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Regulation of the programming of tumour-associated macrophages (TAMs) controls tumour growth and anti-tumour immunity. We examined the role of FGF2 in that regulation. Tumours in mice genetically deficient in low-molecular weight FGF2 (FGF2 LMW ) regress dependent on T cells. Yet, TAMS not T cells express FGF receptors. Bone marrow derived-macrophages from Fgf2 LMW−/− mice co-injected with cancer cells reduce tumour growth and express more inflammatory cytokines. FGF2 is induced in the tumour microenvironment following fractionated radiation in murine tumours consistent with clinical reports. Combination treatment of in vivo tumours with fractionated radiation and a blocking antibody to FGF2 prolongs tumour growth delay, increases long-term survival and leads to a higher iNOS + /CD206 + TAM ratio compared to irradiation alone. These studies show for the first time that FGF2 affects macrophage programming and is a critical regulator of immunity in the tumour microenvironment. Macrophages contribute to tumour progression and response to therapy. Here, the authors show that absence of FGF2 in the tumour microenvironment reduces tumour growth and enhances the anti-tumour immune response by altering macrophage polarization. As a result, disruption of this macrophage programming by anti-FGF2 blocking antibodies enhances the outcome from radiotherapy. 

The stromal microenvironment and particularly the macrophage component of primary tumors influence their malignant potential. However, at the metastatic site the role of these cells and their mechanism of actions for establishment and growth of metastases remain largely unknown. Using animal models of breast cancer metastasis, we show that a population of host macrophages displaying a distinct phenotype is recruited to extravasating pulmonary metastatic cells regardless of species of origin. Ablation of this macrophage population through three independent means (genetic and chemical) showed that these macrophages are required for efficient metastatic seeding and growth. Importantly, even after metastatic growth is established, ablation of this macrophage population inhibited subsequent growth. Furthermore, imaging of intact lungs revealed that macrophages are required for efficient tumor cell extravasation. These data indicate a direct enhancement of metastatic growth by macrophages through their effects on tumor cell extravasation, survival and subsequent growth and identifies these cells as a new therapeutic target for treatment of metastatic disease.

Emerging evidence suggests a role for radiation in eliciting anti‐tumour immunity. We aimed to investigate the role of macrophages in modulating the immune response to radiation. Irradiation to murine tumours generated from colorectal (MC38) and pancreatic (KPC) cell lines induced colony‐stimulating factor 1 (CSF‐1). Coincident with the elevation in CSF‐1, macrophages increased in tumours, peaking 5 days following irradiation. These tumour‐associated macrophages (TAMs) were skewed towards an immunosuppressive phenotype. Macrophage depletion via anti‐CSF (aCSF) reduced macrophage numbers, yet only achieved tumour growth delay when combined with radiation. The tumour growth delay from aCSF after radiation was abrogated by depletion of CD8 T cells. There was enhanced recognition of tumour cell antigens by T cells isolated from irradiated tumours, consistent with increased antigen priming. The addition of anti‐PD‐L1 (aPD‐L1) resulted in improved tumour suppression and even regression in some tumours. In summary, we show that adaptive immunity induced by radiation is limited by the recruitment of highly immunosuppressive macrophages. Macrophage depletion partly reduced immunosuppression, but additional treatment with anti‐PD‐L1 was required to achieve tumour regression. Synopsis Increased CSF‐1 is here observed in response to tumour irradiation. Subsequent recruitment of immunosuppressive macrophages rendered the tumour microenvironment resistant to immune‐mediated tumour cell killing. Blocking CSF‐1 reduced tumour‐associated macrophages and increased sensitivity to immune checkpoint blockade. Irradiation stimulates CSF‐1 secretion by tumour cells. Immunosuppressive macrophages are increased in the tumour microenvironment after irradiation. Macrophage depletion via anti‐CSF permits CD8 + T‐cell‐mediated tumour cell killing. Macrophage depleted tumours are more sensitive to immune checkpoint blockade. Graphical Abstract Increased CSF‐1 is here observed in response to tumour irradiation. Subsequent recruitment of immunosuppressive macrophages rendered the tumour microenvironment resistant to immune‐mediated tumour cell killing. Blocking CSF‐1 reduced tumour‐associated macrophages and increased sensitivity to immune checkpoint blockade.

RhoC is a member of the Rho GTPase family that is implicated in cancer progression by stimulating cancer cell invasiveness. Here we report that RhoC regulates the interaction of cancer cells with vascular endothelial cells (ECs), a crucial step in the metastatic process. RhoC depletion by RNAi reduces PC3 prostate cancer cell adhesion to ECs, intercalation between ECs as well as transendothelial migration in vitro. Depletion of the kinases ROCK1 and ROCK2, two known RhoC downstream effectors, similarly decreases cancer interaction with ECs. RhoC also regulates the extension of protrusions made by cancer cells on vascular ECs in vivo. Transient RhoC depletion is sufficient to reduce both early PC3 cell retention in the lungs and experimental metastasis formation in vivo. Our results indicate RhoC plays a central role in cancer cell interaction with vascular ECs, which is a critical event for cancer progression. •RhoC acts in cancer cells to mediate their interaction with endothelial cells in vitro and in vivo.•RhoC regulates cancer cell attachment to and insertion between endothelial cells prior to transendothelial migration.•The RhoC effectors ROCK1 and ROCK2 act similarly to regulate cancer cell interaction with endothelial cells.•Transient RhoC depletion is sufficient to reduce cancer cell survival in lung blood vessels and metastasis formation.

MicroRNAs (miRNAs) in extracellular vesicles (EVs) play essential roles in cancer initiation and progression. Quantitative measurements of EV miRNAs are critical for cancer diagnosis and longitudinal monitoring. Traditional PCR‐based methods, however, require multi‐step procedures and remain as bulk analysis. Here, the authors introduce an amplification‐free and extraction‐free EV miRNA detection method using a CRISPR/Cas13a sensing system. CRISPR/Cas13a sensing components are encapsulated in liposomes and delivered them into EVs through liposome‐EV fusion. This allows for accurately quantify specific miRNA‐positive EV counts using 1 × 108 EVs. The authors show that miR‐21‐5p‐positive EV counts are in the range of 2%–10% in ovarian cancer EVs, which is significantly higher than the positive EV counts from the benign cells (<0.65%). The result show an excellent correlation between bulk analysis with the gold‐standard method, RT‐qPCR. The authors also demonstrate multiplexed protein‐miRNA analysis in tumor‐derived EVs by capturing EpCAM‐positive EVs and quantifying miR‐21‐5p‐positive ones in the subpopulation, which show significantly higher counts in the plasma of cancer patients than healthy controls. The developed EV miRNA sensing system provides the specific miRNA detection method in intact EVs without RNA extraction and opens up the possibility of multiplexed single EV analysis for protein and RNA markers. An amplification‐free and extraction‐free extracellular vesicle (EV) miRNA detection method using CRISPR/Cas13a technology is reported. The CRISPR/Cas13a sensing components are encapsulated in liposomes and deliver them into EVs through liposome‐EV fusion. The new approach enables multiplexed protein and RNA analysis in intact EVs, quantifying specific miRNA‐positive tumor‐derived EVs in human plasma samples for more accurate cancer diagnosis.

Background Timely administration of antibiotics is one of the most important interventions in reducing mortality in sepsis. However, administering antibiotics within a strict time threshold in all patients suspected with sepsis will require huge amount of effort and resources and may increase the risk of unintentional exposure to broad-spectrum antibiotics in patients without infection with its consequences. Thus, controversy still exists on whether clinicians should target different time-to-antibiotics thresholds for patients with sepsis versus septic shock. Methods This study analyzed prospectively collected data from an ongoing multicenter cohort of patients with sepsis identified in the emergency department. Adjusted odds ratios (ORs) were compared for in-hospital mortality of patients who had received antibiotics within 1 h to that of those who did not. Spline regression models were used to assess the association of time-to-antibiotics as continuous variables and increasing risk of in-hospital mortality. The differences in the association between time-to-antibiotics and in-hospital mortality were assessed according to the presence of septic shock. Results Overall, 3035 patients were included in the analysis. Among them, 601 (19.8%) presented with septic shock, and 774 (25.5%) died. The adjusted OR for in-hospital mortality of patients whose time-to-antibiotics was within 1 h was 0.78 (95% confidence interval [CI] 0.61–0.99; p  = 0.046). The adjusted OR for in-hospital mortality was 0.66 (95% CI 0.44–0.99; p  = 0.049) and statistically significant in patients with septic shock, whereas it was 0.85 (95% CI 0.64–1.15; p  = 0.300) in patients with sepsis but without shock. Among patients who received antibiotics within 3 h, those with septic shock showed 35% ( p  = 0.042) increased risk of mortality for every 1-h delay in antibiotics, but no such trend was observed in patients without shock. Conclusion Timely administration of antibiotics improved outcomes in patients with septic shock; however, the association between early antibiotic administration and outcome was not as clear in patients with sepsis without shock.

Severe fever with thrombocytopenia syndrome virus was first discovered in 2009 as the causative agent of severe fever with thrombocytopenia syndrome. Despite its potential threat to public health, no prophylactic vaccine is yet available. This study developed a heterologous prime-boost strategy comprising priming with recombinant replication-deficient human adenovirus type 5 (rAd5) expressing the surface glycoprotein, Gn, and boosting with Gn protein. This vaccination regimen induced balanced Th1/Th2 immune responses and resulted in potent humoral and T cell-mediated responses in mice. It elicited high neutralizing antibody titers in both mice and non-human primates. Transcriptome analysis revealed that rAd5 and Gn proteins induced adaptive and innate immune pathways, respectively. This study provides immunological and mechanistic insight into this heterologous regimen and paves the way for future strategies against emerging infectious diseases.

•Our study proposed a method for measuring CBF and CSF simultaneously with pCASL.•The measured cranial and caudal CSF pulsations showed high correlation with PC MRI.•The measured CSF pulsation showed a positive correlation with the whole brain CBF.•The CSF-CBF correlations were highest in basal ganglia (caudate, putamen, pallidum).•It detects functional motor changes in CBF and CSF pulsation simultaneously. In the brain clearance system, the movement of cerebrospinal fluid (CSF) plays a key role in processing waste products. Previous studies have shown that CSF flow interacts significantly with cerebral blood flow (CBF) during brain waste clearance, but there are no simultaneous measurements and comparisons of these two metrics in humans. This study introduces a novel method for simultaneously measuring CSF pulsatile movement and CBF using pseudo-continuous arterial spin labeling (pCASL) MRI. We conducted a comparative analysis of the correlation between CBF and CSF pulsatile movement in human subjects during breath-holding and motor task conditions. Our findings demonstrate the effectiveness of our proposed technique in measuring CSF pulsatile movement, as validated by comparing results with phase-contrast MRI at corresponding locations. Importantly, we observed a robust positive correlation between CBF and CSF pulsation concurrently measured through pCASL during breath-holding. Furthermore, through inter-subject comparisons of regional CBF and CSF pulsation, we established that higher blood perfusion in putamen, caudate, and pallidum regions, which are included in basal ganglia structure, corresponds to greater CSF pulsatile movement. Our motor tasks significantly increased CBF in the motor cortex, and CSF pulsation measured in the dorsal part around cisterna magna showed a decreasing tendency in the motor condition compared to the resting state, aligning with the Monroe-Kelly doctrine. Accordingly, these results demonstrate the feasibility of simultaneous measurement of CBF and CSF pulsation using the proposed pCASL technique in humans, which warrants further investigation.

Neuromorphic computing targets the hardware embodiment of neural network, and device implementation of individual neuron and synapse has attracted considerable attention. The emulation of synaptic plasticity has shown promising results after the advent of memristors. However, neuronal intrinsic plasticity, which involves in learning process through interactions with synaptic plasticity, has been rarely demonstrated. Synaptic and intrinsic plasticity occur concomitantly in learning process, suggesting the need of the simultaneous implementation. Here, we report a neurosynaptic device that mimics synaptic and intrinsic plasticity concomitantly in a single cell. Threshold switch and phase change memory are merged in threshold switch-phase change memory device. Neuronal intrinsic plasticity is demonstrated based on bottom threshold switch layer, which resembles the modulation of firing frequency in biological neuron. Synaptic plasticity is also introduced through the nonvolatile switching of top phase change layer. Intrinsic and synaptic plasticity are simultaneously emulated in a single cell to establish the positive feedback between them. A positive feedback learning loop which mimics the retraining process in biological system is implemented in threshold switch-phase change memory array for accelerated training. Synaptic plasticity and neuronal intrinsic plasticity are both involved in the learning process of hardware artificial neural network. Here, Lee et al. integrate a threshold switch and a phase change memory in a single device, which emulates biological synaptic and intrinsic plasticity simultaneously.

We examined the residence time, seepage rate, and submarine groundwater discharge (SGD)-driven dissolved nutrients and organic matter in Hwasun Bay, Jeju Island, Korea during the occurrence of a typhoon, Kong-rey, using a humic fluorescent dissolved organic matter (FDOM H )-Si mass balance model. The study period spanned October 4–10, 2018. One day after the typhoon, the residence time and seepage rate were calculated to be 1 day and 0.51 m day −1 , respectively, and the highest SGD-driven fluxes of chemical constituents were estimated (1.7 × 10 6  mol day −1 for dissolved inorganic nitrogen, 0.1 × 10 6  mol day −1 for dissolved inorganic phosphorus (DIP), 1.1 × 10 6  mol day −1 for dissolved silicon, 0.5 × 10 6  mol day −1 for dissolved organic carbon, 1.6 × 10 6  mol day −1 for dissolved organic nitrogen, 0.4 × 10 6 mol day −1 for particulate organic carbon, and 38 × 10 6  g QS day −1 for FDOM H ). SGD-driven fluxes of dissolved nutrient and organic matter were over 90% of the total input fluxes in Hwasun Bay. Our results highlight the potential of using the FDOM H -Si mass balance model to effectively measure SGD within a specific area (i.e., volcanic islands) under specific weather conditions (i.e., typhoon/storm). In oligotrophic oceanic regions, SGD-driven chemical fluxes from highly permeable islands considerably contribute to coastal nutrient budgets and coastal biological production.