Complete spatially resolved gene expression is not necessary for identifying spatial domains.

Spatially resolved transcriptomics (SRT) technologies have revolutionized the study of tissue organization. We introduce a graph convolutional network with an attention and positive emphasis mechanism, termed BINARY, relying exclusively on binarized SRT data to accurately delineate spatial domains. BINARY outperforms existing methods across various SRT data types while using significantly less input information. Our study suggests that precise gene expression quantification may not always be essential, inspiring further exploration of the broader applications of spatially resolved binarized gene expression data.

Typical and extreme weather datasets for studying the resilience of buildings to climate change and heatwaves.

We present unprecedented datasets of current and future projected weather files for building simulations in 15 major cities distributed across 10 climate zones worldwide. The datasets include ambient air temperature, relative humidity, atmospheric pressure, direct and diffuse solar irradiance, and wind speed at hourly resolution, which are essential climate elements needed to undertake building simulations. The datasets contain typical and extreme weather years in the EnergyPlus weather file (EPW) format and multiyear projections in comma-separated value (CSV) format for three periods: historical (2001-2020), future mid-term (2041-2060), and future long-term (2081-2100). The datasets were generated from projections of one regional climate model, which were bias-corrected using multiyear observational data for each city. The methodology used makes the datasets among the first to incorporate complex changes in the future climate for the frequency, duration, and magnitude of extreme temperatures. These datasets, created within the IEA EBC Annex 80 "Resilient Cooling for Buildings", are ready to be used for different types of building adaptation and resilience studies to climate change and heatwaves.

Podocyte SIRPα reduction aggravates lupus nephritis via promoting T cell inflammatory responses.

Signal-regulatory protein alpha (SIRPα) has recently been found to be highly expressed in podocytes and is essential for maintaining podocyte function. However, its immunoregulatory function in podocytes remains elusive. Here, we report that SIRPα controls podocyte antigen presentation in specific T cell activation via inhibiting spleen tyrosine kinase (Syk) phosphorylation. First, podocyte SIRPα under lupus nephritis (LN) conditions is strongly downregulated. Second, podocyte-specific deletion of SIRPα exacerbates renal disease progression in lupus-prone mice, as evidenced by an increase in T cell infiltration. Third, SIRPα deletion or knockdown enhances podocyte antigen presentation, which activates specific T cells, via enhancing Syk phosphorylation. Supporting this, Syk inhibitor GS-9973 prevents podocyte antigen presentation, resulting in a decrease of T cell activation and mitigation of renal disease caused by SIRPα knockdown or deletion. Our findings reveal an immunoregulatory role of SIRPα loss in promoting podocyte antigen presentation to activate specific T cell immune responses in LN.

Macrophage heterogeneity in bone metastasis.

Previous studies illustrated that macrophage, a type of innate immune cell, plays critical roles in tumour progression and metastasis. Bone is the most frequent site of metastasis for several cancer types including breast, prostate, and lung. In bone metastasis, osteoclast, a macrophage subset specialized in bone resorption, was heavily investigated in the past. Recent studies illustrated that other macrophage subsets, e.g. monocyte-derived macrophages, and bone resident macrophages, promoted bone metastasis independent of osteoclast function. These novel mechanisms further improved our understanding of macrophage heterogeneity in the context of bone metastasis and illustrated new opportunities for future studies.

[Adsorption Performance and Mechanism of Oxytetracycline in Water by KOH Modified Biochar Derived from Corn Straw].

The pollution control of tetracycline antibiotics in the environment has become a hot topic, and biochar adsorption has become an important technology to remove organic pollutants. Pyrolytic biochars (BC400, BC500, and BC600) were prepared from corn straw and then were modified by KOH to obtain KBC400, KBC500, and KBC600. Among them, KBC400 was selected for secondary pyrolysis activation at 400-600℃ to obtain AKBC400, AKBC500, and AKBC600. The structure characteristics and surface properties of AKBC were also characterized. The adsorption kinetics and thermodynamic characteristics of oxytetracycline hydrochloride (OTC) in the solution by AKBC were investigated using batch experiments. Compared to that of BC400, the specific surface area and pore structure of AKBC were significantly improved, and the aromaticity was also enhanced, resulting in the notable enhancement of the adsorption capacities for OTC. The pseudo-second-order kinetics model could better fit the adsorption process, and AKBC500 had the largest adsorption rate constant and capacity. Both the intraparticle diffusion and film diffusion were the rate-limiting steps. The Langmuir, Freundlich, and Temkin models could fit the adsorption isotherms perfectly. The adsorption of OTC on AKBC was a spontaneous, endothermic, and entropy-increasing process by both physisorption and chemisorption. The pH values in the range of 3.0-7.0 were favorable for the adsorption of OTC by AKBC. The adsorption capacity decreased with the humic acid concentration over 10 mg·L-1. The adsorption mechanism of OTC by AKBC involved pore filling, hydrogen bonding, π-π conjugation, cation-π bond, and strong electrostatic effect. AKBC still had good reusability for OTC removal after five times of regeneration. The obtained AKBC is a potential adsorbent for OTC removal from water due to the good pore structure, high adsorption capacity, and stable adsorption effect.

Influence of different baking temperatures of red kojic rice on the physicochemical properties, antioxidant capacity, and functional components of red starter wine.

BACKGROUND: To improve the quality of red starter wine, this study explored the effects of baking red kojic rice at varying temperatures on the physicochemical characteristics of red starter wine. Baking was predicated on understanding crucial enzyme activities and starch granule structure of red kojic rice at 75, 95, and 105 °C, leading to the production of three red starter wine variants (BHQW1, BHQW2, and BHQW3). RESULTS: The results revealed an increased alcohol (increase 0.50%), total sugar (increase 0.14 g L-1 ), and total acid (increase 0.54 g L-1 ) content in red starter wine fermented using baked red kojic rice compared with the control group (wine fermented with unbaked rice, HQW). Furthermore, both the 105 °C baked red kojic rice and its resulting BHQW3 demonstrated significantly higher red color values than HQW (increase 2.03 U g-1 and 0.15 U mL-1 respectively). The highest lovastatin content was presented in red kojic rice baked at 105 °C and its corresponding fermented wine (1420.63 ± 507.9 µg g-1 and 3368.87 ± 228.16 µg L-1 respectively). Additionally, BHQW groups displayed higher total flavonoids and phenols content than HQW. Regarding antioxidant capacity, all BHQW groups showed stronger overall antioxidant capacity than HQW. The determination of volatile components revealed the highest content of volatile compounds in BHQW2 (2621.19 ± 548.24 µg L-1 ) and significantly higher volatile esters in BHQW1 (254.46 ± 16.63 µg L-1 ). Moreover, 16 volatile compounds were identified only in BHQW groups, including isoamyl caprylate, 2-ethylhexyl alcohol, and benzaldehyde. CONCLUSION: Our findings suggested that the baking technique of red kojic rice could enhance the quality of red starter wine through enhancing antioxidant properties, increasing functional components, and enriching volatile flavor compounds, thus providing a foundation for new techniques in red starter wine production. © 2023 Society of Chemical Industry.

Comparison on the Effect and Complications of VATS and Radical Thoracotomy for Lung Cancer in the Treatment of Stages IIB-IIIA Non-Small Cell Lung Cancer.

Objective: Lung adenocarcinoma (NSCLC) is a common subtype of lung cancer, and its prevalence has gradually increased in recent years. There are various treatment methods for NSCLC, and surgical resection, as one of the important treatments, is crucial to improving the survival rate and quality of life of patients. To explore the effect and complications of video-assisted thoracic surgery (VATS) and radical thoracotomy for lung cancer (RTLC) in the treatment of stages IIB-IIIA non-small cell lung cancer (NSCLC). Methods: A total of 80 patients with NSCLC admitted to the hospital were enrolled between June 2019 and January 2021. According to the random number table method, they were divided into the VATS group (40 cases, VATS) and RTLC group (40 cases, RTLC). The operation time, intraoperative blood loss, postoperative drainage time, number of lymph node dissections, score of visual analogue scale (VAS) at 24 h after surgery, and hospitalization time were compared between the two groups. We chose specific inclusion criteria, including patients diagnosed with non-small cell lung cancer (NSCLC) who did not receive radiation therapy or chemotherapy before surgery, to ensure consistency and comparability across studies. We focused on indicators related to lung function and immune system, such as CD3+, CD4+ and CD8+ levels, as well as FEV1, FVC and MVV, to evaluate the impact of surgery on lung function and immune status. The levels of CD3+, CD4+, and CD8+ in both groups were detected by flow cytometry at 1 d before surgery and 3 d after surgery. The forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and maximal voluntary ventilation (MVV) in both groups were detected by spirometry before and at 1 month after surgery. The occurrence of postoperative complications in both groups was recorded. After 12 months of follow-up, survival rates in both groups were statistically analyzed. The progression-free survival (PFS) and 12-month overall survival (OS) in both groups were analyzed by the Kaplan-Meier method. Results: The incision length, operation time, intraoperative blood loss, postoperative drainage time, VAS score at 24 h after surgery, and hospitalization time in VATS group were significantly lower than those in RTLC group (P < .05). The two groups had no significant difference in the number of lymph node dissections (P > .05). At 3 d after surgery, levels of CD3+, CD4+ and CD8+ in VATS group were significantly higher than those in RTLC group (P < .05). At 1 month after surgery, FEV1, FVC, and MVV in VATS group operation were significantly higher than those in RTLC group (P < .05). The incidence of postoperative complications in VATS group was lower than that in RTLC group (5.00% vs. 20.00%) (P < .05). Kaplan-Meier survival analysis showed that there was no significant difference in 12-month OS or PFS between the two groups (P > .05). Conclusions: The long-term curative effect of VATS and RTLC is comparable on patients with stages IIB-IIIA NSCLC. The former has advantages such as less surgical injury, faster postoperative recovery, and higher safety, which can reduce the incidence of postoperative complications. This study provides clinicians with important information about the treatment of stage IIb ~ IIIa NSCLC and helps them choose surgical methods more wisely. These results also alert physicians to focus on operative time, blood loss, and complication risk to maximize patient outcomes.

Radiologic Identification of Pathologic Tumor Invasion in Patients With Lung Adenocarcinoma.

Importance: It is currently unclear whether high-resolution computed tomography can preoperatively identify pathologic tumor invasion for ground-glass opacity lung adenocarcinoma. Objectives: To evaluate the diagnostic value of high-resolution computed tomography for identifying pathologic tumor invasion for ground-glass opacity featured lung tumors. Design, Setting, and Participants: This prospective, multicenter diagnostic study enrolled patients with suspicious malignant ground-glass opacity nodules less than or equal to 30 mm from November 2019 to July 2021. Thoracic high-resolution computed tomography was performed, and pathologic tumor invasion (invasive adenocarcinoma vs adenocarcinoma in situ or minimally invasive adenocarcinoma) was estimated before surgery. Pathologic nonadenocarcinoma, benign diseases, or those without surgery were excluded from analyses; 673 patients were recruited, and 620 patients were included in the analysis. Statistical analysis was performed from October 2021 to January 2022. Exposure: Patients were grouped according to pathologic tumor invasion. Main Outcomes and Measures: Primary end point was diagnostic yield for pathologic tumor invasion. Secondary end point was diagnostic value of radiologic parameters. Results: Among 620 patients (442 [71.3%] female; mean [SD] age, 53.5 [12.0] years) with 622 nodules, 287 (46.1%) pure ground-glass opacity nodules and 335 (53.9%) part-solid nodules were analyzed. The median (range) size of nodules was 12.1 (3.8-30.0) mm; 47 adenocarcinomas in situ, 342 minimally invasive adenocarcinomas, and 233 invasive adenocarcinomas were confirmed. Overall, diagnostic accuracy was 83.0% (516 of 622; 95% CI, 79.8%-85.8%), diagnostic sensitivity was 82.4% (192 of 233; 95% CI, 76.9%-87.1%), and diagnostic specificity was 83.3% (324 of 389; 95% CI, 79.2%-86.9%). For tumors less than or equal to 10 mm, 3.6% (8 of 224) were diagnosed as invasive adenocarcinomas. The diagnostic accuracy was 96.0% (215 of 224; 95% CI, 92.5%-98.1%), diagnostic specificity was 97.2% (210 of 216; 95% CI, 94.1%-99.0%); for tumors greater than 20 mm, 6.9% (6 of 87) were diagnosed as adenocarcinomas in situ or minimally invasive adenocarcinomas. The diagnostic accuracy was 93.1% (81 of 87; 95% CI, 85.6%-97.4%) and diagnostic sensitivity was 97.5% (79 of 81; 95% CI, 91.4%-99.7%). For tumors between 10 to 20 mm, the diagnostic accuracy was 70.7% (220 of 311; 95% CI, 65.3%-75.7%), diagnostic sensitivity was 75.0% (108 of 144; 95% CI, 67.1%-81.8%), and diagnostic specificity was 67.1% (112 of 167; 95% CI, 59.4%-74.1%). Tumor size (odds ratio, 1.28; 95% CI, 1.18-1.39) and solid component size (odds ratio, 1.31; 95% CI, 1.22-1.42) could each independently serve as identifiers of pathologic invasive adenocarcinoma. When the cutoff value of solid component size was 6 mm, the diagnostic sensitivity was 84.6% (95% CI, 78.8%-89.4%) and specificity was 82.9% (95% CI, 75.6%-88.7%). Conclusions and relevance: In this diagnostic study, radiologic analysis showed good performance in identifying pathologic tumor invasion for ground-glass opacity-featured lung adenocarcinoma, especially for tumors less than or equal to 10 mm and greater than 20 mm; these results suggest that a solid component size of 6 mm could be clinically applied to distinguish pathologic tumor invasion.

Strong metal oxide-support interaction in MoO2/N-doped MCNTs heterostructure for boosting lithium storage performance.

The low-rate capability and fast capacity decaying of the molybdenum dioxide anode material have been a bottleneck for lithium-ion batteries (LIBs) due to low carrier transport, drastic volume expansion and inferior reversibility. Furthermore, the lithium-storage mechanism is still controversial at present. Herein, we fabricate a new kind of MoO2 nanoparticles with nitrogen-doped multiwalled carbon nanotubes (MoO2/N-MCNTs) as anode for LIBs. The strong chemical bonding (MoOC) endows MoO2/N-MCNTs a strong metal oxide-support interaction (SMSI), rendering electron/ion transfer and facilitate significant Li+ intercalation pseudocapacitance, which is evidenced by both theoretical computation and detailed experiments. Thus, the MoO2/N-MCNTs exhibits high-rate performance (523.7 mAh/g at 3000 mA g-1) and long durability (507.8 mAh/g at 1000 mA g-1 after 500 cycles). Furthermore, pouch-type full cell composed of MoO2/N-MCNTs anodes and commercial LiNi0.6Co0.2Mn0.2O2 (NCM622) cathodes demonstrate impressive rate performance and cyclic life, which displays an unparalleled energy density of 553.0 Wh kg-1. Ex-situ X-ray absorption spectroscopy (XAS) indicates the enhanced lithium-storage mechanism is originated from a partially irreversible phase transition from Li0.98MoO2 to Li2MoO4 via delithiation. This work not only provides fresh insights into the enhanced lithium-storage mechanism but also proposes new design principles toward efficient LIBs.

AR activates YAP/TAZ differentially in prostate cancer.

The Hippo signalling pathway is a master regulator of cell growth, proliferation, and cancer. The transcriptional coregulators of the Hippo pathway, YAP and TAZ, are central in various cancers. However, how YAP and TAZ get activated in most types of cancers is not well understood. Here, we show that androgens activate YAP/TAZ via the androgen receptor (AR) in prostate cancer (PCa), and that this activation is differential. AR regulates YAP translation while inducing transcription of the TAZ encoding gene, WWTR1 Furthermore, we show that AR-mediated YAP/TAZ activation is regulated by the RhoA GTPases transcriptional mediator, serum response factor (SRF). Importantly, in prostate cancer patients, SRF expression positively correlates with TAZ and the YAP/TAZ target genes CYR61 and CTGF We demonstrate that YAP/TAZ are not essential for sustaining AR activity, however, targeting YAP/TAZ or SRF sensitize PCa cells to AR inhibition in anchorage-independent growth conditions. Our findings dissect the cellular roles of YAP, TAZ, and SRF in prostate cancer cells. Our data emphasize the interplay between these transcriptional regulators and their roles in prostate tumorigenesis and highlight how these insights might be exploited therapeutically.

Fluorescence-amplified nanocrystals in the second near-infrared window for in vivo real-time dynamic multiplexed imaging.

Optical imaging in the second near-infrared window (NIR-II, 1,000-1,700 nm) holds great promise for non-invasive in vivo detection. However, real-time dynamic multiplexed imaging remains challenging due to the lack of available fluorescence probes and multiplexing techniques in the ideal NIR-IIb (1,500-1,700 nm) 'deep-tissue-transparent' sub-window. Here we report on thulium-based cubic-phase downshifting nanoparticles (α-TmNPs) with 1,632 nm fluorescence amplification. This strategy was also validated for the fluorescence enhancement of nanoparticles doped with NIR-II Er3+ (α-ErNPs) or Ho3+ (α-HoNPs). In parallel, we developed a simultaneous dual-channel imaging system with high spatiotemporal synchronization and accuracy. The NIR-IIb α-TmNPs and α-ErNPs facilitated the non-invasive real-time dynamic multiplexed imaging of cerebrovascular vasomotion activity and the single-cell-level neutrophil behaviour in mouse subcutaneous tissue and ischaemic stroke model.

Design, synthesis, and biological activity of dual monoamine oxidase A and heat shock protein 90 inhibitors, N-Methylpropargylamine-conjugated 4-isopropylresorcinol for glioblastoma.

Monoamine oxidase A (MAO A) and heat shock protein 90 (HSP90) inhibitors have been shown to decrease the progression of glioblastoma (GBM) and other cancers. In this study, a series of MAO A/HSP90 dual inhibitors were designed and synthesized in the hope to develop more effective treatment of GBM. Compounds 4-b and 4-c are conjugates of isopropylresorcinol (pharmacophore of HSP90 inhibitor) with the phenyl group of clorgyline (MAO A inhibitor) by a tertiary amide bond substituted with methyl (4-b) or ethyl (4-c) group, respectively. They inhibited MAO A activity, HSP90 binding, and the growth of both TMZ-sensitive and -resistant GBM cells. Western blots showed that they increased HSP70 expression indicating reduced function of HSP90, reduced HER2 and phospho-Akt expression similar to MAO A or HSP90 inhibitor itself. Both compounds decreased IFN-γ induced PD-L1 expression in GL26 cells, suggesting they can act as immune checkpoint inhibitor. Further, they reduced tumor growth in GL26 mouse model. NCI-60 analysis showed they also inhibited the growth of colon cancer, leukemia, non-small cell lung and other cancers. Taken together, this study demonstrates MAO A/HSP90 dual inhibitors 4-b and 4-c reduced the growth of GBM and other cancers, and they have potential to inhibit tumor immune escape.

Lentinan confers protection against type 1 diabetes by inducing regulatory T cell in spontaneous non-obese diabetic mice.

BACKGROUND: Lentinan (LNT) is a complex fungal component that possesses effective antitumor and immunostimulating properties. However, there is a paucity of studies regarding the effects and mechanisms of LNT on type 1 diabetes. OBJECTIVE: In the current study, we investigated whether an intraperitoneal injection of LNT can diminish the risk of developing type 1 diabetes (T1D) in non-obese diabetic (NOD) mice and further examined possible mechanisms of LNT's effects. METHODS: Pre-diabetic female NOD mice 8 weeks of age, NOD mice with 140-160 mg/dL, 200-230 mg/dL or 350-450 mg/dL blood glucose levels were randomly divided into two groups and intraperitoneally injected with 5 mg/kg LNT or PBS every other day. Then, blood sugar levels, pancreas slices, spleen, PnLN and pancreas cells from treatment mice were examined. RESULTS: Our results demonstrated that low-dosage injections (5 mg/kg) of LNT significantly suppressed immunopathology in mice with autoimmune diabetes but increased the Foxp3+ regulatory T cells (Treg cells) proportion in mice. LNT treatment induced the production of Tregs in the spleen and PnLN cells of NOD mice in vitro. Furthermore, the adoptive transfer of Treg cells extracted from LNT-treated NOD mice confirmed that LNT induced Treg function in vivo and revealed an enhanced suppressive capacity as compared to the Tregs isolated from the control group. CONCLUSION: LNT was capable of stimulating the production of Treg cells from naive CD4 + T cells, which implies that LNT exhibits therapeutic values as a tolerogenic adjuvant and may be used to reverse hyperglycaemia in the early and late stages of T1D.

MoErv14 mediates the intracellular transport of cell membrane receptors to govern the appressorial formation and pathogenicity of Magnaporthe oryzae.

Magnaporthe oryzae causes rice blasts posing serious threats to food security worldwide. During infection, M. oryzae utilizes several transmembrane receptor proteins that sense cell surface cues to induce highly specialized infectious structures called appressoria. However, little is known about the mechanisms of intracellular receptor tracking and their function. Here, we described that disrupting the coat protein complex II (COPII) cargo protein MoErv14 severely affects appressorium formation and pathogenicity as the ΔMoerv14 mutant is defective not only in cAMP production but also in the phosphorylation of the mitogen-activated protein kinase (MAPK) MoPmk1. Studies also showed that either externally supplementing cAMP or maintaining MoPmk1 phosphorylation suppresses the observed defects in the ΔMoerv14 strain. Importantly, MoErv14 is found to regulate the transport of MoPth11, a membrane receptor functioning upstream of G-protein/cAMP signaling, and MoWish and MoSho1 function upstream of the Pmk1-MAPK pathway. In summary, our studies elucidate the mechanism by which the COPII protein MoErv14 plays an important function in regulating the transport of receptors involved in the appressorium formation and virulence of the blast fungus.

Nomogram for predicting 90-day mortality in patients with Acinetobacter baumannii-caused hospital-acquired and ventilator-associated pneumonia in the respiratory intensive care unit.

OBJECTIVE: We built a prediction model of mortality risk in patients the with Acinetobacter baumannii (AB)-caused hospital-acquired (HAP) and ventilator-associated pneumonia (VAP). METHODS: In this retrospective study, 164 patients with AB lower respiratory tract infection were admitted to the respiratory intensive care unit (RICU) from January 2019 to August 2021 (29 with HAP, 135 with VAP) and grouped randomly into a training cohort (n = 115) and a validation cohort (n = 49). Least absolute shrinkage and selection operator regression and multivariate Cox regression were used to identify risk factors of 90-day mortality. We built a nomogram prediction model and evaluated model discrimination and calibration using the area under the receiver operating characteristic curve (AUC) and calibration curves, respectively. RESULTS: Four predictors (days in intensive care unit, infection with carbapenem-resistant AB, days of carbapenem use within 90 days of isolating AB, and septic shock) were used to build the nomogram. The AUC of the two groups was 0.922 and 0.823, respectively. The predictive model was well-calibrated; decision curve analysis showed the proposed nomogram would obtain a net benefit with threshold probability between 1% and 100%. CONCLUSIONS: The nomogram model showed good performance, making it useful in managing patients with AB-caused HAP and VAP.

Online-Dynamic-Clustering-Based Soft Sensor for Industrial Semi-Supervised Data Streams.

In the era of big data, industrial process data are often generated rapidly in the form of streams. Thus, how to process such sequential and high-speed stream data in real time and provide critical quality variable predictions has become a critical issue for facilitating efficient process control and monitoring in the process industry. Traditionally, soft sensor models are usually built through offline batch learning, which remain unchanged during the online implementation phase. Once the process state changes, soft sensors built from historical data cannot provide accurate predictions. In practice, industrial process data streams often exhibit characteristics such as nonlinearity, time-varying behavior, and label scarcity, which pose great challenges for building high-performance soft sensor models. To address this issue, an online-dynamic-clustering-based soft sensor (ODCSS) is proposed for industrial semi-supervised data streams. The method achieves automatic generation and update of clusters and samples deletion through online dynamic clustering, thus enabling online dynamic identification of process states. Meanwhile, selective ensemble learning and just-in-time learning (JITL) are employed through an adaptive switching prediction strategy, which enables dealing with gradual and abrupt changes in process characteristics and thus alleviates model performance degradation caused by concept drift. In addition, semi-supervised learning is introduced to exploit the information of unlabeled samples and obtain high-confidence pseudo-labeled samples to expand the labeled training set. The proposed method can effectively deal with nonlinearity, time-variability, and label scarcity issues in the process data stream environment and thus enable reliable target variable predictions. The application results from two case studies show that the proposed ODCSS soft sensor approach is superior to conventional soft sensors in a semi-supervised data stream environment.

Macrophages promote anti-androgen resistance in prostate cancer bone disease.

Metastatic castration-resistant prostate cancer (PC) is the final stage of PC that acquires resistance to androgen deprivation therapies (ADT). Despite progresses in understanding of disease mechanisms, the specific contribution of the metastatic microenvironment to ADT resistance remains largely unknown. The current study identified that the macrophage is the major microenvironmental component of bone-metastatic PC in patients. Using a novel in vivo model, we demonstrated that macrophages were critical for enzalutamide resistance through induction of a wound-healing-like response of ECM-receptor gene expression. Mechanistically, macrophages drove resistance through cytokine activin A that induced fibronectin (FN1)-integrin alpha 5 (ITGA5)-tyrosine kinase Src (SRC) signaling cascade in PC cells. This novel mechanism was strongly supported by bioinformatics analysis of patient transcriptomics datasets. Furthermore, macrophage depletion or SRC inhibition using a novel specific inhibitor significantly inhibited resistant growth. Together, our findings elucidated a novel mechanism of macrophage-induced anti-androgen resistance of metastatic PC and a promising therapeutic approach to treat this deadly disease.

Selective Mediastinal Lymph Node Dissection Strategy for Clinical T1N0 Invasive Lung Cancer: A Prospective, Multicenter, Clinical Trial.

INTRODUCTION: We aimed to prospectively evaluate our previously proposed selective mediastinal lymph node (LN) dissection strategy for peripheral clinical T1N0 invasive NSCLC. METHODS: This is a multicenter, prospective clinical trial in China. We set six criteria for predicting negative LN stations and finally guiding selective LN dissection. Consolidation tumor ratio less than or equal to 0.5, segment location, lepidic-predominant adenocarcinoma (LPA), negative hilar nodes (stations 10-12), and negative visceral pleural invasion (VPI) were used separately or in combination as predictors of negative LN status in the whole, superior, or inferior mediastinal zone. LPA, hilar node involvement, and VPI were diagnosed intraoperatively. All patients actually underwent systematic mediastinal LN dissection. The primary end point was the accuracy of the strategy in predicting LN involvement. If LN metastasis occurred in certain mediastinal zone that was predicted to be negative, it was considered as an "inaccurate" case. RESULTS: A total of 720 patients were enrolled. The median number of LN dissected was 15 (interquartile range: 11-20). All negative node status in certain mediastinal zone was correctly predicted by the strategy. Compared with final pathologic findings, the accuracy of frozen section to diagnose LPA, VPI, and hilar node metastasis was 94.0%, 98.9%, and 99.6%, respectively. Inaccurate intraoperative diagnosis of LPA, VPI, or hilar node metastasis did not lead to inaccurate prediction of node-negative status. CONCLUSIONS: This is the first prospective trial validating the specific mediastinal LN metastasis pattern in cT1N0 invasive NSCLC, which provides important evidence for clinical applications of selective LN dissection strategy.

Microglial P2Y12 Signaling Contributes to Cisplatin-induced Pain Hypersensitivity via IL-18-mediated Central Sensitization in the Spinal Cord.

Administration of cisplatin and other chemotherapy drugs is crucial for treating tumors. However, cisplatin-induced pain hypersensitivity is still a critical clinical issue, and the underlying molecular mechanisms have remained unresolved to date. In this study, we found that repeated cisplatin treatments remarkedly upregulated the P2Y12 expression in the spinal cord. Expression of P2Y12 was predominant in the microglia. Pharmacological inhibition of P2Y12 expression markedly attenuated the cisplatin-induced pain hypersensitivity. Meanwhile, blocking the P2Y12 signal also suppressed cisplatin-induced microglia hyperactivity. Furthermore, the microglia Src family kinase/p38 pathway is required for P2Y12-mediated cisplatin-induced pain hypersensitivity via the proinflammatory cytokine IL-18 production in the spinal cord. Blocking the P2Y12/IL-18 signaling pathway reversed cisplatin-induced pain hypersensitivity, as well as activation of N-methyl-D-aspartate receptor and subsequent Ca2+-dependent signals. Collectively, our data suggest that microglia P2Y12-SFK-p38 signaling contributes to cisplatin-induced pain hypersensitivity via IL-18-mediated central sensitization in the spinal, and P2Y12 could be a potential target for intervention to prevent chemotherapy-induced pain hypersensitivity. PERSPECTIVE: Our work identified that P2Y12/IL-18 played a critical role in cisplatin-induced pain hypersensitivity. This work suggests that P2Y12/IL-18 signaling may be a useful strategy for the treatment of chemotherapy-induced pain hypersensitivity.