Relations between near-field enhancements and Purcell factors in hybrid nanostructures of plasmonic antennas and dielectric cavities.

Strong near-field enhancements (NFEs) of nanophotonic structures are believed to be closely related to high Purcell factors (FP). Here, we theoretically show that the correlation is partially correct; the extinction cross section (σ) response is also critical in determining FP. The divergence between NFE and FP is especially pronounced in plasmonic-dielectric hybrid systems, where the plasmonic antenna supports dipolar plasmon modes and the dielectric cavity hosts Mie-like resonances. The cavity's enhanced-field environment can boost the antenna's NFEs, but the FP is not increased concurrently due to the larger effective σ that is intrinsic to the FP calculations. Interestingly, the peak FP for the coupled system can be predicted by using the NFE and σ responses. Furthermore, the limits for FP of coupled systems are considered; they are determined by the sum of the FP of a redshifted (or modified, if applicable) antenna and an individual cavity. This contrasts starkly with the behavior of NFE which is closely associated with the multiplicative effects of the NFEs provided by the antenna and the dielectric cavity. The differing behaviors of NFE and FP in hybrid cavities have varied impacts on relevant nanophotonic applications such as fluorescence, Raman scattering and enhanced light-matter interactions.

Tumor-repopulating cells evade ferroptosis via PCK2-dependent phospholipid remodeling.

Whether stem-cell-like cancer cells avert ferroptosis to mediate therapy resistance remains unclear. In this study, using a soft fibrin gel culture system, we found that tumor-repopulating cells (TRCs) with stem-cell-like cancer cell characteristics resist chemotherapy and radiotherapy by decreasing ferroptosis sensitivity. Mechanistically, through quantitative mass spectrometry and lipidomic analysis, we determined that mitochondria metabolic kinase PCK2 phosphorylates and activates ACSL4 to drive ferroptosis-associated phospholipid remodeling. TRCs downregulate the PCK2 expression to confer themselves on a structural ferroptosis-resistant state. Notably, in addition to confirming the role of PCK2-pACSL4(T679) in multiple preclinical models, we discovered that higher PCK2 and pACSL4(T679) levels are correlated with better response to chemotherapy and radiotherapy as well as lower distant metastasis in nasopharyngeal carcinoma cohorts.

NGCN: Drug-target interaction prediction by integrating information and feature learning from heterogeneous network.

Drug-target interaction (DTI) prediction is essential for new drug design and development. Constructing heterogeneous network based on diverse information about drugs, proteins and diseases provides new opportunities for DTI prediction. However, the inherent complexity, high dimensionality and noise of such a network prevent us from taking full advantage of these network characteristics. This article proposes a novel method, NGCN, to predict drug-target interactions from an integrated heterogeneous network, from which to extract relevant biological properties and association information while maintaining the topology information. It focuses on learning the topology representation of drugs and targets to improve the performance of DTI prediction. Unlike traditional methods, it focuses on learning the low-dimensional topology representation of drugs and targets via graph-based convolutional neural network. NGCN achieves substantial performance improvements over other state-of-the-art methods, such as a nearly 1.0% increase in AUPR value. Moreover, we verify the robustness of NGCN through benchmark tests, and the experimental results demonstrate it is an extensible framework capable of combining heterogeneous information for DTI prediction.

Evaluation of a novel model incorporating serological indicators into the conventional TNM staging system for nasopharyngeal carcinoma.

BACKGROUND: Non-anatomical factors significantly affect treatment guidance and prognostic prediction in nasopharyngeal carcinoma (NPC) patients. Here, we developed a novel survival model by combining conventional TNM staging and serological indicators. METHODS: We retrospectively enrolled 10,914 eligible patients with nonmetastatic NPC over 2009-2017 and randomly divided them into training (n = 7672) and validation (n = 3242) cohorts. The new staging system was constructed based on T category, N category, and pretreatment serological markers by using recursive partitioning analysis (RPA). RESULTS: In multivariate Cox analysis, pretreatment cell-free Epstein-Barr virus (cfEBV) DNA levels of >2000 copies/mL [HROS (95 % CI) = 1.78 (1.57-2.02)], elevated lactate dehydrogenase (LDH) levels [HROS (95 % CI) = 1.64 (1.41-1.92)], and C-reactive protein-to-albumin ratio (CAR) of >0.04 [HROS (95 % CI) = 1.20 (1.07-1.34)] were associated with negative prognosis (all P < 0.05). Through RPA, we stratified patients into four risk groups: RPA I (n = 3209), RPA II (n = 2063), RPA III (n = 1263), and RPA IV (n = 1137), with 5-year overall survival (OS) rates of 93.2 %, 86.0 %, 80.6 %, and 71.9 % (all P < 0.001), respectively. Compared with the TNM staging system (eighth edition), RPA risk grouping demonstrated higher prognostic prediction efficacy in the training [area under the curve (AUC) = 0.661 vs. 0.631, P < 0.001] and validation (AUC = 0.687 vs. 0.654, P = 0.001) cohorts. Furthermore, our model could distinguish sensitive patients suitable for induction chemotherapy well. CONCLUSION: Our novel RPA staging model outperformed the current TNM staging system in prognostic prediction and clinical decision-making. We recommend incorporating cfEBV DNA, LDH, and CAR into the TNM staging system.

HK2 promotes migration and invasion of intrahepatic cholangiocarcinoma via enhancing cancer stem-like cells' resistance to anoikis.

Cancer stem-like cells (CSLCs) and anoikis resistance play crucial roles in the metastasis of cancers. However, it remains unclear whether CSLCs are related to anoikis resistance in intrahepatic cholangiocarcinoma (ICC). Here we identified a group of stemness-related anoikis genes (SRAGs) via bioinformatic analysis of public data. Accordingly, a novel anoikis-related classification was established and it divided ICC into C1 and C2 type. Different type ICC displayed distinct prognosis, molecular as well immune characteristics. Furthermore, we found one key SRAGs via several machine learning algorithms. HK2 was up-regulated in tumor-repopulating cells (TRCs) of ICC, a kind of CSLCs with a potent resistance to anoikis. Its up-regulation may be caused by the activation of MTORC1 signaling in ICC-TRCs. And inhibition of HK2 significantly increased anoikis and decreased migration as well invasion in ICC-TRCs. Our studies provide an insight into the molecular mechanism underlying the resistance of ICC-TRCs to anoikis and enhance the evidences for targeting HK2 in ICC.

Refining the 8th edition TNM classification for EBV related nasopharyngeal carcinoma.

The AJCC/UICC TNM classification describes anatomic extent of tumor progression and guides treatment decisions. Our comprehensive analysis of 8,834 newly diagnosed patients with non-metastatic Epstein-Barr virus related nasopharyngeal carcinoma (NPC) from six Chinese centers indicates certain limitations in the current staging system. The 8th edition of the AJCC/UICC TNM classification inadequately differentiates patient outcomes, particularly between T2 and T3 categories and within the N classification. We propose reclassifying cases of T3 NPC with early skull-base invasion as T2, and elevating N1-N2 cases with grade 3 image-identified extranodal extension (ENE) to N3. Additionally, we suggest combining T2N0 with T1N0 into a single stage IA. For de novo metastatic (M1) NPC, we propose subdivisions of M1a, defined by 1-3 metastatic lesions without liver involvement, and M1b, characterized by >3 metastatic lesions or liver involvement. This proposal better reflects responses of NPC patients to the up-to-date treatments and their evolving risk profiles.

TRPM8 inhibits substance P release from primary sensory neurons via PKA/GSK-3beta to protect colonic epithelium in colitis.

Transient receptor potential melastatin 8 (TRPM8) is a cold sensory receptor in primary sensory neurons that regulates various neuronal functions. Substance P (SP) is a pro-inflammatory neuropeptide secreted by the neurons, and it aggravates colitis. However, the regulatory role of TRPM8 in SP release is still unclear. Our study aimed to investigate TRPM8's role in SP release from primary sensory neurons during colitis and clarify the effect of SP on colonic epithelium. We analyzed inflammatory bowel disease patients' data from the Gene Expression Omnibus dataset. Dextran sulfate sodium (DSS, 2.5%)-induced colitis in mice, mouse dorsal root ganglion (DRG) neurons, ND7/23 cell line, and mouse or human colonic organoids were used for this experiment. Our study found that TRPM8, TAC1 and WNT3A expression were significantly correlated with the severity of ulcerative colitis in patients and DSS-induced colitis in mice. The TRPM8 agonist (menthol) and the SP receptor antagonist (Aprepitant) can attenuate colitis in mice, but the effects were not additive. Menthol promoted calcium ion influx in mouse DRG neurons and inhibited the combination and phosphorylation of PKAca from the cAMP signaling pathway and GSK-3ß from the Wnt/ß-catenin signaling pathway, thereby inhibiting the effect of Wnt3a-driven ß-catenin on promoting SP release in ND7/23 cells. Long-term stimulation with SP inhibited proliferation and enhanced apoptosis in both mouse and human colonic organoids. Conclusively, TRPM8 inhibits SP release from primary sensory neurons by inhibiting the interaction between PKAca and GSK-3ß, thereby inhibiting the role of SP in promoting colonic epithelial apoptosis and relieving colitis.

HELLS modulates the stemness of intrahepatic cholangiocarcinoma through promoting senescence-associated secretory phenotype.

The senescence-associated secretory phenotype (SASP) is closely associated with the tumorigenesis and progression of intrahepatic cholangiocarcinoma (ICC). However, it remains unclear its relation to stemness of ICC. In the study, the stemness indices of ICC were calculated using one-class linear regression (OCLR) and single-sample gene set enrichment analysis (ssGSEA) algorithms. A total of 14 senescence-related stemness genes (SRSGs) were identified using Pearson correlation analysis in ICC. Subsequently, a SRSGs-related classification was established using a consensus clustering for ICC. Different types of ICC exhibit distinct prognosis, immunity, metabolisms, and oncogenic signatures. Additionally, we constructed a risk score model for ICC using principal component analysis (PCA). The risk score was positively correlated with stemness, immune infiltration, metabolisms and oncogenic signatures, but negatively with prognosis in ICC. Patients with a high risk score may respond well to immunotherapy. Furthermore, we employed 3D fibrin gels to select tumor-repopulating cells (TRC) with stemness features. We found that HELLS, belonging to the 14 SRSGs, was up-regulated in ICC-TRC. And silencing HELLS significantly reduced the colony size, inhibited migration and invasion, and attenuated SASP in ICC-TRC. In summary, we provided a novel classification and risk score for ICC and uncovered a molecular mechanism via which CSLCs could obtain an active SASP.

HMGB1/RAGE Signaling Regulates Th17/IL-17 and Its Role in Bronchial Epithelial-Mesenchymal Transformation.

BACKGROUND: Airway remodeling is one of the reasons for severe steroidresistant asthma related to HMGB1/RAGE signaling or Th17 immunity. OBJECTIVE: Our study aims to investigate the relationship between the HMGB1/RAGE signaling and the Th17/IL-17 signaling in epithelial-mesenchymal transformation (EMT) of airway remodeling. METHODS: CD4+ T lymphocytes were collected from C57 mice. CD4+ T cell and Th17 cell ratio was analyzed by flow cytometry. IL-17 level was detected by ELISA. The Ecadherin and α-SMA were analyzed by RT-qPCR and immunohistochemistry. The Ecadherin, α-SMA, and p-Smad3 expression were analyzed by western blot. RESULTS: The HMGB1/RAGE signaling promoted the differentiation and maturation of Th17 cells in a dose-dependent manner in vitro. The HMGB1/RAGE signaling also promoted the occurrence of bronchial EMT. The EMT of bronchial epithelial cells was promoted by Th17/IL-17 and the HMGB1 treatment in a synergic manner. Silencing of RAGE reduced the signaling transduction of HMGB1 and progression of bronchial EMT. CONCLUSION: HMGB1/RAGE signaling synergistically enhanced TGF-ß1-induced bronchial EMT by promoting the differentiation of Th17 cells and the secretion of IL-17.

Transcriptome and Lipidomic Analysis Suggests Lipid Metabolism Reprogramming and Upregulating SPHK1 Promotes Stemness in Pancreatic Ductal Adenocarcinoma Stem-like Cells.

Cancer stem cells (CSCs) are considered to play a key role in the development and progression of pancreatic ductal adenocarcinoma (PDAC). However, little is known about lipid metabolism reprogramming in PDAC CSCs. Here, we assigned stemness indices, which were used to describe and quantify CSCs, to every patient from the Cancer Genome Atlas (TCGA-PAAD) database and observed differences in lipid metabolism between patients with high and low stemness indices. Then, tumor-repopulating cells (TRCs) cultured in soft 3D (three-dimensional) fibrin gels were demonstrated to be an available PDAC cancer stem-like cell (CSLCs) model. Comprehensive transcriptome and lipidomic analysis results suggested that fatty acid metabolism, glycerophospholipid metabolism, and, especially, the sphingolipid metabolism pathway were mostly associated with CSLCs properties. SPHK1 (sphingosine kinases 1), one of the genes involved in sphingolipid metabolism and encoding the key enzyme to catalyze sphingosine to generate S1P (sphingosine-1-phosphate), was identified to be the key gene in promoting the stemness of PDAC. In summary, we explored the characteristics of lipid metabolism both in patients with high stemness indices and in novel CSLCs models, and unraveled a molecular mechanism via which sphingolipid metabolism maintained tumor stemness. These findings may contribute to the development of a strategy for targeting lipid metabolism to inhibit CSCs in PDAC treatment.

Turning whispering-gallery-mode responses through Fano interferences in coupled all-dielectric block-disk cavities.

Here, we theoretically demonstrate a strategy for efficiently turning whispering-gallery-mode (WGM) responses of a subwavelength dielectric disk through their near-field couplings with common low-order electromagnetic resonances of a dielectric block. Both simulations and an analytical coupled oscillator model show that the couplings are Fano interferences between dark high-quality WGMs and bright modes of the block. The responses of a WGM in the coupled system are highly dependent on the strengths and the relative phases of the block modes, the coupling strength, and the decay rate of the WGM. The WGM responses of coupled systems can exceed that of the individual disk. In addition, such a configuration will also facilitate the excitation of WGMs by a normal incident plane wave in experiments. These results could enable new applications for enhancing light-matter interactions.

The value of integrating tumor volume and plasma Epstein-Barr virus DNA load during sequential chemoradiotherapy for prognostic prediction and therapeutic guidance in high-risk locoregionally advanced nasopharyngeal carcinoma.

OBJECTIVES: To investigate the value of integrating primary gross tumor volume (GTVp) and gross tumor volume of nodes (GTVn) after induction chemotherapy (IC) and dynamic changes in plasma cell-free Epstein-Barr virus DNA (cfEBV DNA) during sequential chemoradiotherapy (CRT) in high-risk locoregionally advanced nasopharyngeal carcinoma (LA-NPC). MATERIALS AND METHODS: We retrospectively reviewed 988 patients with LA-NPC undergoing IC plus concurrent chemoradiotherapy (CCRT) between 2014 and 2018. The entire cohort was divided into four subgroups according to tumor volume and the cfEBV DNA load. Using a supervised statistical clustering approach, we stratified the subgroups into three clusters. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRRFS) were calculated using Kaplan-Meier analysis and inter-group differences were compared using the log-rank test. RESULTS: We observed that GTVp & GTVn and cfEBV DNApostIC & cfEBV DNApostCRT were powerful prognostic factors for OS (p = 0.004, p < 0.001, p < 0.001, and p < 0.001, respectively). The survival curves of the three clusters were significantly different. The 5-year OS for the low-risk, intermediate-risk and high-risk clusters were 97.0%, 86.2% and 77.1% (all P values < 0.001), respectively. The risk stratification system showed better predictive performance than the current tumor-node-metastasis (TNM) classification for OS (area under curve [AUC]: 0.653 versus 0.560, p < 0.001), DFS (AUC: 0.639 versus 0.540, p < 0.001), DMFS (AUC: 0.628 versus 0.535, p < 0.001) and LRRFS (AUC: 0.616 versus 0.513, p < 0.001). CONCLUSION: Both tumor volume and the cfEBV DNA level during sequential CRT are effective prognostic indicators for patients with high-risk LA-NPC. The developed risk stratification system incorporating above factors improved survival prediction and demonstrated potential value in decision-making.

Preparation, identification, and inhibitory mechanism of dipeptidyl peptidase IV inhibitory peptides from goat milk whey protein.

This study explores potential hypoglycemic mechanisms by preparing and identifying novel dipeptidyl peptidase IV (DPP-IV) inhibitory peptides from goat milk (GM) whey protein. Papain was used to hydrolyze the GM whey protein. After purification by ultrafiltration, the Sephadex column, and preparative RP-HPLC, the peptide inhibited DPP-IV, α-glucosidase, and α-amylase with IC50 of 0.34, 0.37, and 0.72 mg/mL, respectively. To further explore the inhibitory mechanism of peptides on DPP-IV, SPPEFLR, LDADGSY, YPVEPFT, and FNPTY were identified and synthesized for the first time, with IC50 values of 56.22, 52.16, 175.7, and 62.32 µM, respectively. Molecular docking and dynamics results show that SPPEFLR, LDADGSY, and FNPTY bind more tightly to the active pocket of DPP-IV, which was consistent with the in vitro activity. Furthermore, the first three N-terminals of SPPEFLR and FNPTY peptides exhibit proline characteristics and competitively inhibit DPP-IV. Notably, the first N-terminal leucine of LDADGSY may play a key role in inhibiting DPP-IV.

Goat and cow milk differ in altering the microbiota composition and neurotransmitter levels in insomnia mouse models.

Milk can improve sleep, and the effects of different animal milks vary. Accordingly, we evaluated the effectiveness of goat milk and cow milk in alleviating insomnia. The findings demonstrated that both goat milk and cow milk significantly increased the length of time that mice with insomnia slept compared to the model group and lowered the relative abundance of Colidextribacter, Escherichia-Shigella, and Proteus in these mice. A notable finding was that goat milk considerably increased the relative abundance of Dubosiella, Bifidobacterium, Lactobacillus, and Mucispirillum, whereas cow milk dramatically increased the relative abundance of Lactobacillus and Acinetobacter. Diazepam therapy could lengthen the slumber of mice; however, analysis of bacteria indicated that although the relative abundance of dangerous bacteria such as Mucispirillum, Parasutterella, Helicobacter, and Romboutsia increased, that of Blautia and Faecalibaculum decreased. Both Listeria and Clostridium experienced a large increase in relative abundance. Additionally, goat milk provided efficient restoration of neurotransmitters including 5-HT, GABA, DA, and NE. Besides that, the expression of genes and proteins for CREB, BDNF, and TrkB in the hypothalamus was up-regulated, and the pathophysiology of the hypothalamus was improved. Overall, the effects of goat and cow milk on insomnia in mouse models differed, and goat milk is preferred over cow milk.

Glacial changes in sea level modulated millennial-scale variability of Southeast Asian autumn monsoon rainfall.

Most paleoclimate studies of Mainland Southeast Asia hydroclimate focus on the summer monsoon, with few studies investigating rainfall in other seasons. Here, we present a multiproxy stalagmite record (45,000 to 4,000 years) from central Vietnam, a region that receives most of its annual rainfall in autumn (September-November). We find evidence of a prolonged dry period spanning the last glacial maximum that is punctuated by an abrupt shift to wetter conditions during the deglaciation at ~14 ka. Paired with climate model simulations, we show that sea-level change drives autumn monsoon rainfall variability on glacial-orbital timescales. Consistent with the dry signal in the stalagmite record, climate model simulations reveal that lower glacial sea level exposes land in the Gulf of Tonkin and along the South China Shelf, reducing convection and moisture delivery to central Vietnam. When sea level rises and these landmasses flood at ~14 ka, moisture delivery to central Vietnam increases, causing an abrupt shift from dry to wet conditions. On millennial timescales, we find signatures of well-known Heinrich Stadials (HS) (dry conditions) and Dansgaard-Oeschger Events (wet conditions). Model simulations show that during the dry HS, changes in sea surface temperature related to meltwater forcing cause the formation of an anomalous anticyclone in the Western Pacific, which advects dry air across central Vietnam, decreasing autumn rainfall. Notably, sea level modulates the magnitude of millennial-scale dry and wet phases by muting dry events and enhancing wet events during periods of low sea level, highlighting the importance of this mechanism to autumn monsoon variability.

Genetic associations of leisure sedentary behaviors and the risk of 15 site-specific cancers: A Mendelian randomization study.

BACKGROUND AND AIMS: Leisure sedentary behavior (LSB) is associated with the risk of cancer, but the causal relationship between them has not been clarified. The aim of this study was to assess the potential causal association between LSB and risk of 15 site-specific cancers. METHODS: The causal association between LSB and cancer were assessed with univariate Mendelian randomization (UVMR) and multivariate Mendelian randomization (MVMR). 194 SNPs associated with LSB (from the UK Biobank 408,815 individuals) were adopted as the instrument variables. Sensitivity analyses were performed to ensure the robustness of the results. RESULTS: UVMR analysis revealed that television watching significantly increased the risk of endometrial cancer (OR = 1.29, 95% CI = 1.02-1.64, p = 0.04) (mainly the endometrioid histology [OR = 1.28, 95% CI = 1.02-1.60, p = 0.031])，breast cancer (OR = 1.16, 95% CI = 1.04-1.30, p = 0.007) (both ER+ breast cancer [OR = 1.17, 95% CI = 1.03-1.33, p = 0.015], and ER- breast cancer [OR = 1.55, 95% CI = 1.26-1.89, p = 2.23 × 10-5 ]). Although causal association was not found between television watching and ovarian cancer, it was seen in low grade and low malignant potential serous ovarian cancer (OR = 1.49, 95% CI = 1.07-2.08, p = 0.018). However, significant results were not obtained in the UVMR analysis between driving, computer use and the 15 types of cancer. Further MVMR analysis indicated that the above results are independent from most metabolic factors and dietary habits, but mediated by educational attainment. CONCLUSION: LSB in form of television watching has independent causal association with the risk of endometrial cancer, breast cancer, and ovarian cancer.

Methyl-cpg-binding Domain Protein 2 Silencing Inhibits Th17 Differentiation of CD4+T cells Induced by Ovalbumin.

Background: Little is known about MBD2's epigenetic regulation in the immune pathogenesis of CD4+T cell differentiation. Objective: This study attempted to explore the mechanism of methyl-cpg-binding domain protein 2 (MBD2) in CD4+T cell differentiation stimulated by environmental allergen ovalbumin (OVA). Methods: Mononuclear cells were separated from the spleen tissues of male C57BL/6 mice. The OVA interfered with the differentiation of splenic mononuclear cells and CD4+T cells. The CD4+T cells were obtained by magnetic beads and identified by CD4 labeled antibody. CD4+T cells were transfected with lentivirus to silence MBD2 gene. A methylation quantification kit was used to detect 5-mC levels. Results: The purity of CD4+T cells reached 95.99% after magnetic beads sorting. Treatment with 200 µg/mL OVA stimulated the CD4+T cells differentiation to Th17 cells and promoted the secretion of IL-17. After being induced, the Th17 cell ratio increased. 5-Aza inhibited the Th17 cell differentiation and the IL-17 level in a dose-dependent manner. Under the intervention of the Th17 induction and 5-Aza, MBD2 silencing inhibited the differentiation of Th17 cell, and decreased the IL-17 and 5-mC levels in the cell supernatants. MBD2 silencing reduced the scale of the Th17 cell and IL-17 levels in the OVA-treated CD4+T cells. Conclusion: MBD2 affected IL-17 and 5-mC levels by mediating the Th17 cell differentiation in splenic CD4+T cells that were interfered with 5-Aza. OVA induced Th17 differentiation and increased IL-17 levels, inhibited by MBD2 silencing.

Survival Benefits of Radiotherapy and Surgery in Lung Cancer Brain Metastases with Poor Prognosis Factors.

BACKGROUND: Radiotherapy and surgery are the standard local treatments for lung cancer brain metastases (BMs). However, limited studies focused on the effects of radiotherapy and surgery in lung cancer BMs with poor prognosis factors. METHODS: We retrospectively analyzed 714 patients with lung cancer BMs. Analyses of overall survival (OS) and risk factors for OS were assessed by the log-rank test and Cox proportional hazard model. RESULTS: Age ≥ 65 years, a Karnofsky Performance Scale (KPS) score ≤ 70, anaplastic large-cell lymphoma kinase (ALK)/epidermal growth factor receptor (EGFR) wild type, and extracranial metastases were related to poor prognosis. Patients were stratified according to these poor prognosis factors. In patients with the ALK/EGFR wild type, whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and surgery improved the OS of patients. WBRT and SRS were the independent protective factors for OS. In patients with extracranial metastases, patients who received WBRT plus SRS or WBRT alone had longer OS than those who did not receive radiotherapy. WBRT plus SRS and WBRT were the independent protective factors for OS. CONCLUSIONS: Radiotherapy and surgery are associated with improved survival for lung cancer BMs with the ALK/EGFR wild type. Radiotherapy is associated with improved survival in lung cancer BMs with extracranial metastases.

North Atlantic cooling triggered a zonal mode over the Indian Ocean during Heinrich Stadial 1.

Abrupt changes in the Atlantic meridional overturning circulation (AMOC) are thought to affect tropical hydroclimate through adjustment of the latitudinal position of the intertropical convergence zone (ITCZ). Heinrich Stadial 1 (HS1) involves the largest AMOC reduction in recent geological time; however, over the tropical Indian Ocean (IO), proxy records suggest zonal anomalies featuring intense, widespread drought in tropical East Africa versus generally wet but heterogeneous conditions in the Maritime Continent. Here, we synthesize proxy data and an isotope-enabled transient deglacial simulation and show that the southward ITCZ shift over the eastern IO during HS1 strengthens IO Walker circulation, triggering an east-west precipitation dipole across the basin. This dipole reverses the zonal precipitation anomalies caused by the exposed Sunda and Sahul shelves due to glacial lower sea level. Our study illustrates how zonal modes of atmosphere-ocean circulation can amplify or reverse global climate anomalies, highlighting their importance for future climate change.