Microglia lactylation in relation to central nervous system diseases.

The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis. Microglia, as innate immune cells, play important roles in the maintenance of central nervous system homeostasis, injury response, and neurodegenerative diseases. Lactate has been considered a metabolic waste product, but recent studies are revealing ever more of the physiological functions of lactate. Lactylation is an important pathway in lactate function and is involved in glycolysis-related functions, macrophage polarization, neuromodulation, and angiogenesis and has also been implicated in the development of various diseases. This review provides an overview of the lactate metabolic and homeostatic regulatory processes involved in microglia lactylation, histone versus non-histone lactylation, and therapeutic approaches targeting lactate. Finally, we summarize the current research on microglia lactylation in central nervous system diseases. A deeper understanding of the metabolic regulatory mechanisms of microglia lactylation will provide more options for the treatment of central nervous system diseases.

Tumor-associated NK cells drive MDSC-mediated tumor immune tolerance through the IL-6/STAT3 axis.

Apart from their killer identity, natural killer (NK) cells have integral roles in shaping the tumor microenvironment. Through immune gene deconvolution, the present study revealed an interplay between NK cells and myeloid-derived suppressor cells (MDSCs) in nonresponders of immune checkpoint therapy. Given that the mechanisms governing the outcome of NK cell-to-myeloid cell interactions remain largely unknown, we sought to investigate the cross-talk between NK cells and suppressive myeloid cells. Upon contact with tumor-experienced NK cells, monocytes and neutrophils displayed increased expression of MDSC-related suppressive factors along with increased capacities to suppress T cells. These changes were accompanied by impaired antigen presentation by monocytes and increased ER stress response by neutrophils. In a cohort of patients with sarcoma and breast cancer, the production of interleukin-6 (IL-6) by tumor-infiltrating NK cells correlated with S100A8/9 and arginase-1 expression by MDSCs. At the same time, NK cell-derived IL-6 was associated with tumors with higher major histocompatibility complex class I expression, which we further validated with b2m-knockout (KO) tumor mice models. Similarly in syngeneic wild-type and IL-6 KO mouse models, we then demonstrated that the accumulation of MDSCs was influenced by the presence of such regulatory NK cells. Inhibition of the IL-6/signal transducer and activator of transcription 3 (STAT3) axis alleviated suppression of T cell responses, resulting in reduced tumor growth and metastatic dissemination. Together, these results characterize a critical NK cell-mediated mechanism that drives the development of MDSCs during tumor immune escape.

LiViT-Net: A U-Net-like, lightweight Transformer network for retinal vessel segmentation.

The intricate task of precisely segmenting retinal vessels from images, which is critical for diagnosing various eye diseases, presents significant challenges for models due to factors such as scale variation, complex anatomical patterns, low contrast, and limitations in training data. Building on these challenges, we offer novel contributions spanning model architecture, loss function design, robustness, and real-time efficacy. To comprehensively address these challenges, a new U-Net-like, lightweight Transformer network for retinal vessel segmentation is presented. By integrating MobileViT+ and a novel local representation in the encoder, our design emphasizes lightweight processing while capturing intricate image structures, enhancing vessel edge precision. A novel joint loss is designed, leveraging the characteristics of weighted cross-entropy and Dice loss to effectively guide the model through the task's challenges, such as foreground-background imbalance and intricate vascular structures. Exhaustive experiments were performed on three prominent retinal image databases. The results underscore the robustness and generalizability of the proposed LiViT-Net, which outperforms other methods in complex scenarios, especially in intricate environments with fine vessels or vessel edges. Importantly, optimized for efficiency, LiViT-Net excels on devices with constrained computational power, as evidenced by its fast performance. To demonstrate the model proposed in this study, a freely accessible and interactive website was established (https://hz-t3.matpool.com:28765?token=aQjYR4hqMI), revealing real-time performance with no login requirements.

A phenotypic screening approach to target p60AmotL2-expressing invasive cancer cells.

BACKGROUND: Tumor cells have the ability to invade and form small clusters that protrude into adjacent tissues, a phenomenon that is frequently observed at the periphery of a tumor as it expands into healthy tissues. The presence of these clusters is linked to poor prognosis and has proven challenging to treat using conventional therapies. We previously reported that p60AmotL2 expression is localized to invasive colon and breast cancer cells. In vitro, p60AmotL2 promotes epithelial cell invasion by negatively impacting E-cadherin/AmotL2-related mechanotransduction. METHODS: Using epithelial cells transfected with inducible p60AmotL2, we employed a phenotypic drug screening approach to find compounds that specifically target invasive cells. The phenotypic screen was performed by treating cells for 72 h with a library of compounds with known antitumor activities in a dose-dependent manner. After assessing cell viability using CellTiter-Glo, drug sensitivity scores for each compound were calculated. Candidate hit compounds with a higher drug sensitivity score for p60AmotL2-expressing cells were then validated on lung and colon cell models, both in 2D and in 3D, and on colon cancer patient-derived organoids. Nascent RNA sequencing was performed after BET inhibition to analyse BET-dependent pathways in p60AmotL2-expressing cells. RESULTS: We identified 60 compounds that selectively targeted p60AmotL2-expressing cells. Intriguingly, these compounds were classified into two major categories: Epidermal Growth Factor Receptor (EGFR) inhibitors and Bromodomain and Extra-Terminal motif (BET) inhibitors. The latter consistently demonstrated antitumor activity in human cancer cell models, as well as in organoids derived from colon cancer patients. BET inhibition led to a shift towards the upregulation of pro-apoptotic pathways specifically in p60AmotL2-expressing cells. CONCLUSIONS: BET inhibitors specifically target p60AmotL2-expressing invasive cancer cells, likely by exploiting differences in chromatin accessibility, leading to cell death. Additionally, our findings support the use of this phenotypic strategy to discover novel compounds that can exploit vulnerabilities and specifically target invasive cancer cells.

Natural killer cells drive 4-1BBL positive uveal melanoma towards EMT and metastatic disease.

BACKGROUND: Inflammation in the eye is often associated with aggravated ocular diseases such as uveal melanoma (UM). Poor prognosis of UM is generally associated with high potential of metastatic liver dissemination. A strong driver of metastatic dissemination is the activation of the epithelial-mesenchymal transition (EMT) regulating transcription factor ZEB1, and high expression of ZEB1 is associated with aggressiveness of UM. While ZEB1 expression can be also associated with immune tolerance, the underlying drivers of ZEB1 activation remain unclear. METHODS: Transcriptomic, in vitro, ex vivo, and in vivo analyses were used to investigate the impact on clinical prognosis of immune infiltration in the ocular tumor microenvironment. A metastatic liver dissemination model of was developed to address the role of natural killer (NK) cells in driving the migration of UM. RESULTS: In a pan-cancer TCGA analysis, natural killer (NK) cells were associated with worse overall survival in uveal melanoma and more abundant in high-risk monosomy 3 tumors. Furthermore, uveal melanoma expressed high levels of the tumor necrosis factor superfamily member 4-1BB ligand, particularly in tumors with monosomy 3 and BAP1 mutations. Tumors expressing 4-1BB ligand induced CD73 expression on NK cells accompanied with the ability to promote tumor dissemination. Through ligation of 4-1BB, NK cells induced the expression of the ZEB1 transcription factor, leading to the formation of liver metastasis of uveal melanoma. CONCLUSIONS: Taken together, the present study demonstrates a role of NK cells in the aggravation of uveal melanoma towards metastatic disease.

Clinical characteristics of tuberculous meningitis in older patients compared with younger and middle-aged patients: a retrospective analysis.

BACKGROUND: Few studies have analyzed the clinical characteristics and adverse factors affecting prognosis in older patients with tuberculous meningitis (TBM). This study aimed to compare the clinical characteristics of TBM in older patients with those in younger and middle-aged patients. METHODS: This single-center retrospective study extracted data on the clinical features, cerebrospinal fluid changes, laboratory results, imaging features, and outcomes of patients with TBM from patient medical records and compared the findings in older patients (aged 60 years and older) with those of younger and middle-aged patients (aged 18-59 years). RESULTS: The study included 197 patients with TBM, comprising 21 older patients aged 60-76 years at onset, and 176 younger and middle-aged patients aged 18-59 years at onset. Fever was common in both older (81%) and younger and middle-aged patients (79%). Compared with younger and middle-aged patients, older patients were more likely to have changes in awareness levels (67% vs. 40%), peripheral nerve dysfunction (57% vs. 29%), changes in cognitive function (48% vs. 20%), and focal seizures (33% vs. 6%), and less likely to have headache (71% vs. 93%), neck stiffness on meningeal stimulation (38% vs. 62%), and vomiting (47% vs. 68%). The Medical Research Council staging on admission of older patients was stage II (52%) and stage III (38%), whereas most younger and middle-aged patients had stage I (33%) and stage II (55%) disease. Neurological function evaluated on the 28th day of hospitalization was more likely to show poor prognosis in older patients than in younger and middle-aged patients (76% vs. 25%). Older patients had significantly higher red blood cell counts and blood glucose levels, and significantly lower serum albumin and sodium levels than those in younger and middle-aged patients. The cerebrospinal fluid protein levels, nucleated cell counts, glucose levels, and chloride levels did not differ significantly by age. CONCLUSION: In patients with TBM, older patients have more severe clinical manifestations, a higher incidence of hydrocephalus and cerebral infarction, and longer hospital stays than younger and middle-aged patients. Older patients thus require special clinical attention.

Deciphering the Role of p60AmotL2 in Epithelial Extrusion and Cell Detachment.

Preserving an accurate cell count is crucial for maintaining homeostasis. Apical extrusion, a process in which redundant cells are eliminated by neighboring cells, plays a key role in this regard. Recent studies have revealed that apical extrusion can also be triggered in cells transformed by oncogenes, suggesting it may be a mechanism through which tumor cells escape their microenvironment. In previous work, we demonstrated that p60AmotL2 modulates the E-cadherin function by inhibiting its connection to radial actin filaments. This isoform of AmotL2 is expressed in invasive breast and colon tumors and promotes invasion in vitro and in vivo. Transcriptionally regulated by c-Fos, p60AmotL2 is induced by local stress signals such as severe hypoxia. In this study, we investigated the normal role of p60AmotL2 in epithelial tissues. We found that this isoform is predominantly expressed in the gut, where cells experience rapid turnover. Through time-lapse imaging, we present evidence that cells expressing p60AmotL2 are extruded by their normal neighboring cells. Based on these findings, we hypothesize that tumor cells exploit this pathway to detach from normal epithelia and invade surrounding tissues.

Association of blood neutrophil-lymphocyte ratio with short-term prognosis and severity of tuberculosis meningitis patients without HIV infection.

BACKGROUND: Predicting the short-term prognosis and severity of tuberculosis meningitis (TBM) patients without HIV infection can be challenging, and there have been no prior studies examining the neutrophil lymphocyte ratio (NLR) as a potential predictor of short-term prognosis or its relationship to TBM severity. We hypothesized that NLR might serve as an independent indicator of short-term prognostic significance and that there might be a correlation between NLR and severity. The aim of this study was to investigate the role of NLR as a predictor of short-term prognosis and its relationship to severity of tuberculosis meningitis patients without HIV infection. METHODS: We retrospectively collected data from patients diagnosed with TBM in the West China Hospital, Sichuan University, from the period between January 1st, 2018 and August 1st, 2019. Multivariable analysis was executed by the logistic regression model to verify the independence of the 28-day mortality, the discriminative power for predicting short-term prognosis was evaluated using a Receiver Operating Characteristic (ROC) curve, survival outcomes were analyzed using the Kaplan-Meier method and Pearson's correlation analysis was performed to discuss correlation between NLR and the severity of TBM. RESULTS: We collected data from 231 TBM patients without HIV infection. 68 (29.4%) patients are classified as stage (I) 138(59.8%) patients are stage (II) 25(10.8%) patients are stage (III) 16(6.9%) patients died during the follow-up period of 28 days. By multiple logistic regression analyses, the NLR (OR = 1.065, 95% CI = 1.001-1.133, P = 0.045), peripheral neurological deficit (OR 7.335, 95% CI 1.964-27.385, P = 0 0.003) and hydrocephalus (OR 11.338, 95% CI 2.397-53.633, P = 0 0.002) are independent risk factors of 28-day mortality. The area under the ROC curve (AUC) for predicting short prognosis using NLR is 0.683 (95% CI 0.540-0.826, P = 0.015), the optimal cutoff value is 9.99(sensitivity: 56.3%, specificity: 80.9%). The Kaplan-Meier analysis demonstrated that patients with higher NLR(>9.99) had significantly worse survival outcomes(P<0.01).Pearson's correlation analysis presents a significant positive correlation between the severity of TBM and NLR (r = 0.234, P<0.01). CONCLUSIONS: NLR, peripheral neurological deficit, and hydrocephalus are independent risk factors of 28-day mortality, NLR can predict the short-term prognosis of TBM patients without HIV infection. NLR is also found to be significantly and positively correlated with the severity of TBM.

Gravity-driven membrane system treating heavy metals-containing secondary effluent: Improved removal of heavy metals and mechanism.

This study aimed at investigating the removal performance of the gravity-driven membrane (GDM) system in treating the heavy metals-containing secondary effluent, as well as evaluating the respective roles of Fe and Mn addition on the removal of heavy metals. GDM process with the formation of biocake layer exerted effective removals of Cr, Pb and Cd, with an average removal efficiency of 98%, 95% and 40%, respectively, however, after removing the biocake layer, the removal efficiencies of Cr, Pb and Cd reduced to 59%, 85% and 19%, respectively, indicating that the biocake layer played a fundamental role in removing heavy metals. With the assistance of Fe, the removal efficiency of heavy metals increased, and exhibited a positive response to the Fe dosage, due to the adsorption by the freshly generated iron oxides. On the contrary, the Mn involvement would result in the reduction of Cd removal due to the competitive adsorption of residual dissolved Mn2+ and Cd. Furthermore, the addition of a high dosage of Fe increased the diversity of eukaryotic communities and facilitated the elimination of heavy metals, however, the involvement of Mn would lead to a reduction in microbial diversity, resulting in a decrease of heavy metal removal efficiency. These findings are expected to develop new tactics to enhance heavy metal removal and promote widespread application of GDM technology in the fields of deep treatment of heavy metals-containing wastewater and reclamation of secondary effluent.

Enabling Ultrafast Single Mg2+ Insertion Kinetics of Magnesium-Ion Batteries via In Situ Dynamic Catalysis and Re-equilibration Effects.

Magnesium-ion batteries (MIBs) have great potential in large-scale energy storage field with high capacity, excellent safety, and low cost. However, the strong solvation effect of Mg2+ will lead to the formation of solvated ions in electrolytes with larger size and sluggish diffusion/reaction kinetics. Here, the concept of interfacial catalytic bond breaking is first introduced into the cathode design of MIBs by hybriding MoS2 quantum dots with VS4 (VS4@MQDs) as the cathode. The "in situ dynamic catalysis and re-equilibration" effects can catalyze the Cl-Mg bond breaking and trigger single Mg2+ insertion/extraction chemistries, which can significantly accelerate the diffusion and reaction kinetics, as verified by the decreased diffusion energy barriers (0.26 eV for Mg2+ vs 2.47 eV for MgCl+) and fast diffusion coefficient. Benefitting from these dynamic catalysis effects, the constructed VS4@MQD-based MIBs deliver a high discharge capacity of ∼120 mA h g-1 at 200 mA g-1 and a long-term cyclic stability of 1000 cycles at 1 A g-1. The improved performance and detailed characterizations well prove that the active ions in MIBs change from MgCl+/Mg2Cl3+ to Mg2+ with fast kinetics.

Effect of nimodipine combined with atorvastatin calcium on microinflammation and oxidative stress levels in patients with cerebral vasospasm after subarachnoid hemorrhage.

Objective: To evaluate the effect of nimodipine combined with atorvastatin calcium on the micro inflammation and oxidative stress levels in patients with cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) and its clinical implications. Methods: A total of 80 patients with CVS caused by SAH who had been admitted to Baoding First Central Hospital from August 2021 to August 2022 were selected and randomly divided into two groups. The control group underwent conventional symptomatic treatment, while the experimental group was administered nimodipine combined with atorvastatin calcium on the basis of conventional treatment. The changes in the micro inflammatory cytokines and oxidative stress factors in the two groups were compared, as well as the differences in clinical efficacy and incidence of adverse drug reactions. Result: After treatment, the levels of inflammatory cytokines in the experimental group decreased more significantly than those in the control group (p=0.00). After treatment, the serum levels of oxidative stress factors were obviously higher in the experimental group than in the control group (p=0.00). After treatment, the total efficacy was 77.5% in the experimental group and 55% in the control group, and the difference was statistically significant (p=0.04). Conclusions: Nimodipine combined with atorvastatin calcium could significantly improve the clinical symptoms in patients with CVS after SAH, which would be beneficial, safe, and effective for the patient's recovery.

CD25bright NK cells display superior function and metabolic activity under regulatory T cell-mediated suppression.

Infusion of natural killer (NK) cells is an attractive therapeutic modality in patients with cancer. However, the activity of NK cells is regulated by several mechanisms operating within solid tumors. Regulatory T (Treg) cells suppress NK cell activity through various mechanisms including deprivation of IL-2 via the IL-2 receptor alpha (CD25). Here, we investigate CD25 expression on NK cells to confer persistence in Treg cells containing solid tumor models of renal cell carcinoma (RCC). Compared with IL-2, stimulation with IL-15 increases the expression of CD25 resulting in enhanced response to IL-2 as evidenced by increased phosphorylation of STAT5. Compared with CD25dim NK cells, CD25bright NK cells isolated from IL-15 primed NK cells display increased proliferative and metabolic activity as well as increased ability to persist in Treg cells containing RCC tumor spheroids. These results support strategies to enrich for or selectively expand CD25bright NK cells for adoptive cellular therapy of NK cells.

A self-microemulsion enhances oral absorption of docetaxel by inhibiting P-glycoprotein and CYP metabolism.

Oral absorption of docetaxel was limited by drug efflux pump p-glycoprotein (P-gp) and cytochrome P450 enzyme (CYP 450). Therefore, co-loading agent that inhibits P-gp and CYP450 in self-nanoemulsifying drug delivery systems (SMEs) is considered a promising strategy for oral delivery of docetaxel. In this study, curcumin was selected as an inhibitor of P-gp and CYP450, and it was co-encapsuled in SMEs to improve the oral bioavailability of docetaxel. SMEs quickly dispersed in water within 20 s, and the droplet size was 32.23 ± 2.21 nm. The release rate of curcumin from DC-SMEs was higher than that of docetaxel in vitro. Compared with free docetaxel, SMEs significantly increased the permeability of docetaxel by 4.6 times. And competitive experiments showed that the increased permeability was the result of inhibition of p-gp. The half-life and oral bioavailabilty of DC-SMEs increased about 1.7 times and 1.6 times than docetaxel SMEs, which indicated that its good pharmacokinetic behavior was related to the restriction of hepatic first-pass metabolism. In conclusion, DC-SME was an ideal platform to facilitate oral delivery of docetaxel through inhibited P-gp and CYP 450.

Breast cancer patient-derived whole-tumor cell culture model for efficient drug profiling and treatment response prediction.

Breast cancer (BC) is a complex disease comprising multiple distinct subtypes with different genetic features and pathological characteristics. Although a large number of antineoplastic compounds have been approved for clinical use, patient-to-patient variability in drug response is frequently observed, highlighting the need for efficient treatment prediction for individualized therapy. Several patient-derived models have been established lately for the prediction of drug response. However, each of these models has its limitations that impede their clinical application. Here, we report that the whole-tumor cell culture (WTC) ex vivo model could be stably established from all breast tumors with a high success rate (98 out of 116), and it could reassemble the parental tumors with the endogenous microenvironment. We observed strong clinical associations and predictive values from the investigation of a broad range of BC therapies with WTCs derived from a patient cohort. The accuracy was further supported by the correlation between WTC-based test results and patients' clinical responses in a separate validation study, where the neoadjuvant treatment regimens of 15 BC patients were mimicked. Collectively, the WTC model allows us to accomplish personalized drug testing within 10 d, even for small-sized tumors, highlighting its potential for individualized BC therapy. Furthermore, coupled with genomic and transcriptomic analyses, WTC-based testing can also help to stratify specific patient groups for assignment into appropriate clinical trials, as well as validate potential biomarkers during drug development.

NK cells and solid tumors: therapeutic potential and persisting obstacles.

Natural killer (NK) cells, which are innate lymphocytes endowed with potent cytotoxic activity, have recently attracted attention as potential anticancer therapeutics. While NK cells mediate encouraging responses in patients with leukemia, the therapeutic effects of NK cell infusion in patients with solid tumors are limited. Preclinical and clinical data suggest that the efficacy of NK cell infusion against solid malignancies is hampered by several factors including inadequate tumor infiltration and persistence/activation in the tumor microenvironment (TME). A number of metabolic features of the TME including hypoxia as well as elevated levels of adenosine, reactive oxygen species, and prostaglandins negatively affect NK cell activity. Moreover, cancer-associated fibroblasts, tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells actively suppress NK cell-dependent anticancer immunity. Here, we review the metabolic and cellular barriers that inhibit NK cells in solid neoplasms as we discuss potential strategies to circumvent such obstacles towards superior therapeutic activity.

Codelivery of minocycline hydrochloride and dextran sulfate via bionic liposomes for the treatment of spinal cord injury.

After primary injury to the spinal cord, a series of microenvironmental changes can lead to secondary injury. The use of nano-targeted drug delivery systems to improve the postinjury microenvironment, inhibit inflammation and reduce neuronal apoptosis can be of great help during spinal cord injury (SCI) recovery. In this study, we prepared primary macrophage membranes bionic modified nanoliposomes (MH-DS@M-Lips) loaded with minocycline hydrochloride (MH) and dextran sulfate (DS) to target their delivery to the site of injury to bind calcium ions in situ and form metal ion complexes. Complex formation reduced calcium ion concentrations and calcium-associated neuronal apoptosis, while MH was slowly released to produce better anti-inflammatory effects. The successful preparation of MH-DS@M-Lips was verified using transmission electron microscopy (TEM), confocal laser scanning microscopy (CLSM), western blotting and dynamic light scattering (DLS). The targeting capability of the MH-DS@M-Lips was demonstrated using a Transwell system and an in vivo imaging system. The therapeutic efficacy of MH-DS@M-Lips was examined in vitro and in vivo using flow cytometry, immunofluorescence, ELISA kits and western blotting. The results showed that SCI mice treated with MH-DS@M-Lips received high behavioral scores, which led to the conclusion that MH-DS@M-Lips have great potential for the treatment of SCI.

Tumor MHC class I expression alters cancer-associated myelopoiesis driven by host NK cells.

Downregulation of MHC class I (MHCI) molecules on tumor cells is recognized as a resistance mechanism of cancer immunotherapy. Given that MHCI molecules are potent regulators of immune responses, we postulated that the expression of MHCI by tumor cells influences systemic immune responses. Accordingly, mice-bearing MHCI-deficient tumor cells showed reduced tumor-associated extramedullary myelopoiesis in the spleen. Depletion of natural killer (NK) cells abrogated these differences, suggesting an integral role of immune-regulatory NK cells during tumor progression. Cytokine-profiling revealed an upregulation of TNF-α by NK cells in tumors and spleen in mice-bearing MHCI expressing tumors, and inhibition of TNF-α enhanced host myelopoiesis in mice receiving adoptive transfer of tumor-experienced NK cells. Our study highlights a critical role of NK cells beyond its identity as a killer lymphocyte and more importantly, the potential host responses to a localized tumor as determined by its MHCI expression.

Development of a novel autophagy-related gene model for gastric cancer prognostic prediction.

Gastric cancer (GC) is a major global health issue and one of the leading causes of tumor-associated mortality worldwide. Autophagy is thought to play a critical role in the development and progression of GC, and this process is controlled by a set of conserved regulators termed autophagy-related genes (ATGs). However, the complex contribution of autophagy to cancers is not completely understood. Accordingly, we aimed to develop a prognostic model based on the specific role of ATGs in GC to improve the prediction of GC outcomes. First, we screened 148 differentially expressed ATGs between GC and normal tissues in The Cancer Genome Atlas (TCGA) cohort. Consensus clustering in these ATGs was performed, and based on that, 343 patients were grouped into two clusters. According to Kaplan-Meier survival analysis, cluster C2 had a worse prognosis than cluster C1. Then, a disease risk model incorporating nine differentially expressed ATGs was constructed based on the least absolute shrinkage and selection operator (LASSO) regression analysis, and the ability of this model to stratify patients into high- and low-risk groups was verified. The predictive value of the model was confirmed using both training and validation cohorts. In addition, the results of functional enrichment analysis suggested that GC risk is correlated with immune status. Moreover, autophagy inhibition increased sensitivity to cisplatin and exacerbated reactive oxygen species accumulation in GC cell lines. Collectively, the results indicated that this novel constructed risk model is an effective and reliable tool for predicting GC outcomes and could help with individual treatment through ATG targeting.

Generation of mega brown adipose tissue in adults by controlling brown adipocyte differentiation in vivo.

Brown adipose tissue (BAT) is a highly specialized adipose tissue in its immobile location and size during the entire adulthood. In response to cold exposure and other ß3-adrenoreceptor stimuli, BAT commits energy consumption by nonshivering thermogenesis (NST). However, the molecular machinery in controlling the BAT mass in adults is unknown. Here, we show our surprising findings that the BAT mass and functions can be manipulated in adult animals by controlling BAT adipocyte differentiation in vivo. Platelet-derived growth factor receptor α (PDGFα) expressed in BAT progenitor cells served a signaling function to avert adipose progenitor differentiation. Genetic and pharmacological loss-of-function of PDGFRα eliminated the differentiation barrier and permitted progenitor cell differentiation to mature and functional BAT adipocytes. Consequently, an enlarged BAT mass (megaBAT) was created by PDGFRα inhibition owing to increases of brown adipocyte numbers. Under cold exposure, a microRNA-485 (miR-485) was identified as a master suppressor of the PDGFRα signaling, and delivery of miR-485 also produced megaBAT in adult animals. Noticeably, megaBAT markedly improved global metabolism, insulin sensitivity, high-fat-diet (HFD)-induced obesity, and diabetes by enhancing NST. Together, our findings demonstrate that the adult BAT mass can be increased by blocking the previously unprecedented inhibitory signaling for BAT progenitor cell differentiation. Thus, blocking the PDGFRα for the generation of megaBAT provides an attractive strategy for treating obesity and type 2 diabetes mellitus (T2DM).