miRNA-21-5p is an important contributor to the promotion of injured peripheral nerve regeneration using hypoxia-pretreated bone marrow-derived neural crest cells.

JOURNAL/nrgr/04.03/01300535-202501000-00035/figure1/v/2024-05-14T021156Z/r/image-tiff Our previous study found that rat bone marrow-derived neural crest cells (acting as Schwann cell progenitors) have the potential to promote long-distance nerve repair. Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication. Nevertheless, the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear. To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves, we collected conditioned culture medium from hypoxia-pretreated neural crest cells, and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation. The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells. We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells. Subsequently, to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons, we used a microfluidic axonal dissociation model of sensory neurons in vitro, and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons, which was greatly dependent on loaded miR-21-5p. Finally, we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb, as well as muscle tissue morphology of the hind limbs, were obviously restored. These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p. miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome. This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves, and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.

The Chinese version of the Nursing Student Academic Resilience Inventory: A validity and reliability study.

AIM: To translate and adapt the Nursing Student Academic Resilience Inventory (NSARI) into Chinese and assess its validity and reliability among Chinese nursing students. BACKGROUND: Nursing students frequently encounter stress during their clinical education and academic resilience is an important skill to help students withstand stress. The NSARI is a valid and reliable tool for assessing the level of academic resilience of nursing students during clinical practice. Currently, there is no valid and reliable measurement tool to assess academic resilience for nursing students in China. DESIGN: A descriptive, methodological and cross-sectional design was used. METHOD: This study was conducted on 600 nursing students in Northeast China. A socio-demographic form, the Chinese version of the NSARI and the nurse resilience scale were used for data collection between May to November 2023. The exploratory factor analysis and confirmatory factor analysis samples comprised 300 students, respectively, to test the structural validity of the inventory. In addition, internal consistency and invariance analyses were conducted to assess the reliability of the inventory. RESULTS: The Chinese version of NSARI comprises 24 items separated into six dimensions. Exploratory factor analysis extracted six factors, with a cumulative variance contribution rate of 71.908 %. Confirmatory factor analysis showed a satisfactory fit. Cronbach's alpha coefficient for the internal consistency of the total inventory was 0.939 with a test-retest stability reliability value of 0.957. CONCLUSION: The Chinese version of NSARI is a valid and reliable measurement tool for assessing the level of academic resilience of nursing students during clinical placement.

Effects of a Remote Multimodal Psychoeducational Intervention Nursing Program on Mental Health and Quality of Life of Renal Cell Carcinoma Survivors: A Retrospective Study.

BACKGROUND: Undergoing surgery for renal cell carcinoma can potentially compromise the mental well-being and overall quality of life of survivors. Long-term psychological education interventions that are delivered remotely through various modalities have shown promise in enhancing the psychological well-being and quality of life of cancer patients. This study investigates the effect of remote multimodal psychoeducational interventions on mental well-being and quality of life of renal cell carcinoma survivors. METHODS: A retrospective study was conducted to compare patients receiving remote psychological interventions (exposure group) with those receiving standard care (control group). Following the interventions, various data sets including general demographic information, and assessments from the Hamilton anxiety scale (HAMA), Hamilton depression scale (HAMD), the Brief Fatigue Inventory-Chinese version (BFI-C), the Distress Thermometer (DT), and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) were gathered and analysed for comparison. RESULTS: This study included 116 renal cell carcinoma survivors, with 52 in the exposure group and 64 in the control group. Baseline characteristics were not significantly different between the two groups (p > 0.05). After the intervention, the exposure group had significantly lower scores than the control group on HAMA (14.63 vs. 16.66, p < 0.001), HAMD (13.63 vs. 16.36, p < 0.001), BFI-C (52.31 vs. 57.65, p < 0.001), and DT (3.94 vs. 4.98, p < 0.001). Additionally, the exposure group had significantly higher total score of EORTC QLQ-C30 (69.22 vs. 65.59, p < 0.001) than the control group. CONCLUSIONS: Remote multimodal psychoeducational interventions demonstrate a notable impact in mitigating adverse emotions, exhaustion, and discomfort experienced by survivors of renal cell carcinoma. Such interventions should be actively promoted in clinical practice.

40 Hz light flickering facilitates the glymphatic flow via adenosine signaling in mice.

The glymphatic-lymphatic system is increasingly recognized as fundamental for the homeostasis of the brain milieu since it defines cerebral spinal fluid flow in the brain parenchyma and eliminates metabolic waste. Animal and human studies have uncovered several important physiological factors regulating the glymphatic system including sleep, aquaporin-4, and hemodynamic factors. Yet, our understanding of the modulation of the glymphatic system is limited, which has hindered the development of glymphatic-based treatment for aging and neurodegenerative disorders. Here, we present the evidence from fluorescence tracing, two-photon recording, and dynamic contrast-enhanced magnetic resonance imaging analyses that 40 Hz light flickering enhanced glymphatic influx and efflux independently of anesthesia and sleep, an effect attributed to increased astrocytic aquaporin-4 polarization and enhanced vasomotion. Adenosine-A2A receptor (A2AR) signaling emerged as the neurochemical underpinning of 40 Hz flickering-induced enhancement of glymphatic flow, based on increased cerebrofluid adenosine levels, the abolishment of enhanced glymphatic flow by pharmacological or genetic inactivation of equilibrative nucleotide transporters-2 or of A2AR, and by the physical and functional A2AR-aquaporin-4 interaction in astrocytes. These findings establish 40 Hz light flickering as a novel non-invasive strategy of enhanced glymphatic flow, with translational potential to relieve brain disorders.

An Internal Marking Method for Adult Spodoptera frugiperda Smith Using an Artificial Diet Containing Calco Oil Red N-1700.

As a migratory invasive pest, Spodoptera frugiperda (fall armyworm, FAW) has recently posed a serious threat to food security in newly invaded areas (especially in Africa and Asia). Understanding its migration (or dispersal) patterns in newly invaded areas is crucial for regional forecasting and management efforts. By screening an appropriate marking technique to conduct mark-release-recapture (MRR) experiments, the migration patterns of the FAW can be effectively studied. In this study, we added different concentrations of Calco Oil Red N-1700 (an oil-soluble marker) to a self-made artificial diet and assessed the rearing and marking efficacy. The results indicated that a concentration of 0.2% of Calco Oil Red N-1700 in the diet was optimal for marking adult FAWs. The biological indicators (e.g., developmental duration, reproductive parameters, and flight ability) of FAWs fed this diet were basically consistent with those of FAWs fed a normal diet, with a larval stage of 15.46 days, a pupal stage of 9.81 days, a pupal mass of 278.18 mg, an adult longevity of 15.41 days, and an egg deposition count of 1503.51. Meanwhile, the flight distance, duration, and velocity were 24.91 km, 7.16 h, and 3.40 km/h, respectively (12 h tethered-flight tests), without difference with the control. Females and males exhibited distinctive marking colors (red or pink) that persisted for at least 5 and 9 days, respectively. This study developed an economically effective internal marking method for the adult FAW, laying the foundation for conducting MRR experiments. This will help clarify the migration behavior and routes of the FAW, providing a scientific basis for formulating effective pest management strategies.

Effective Prevention and Treatment of Acute Leukemias in Mice by Activation of Thermogenic Adipose Tissues.

Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are common hematological malignancies in adults. Despite considerable research advances, the development of standard therapies, supportive care, and prognosis for the majority of AML and ALL patients remains poor and the development of new effective therapy is urgently needed. Here, it is reported that activation of thermogenic adipose tissues (TATs) by cold exposure or ß3-adrenergic receptor agonists markedly alleviated the development and progression of AML and ALL in mouse leukemia models. TAT activation (TATA) monotherapy substantially reduces leukemic cells in bone marrow and peripheral blood, and suppresses leukemic cell invasion, including hepatomegaly and splenomegaly. Notably, TATA therapy prolongs the survivals of AML- and ALL-bearing mice. Surgical removal of thermogenic brown adipose tissue (BAT) or genetic deletion of uncoupling protein 1 (UCP1) largely abolishes the TATA-mediated anti-leukemia effects. Metabolomic pathway analysis demonstrates that glycolytic metabolism, which is essential for anabolic leukemic cell growth, is severely impaired in TATA-treated leukemic cells. Moreover, a combination of TATA therapy with chemotherapy produces enhanced anti-leukemic effects and reduces chemotoxicity. These data provide a new TATA-based therapeutic paradigm for the effective treatment of AML, ALL, and likely other types of hematological malignancies.

Tumor angiogenesis and anti-angiogenic therapy.

ABSTRACT: Anti-angiogenic drugs (AADs), which mainly target the vascular endothelial growth factor-A signaling pathway, have become a therapeutic option for cancer patients for two decades. During this period, tremendous clinical experience of anti-angiogenic therapy has been acquired, new AADs have been developed, and the clinical indications for AAD treatment of various cancers have been expanded using monotherapy and combination therapy. However, improvements in the therapeutic outcomes of clinically available AADs and the development of more effective next-generation AADs are still urgently required. This review aims to provide historical and perspective views on tumor angiogenesis to allow readers to gain mechanistic insights and learn new therapeutic development. We revisit the history of concept initiation and AAD discovery, and summarize the up-to-date clinical translation of anti-angiogenic cancer therapy in this field.

Identifying determinants of spatial agglomeration of healthcare resources by using spatial econometric methods: a longitudinal study in China.

Background: Healthcare resources are necessary for individuals to maintain their health. The Chinese government has implemented policies to optimize the allocation of healthcare resources and achieve the goal of equality in healthcare for the Chinese people since the implementation of the new medical reform in 2009. Given that no study has investigated regional differences from the perspective of healthcare resource agglomeration, this study aimed to investigate China's healthcare agglomeration from 2009 to 2017 in China and identify its determinants to provide theoretical evidence for the government to develop and implement scientific and rational healthcare policies. Methods: The study was conducted using 2009-2017 data to analyze health-resource agglomeration on institutions, beds, and workforce in China. An agglomeration index was applied to evaluate the degree of regional differences in healthcare resource allocation, and spatial econometric models were constructed to identify determinants of the spatial agglomeration of healthcare resources. Results: From 2009 to 2017, all the agglomeration indexes of healthcare exhibited a downward trend except for the number of institutions in China. Population density (PD), government health expenditures (GHE), urban resident's disposable income (URDI), geographical location (GL), and urbanization level (UL) all had positive significant effects on the agglomeration of beds, whereas both per capita health expenditures (PCHE), number of college students (NCS), and maternal mortality rate (MMR) had significant negative effects on the agglomeration of institutions, beds, and the workforce. In addition, population density (PD) and per capita gross domestic product (PCGDP) in one province had negative spatial spillover effects on the agglomeration of beds and the workforce in neighboring provinces. However, MMR had a positive spatial spillover effect on the agglomeration of beds and the workforce in those regions. Conclusion: The agglomeration of healthcare resources was observed to remain at an ideal level in China from 2009 to 2017. According to the significant determinants, some corresponding targeted measures for the Chinese government and other developing countries should be fully developed to balance regional disparities in the agglomeration of healthcare resources across administrative regions.

Effectiveness of shared decision-making for mode of delivery after caesarean section: A systematic review and meta-analysis of randomized controlled trials.

AIM: To review the content, format and effectiveness of shared decision-making interventions for mode of delivery after caesarean section for pregnant women. DESIGN: Systematic review and meta-analysis. METHODS: Six databases (PubMed, Web of science Core Collection, Cochrance Network, Embase, CINAHL, PsycINFO) were searched starting at the time of establishment of the database to May 2023. Following the PRISMAs and use Review Manager 5.3 software for meta-analysis. Two review authors independently assessed the quality of the studies using the risk of bias 2 tool. The protocol was registered in PROSPERO (CRD42023410536). RESULTS: The search strategy obtained 1675 references. After abstract and full text screening, a total of seven studies were included. Shared decision-making interventions include decision aids and counselling that can help pregnant women analyse the pros and cons of various options and help them make decisions that are consistent with their values. The pooled results showed that shared decision-making intervention alleviated decisional conflicts regarding mode of delivery after caesarean section, but had no effect on knowledge and informed choice. CONCLUSION: The results of our review suggest that shared decision-making is an effective intervention to improve the quality of decision-making about the mode of delivery of pregnant women after caesarean section. However, due to the low quality of the evidence, it is recommended that more studies be conducted in the future to improve the quality of the evidence. CORRELATION WITH CLINICAL PRACTICE: This systematic review and meta-analysis provides evidence for the effectiveness of shared decision-making for mode of delivery after cesarean section and may provide a basis for the development of intervention to promote the participation of pregnant women in the decision-making process.

Assessing the Content and Effect of Web-Based Decision Aids for Postmastectomy Breast Reconstruction: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Web-based decision aids have been shown to have a positive effect when used to improve the quality of decision-making for women facing postmastectomy breast reconstruction (PMBR). However, the existing findings regarding these interventions are still incongruent, and the overall effect is unclear. OBJECTIVE: We aimed to assess the content of web-based decision aids and its impact on decision-related outcomes (ie, decision conflict, decision regret, informed choice, and knowledge), psychological-related outcomes (ie, satisfaction and anxiety), and surgical decision-making in women facing PMBR. METHODS: This systematic review and meta-analysis followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A total of 6 databases, PubMed, Embase, Cochrane Library, CINAHL, PsycINFO, and Web of Science Core Collection, were searched starting at the time of establishment of the databases to May 2023, and an updated search was conducted on April 1, 2024. MeSH (Medical Subject Headings) terms and text words were used. The Cochrane Risk of Bias Tool for randomized controlled trials was used to assess the risk of bias. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: In total, 7 studies included 579 women and were published between 2008 and 2023, and the sample size in each study ranged from 26 to 222. The results showed that web-based decision aids used audio and video to present the pros and cons of PMBR versus no PMBR, implants versus flaps, and immediate versus delayed PMBR and the appearance and feel of the PMBR results and the expected recovery time with photographs of actual patients. Web-based decision aids help improve PMBR knowledge, decisional conflict (mean difference [MD]=-5.43, 95% CI -8.87 to -1.99; P=.002), and satisfaction (standardized MD=0.48, 95% CI 0.00 to 0.95; P=.05) but have no effect on informed choice (MD=-2.80, 95% CI -8.54 to 2.94; P=.34), decision regret (MD=-1.55, 95% CI -6.00 to 2.90 P=.49), or anxiety (standardized MD=0.04, 95% CI -0.50 to 0.58; P=.88). The overall Grading of Recommendations, Assessment, Development, and Evaluation quality of the evidence was low. CONCLUSIONS: The findings suggest that the web-based decision aids provide a modern, low-cost, and high dissemination rate effective method to promote the improved quality of decision-making in women undergoing PMBR. TRIAL REGISTRATION: PROSPERO CRD42023450496; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=450496.

Selective Oxidation of sp-Bonded Carbon in Graphdiyne/Carbon Nanotubes Heterostructures to Form Dominant Epoxy Groups for Two-Electron Oxygen Reduction.

Two-electron oxygen reduction reaction (2e- ORR) is of great significance to H2O2 production and reversible nonalkaline Zn-air batteries (ZABs). Multiple oxygen-containing sp2-bonded nanocarbons have been developed as electrocatalysts for 2e- ORR, but they still suffer from poor activity and stability due to the limited and mixed active sites at the edges as well as hydrophilic character. Herein, graphdiyne (GDY) with rich sp-C bonds is studied for enhanced 2e- ORR. First, computational studies show that GDY has a favorable formation energy for producing five-membered epoxy ring-dominated groups, which is selective toward the 2e- ORR pathway. Then based on the difference in chemical activity of sp-C bonds in GDY and sp2-C bonds in CNTs, we experimentally achieved conductive and hydrophobic carbon nanotubes (CNTs) covering O-modified GDY (CNTs/GDY-O) through a mild oxidation treatment combined with an in situ CNTs growth approach. Consequently, the CNTs/GDY-O exhibits an average Faraday efficiency of 91.8% toward H2O2 production and record stability over 330 h in neutral media. As a cathode electrocatalyst, it greatly extends the lifetime of 2e- nonalkaline ZABs at both room and subzero temperatures.

Exploring T7 RNA polymerase-assisted CRISPR/Cas13a amplification for the detection of BNP via electrochemiluminescence sensing platform.

Brain natriuretic peptide (BNP) is considered to be an important biomarker of heart failure (HF) attracting attention. However, its low concentration and short half-life in blood lead to a low-sensitivity detection of BNP, which is a challenge that has to be overcome. In this work, we propose a highly specific, highly sensitive T7 RNA polymerase-assisted clustered regularly interspaced short palindromic repeats (CRISPR)/Cas13a system to detect BNP via an electrochemiluminescence (ECL) sensing platform and incorporate exonuclease III (Exo III)-hairpin and dumbbell-shaped hybridization chain reaction (HCR) technologies. In this detection scheme, the ECL sensing platform possesses low background signal and high sensitivity. Firstly, the T7 promoter-initiated T7 RNA polymerase acts as a signal amplification technique to generate large amounts of RNAs that can activate CRISPR/Cas13a activity. Secondly, CRISPR/Cas13a is able to trans-cleave the surrounding trigger strand to produce DNA1. Thirdly, DNA1 is involved in the co-amplification reaction of Exo III and hairpin DNA, which subsequently triggers a dumbbell-shaped HCR technology. Eventually, a large number of Ru (II) molecules are inserted into the interstitial space of the dumbbell-shaped HCR to generate a strong ECL signal. The CRISPR/Cas13a possesses outstanding specificity for a single base and increased sensitivity. The tightly conformed dumbbell-shaped HCR provides higher sensitivity than the traditional linear HCR amplification technique. Ultimately, the clever combination of several amplification reactions enables the limit of detection (LOD) as low as 3.2 fg/mL. It showed promise for clinical sample testing, with recovery rates ranging from 98.4% to 103% in 5% human serum samples. This detection method offered a valuable tool for early HF detection, emphasizing the synergy of amplification strategies and specificity conferred by CRISPR/Cas13a technology.

Suppressing Zn pulverization with three-dimensional inert-cation diversion dam for long-life Zn metal batteries.

Tremendous attention has been paid to the water-associated side reactions and zinc (Zn) dendrite growth on the electrode-electrolyte interface. However, the Zn pulverization that can cause continuous depletion of active Zn metal and exacerbate hydrogen evolution is severely neglected. Here, we disclose that the excessive Zn feeding that causes incomplete crystallization is responsible for Zn pulverization formation through analyzing the thermodynamic and kinetics process of Zn deposition. On the basis, we introduce 1-ethyl-3-methylimidazolium cations (EMIm+) into the electrolyte to form a Galton-board-like three-dimensional inert-cation (3DIC) region. Modeling test shows that the 3DIC EMIm+ can induce the Zn2+ flux to follow in a Gauss distribution, thus acting as elastic sites to buffer the perpendicular diffusion of Zn2+ and direct the lateral diffusion, thus effectively avoiding the local Zn2+ accumulation and irreversible crystal formation. Consequently, anti-pulverized Zn metal deposition behavior is achieved with an average Coulombic efficiency of 99.6% at 5 mA cm-2 over 2,000 cycles and superb stability in symmetric cell over 1,200 h at -30 °C. Furthermore, the Zn||KVOH pouch cell can stably cycle over 1,200 cycles at 2 A g-1 and maintain a capacity of up to 12 mAh.

Targeting adenosine A2A receptors for early intervention of retinopathy of prematurity.

Retinopathy of prematurity (ROP) continues to pose a significant threat to the vision of numerous children worldwide, primarily owing to the increased survival rates of premature infants. The pathologies of ROP are mainly linked to impaired vascularization as a result of hyperoxia, leading to subsequent neovascularization. Existing treatments, including anti-vascular endothelial growth factor (VEGF) therapies, have thus far been limited to addressing pathological angiogenesis at advanced ROP stages, inevitably leading to adverse side effects. Intervention to promote physiological angiogenesis during the initial stages could hold the potential to prevent ROP. Adenosine A2A receptors (A2AR) have been identified in various ocular cell types, exhibiting distinct densities and functionally intricate connections with oxygen metabolism. In this review, we discuss experimental evidence that strongly underscores the pivotal role of A2AR in ROP. In particular, A2AR blockade may represent an effective treatment strategy, mitigating retinal vascular loss by reversing hyperoxia-mediated cellular proliferation inhibition and curtailing hypoxia-mediated neovascularization in oxygen-induced retinopathy (OIR). These effects stem from the interplay of endothelium, neuronal and glial cells, and novel molecular pathways (notably promoting TGF-ß signaling) at the hyperoxia phase. We propose that pharmacological targeting of A2AR signaling may confer an early intervention for ROP with distinct therapeutic benefits and mechanisms than the anti-VEGF therapy.

Research advances in microfluidic collection and detection of virus, bacterial, and fungal bioaerosols.

Bioaerosols are airborne suspensions of fine solid or liquid particles containing biological substances such as viruses, bacteria, cellular debris, fungal spores, mycelium, and byproducts of microbial metabolism. The global Coronavirus disease 2019 (COVID-19) pandemic and the previous emergence of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and influenza have increased the need for reliable and effective monitoring tools for bioaerosols. Bioaerosol collection and detection have aroused considerable attention. Current bioaerosol sampling and detection techniques suffer from long response time, low sensitivity, and high costs, and these drawbacks have forced the development of novel monitoring strategies. Microfluidic technique is considered a breakthrough for high performance analysis of bioaerosols. In recent years, several emerging methods based on microfluidics have been developed and reported for collection and detection of bioaerosols. The unique advantages of microfluidic technique have enabled the integration of bioaerosol collection and detection, which has a higher efficiency over conventional methods. This review focused on the research progress of bioaerosol collection and detection methods based on microfluidic techniques, with special attention on virus aerosols and bacterial aerosols. Different from the existing reviews, this work took a unique perspective of the targets to be collected and detected in bioaerosols, which would provide a direct index of bioaerosol categories readers may be interested in. We also discussed integrated microfluidic monitoring system for bioaerosols. Additionally, the application of bioaerosol detection in biomedicine was presented. Finally, the current challenges in the field of bioaerosol monitoring are presented and an outlook given of future developments.

Saliva Analysis Based on Microfluidics: Focusing the Wide Spectrum of Target Analyte.

Saliva is one of the most critical human body fluids that can reflect the state of the human body. The detection of saliva is of great significance for disease diagnosis and health monitoring. Microfluidics, characterized by microscale size and high integration, is an ideal platform for the development of rapid and low-cost disease diagnostic techniques and devices. Microfluidic-based saliva testing methods have aroused considerable interest due to the increasing need for noninvasive testing and frequent or long-term testing. This review briefly described the significance of saliva analysis and generally classified the targets in saliva detection into pathogenic microorganisms, inorganic substances, and organic substances. By using this classification as a benchmark, the state-of-the-art research results on microfluidic detection of various substances in saliva were summarized. This work also put forward the challenges and future development directions of microfluidic detection methods for saliva.

Mirabegron displays anticancer effects by globally browning adipose tissues.

Metabolic reprogramming in malignant cells is a hallmark of cancer that relies on augmented glycolytic metabolism to support their growth, invasion, and metastasis. However, the impact of global adipose metabolism on tumor growth and the drug development by targeting adipose metabolism remain largely unexplored. Here we show that a therapeutic paradigm of drugs is effective for treating various cancer types by browning adipose tissues. Mirabegron, a clinically available drug for overactive bladders, displays potent anticancer effects in various animal cancer models, including untreatable cancers such as pancreatic ductal adenocarcinoma and hepatocellular carcinoma, via the browning of adipose tissues. Genetic deletion of the uncoupling protein 1, a key thermogenic protein in adipose tissues, ablates the anticancer effect. Similarly, the removal of brown adipose tissue, which is responsible for non-shivering thermogenesis, attenuates the anticancer activity of mirabegron. These findings demonstrate that mirabegron represents a paradigm of anticancer drugs with a distinct mechanism for the effective treatment of multiple cancers.

Quantitative assessment of near-infrared fluorescent proteins.

Recent progress in fluorescent protein development has generated a large diversity of near-infrared fluorescent proteins (NIR FPs), which are rapidly becoming popular probes for a variety of imaging applications. However, the diversity of NIR FPs poses a challenge for end-users in choosing the optimal one for a given application. Here we conducted a systematic and quantitative assessment of intracellular brightness, photostability, oligomeric state, chemical stability and cytotoxicity of 22 NIR FPs in cultured mammalian cells and primary mouse neurons and identified a set of top-performing FPs including emiRFP670, miRFP680, miRFP713 and miRFP720, which can cover a majority of imaging applications. The top-performing proteins were further validated for in vivo imaging of neurons in Caenorhabditis elegans, zebrafish, and mice as well as in mice liver. We also assessed the applicability of the selected NIR FPs for multicolor imaging of fusions, expansion microscopy and two-photon imaging.

KRAS mutation-driven angiopoietin 2 bestows anti-VEGF resistance in epithelial carcinomas.

Defining reliable surrogate markers and overcoming drug resistance are the most challenging issues for improving therapeutic outcomes of antiangiogenic drugs (AADs) in cancer patients. At the time of this writing, no biomarkers are clinically available to predict AAD therapeutic benefits and drug resistance. Here, we uncovered a unique mechanism of AAD resistance in epithelial carcinomas with KRAS mutations that targeted angiopoietin 2 (ANG2) to circumvent antivascular endothelial growth factor (anti-VEGF) responses. Mechanistically, KRAS mutations up-regulated the FOXC2 transcription factor that directly elevated ANG2 expression at the transcriptional level. ANG2 bestowed anti-VEGF resistance as an alternative pathway to augment VEGF-independent tumor angiogenesis. Most colorectal and pancreatic cancers with KRAS mutations were intrinsically resistant to monotherapies of anti-VEGF or anti-ANG2 drugs. However, combination therapy with anti-VEGF and anti-ANG2 drugs produced synergistic and potent anticancer effects in KRAS-mutated cancers. Together, these data demonstrate that KRAS mutations in tumors serve as a predictive marker for anti-VEGF resistance and are susceptible to combination therapy with anti-VEGF and anti-ANG2 drugs.

Disruption of the Clock Component Bmal1 in Mice Promotes Cancer Metastasis through the PAI-1-TGF-ß-myoCAF-Dependent Mechanism.

The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here, it is demonstrated that the disruption of the circadian rhythm by genetic deletion of mouse brain and muscle ARNT-like 1 (Bmal1) gene, coding for the key clock transcription factor, augments an exacerbated fibrotic phenotype in various tumors. Accretion of cancer-associated fibroblasts (CAFs), especially the alpha smooth muscle actin positive myoCAFs, accelerates tumor growth rates and metastatic potentials. Mechanistically, deletion of Bmal1 abrogates expression of its transcriptionally targeted plasminogen activator inhibitor-1 (PAI-1). Consequently, decreased levels of PAI-1 in the tumor microenvironment instigate plasmin activation through upregulation of tissue plasminogen activator and urokinase plasminogen activator. The activated plasmin converts latent TGF-ß into its activated form, which potently induces tumor fibrosis and the transition of CAFs into myoCAFs, the latter promoting cancer metastasis. Pharmacological inhibition of the TGF-ß signaling largely ablates the metastatic potentials of colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma. Together, these data provide novel mechanistic insights into disruption of the circadian clock in tumor growth and metastasis. It is reasonably speculated that normalization of the circadian rhythm in patients provides a novel paradigm for cancer therapy.