cells and establishment of parathyroid organoids.

Differentiation of human embryonic stem cells (hESCs) into human embryonic stem cells-derived parathyroid-like cells (hESC-PT) has clinical significance in providing new therapies for congenital and acquired parathyroid insufficiency conditions. However, a highly reproducible, well-documented method for parathyroid differentiation remains unavailable. By imitating the natural process of parathyroid embryonic development, we proposed a new hypothesis about the in vitro differentiation of parathyroid-like cells. Transcriptome, differentiation marker protein detection and parathyroid hormone (PTH) secretion assays were performed after the completion of differentiation. To optimize the differentiation protocol and further improve the differentiation rate, we designed glial cells missing transcription factor 2 (GCM2) overexpression lentivirus transfection assays and constructed hESCs-derived parathyroid organoids. The new protocol enabled hESCs to differentiate into hESC-PT. HESC-PT cells expressed PTH, GCM2 and CaSR proteins, low extracellular calcium culture could stimulate hESC-PT cells to secrete PTH. hESC-PT cells overexpressing GCM2 protein secreted PTH earlier than their counterpart hESC-PT cells. Compared with the two-dimensional cell culture environment, hESCs-derived parathyroid organoids secreted more PTH. Both GCM2 lentiviral transfection and three-dimensional cultures could make hESC-PT cells functionally close to human parathyroid cells. Our study demonstrated that hESCs could differentiate into hESC-PT in vitro, which paves the road for applying the technology to treat hypoparathyroidism and introduces new approaches in the field of regenerative medicine.

Fertilizer management for global ammonia emission reduction.

Crop production is a large source of atmospheric ammonia (NH3), which poses risks to air quality, human health and ecosystems1-5. However, estimating global NH3 emissions from croplands is subject to uncertainties because of data limitations, thereby limiting the accurate identification of mitigation options and efficacy4,5. Here we develop a machine learning model for generating crop-specific and spatially explicit NH3 emission factors globally (5-arcmin resolution) based on a compiled dataset of field observations. We show that global NH3 emissions from rice, wheat and maize fields in 2018 were 4.3 ± 1.0 Tg N yr-1, lower than previous estimates that did not fully consider fertilizer management practices6-9. Furthermore, spatially optimizing fertilizer management, as guided by the machine learning model, has the potential to reduce the NH3 emissions by about 38% (1.6 ± 0.4 Tg N yr-1) without altering total fertilizer nitrogen inputs. Specifically, we estimate potential NH3 emissions reductions of 47% (44-56%) for rice, 27% (24-28%) for maize and 26% (20-28%) for wheat cultivation, respectively. Under future climate change scenarios, we estimate that NH3 emissions could increase by 4.0 ± 2.7% under SSP1-2.6 and 5.5 ± 5.7% under SSP5-8.5 by 2030-2060. However, targeted fertilizer management has the potential to mitigate these increases.

Isotope-Coded On-Tissue Derivatization for Quantitative Mass Spectrometry Imaging of Short-Chain Fatty Acids in Biological Tissues.

Short-chain fatty acids (SCFAs), as the main metabolites of gut microbiota, are recognized as crucial players in the host's inflammatory response and metabolic disease. Imaging the spatial distributions and calculating the accurate contents of SCFAs in the heterogeneous intestinal tissue are critical to reveal their biological functions. Here, we develop an isotope-coded on-tissue derivatization method combined with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to map the spatial expressions of SCFAs in the colon tissue based on pair-labeled N,N,N-trimethyl-2-(piperazin-1-yl)ethan-1-aminium iodide (TMPA) and D3-TMPA. A noticeable increase in the MALDI-MSI sensitivity of SCFAs was achieved after on-tissue derivatization, which enables the visualization of acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, hydroxy acetic acid, and hydroxy propionic acid in the colon tissue. Moreover, the introduction of D3-TMPA-tagged SCFAs as internal standards can significantly reduce quantitation deviation from the matrix effects, ensuring the quantitative MALDI-MSI of SCFAs. We further used this method to characterize the spatial alterations of SCFAs in the colon tissues of mice with enterocolitis. The development of this strategy provides a reliable approach to image the spatial expressions of SCFAs in tissues and paves an insight way to study the roles of SCFAs in the gut microbiota and disease.

Variation of endosymbiont and citrus tristeza virus (CTV) titers in the Huanglongbing insect vector, Diaphorina citri, on CTV-infected plants.

"Candidatus Liberibacter asiaticus" (CLas) is a notorious agent that causes Citrus Huanglongbing (HLB), which is transmitted by Diaphorina citri (D. citri). We recently found that the acquisition and transmission of CLas by D. citri was facilitated by Citrus tristeza virus (CTV), a widely distributed virus in the field. In this study, we further studied whether different CTV strains manipulate the host preference of D. citri, and whether endosymbionts variation is related to CTV strains in D. citri. The results showed that the non-viruliferous D. citri preferred to select the shoots infected with CTV, without strain differences was observed in the selection. However, the viruliferous D. citri prefered to select the mixed strain that is similar to the field's. Furthermore, D. citri effectively acquired the CTV within 2-12 h depending on the strains of the virus. The persistence period of CTV in D. citri was longer than 24 days, without reduction of the CTV titers being observed. These results provide a foundation for understanding the transmission mode of D. citri on CTV. During the process of CTV acquisition and persistence, the titers of main endosymbionts in D. citri showed similar variation trend, but their relative titers were different at different time points. The titers of the "Candidatus Profftella armatura" and CTV tended to be positively correlated, and the titers of Wolbachia and "Candidatus Carsonella ruddii" were mostly negatively related with titers of CT31. These results showed the relationship among D. citri, endosymbionts, and CTV and provided useful information for further research on the interactions between D. citri and CLas, which may benefit the development of approaches for the prevention of CLas transmission and control of citrus HLB.

In-depth profiling of carbohydrate isomers in biological tissues by chemical derivatization-assisted mass spectrometry imaging.

Carbohydrates play crucial regulatory roles in various physiological and pathological processes. However, the low ionization efficiency and the presence of linkage pattern, monosaccharide composition and anomeric configuration isomers make their in-depth analysis very challenging, especially for heterogeneous biological tissues. In this study, we propose a high-sensitive and isomer-specific imaging approach to visualize the spatial distributions of monosaccharide and disaccharide isomers by integrating chemical derivatization and matrix-assisted laser desorption/ionization tandem mass spectrometry imaging (MALDI-MS2I). 2-Pyridinecarbohydrazide (PYD) is developed as a novel derivatization reagent which can not only improves the MS sensitivity of carbohydrates, but also enables the identification and visualization of ketose and aldose monosaccharide isomers, as well as linkage pattern, monosaccharide composition and anomeric configuration disaccharide isomers by mass spectrometry imaging of isomer-specific MS/MS fragment ions. Moreover, we build quantitative MALDI-MS2 and MALDI-MS2I methods for disaccharide isomers based on the diagnostic fragment ions, and good linear relationships could be achieved both in solution and on glass slides. We expect that this study should provide new ideas for in-depth profiling of the spatial signatures of carbohydrates in biological tissues and lay the foundation for a deeper understanding of carbohydrates' structure.

Global crop-specific nitrogen fertilization dataset in 1961-2020.

Nitrogen (N) is an important nutrient for crop growth. However, the overuse of N fertilizers has led to a series of devastating global environmental issues. Recent studies show that multiple datasets have been created for agricultural N fertilizer application with varied temporal or spatial resolutions, nevertheless, how to synchronize and use these datasets becomes problematic due to the inconsistent temporal coverages, spatial resolutions, and crop-specific allocations. Here we reconstructed a comprehensive dataset for crop-specific N fertilization at 5-arc-min resolution (~10 km by 10 km) during 1961-2020, including N application rate, types, and placements. The N fertilization data was segmented by 21 crop groups, 13 fertilizer types, and 2 fertilization placements. Comparison analysis showed that our dataset is aligned with previous estimates. Our spatiotemporal N fertilization dataset could be used for the land surface models to quantify the effects of agricultural N fertilization practices on food security, climate change, and environmental sustainability.

Extreme rainfall reduces one-twelfth of China's rice yield over the last two decades.

Extreme climate events constitute a major risk to global food production. Among these, extreme rainfall is often dismissed from historical analyses and future projections, the impacts and mechanisms of which remain poorly understood. Here we used long-term nationwide observations and multi-level rainfall manipulative experiments to explore the magnitude and mechanisms of extreme rainfall impacts on rice yield in China. We find that rice yield reductions due to extreme rainfall were comparable to those induced by extreme heat over the last two decades, reaching 7.6 ± 0.9% (one standard error) according to nationwide observations and 8.1 ± 1.1% according to the crop model incorporating the mechanisms revealed from manipulative experiments. Extreme rainfall reduces rice yield mainly by limiting nitrogen availability for tillering that lowers per-area effective panicles and by exerting physical disturbance on pollination that declines per-panicle filled grains. Considering these mechanisms, we projected ~8% additional yield reduction due to extreme rainfall under warmer climate by the end of the century. These findings demonstrate that it is critical to account for extreme rainfall in food security assessments.

Targeting the inward rectifier potassium channel 5.1 in thyroid cancer: artificial intelligence-facilitated molecular docking for drug discovery.

BACKGROUND: Recurrent and metastatic thyroid cancer is more invasive and can transform to dedifferentiated thyroid cancer, thus leading to a severe decline in the 10-year survival. The thyroid-stimulating hormone receptor (TSHR) plays an important role in differentiation process. We aim to find a therapeutic target in redifferentiation strategies for thyroid cancer. METHODS: Our study integrated the differentially expressed genes acquired from the Gene Expression Omnibus database by comparing TSHR expression levels in the Cancer Genome Atlas database. We conducted functional enrichment analysis and verified the expression of these genes by RT-PCR in 68 pairs of thyroid tumor and paratumor tissues. Artificial intelligence-enabled virtual screening was combined with the VirtualFlow platform for deep docking. RESULTS: We identified five genes (KCNJ16, SLC26A4, TG, TPO, and SYT1) as potential cancer treatment targets. TSHR and KCNJ16 were downregulated in the thyroid tumor tissues, compared with paired normal tissues. In addition, KCNJ16 was lower in the vascular/capsular invasion group. Enrichment analyses revealed that KCNJ16 may play a significant role in cell growth and differentiation. The inward rectifier potassium channel 5.1 (Kir5.1, encoded by KCNJ16) emerged as an interesting target in thyroid cancer. Artificial intelligence-facilitated molecular docking identified Z2087256678_2, Z2211139111_1, Z2211139111_2, and PV-000592319198_1 (-7.3 kcal/mol) as the most potent commercially available molecular targeting Kir5.1. CONCLUSION: This study may provide greater insights into the differentiation features associated with TSHR expression in thyroid cancer, and Kir5.1 may be a potential therapeutic target in the redifferentiation strategies for recurrent and metastatic thyroid cancer.

Citrus tristeza virus Promotes the Acquisition and Transmission of 'Candidatus Liberibacter Asiaticus' by Diaphorina citri.

Diaphorina citri Kuwayama (D. citri) is an insect vector of phloem-limited 'Candidatus Liberibacter asiatus' (CLas), the presumed pathogen of citrus Huanglongbing (HLB). Recently, our lab has preliminarily found it acquired and transmitted Citrus tristeza virus (CTV), which was previously suggested to be vectored by species of aphids. However, the influences of one of the pathogens on the acquisition and transmission efficiency of the other pathogen remain unknown. In this study, CLas and CTV acquisition and transmission by D. citri at different development stages under field and laboratory conditions were determined. CTV could be detected from the nymphs, adults, and honeydew of D. citri but not from the eggs and exuviates of them. CLas in plants might inhibit CTV acquisition by D. citri as lower CTV-positive rates and CTV titers were detected in D. citri collected from HLB-affected trees compared to those from CLas-free trees. D. citri were more likely to obtain CTV than CLas from host plants co-infected with the two pathogens. Intriguingly, CTV in D. citri facilitated the acquisition and transmission of CLas, but CLas carried by D. citri had no significant effect on the transmission of CTV by the same vector. Molecular detection and microscopy methods confirmed the enrichment of CTV in the midgut after a 72-h acquisition access period. Collectively, these results raise essential scientific questions for further research on the molecular mechanism of pathogen transmission by D. citri and provide new ideas for the comprehensive prevention and control of HLB and CTV.

Current Epidemic Situation and Control Status of Citrus Huanglongbing in Guangdong China: The Space-Time Pattern Analysis of Specific Orchards.

Huanglongbing (HLB) is the most harmful bacterial disease in citrus production in the world, and has been seriously ravaging the citrus groves of South China since the 1930s. The surveillance of the epidemiological characteristics of HLB is of utmost priority for citrus production in this region. In order to explore the effects of disease control measures, analyses on the space-time statistical features of the HLB epidemic, from 2019 to 2021, within six orchards in the Guangdong province are presented. Overall, the number of citrus plants in the orchards usually slightly decreased year by year. The reduction was mainly related to the level of plant susceptibility, which is correlated with citrus varieties. The maximum disease severity (incidence and race increment) was correlated with the awareness of this disease and the management intensity applied by the manager. A higher disease index was found in the conventional management orchards than in the comprehensive prevention and control orchards. Proper insect-protective screen houses can effectively prevent the epidemic of HLB, without affecting the fruit quality, and can also aid with higher yields. A high correlation was found between the geometry and topography of orchards and the HLB epidemic due to the wind direction from May to September and the Asia citrus psyllid activity characteristics. For flat orchards, the incidence of HLB in the north and entrance areas was higher than that in the southwest. In the mountain area, the incidence of the windward side in the south was higher than that of the leeward side in the north. Diseased trees tended to have an edge effect in the grove, whereas the trees of the same disease scale were found clustered in their distribution. These results allow a better understanding of HLB epidemiology and provide guidance for the early warning of HLB in new groves in areas that are severely affected by this disease. Furthermore, they also provide a scientific basis for the comprehensive prevention and control of HLB in old groves.

Integrated Transcriptome and Metabolome Analysis Reveals Phenylpropanoid Biosynthesis and Phytohormone Signaling Contribute to "Candidatus Liberibacter asiaticus" Accumulation in Citrus Fruit Piths (Fluffy Albedo).

"Candidatus Liberibacter asiaticus" (CLas) is a phloem-restricted α-proteobacterium that is associated with citrus huanglongbing (HLB), which is the most destructive disease that affects all varieties of citrus. Although midrib is usually used as a material for CLas detection, we recently found that the bacterium was enriched in fruits, especially in the fruit pith. However, no study has revealed the molecular basis of these two parts in responding to CLas infection. Therefore, we performed transcriptome and UHPLC-MS-based targeted and untargeted metabolomics analyses in order to organize the essential genes and metabolites that are involved. Transcriptome and metabolome characterized 4834 differentially expressed genes (DEGs) and 383 differentially accumulated metabolites (DAMs) between the two materials, wherein 179 DEGs and 44 DAMs were affected by HLB in both of the tissues, involving the pathways of phenylpropanoid biosynthesis, phytohormone signaling transduction, starch and sucrose metabolism, and photosynthesis. Notably, we discovered that the gene expression that is related to beta-glucosidase and endoglucanase was up-regulated in fruits. In addition, defense-related gene expression and metabolite accumulation were significantly down-regulated in infected fruits. Taken together, the decreased amount of jasmonic acid, coupled with the reduced accumulation of phenylpropanoid and the increased proliferation of indole-3-acetic acid, salicylic acid, and abscisic acid, compared to leaf midribs, may contribute largely to the enrichment of CLas in fruit piths, resulting in disorders of photosynthesis and starch and sucrose metabolism.

Regulation of antitumor miR-205 targets oncogenes: Direct regulation of lymphoid specific helicase and its clinical significance.

HEADING AIMS: Breast cancer is one of the most common malignant tumors with a high incidence and leading cancer-related death in women worldwide. MiR-205 plays a crucial role in breast cancer initiation and progression. Here, we identified the relationship between miR-205 and lymphoid specific helicase and confirmed the significance of the miR-205/lymphoid specific helicase (miR-205/HELLS) axis. MATERIALS AND METHODS: Data from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database were analyzed to investigate the expression level of miR-205 and HELLS in breast cancer. The TargetScan, Starbase and miRWalk databases were used to predict the candidate target genes of miR-205. Proliferation and migration abilities were examined using cell counting kit-8 assay, colony formation assays, transwell assay and wound-healing assay. Dual-luciferase reporter assay was utilized to confirm the binding of miR-205 and HELLS. Quantitative RT-PCR, western blot assays or immunohistochemistry were conducted to detect the expression level of genes in breast cancer cells or tissues. Mice xenograft models were constructed to explore the function of miR-205 and HELLS in vivo. KEY FINDINGS: Overexpressed miR-205 alleviated cancer cell proliferation and migration and influenced patients' prognosis by negatively regulating the HELLS gene. Consistently, animal experiments revealed that both overexpressing miR-205 and knocking down HELLS exhibited significant tumor growth inhibition in vivo. SIGNIFICANCE: Our study demonstrated that miR-205 targets HELLS to regulate tumor progression. MiR-205 and HELLS could be considered a novel diagnosis and therapeutic molecular marker of breast cancer.

Development of a prognostic signature based on immune-related genes and the correlation with immune microenvironment in breast cancer.

Breast cancer (BC) is an inflammatory tumor caused by a variety of pathological factors, and is still the most common malignant tumor in women. Immune-related genes (IRGs) play a prominent role in the oncogenesis and progression of BC, and are of tumor-specific expression patterns that would benefit the prognosis evaluation. However, there were no systematic studies concerning the possibilities of IRGs in BC prognosis. In this study, the Cancer Genome Atlas (TCGA) database was used to integrate the expression profiles of IRG with the overall survival (OS) rate of 1039 breast cancer patients. The Cox regression analysis was used to predict the survival-related IRGs in BC. Then, we successfully screened a total of 6 IRGs, including PSME2, ULBP2, IGHE, SCG2, SDC1, and SSTR1, and accordingly constructed a prognosis prediction model of BC. Based on the IRG-related model, the BC patients were divided into high- and low-risk groups, and the association between the prognostic model and tumor immune microenvironment (TME) was further explored. The prognostic model reflected the infiltration of various immune cells. Moreover, the low-risk group was found to be with higher immunophenoscore and distinct mutation signatures compared with the high-risk group. The histological validation showed that SDC1, as well as M2 macrophage biomarker CD206, were both of higher abundance in BC samples of high-risk patients, compared with those of low-risk patients. Our results identify the clinically significant IRGs and demonstrate the importance of the IRG-based immune prognostic model in BC monitoring, prognosis prediction, and therapy.

A wearable electrochemical sensor based on ß-CD functionalized graphene for pH and potassium ion analysis in sweat.

Here, we developed a wearable electrochemical sensor for pH and K+ monitoring in sweat. The sensor was composed of flexible reference electrode, pH response electrode and K+ selective electrode, which were prepared through printing ß-CD functionalized graphene (ß-CD/RGO) water suspension on conductive PET substrate with microelectronic printer. ß-CD/RGO not only served as the pH sensitive material for pH response electrode with good sensitivity, selectivity and reproducibility due to its abundant oxygen-containing functional groups, but also worked as the ion-to-electron transducer for K+ selective electrode with good sensitivity. The wearable sensor exhibited good potential stability at different bending states. On-body sweat pH and K+ measurements showed high accuracy compared with ex-situ analysis.

Deceleration of Cropland-N2O Emissions in China and Future Mitigation Potentials.

Agricultural soils are the largest anthropogenic emission source of nitrous oxide (N2O). National agricultural policies have been implemented to increase crop yield and reduce nitrogen (N) losses to the environment. However, it is difficult to effectively quantify crop-specific and regional N2O mitigation priorities driven by policies, due to lack of long-term, high-resolution crop-specific activity data, and oversimplified models. Here, we quantify the spatiotemporal changes and key drivers of crop-specific cropland-N2O emissions from China between 1980 and 2017, and future N2O mitigation potentials, using a linear mixed-effect model and survey-based data set of agricultural management measures. Cropland-N2O emissions from China tripled from 102.5 to 315.0 Gg N yr-1 between 1980 and 2017, and decelerated since 1998 mainly driven by country-wide deceleration and decrease in N rate and the changes in sowing structure. About 63% of N2O emissions could be reduced in 2050, primarily in the North China Plain and Northeast China Plain; 83% of which is from the production of maize (33%), vegetables (27%), and fruits (23%). The deceleration of N2O emissions highlights that policy interventions and agronomy practices (i.e., optimizing N rate and sowing structure) are potential pathways for further ambitious N2O mitigation in China and other developing countries.

MiR-205-5p/GGCT Attenuates Growth and Metastasis of Papillary Thyroid Cancer by Regulating CD44.

Papillary thyroid cancer (PTC) remains the most common endocrine malignancy, despite marked achieves in recent decades, and the mechanisms underlying the pathogenesis and progression for PTC are incompletely elucidated. Accumulating evidence show that γ-glutamylcyclotransferase (GGCT), an enzyme participating in glutathione homeostasis and is elevated in multiple types of tumors, represents an attractive therapeutic target. Using bioinformatics, immunohistochemistry, qRT-PCR, and Western blot assays, we found that GGCT expression was upregulated in PTC and correlated with more aggressive clinicopathological characteristics and worse prognosis. GGCT knockdown inhibited the growth and metastasis ability of PTC cells both in vitro and in vivo and reduced the expression of mesenchymal markers (N-cadherin, CD44, MMP2, and MMP9) while increasing epithelial marker (E-cadherin) in PTC cells. We confirmed binding of microRNA-205-5p (miR-205-5p) on the 3'-UTR regions of GGCT by dual-luciferase reporter assay and RNA-RNA pull-down assay. Delivery of miR-205-5p reversed the pro-malignant capacity of GGCT both in vitro and in vivo. Lastly, we found that GGCT interacted with and stabilized CD44 in PTC cells by co-immunoprecipitation and immunohistochemistry assays. Our findings illustrate a novel signaling pathway, miR-205-5p/GGCT/CD44, that involves in the carcinogenesis and progression of PTC. Development of miR-205-mimics or GGCT inhibitors as potential therapeutics for PTC may have remarkable applications.

CAR-T Cells Targeting TSHR Demonstrate Safety and Potent Preclinical Activity Against Differentiated Thyroid Cancer.

BACKGROUND: Chimeric antigen receptor T cells (CAR-Ts) have demonstrated remarkable efficacy in hematological cancers but have not yet translated in treating solid tumors. The significant hurdles limiting CAR-T therapy were from a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present TSH receptor (TSHR) as a putative target for CAR-T therapy of differentiated thyroid cancer (DTC). METHODS: We undertook a large-scale screen on thyroid cancer tissues and multiple internal organs through bioinformatical analysis and immunohistochemistry to date TSHR expression. Using 3 previously described monoclonal antibodies, we generated 3 third-generation CAR-Ts. We tested anti-TSHR CAR-T in vitro activity by T-cell function and killing assay. Then we tested preclinical therapeutical efficacy in a xenograft mouse model of DTC and analyzed mice's physical conditions and histological abnormalities to evaluate anti-TSHR CAR-T's safety. RESULTS: TSHR is highly and homogeneously expressed on 90.8% (138/152) of papillary thyroid cancer, 89.2% (33/37) of follicular thyroid cancer, 78.2% (18/23) of cervical lymph node metastases, and 86.7% of radioactive iodine resistance diseases. We developed 3 novel anti-TSHR CAR-Ts from monoclonal antibodies M22, K1-18, and K1-70; all 3 CAR-Ts mediate significant antitumor activity in vitro. Among these, we demonstrate that K1-70 CAR-T can have therapeutical efficacy in vivo, and no apparent toxicity has been observed. CONCLUSION: TSHR is a latent target antigen of CAR-T therapy for DTC. Anti-TSHR CAR-T could represent a therapeutic option for patients with locoregional relapsed or distant metastases of thyroid cancer and should be tested in carefully designed clinical trials.

Changes in precipitation and atmospheric N deposition affect the correlation between N, P and K but not the coupling of water-element in Haloxylon ammodendron.

Global changes in precipitation and atmospheric N deposition affect the geochemical cycle of the element and its hydrological cycle in the ecosystem. It may also affect the relationship between plant water use efficiency (WUE) and nutrients, as well as the relationship between plant nutrients. Desert ecosystems are vulnerable to global changes. Haloxylon ammodendron is the dominant species in the Asian desert. Revealing the variations in these relationships in H. ammodendron with precipitation and N deposition will enhance our understanding of the responses of plants to global change in terms of trade-off strategies of nutrient absorption, water and element geochemical cycles in desert ecosystems. Thus, we conducted field experiments with different amounts of water and N. This study showed that WUE of H. ammodendron was not correlated with nitrogen content (N), phosphorus content (P), and potassium content (K) when water and N supply were varied (p > 0.05 for WUE vs. N, P, and K), suggesting lack of coupling between water use and nutrient economics. This result was associated with the lack of correlation between plant nutrients and gas exchang in H. ammodendron. However, water addition, N addition and the interaction between both of them all played a role in the correlation between plant N, P and K owing to their different responses to water and N supplies. This indicates that global changes in precipitation and N deposition will affect N, P and K geochemical cycles in the Asian deserts dominated by H. ammodendron, and drive changes in the relationships between plant nutrients, resulting in changes in the trade-off strategy of plant absorption of N, P, and K.