Brown-fat-mediated tumour suppression by cold-altered global metabolism.

Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues1-6. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis2,7,8. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes4,5,9. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1-the key mediator for BAT-thermogenesis-ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.

Inflammatory cell-derived CXCL3 promotes pancreatic cancer metastasis through a novel myofibroblast-hijacked cancer escape mechanism.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy and lacks effective treatment. We aimed to understand molecular mechanisms of the intertwined interactions between tumour stromal components in metastasis and to provide a new paradigm for PDAC therapy. DESIGN: Two unselected cohorts of 154 and 20 patients with PDAC were subjected to correlation between interleukin (IL)-33 and CXCL3 levels and survivals. Unbiased expression profiling, and genetic and pharmacological gain-of-function and loss-of-function approaches were employed to identify molecular signalling in tumour-associated macrophages (TAMs) and myofibroblastic cancer-associated fibroblasts (myoCAFs). The role of the IL-33-ST2-CXCL3-CXCR2 axis in PDAC metastasis was evaluated in three clinically relevant mouse PDAC models. RESULTS: IL-33 was specifically elevated in human PDACs and positively correlated with tumour inflammation in human patients with PDAC. CXCL3 was highly upregulated in IL-33-stimulated macrophages that were the primary source of CXCL3. CXCL3 was correlated with poor survival in human patients with PDAC. Mechanistically, activation of the IL-33-ST2-MYC pathway attributed to high CXCL3 production. The highest level of CXCL3 was found in PDAC relative to other cancer types and its receptor CXCR2 was almost exclusively expressed in CAFs. Activation of CXCR2 by CXCL3 induced a CAF-to-myoCAF transition and α-smooth muscle actin (α-SMA) was uniquely upregulated by the CXCL3-CXCR2 signalling. Type III collagen was identified as the CXCL3-CXCR2-targeted adhesive molecule responsible for myoCAF-driven PDAC metastasis. CONCLUSIONS: Our work provides novel mechanistic insights into understanding PDAC metastasis by the TAM-CAF interaction and targeting each of these signalling components would provide an attractive and new paradigm for treating pancreatic cancer.

Skin-inspired, sensory robots for electronic implants.

Drawing inspiration from cohesive integration of skeletal muscles and sensory skins in vertebrate animals, we present a design strategy of soft robots, primarily consisting of an electronic skin (e-skin) and an artificial muscle. These robots integrate multifunctional sensing and on-demand actuation into a biocompatible platform using an in-situ solution-based method. They feature biomimetic designs that enable adaptive motions and stress-free contact with tissues, supported by a battery-free wireless module for untethered operation. Demonstrations range from a robotic cuff for detecting blood pressure, to a robotic gripper for tracking bladder volume, an ingestible robot for pH sensing and on-site drug delivery, and a robotic patch for quantifying cardiac function and delivering electrotherapy, highlighting the application versatilities and potentials of the bio-inspired soft robots. Our designs establish a universal strategy with a broad range of sensing and responsive materials, to form integrated soft robots for medical technology and beyond.

Dual Space Coupling Model Guided Overlap-Free Scatterplot.

The overdraw problem of scatterplots seriously interferes with the visual tasks. Existing methods, such as data sampling, node dispersion, subspace mapping, and visual abstraction, cannot guarantee the correspondence and consistency between the data points that reflect the intrinsic original data distribution and the corresponding visual units that reveal the presented data distribution, thus failing to obtain an overlap-free scatterplot with unbiased and lossless data distribution. A dual space coupling model is proposed in this paper to represent the complex bilateral relationship between data space and visual space theoretically and analytically. Under the guidance of the model, an overlap-free scatterplot method is developed through integration of the following: a geometry-based data transformation algorithm, namely DistributionTranscriptor; an efficient spatial mutual exclusion guided view transformation algorithm, namely PolarPacking; an overlap-free oriented visual encoding configuration model and a radius adjustment tool, namely frdraw. Our method can ensure complete and accurate information transfer between the two spaces, maintaining consistency between the newly created scatterplot and the original data distribution on global and local features. Quantitative evaluation proves our remarkable progress on computational efficiency compared with the state-of-the-art methods. Three applications involving pattern enhancement, interaction improvement, and overdraw mitigation of trajectory visualization demonstrate the broad prospects of our method.

Enterobacter sp. E1 increased arsenic uptake in Pteris vittata by promoting plant growth and dissolving Fe-bound arsenic.

Microbes affect arsenic accumulation in the arsenic-hyperaccumulator Pteris vittata, but the associated molecular mechanism remains uncertain. Here, we investigated the effect of Enterobacter sp. E1 on arsenic accumulation by P. vittata. Strain E1 presented capacities of arsenate [As(V)] and Fe(III) reduction during cultivation. In the pot experiment with P. vittata, the biomass, arsenic content, and chlorophyll content of P. vittata significantly increased by 30.03%, 74.9%, and 112.1%, respectively. Strikingly, the water-soluble plus exchangeable arsenic (WE-As) significantly increased by 52.05%, while Fe-bound arsenic (Fe-As) decreased by 29.64% in the potted soil treated with strain E1. The possible role of activation of arsenic by strain E1 was subsequently investigated by exposing As(V)-absorbed ferrihydrite to the bacterial culture. Speciation analyses of As showed that strain E1 significantly increased soluble levels of As and Fe and that more As(V) was reduced to arsenite. Additionally, increased microbial diversity and soil enzymatic activities in soils indicated that strain E1 posed few ecological risks. These results indicate that strain E1 effectively increased As accumulation in P. vittata mainly by promoting plant growth and dissolving soil arsenic. Our findings suggest that As(V) and Fe(III)-reducer E1 could be used to enhance the phytoremediation of P. vittata in arsenic-contaminated soils.

MuLHiTA: A Novel Multiclass Classification Framework With Multibranch LSTM and Hierarchical Temporal Attention for Early Detection of Mental Stress.

Mental stress is an increasingly common psychological issue leading to diseases such as depression, addiction, and heart attack. In this study, an early detection framework based on electroencephalogram (EEG) data is developed for reducing the risk of these diseases. In existing frameworks, signals are often segmented into smaller sections prior to being input to a deep neural network. However, this approach ignores the fundamental nature of EEG signals as a carrier of valuable information (e.g., the integrity of frequency and phase, and temporal fluctuations of EEG components). As such, this type of segmenting may lead to information loss and a failure to effectively identify mental stress levels. Thus, we propose a novel multiclass classification framework termed multibranch LSTM and hierarchical temporal attention (MuLHiTA) for the early identification of mental stress levels. It specifically focuses on not only intraslice (within each slice) but also interslice (between different slices) samples in parallel. This was achieved by including two complementary branches, each of which integrated a specifically designed attention module into a bidirectional long short-term memory (BLSTM) network, enabling extraction of the most discriminative features from interslice and intraslice EEG signals simultaneously. The outputs of attention modules were then summed to obtain a feature representation that contributes to reduce overfitting and more effective multiclass classification. In addition, electrode positions were optimized using neural activity areas under high-stress conditions, thereby reducing computational costs by minimizing the number of critical electrodes. MuLHiTA was evaluated across one private [Montreal imaging stress task (MIST)] and two publicly available EEG datasets [EEG during mental arithmetic tasks (DMAT) and Simultaneous task EEG workload (STEW)]. These were divided into training and test sets using an 8:2 ratio, and the training data were further divided into training and validation sets using a fivefold cross-validation (CV) method, in which the model with the highest accuracy among the five was selected. The model was trained once more with the full training set, and the test data were then used to evaluate its performance. This approach achieved average classification accuracies of 93.58%, 91.80%, and 99.71% for the MIST, STEW, and DMAT datasets, respectively. Experimental results showed MuLHiTA was superior to state-of-the-art algorithms, including EEGNet, BLSTM, EEGLearn, convolutional neural network (CNN)-long short-term memory (LSTM), and convolutional recurrent attention model (CRAM), for multiclass classification. This demonstrates the viability of MuLHiTA for the early detection of mental stress.

Skin-inspired, sensory robots for electronic implants.

Living organisms with motor and sensor units integrated seamlessly demonstrate effective adaptation to dynamically changing environments. Drawing inspiration from cohesive integration of skeletal muscles and sensory skins in these organisms, we present a design strategy of soft robots, primarily consisting of an electronic skin (e-skin) and an artificial muscle, that naturally couples multifunctional sensing and on-demand actuation in a biocompatible platform. We introduce an in situ solution-based method to create an e-skin layer with diverse sensing materials (e.g., silver nanowires, reduced graphene oxide, MXene, and conductive polymers) incorporated within a polymer matrix (e.g., polyimide), imitating complex skin receptors to perceive various stimuli. Biomimicry designs (e.g., starfish and chiral seedpods) of the robots enable various motions (e.g., bending, expanding, and twisting) on demand and realize good fixation and stress-free contact with tissues. Furthermore, integration of a battery-free wireless module into these robots enables operation and communication without tethering, thus enhancing the safety and biocompatibility as minimally invasive implants. Demonstrations range from a robotic cuff encircling a blood vessel for detecting blood pressure, to a robotic gripper holding onto a bladder for tracking bladder volume, an ingestible robot residing inside stomach for pH sensing and on-site drug delivery, and a robotic patch wrapping onto a beating heart for quantifying cardiac contractility, temperature and applying cardiac pacing, highlighting the application versatilities and potentials of the nature-inspired soft robots. Our designs establish a universal strategy with a broad range of sensing and responsive materials, to form integrated soft robots for medical technology and beyond.

3D morphable systems via deterministic microfolding for vibrational sensing, robotic implants, and reconfigurable telecommunication.

DNA and proteins fold in three dimensions (3D) to enable functions that sustain life. Emulation of such folding schemes for functional materials can unleash enormous potential in advancing a wide range of technologies, especially in robotics, medicine, and telecommunication. Here, we report a microfolding strategy that enables formation of 3D morphable microelectronic systems integrated with various functional materials, including monocrystalline silicon, metallic nanomembranes, and polymers. By predesigning folding hosts and configuring folding pathways, 3D microelectronic systems in freestanding forms can transform across various complex configurations with modulated functionalities. Nearly all transitional states of 3D microelectronic systems achieved via the microfolding assembly can be easily accessed and modulated in situ, offering functional versatility and adaptability. Advanced morphable microelectronic systems including a reconfigurable microantenna for customizable telecommunication, a 3D vibration sensor for hand-tremor monitoring, and a bloomable robot for cardiac mapping demonstrate broad utility of these assembly schemes to realize advanced functionalities.

Interleukin-33 is a Novel Immunosuppressor that Protects Cancer Cells from TIL Killing by a Macrophage-Mediated Shedding Mechanism.

Recognition of specific antigens expressed in cancer cells is the initial process of cytolytic T cell-mediated cancer killing. However, this process can be affected by other non-cancerous cellular components in the tumor microenvironment. Here, it is shown that interleukin-33 (IL-33)-activated macrophages protect melanoma cells from tumor-infiltrating lymphocyte-mediated killing. Mechanistically, IL-33 markedly upregulates metalloprotease 9 (MMP-9) expression in macrophages, which acts as a sheddase to trim NKG2D, an activating receptor expressed on the surface of natural killer (NK) cells, CD8+ T cells, subsets of CD4+ T cells, iNKT cells, and γδ T cells. Further, MMP-9 also cleaves the MHC class I molecule, cell surface antigen-presenting complex molecules, expressed in melanoma cells. Consequently, IL-33-induced macrophage MMP-9 robustly mitigates the tumor killing-effect by T cells. Genetic and pharmacological loss-of-function of MMP-9 sheddase restore T cell-mediated cancer killing. Together, these data provide compelling in vitro and in vivo evidence showing novel mechanisms underlying the IL-33-macrophage-MMP-9 axis-mediated immune tolerance against cancer cells. Targeting each of these signaling components, including IL-33 and MMP-9 provides a new therapeutic paradigm for improving anticancer efficacy by immune therapy.

An open label, multicenter clinical trial that investigated the efficacy and safety of leuprorelin treatment of central precocious puberty in Chinese children.

BACKGROUND: Leuprorelin is an analog of gonadotropin-releasing hormone that is used for the therapy of central precocious puberty (CPP). The aims of this prospective, open label, multicenter clinical trial were to establish its efficacy and safety during long-term use. METHODS: Patients, who were all children, were treated with 1.88 to 3.75 mg leuprorelin subcutaneously once every 4 weeks for a total of 96 weeks between 2015 and 2018. The primary endpoint was the rate of occurrence of adverse events (AEs) and the secondary endpoint was no progression in the Tanner stage or regression by week 96 compared to baseline. RESULTS: A total of 307 CPP patients, 305 (99.3%) females and 2 males (0.7%), completed the 96-weeks of treatment. Due to limited data for male patients, they are not discussed in the efficacy results. Treatment-emergent AEs (TEAEs) were reported for 252 (82.1%) patients, mostly (79.5%) being mild or moderate and only 33 (10.7%) of patients experienced TEAEs related to leuprorelin therapy. The most frequent (>2%) drug-related TEAEs were injection site induration (4.6%, 14/307) and vaginal bleeding (2.3%, 7/305). After treatment, 83.5% of patients had regression or no progression in the Tanner stage (95% confidence interval: 78.68%, 87.62%) and the majority had decreased gonadotropin-releasing hormone-stimulated peak luteinizing hormone and follicle-stimulating hormone concentrations, as well as reduced sex hormone concentrations and a reduction in the bone age/chronological age ratio compared to baseline. CONCLUSIONS: The trial revealed that CPP was effectively treated in most patients who received leuprorelin for nearly 2 years. Any drug-related AEs were reported with low incidence (<5%) and were consistent with the known safety profile of leuprorelin. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (registration number: NCT02427958).

Integrated epigenetic biomarkers in circulating cell-free DNA as a robust classifier for pancreatic cancer.

BACKGROUND: The high lethal rate of pancreatic cancer is partly due to a lack of efficient biomarkers for screening and early diagnosis. We attempted to develop effective and noninvasive methods using 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) markers from circulating cell-free DNA (cfDNA) for the detection of pancreatic ductal adenocarcinoma (PDAC). RESULTS: A 24-feature 5mC model that can accurately discriminate PDAC from healthy controls (area under the curve (AUC) = 0.977, sensitivity = 0.824, specificity = 1) and a 5hmC prediction model with 27 features demonstrated excellent detection power in two distinct validation sets (AUC = 0.992 and 0.960, sensitivity = 0.786 and 0.857, specificity = 1 and 0.993). The 51-feature model combining 5mC and 5hmC markers outperformed both of the individual models, with an AUC of 0.997 (sensitivity = 0.938, specificity = 0.955) and particularly an improvement in the prediction sensitivity of PDAC. In addition, the weighted diagnosis score (wd-score) calculated with the 5hmC model can distinguish stage I patients from stage II-IV patients. CONCLUSIONS: Both 5mC and 5hmC biomarkers in cfDNA are effective in PDAC detection, and the 5mC-5hmC integrated model significantly improve the detection sensitivity.

Prodrug-Loaded Zirconium Carbide Nanosheets as a Novel Biophotonic Nanoplatform for Effective Treatment of Cancer.

Conventional chemotherapy and photothermal therapy (PTT) face many major challenges, including systemic toxicity, low bioavailability, ineffective tissue penetration, chemotherapy/hyperthermia-induced inflammation, and tumor angiogenesis. A versatile nanomedicine offers an exciting opportunity to circumvent the abovementioned limitations for their successful translation into clinical practice. Here, a promising biophotonic nanoplatform is developed based on the zirconium carbide (ZrC) nanosheet as a deep PTT-photosensitizer and on-demand designed anticancer prodrug SN38-Nif, which is released and activated by photothermia and tumor-overexpressed esterase. In vitro and in vivo experimental evidence shows the potent anticancer effects of the integrated ZrC@prodrug biophotonic nanoplatform by specifically targeting malignant cells, chemotherapy/hyperthermia-induced tumor inflammation, and angiogenesis. In mouse models, the ZrC@prodrug system markedly inhibits tumor recurrence, metastasis, inflammation and angiogenesis. The findings unravel a promising biophotonic strategy for precision treatment of cancer.

Eradication of tumor growth by delivering novel photothermal selenium-coated tellurium nanoheterojunctions.

Two-dimensional nanomaterial-based photothermal therapy (PTT) is currently under intensive investigation as a promising approach toward curative cancer treatment. However, high toxicity, moderate efficacy, and low uniformity in shape remain critical unresolved issues that hamper their clinical application. Thus, there is an urgent need for developing versatile nanomaterials to meet clinical expectations. To achieve this goal, we developed a stable, highly uniform in size, and nontoxic nanomaterials made of tellurium-selenium (TeSe)-based lateral heterojunction. Systemic delivery of TeSe nanoparticles in mice showed highly specific accumulation in tumors relative to other healthy tissues. Upon exposure to light, TeSe nanoparticles nearly completely eradicated lung cancer and hepatocellular carcinoma in preclinical models. Consistent with tumor suppression, PTT altered the tumor microenvironment and induced immense cancer cell apoptosis. Together, our findings demonstrate an exciting and promising PTT-based approach for cancer eradication.

Switching harmful visceral fat to beneficial energy combustion improves metabolic dysfunctions.

Visceral fat is considered the genuine and harmful white adipose tissue (WAT) that is associated to development of metabolic disorders, cardiovascular disease, and cancer. Here, we present a new concept to turn the harmful visceral fat into a beneficial energy consumption depot, which is beneficial for improvement of metabolic dysfunctions in obese mice. We show that low temperature-dependent browning of visceral fat caused decreased adipose weight, total body weight, and body mass index, despite increased food intake. In high-fat diet-fed mice, low temperature exposure improved browning of visceral fat, global metabolism via nonshivering thermogenesis, insulin sensitivity, and hepatic steatosis. Genome-wide expression profiling showed upregulation of WAT browning-related genes including Cidea and Dio2. Conversely, Prdm16 was unchanged in healthy mice or was downregulated in obese mice. Surgical removal of visceral fat and genetic knockdown of UCP1 in epididymal fat largely ablated low temperature-increased global thermogenesis and resulted in the death of most mice. Thus, browning of visceral fat may be a compensatory heating mechanism that could provide a novel therapeutic strategy for treating visceral fat-associated obesity and diabetes.

Applications of a novel tumor-grading-metastasis staging system for pancreatic neuroendocrine tumors: An analysis of surgical patients from a Chinese institution.

The ability to stratify patients with pancreatic neuroendocrine tumors (p-NETs) into prognostic groups has been hindered by the absence of a commonly accepted staging system. Both the 7th tumor-node-metastasis (TNM) staging guidelines by the American Joint Committee on Cancer (AJCC) and the 2010 grading classifications by the World Health Organization (WHO) were validated to be unsatisfactory.We aim to evaluate the feasibility of combining the latest AJCC and WHO criteria to devise a novel tumor-grading-metastasis (TGM) staging system. We also sought to examine the stage-specific survival rates and the prognostic value of this new TGM system for p-NETs.Data of 120 patients with surgical resection and histopathological diagnosis of p-NETs from January 2004 to February 2014 in our institution were retrospectively collected and analyzed. Based on the AJCC and WHO criteria, we replaced the stage N0 and N1 with stage Ga (NET G1 and NET G2) and Gb (NET G3 and MANEC) respectively, without changes of the definition of T or M stage. The present novel TGM staging system was grouped as follows: stage I was defined as T1-2, Ga, M0; stage II as T3, Ga, M0 or as T1-3, Gb, M0; stage III as T4, Ga-b, M0 and stage IV as any T, M1.The new TGM staging system successfully distributed 55, 42, 12, and 11 eligible patients in stage I to IV, respectively. Differences of survival compared stage I with III and IV for patients with p-NETs were both statistically significant (P < 0.001), as well as those of stage II with III and IV (P < 0.001). Patients in stage I showed better a survival than those in stage II, whereas difference between stages III and IV was not notable (P = 0.001, P = 0.286, respectively). In multivariate models, when the TGM staging system was evaluated in place of the individual T, G, and M variables, this new criteria were proven to be an independent predictor of survival for surgically resected p-NETs (P < 0.05).Stratifying patients well, the current proposed TGM staging system was predictive for overall survival of p-NETs and could be more widely applied in clinical practice.

Role of Notch signaling pathway in gastric cancer: a meta-analysis of the literature.

AIM: To perform a meta-analysis to quantitatively summarize the evidence for the association between the Notch signaling pathway and gastric cancer (GC). METHODS: An electronic search of the MEDLINE, EMBASE and Chinese National Knowledge Infrastructure, which contain articles published from 1966 onwards, was conducted to select studies for this meta-analysis. RESULTS: Fifteen studies with a total of 1547 gastric cancer cases and 450 controls were included in this meta-analysis. Overall, the expression of Notch1, Notch2, Delta-like 4 and Hes1 was significantly higher in tumor tissues of GC compared to normal tissues. Specifically, stratified analyses showed that significantly increased expression of Notch1 was associated with non-cardia location, > 5 cm size, diffuse type, positive lymphovascular invasion and distal metastasis. Statistically significant higher expression of Notch3 was found in diffuse type GC. Jagged1 was also significantly over-expressed in diffuse type and poor differentiation type of GC. DLL4 was significantly over-expressed in advanced T stage, N stage and TNM stage in GC patients. However, the stratified analysis showed that there was no statistically significant difference in Hes1 expression between different subgroups. Sporadic reports showed that Notch1 and Jagged1 were independent poor prognostic predictors in GC. CONCLUSION: The Notch signaling pathway plays an important role in tumor progression of gastric cancer.

Preventive effects of Mycobacterium vaccae on HIV-associated tuberculosis: a systematic review.

OBJECTIVE: To evaluate the effectiveness and safety of Mycobacterium vaccae (M.vaccae, MV) for prevention of HIV-associated tuberculosis (TB). METHODS: MEDLINE, Embase, Biosis, the Cochrane Central Register of Controlled Trials, SCI, CBM, VIP, and CNKI were searched for relevant randomized controlled trials (RCTs) and non-randomized controlled trials (NRCTs). The GRADE approach was used for quality assessment. Data were analyzed using RevMan 5.0 software. RESULTS: were described or pooled using relative risks (RRs) for binary outcomes with 95% confidence intervals (CIs). Results Seven studies were included, and the methodological quality assessment found there was a risk of methodological bias. The evidence quality of the critical endpoint was moderate. The incidence of definite TB was (33/1006 vs. 52/1007, P = 0.03). The levels of IFN-γ response to M. vaccae sonicate (MVS) in MV recipients increased compared to baseline or control groups after three or five doses. MV recipients' level of lymphocyte proliferation assays (LPAs) in response to MVS was higher than that of the saline group after a five-dose series (RR = 2.49, 95% CI 1.40 to 4.41, P = 0.002). Compared to hepatitis B vaccine (HBV) recipients, LPAs to MVS were not significantly different in the MV group vs. saline group, or vs. HBV, after a three-dose series (RR and 95% CI were 0.20 (-0.03 to 0.44) and 1.13 (0.26 to 4.91), respectively). Changes in CD4+ cell count and HIV viral load after immunization were not statistically significant. MV immunization had no systematic adverse effects. CONCLUSION: The current evidence indicates that MV is safe and well-tolerated. It appears to prevent HIV-infected patients with CD4+≥ 200/mm(3) from contracting TB by enhancing their immunogenicity. Yet, because of the relatively low quality of the available evidence, well-designed and -conducted RCTs are needed.