Injectable polypeptide-polysaccharide depot for preventing postoperative tumor recurrence by concurrent in situ chemotherapy and brachytherapy.

Chemotherapy and radiotherapy in combination with sequence regimens are recognized as the current major strategy for suppressing postoperative tumor recurrence. However, systemic side effects and poor in-field cooperation of the two therapies seriously impair the therapeutic efficacy of patients. The combination of brachytherapy and chemotherapy through innovative biomaterials has proven to be an important strategy to achieve synergistic effects of radiotherapy and chemotherapy in-time and in-field. However, for postoperative chemoradiotherapy, as far as we know, there are few relevant reports. Herein, an injectable pH-responsive polypeptide-polysaccharide depot for concurrent in situ chemotherapy and brachytherapy was developed by encapsulating vincristine into iodine-125 radionuclide labeled hydrogel. This depot hydrogel was prepared by dynamic covalent bonds of Schiff base between aldehydeated hyaluronic acid and polyethylene glycol-polytyrosine. Therefore, this hydrogel enables smart response to tumor acidic microenvironment, rapid release of the encapsulated vincristine and an enhanced uptake effect by tumor cells, which significantly reduces IC50 of vincristine for the anaplasia Wilms' tumor cells in vitro. This depot hydrogel shows excellent stability and biocompatibility, and maintains for 14 days after in situ injection in a postoperative model of anaplasia Wilms' tumor. After injection at the cavity of tumor excision, responsively-released vincristine and the radioactive iodine-125 exerted excellent killing effects on residual tumor cells, inhibiting tumor relapse and liver metastasis of the recurrent tumor. Hence, this study proposes an effective therapeutic strategy for inhibiting anaplasia Wilms' tumor recurrence, which provides a new approach for concurrent postoperative chemo-radiotherapy and a desirable guidance in regimen execution of pediatric refractory tumors.

Probing spin hydrodynamics on a superconducting quantum simulator.

Characterizing the nature of hydrodynamical transport properties in quantum dynamics provides valuable insights into the fundamental understanding of exotic non-equilibrium phases of matter. Experimentally simulating infinite-temperature transport on large-scale complex quantum systems is of considerable interest. Here, using a controllable and coherent superconducting quantum simulator, we experimentally realize the analog quantum circuit, which can efficiently prepare the Haar-random states, and probe spin transport at infinite temperature. We observe diffusive spin transport during the unitary evolution of the ladder-type quantum simulator with ergodic dynamics. Moreover, we explore the transport properties of the systems subjected to strong disorder or a tilted potential, revealing signatures of anomalous subdiffusion in accompany with the breakdown of thermalization. Our work demonstrates a scalable method of probing infinite-temperature spin transport on analog quantum simulators, which paves the way to study other intriguing out-of-equilibrium phenomena from the perspective of transport.

Heme-Mimetic Photosensitizer with Iron-Targeting and Internalizing Properties for Enhancing PDT Activity and Promoting Infected Diabetic Wound Healing.

The management of multibacterial infections remains clinically challenging in the care and treatment of chronic diabetic wounds. Photodynamic therapy (PDT) offers a promising approach to addressing bacterial infections. However, the limited target specificity and internalization properties of traditional photosensitizers (PSs) toward Gram-negative bacteria pose significant challenges to their antibacterial efficacy. In this study, we designed an iron heme-mimetic PS (MnO2@Fe-TCPP(Zn)) based on the iron dependence of bacteria that can be assimilated by bacteria and retained in different bacteria strains (Escherichia coli, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus) and which shows high PDT antibacterial efficacy. For accelerated wound healing after antibacterial treatment, MnO2@Fe-TCPP(Zn) was loaded into a zwitterionic hydrogel with biocompatibility and antifouling properties to form a nanocomposite antibacterial hydrogel (PSB-MnO2@Fe-TCPP(Zn)). In the multibacterial infectious diabetic mouse wound model, the PSB-MnO2@Fe-TCPP(Zn) hydrogel dressing rapidly promoted skin regeneration by effectively inhibiting bacterial infections, eliminating inflammation, and promoting angiogenesis. This study provides an avenue for developing broad-spectrum antibacterial nanomaterials for combating the antibiotic resistance crisis and promoting the healing of complex bacterially infected wounds.

Quantum Simulation of Topological Zero Modes on a 41-Qubit Superconducting Processor.

Quantum simulation of different exotic topological phases of quantum matter on a noisy intermediate-scale quantum (NISQ) processor is attracting growing interest. Here, we develop a one-dimensional 43-qubit superconducting quantum processor, named Chuang-tzu, to simulate and characterize emergent topological states. By engineering diagonal Aubry-André-Harper (AAH) models, we experimentally demonstrate the Hofstadter butterfly energy spectrum. Using Floquet engineering, we verify the existence of the topological zero modes in the commensurate off-diagonal AAH models, which have never been experimentally realized before. Remarkably, the qubit number over 40 in our quantum processor is large enough to capture the substantial topological features of a quantum system from its complex band structure, including Dirac points, the energy gap's closing, the difference between even and odd number of sites, and the distinction between edge and bulk states. Our results establish a versatile hybrid quantum simulation approach to exploring quantum topological systems in the NISQ era.

Simulating Chern insulators on a superconducting quantum processor.

The quantum Hall effect, fundamental in modern condensed matter physics, continuously inspires new theories and predicts emergent phases of matter. Here we experimentally demonstrate three types of Chern insulators with synthetic dimensions on a programable 30-qubit-ladder superconducting processor. We directly measure the band structures of the 2D Chern insulator along synthetic dimensions with various configurations of Aubry-André-Harper chains and observe dynamical localisation of edge excitations. With these two signatures of topology, our experiments implement the bulk-edge correspondence in the synthetic 2D Chern insulator. Moreover, we simulate two different bilayer Chern insulators on the ladder-type superconducting processor. With the same and opposite periodically modulated on-site potentials for two coupled chains, we simulate topologically nontrivial edge states with zero Hall conductivity and a Chern insulator with higher Chern numbers, respectively. Our work shows the potential of using superconducting qubits for investigating different intriguing topological phases of quantum matter.

EISA in Tandem with ICD to Form In Situ Nanofiber Vaccine for Enhanced Tumor Radioimmunotherapy.

Radiotherapy (RT) can produce a vaccine effect and remodel a tumor microenvironment (TME) by inducing immunogenic cell death (ICD) and inflammation in tumors. However, RT alone is insufficient to elicit a systemic antitumor immune response owing to limited antigen presentation, immunosuppressive microenvironment, and chronic inflammation within the tumor. Here, a novel strategy is reported for the generation of in situ peptide-based nanovaccines via enzyme-induced self-assembly (EISA) in tandem with ICD. As ICD progresses, the peptide Fbp-GD FD FD pY (Fbp-pY), dephosphorylated by alkaline phosphatase (ALP) forms a fibrous nanostructure around the tumor cells, resulting in the capture and encapsulation of the autologous antigens produced by radiation. Utilizing the adjuvant and controlled-release advantages of self-assembling peptides, this nanofiber vaccine effectively increases antigen accumulation in the lymph nodes and cross-presentation by antigen-presenting cells (APCs). In addition, the inhibition of cyclooxygenase 2 (COX-2) expression by the nanofibers promotes the repolarization of M2-macrophages into M1 and reduces the number of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) required for TME remodeling. As a result, the combination of nanovaccines and RT significantly enhances the therapeutic effect on 4T1 tumors compared with RT alone, suggesting a promising treatment strategy for tumor radioimmunotherapy.

Spatial distribution, contamination characteristics and ecological-health risk assessment of toxic heavy metals in soils near a smelting area.

Soil heavy metals (HMs) contamination stemming from smelting and mining activities is becoming a global concern due to its devastating impacts on the environment and human health. In this study, 128 soil samples were investigated to assess the spatial distribution, contamination characteristics, ecological and human health risk of HMs in soils near a smelting area by using BP artificial neural network (BP-ANN) and Monte Carlo simulation. The results showed that the concentrations of all five HMs in the soil greatly exceeded the background value of study area with a basic trend: Pb > As > Cr > Cd > Hg, indicating a high pollution level. Arsenic and lead were the major pollutants in the study area with an exceedance rate of 78.95% and 28.95%, respectively. The toxic fume and dust emitted during the smelting process were identified as the major sources of HMs pollution in soil, while Cd pollution was mainly caused by agricultural activities near the study area. The probabilistic risk assessment suggested that the average HQ values of five HMs for children and adults exceeded the acceptable threshold with a trend: As > Pb > Cr > Cd > Hg. The average CR values of As, Cr and Pb for all population were greatly larger than the acceptable threshold (CR ≥ 1), indicating a high cancer risk. However, the CR values of Cd for adults and children were within the acceptable threshold (CR < 1), implying no cancer risk. The results of the present study can provide some insight into the contamination characteristics, ecological and human health risk of HMs in contaminated soils by mining and smelting activities, which can help prevent and control soil pollution and environmental risk.

CT perfusion combined with energy spectrum imaging to evaluate the short-term efficacy of bronchial arterial chemoembolization for lung cancer / 中华内科杂志

Objective: To evaluate the clinical value of dynamic volumetric CT perfusion combined with energy spectrum imaging in bronchial arterial chemoembolization (BACE) in patients with lung cancer. Methods: The data of 31 patients with lung cancer confirmed by pathology and treated with BACE in Lishui Central Hospital from January 2018 to February 2022 were retrospectively collected, including 23 men and 8 women, aged 31-84 (67) years. All patients received perfusion scans of lesion sites within 1 week before surgery and 1 month after surgery. We collected and compared the changes in preoperative and postoperative perfusion parameters such as blood flow (BF), blood volume (BV), mean through time (MTT), permeability surface (PS) and energy spectrum parameters including arterial phase CT value (CTA), venous phase CT value (CTV), arterial phase iodine concentration (ICA), venous phase of iodine concentration (ICV), arterial standardization iodine concentration (NICA), and intravenous standardized iodine concentration (NICV) to confirm the significance of these parameters in evaluating the short-term efficacy of BACE in the treatment of advanced lung cancer. Data normality was tested using the Kolmogorov-Smirnov test and normally distributed measurement data are expressed here as mean ± standard deviation; the independent-samples t-test was used for comparisons between two groups. The measurement data that were not normally distributed are expressed as median (interquartile interval) [M (Q1, Q3)], and the comparison between the two groups used the Kruskal-Wallis test. Count data are expressed as cases (%), and comparisons between groups used the χ2 test. Results: The objective response rate (ORR) and disease control rate (DCR) at 1 month after BACE were 54.8% (17/31) and 96.8% (30/31), respectively. CT perfusion parameters and energy spectrum parameters of patients before and after BACE treatment were compared. The results showed that BF, BV, MTT, ICA, ICV and NICV were significantly decreased after BACE treatment compared with before treatment, and the differences were statistically significant[58.06 (40.47,87.22) vs.23.57(10.92, 36.24) ml·min-1·100g-1,3.33(2.86,6.09) vs.2.12(1.96,3.61)ml/100g,2.70(2.19,3.88) vs.1.53 (1.12,2.25)s, 3.51 (3.11,4.14)vs.1.74 (1.26,2.50)mg/ml,2.00 (1.30,2.45) vs.1.32(0.92,1.76)mg/ml,0.51(0.42,0.57) vs.0.33(0.23,0.39)](all P<0.05). At the same time, compared with the non-remission group, the study results showed that the difference of parameters in remission group before and after BACE was more obvious, including ΔBF, ΔBV, ΔMTT, ΔPS, ΔCTA, ΔCTV, ΔICA, ΔICV, ΔNICA, ΔNICV were significantly increased, and the difference was statistically significant [36.82(32.38, 45.34) vs.9.50(-1.43, 12.34) ml·min-1·100g-1,4.46(2.52, 5.79) vs.0.22(-0.76, 4.09) ml/100g,4.22(2.25, 6.77) vs.0.43(-2.53, 1.88) s,10.07 (2.89, 13.13) vs.-2.01(-6.77, 4.28) ml·min-1·100g-1,14.22(11.88, 20.57) vs.4.18(-5.25, 6.37) HU, 34.6(14.88, 43.15) vs.11.60(0.26, 25.05) HU,0.95(0.54, 1.47) vs.0.11(0.20, 0.59) mg/ml,1.57(1.10, 2.38) vs. 0.26(-0.21, 0.63) mg/ml,0.05(0.03, 0.08) vs.-0.02(-0.04, 0.01),0.18(0.13, 0.21)vs. 0.11(-0.06, 0.16)](all P<0.05). Conclusions: CT perfusion combined with spectral imaging could effectively evaluate the changes in tumor vascular perfusion in patients with advanced lung cancer before and after BACE treatment, which has important value in judging the short-term efficacy after treatment.

Supramolecular Coassembled Peptide Hydrogels for Efficient Anticancer Therapy by RNS-Based PDT and Immune Microenvironment Regulation.

Photodynamic therapy (PDT) has attracted much attention in cancer treatment due to its tumor selectivity and noninvasive nature. Recent studies have demonstrated that PDT mediated reactive oxygen species (ROS) generation in tumor microenvironment (TME) synergistically improves the efficacy of immune checkpoint blockade (ICB) therapy. However, the instability and short half-life of the ROS generated by PDT limit its clinical applications. Herein, a coassembled peptide hydrogel comprising two short peptides that contained the same assembly unit, Ce6-KKFKFEFEF (KEF-Ce6) and RRRRRRRR-KFKFEFEF (KEF-R8) is developed. When exposed to 635 nm laser irradiation, KEF-Ce6 released ROS, while KEF-R8 plays as nitric oxide (NO) donor. Subsequently, ROS reacts with NO to produce reactive nitrogen species (RNS). Both in vitro and in vivo experiments prove that converting ROS into more cytotoxic RNS caused intense cell death. Importantly, it is observed that tumor-associated macrophages (TAMs) are polarized to proinflammatory types (M1-type) by the RNS-based PDT. The increase of M1 macrophages relieves the immunosuppressive situation in TME. Thus, when combined with αPD-L1 treatment, the survival time of tumor-bearing mice is prolonged. Overall, a simple yet efficient coassembled hydrogel that can cascade release ROS/NO/RNS and strengthen antitumor T cell responses to boost cancer immunotherapy by reprogramming TAMs is provided.

Macrophage-Membrane-Camouflaged Nonviral Gene Vectors for the Treatment of Multidrug-Resistant Bacterial Sepsis.

Sepsis is a life-threatening disease caused by systemic bacterial infections, with high morbidity and mortality worldwide. As the standard treatment for sepsis, antibiotic therapy faces the challenge of impaired macrophages and drug-resistant bacteria. In this study, we developed a membrane-camouflaged metal-organic framework (MOF) system for plasmid DNA (pDNA) delivery to combat sepsis. The antimicrobial gene LL37 was efficiently encapsulated in the pH-sensitive MOF, and the nanoparticles were decorated with macrophage membranes in a compatible manner. Macrophage membrane coating allows targeted delivery of LL37 to macrophages and creates macrophage factories for the continuous generation of antimicrobial peptides. Compared to naked nanoparticles, primary bone marrow mesenchymal macrophage membrane-modified nanoparticles greatly improved the survival rate of immunodeficient septic mice through the synergistic effect of efficient gene therapy and inflammatory cytokine sequestration. This study demonstrates an effective membrane biomimetic strategy for efficiently delivering pDNA, offering an excellent option for overcoming sepsis.

Tumor-Targeted Injectable Double-Network Hydrogel for Prevention of Breast Cancer Recurrence and Wound Infection via Synergistic Photothermal and Brachytherapy.

The high locoregional recurrence rate and potential wound infection in breast cancer after surgery pose enormous risks to patient survival. In this study, a polyethylene glycol acrylate (PEGDA)-alginate double-network nanocomposite hydrogel (GPA) embedded with 125 I-labeled RGDY peptide-modified gold nanorods (125 I-GNR-RGDY) is fabricated. The double-network hydrogel is formed by injection of GPA precursor solutions into the cavity of resected cancerous breasts of mice where gelation occurred rapidly. The enhanced temperature-induced PEGDA polymerization driven by near-infrared light irradiation, and then, the second polymer network is crosslinked between alginate and endogenous Ca2+ around the tumor. The double-network hydrogel possesses a dense polymer network and tightly fixes 125 I-GNR-RGDY, which exhibit superior persistent photothermal and radioactive effects. Hyperthermia induced by photothermal therapy can inhibit self-repair of damaged DNA and promote blood circulation to improve the hypoxic microenvironment, which can synergistically enhance the therapeutic efficacy of brachytherapy and simultaneously eliminate pathogenic bacteria. Notably, this nanocomposite hydrogel facilitates antibacterial activity to prevent potential wound infection and is tracked by single-photon emission computerized tomography imaging owing to isotope labeling of loaded 125 I-GNR-RGDY. The combination of photothermal therapy and brachytherapy has enabled the possibility of proposing a novel postoperative adjuvant strategy for preventing tumor recurrence and wound infection.

Cumulative burden of inflammation predicts colorectal neoplasia risk in ulcerative colitis: a large single-centre study.

OBJECTIVE: Ulcerative colitis (UC) is a dynamic disease with its severity continuously changing over time. We hypothesised that the risk of colorectal neoplasia (CRN) in UC closely follows an actuarial accumulative inflammatory burden, which is inadequately represented by current risk stratification strategies. DESIGN: This was a retrospective single-centre study. Patients with extensive UC who were under colonoscopic surveillance between 2003 and 2012 were studied. Each surveillance episode was scored for a severity of microscopic inflammation (0=no activity; 1=mild; 2=moderate; 3=severe activity). The cumulative inflammatory burden (CIB) was defined as sum of: average score between each pair of surveillance episodes multiplied by the surveillance interval in years. Potential predictors were correlated with CRN outcome using time-dependent Cox regression. RESULTS: A total of 987 patients were followed for a median of 13 years (IQR, 9-18), 97 (9.8%) of whom developed CRN. Multivariate analysis showed that the CIB was significantly associated with CRN development (HR, 2.1 per 10-unit increase in CIB (equivalent of 10, 5 or 3.3 years of continuous mild, moderate or severe active microscopic inflammation); 95% CI 1.4 to 3.0; P<0.001). Reflecting this, while inflammation severity based on the most recent colonoscopy alone was not significant (HR, 0.9 per-1-unit increase in severity; 95% CI 0.7 to 1.2; P=0.5), a mean severity score calculated from all colonoscopies performed in preceding 5 years was significantly associated with CRN risk (HR, 2.2 per-1-unit increase; 95% CI 1.6 to 3.1; P<0.001). CONCLUSION: The risk of CRN in UC is significantly associated with accumulative inflammatory burden. An accurate CRN risk stratification should involve assessment of multiple surveillance episodes to take this into account.

Long non-coding RNAs within the tumour microenvironment and their role in tumour-stroma cross-talk.

Long non-coding RNAs (lncRNAs) are a diverse class of RNA transcripts which have limited protein coding potential. They perform a variety of cellular functions in health, but have also been implicated during malignant transformation. A further theme in recent years is the critical role of the tumour microenvironment and the dynamic interactions between cancer and stromal cells in promoting invasion and disease progression. Whereas the contribution of deregulated lncRNAs within cancer cells has received considerable attention, their significance within the tumour microenvironment is less well understood. The tumour microenvironment consists of cancer-associated stromal cells and structural extracellular components which interact with one another and with the transformed epithelium via complex extracellular signalling pathways. LncRNAs are directly and indirectly involved in tumour/stroma cross-talk and help stimulate a permissive tumour microenvironment which is more conducive for invasive tumour growth. Furthermore, lncRNAs play key roles in determining the phenotype of cancer associated stromal cells and contribute to angiogenesis and immune evasion pathways, extracellular-matrix (ECM) turnover and the response to hypoxic stress. Here we explore the multifaceted roles of lncRNAs within the tumour microenvironment and their putative pathophysiological effects.

Exosomal microRNAs (exomiRs): Small molecules with a big role in cancer.

Exosomes are secreted vesicles which can transmit molecular cargo between cells. Exosomal microRNAs (exomiRs) have drawn much attention in recent years because there is increasing evidence to suggest that loading of microRNAs into exosomes is not a random process. Preclinical studies have identified functional roles for exomiRs in influencing many hallmarks of cancer. Mechanisms underpinning their actions, such as exomiR receptors ("miRceptors"), are now becoming apparent. Even more exciting is the fact that exomiRs are highly suitable candidates for use as non-invasive biomarkers in an era of personalized cancer medicine.

Detection of cofilin mRNA by hybridization-sensitive double-stranded fluorescent probes.

We have developed hybridization-sensitive fluorescent oligonucleotide probes that, in the presence of quencher strands, undergo efficient fluorescence quenching through the formation of partial DNA/DNA duplexes. In the presence of target RNA, rapid displacement of the quencher strands results in highly enhanced fluorescence.

Fluorescence properties of 6-aryl-2'-deoxy-furanouridine and -pyrrolocytidine and their derivatives.

2'-deoxyfuranouridine derivatives presenting various aryl groups have been synthesized through Cu(I)-catalyzed intramolecular cyclizations. Moreover, corresponding pyrrolo-dC derivatives have been synthesized and both families of compounds thoroughly characterized using UV/vis and fluorescence spectroscopy as well as time-dependent density functional theory calculations. The photophysical characterization, show that our newly synthesized derivatives of the important pyrrolo-dC family have high fluorescence quantum yields (QYs) and brightness values. Pyrrolo-dC derivative, 3a, shows an environment sensitive QY of up to >60% and brightness of almost 3000, in low polarity solvents and excitation and emission maxima between 365-381 nm and 479-510 nm, respectively, in solvents of different polarities. Two other derivatives, 3b and 3c, show high QYs and brightness values of up to 3300 that are fairly insensitive to their microenvironment. These promising photophysical features suggest future applicability as fluorescent nucleobase analogs.

Galvanic corrosion couple-induced Marangoni flow of liquid metal.

The Marangoni flow of room temperature liquid metal has recently attracted significant attention in developing advanced flexible drivers. However, most of its induction methods are limited to an external electric field. This study disclosed a new Marangoni flow phenomenon of liquid gallium induced by the gallium-copper galvanic corrosion couple. To better understand this effect, the flow field distribution of liquid gallium was modeled and quantitatively calculated. Then, the intrinsic mechanism of this flow phenomenon was interpreted, during which natural convection and temperature gradient were both excluded and the galvanic corrosion couple was identified as the main reason. In addition, this conclusion was further confirmed by combining the experimental measurement of liquid gallium surface potential and the thermocapillary effect. Moreover, the temperature condition was found to be an indirect factor to the Marangoni flow. This finding broadens the classical understanding of liquid metal surface flow, which also suggests a new way for the application of soft machines.

Body composition of the host influences dendritic cell phenotype in patients treated for colorectal cancer.

Dendritic cells (DCs) are antigen-presenting cells that can acquire tumour antigens and initiate cytotoxic T cell reactions. Obesity has been proposed as a cause for tumours escaping immune surveillance, but few studies investigate the impact of other body composition parameters. We examined the relationship of DC phenotype with computer tomography (CT)-defined parameters in patients with colorectal cancer (CRC). DCs were identified within peripheral blood mononuclear cells by flow cytometry as HLA-DR positive and negative for markers of other cell lineages in 21 patients. Analysis of CT scans was used to calculate lumbar skeletal muscle index (LSMI) and mean muscle attenuation (MA). Positive correlation between the LSMI and expression of CD40 in all DCs (r = 0.45; p = 0.04) was demonstrated. The MA was positively correlated with scavenger receptor CD36 [all DCs (r = 0.60; p = 0.01) and myeloid DCs (r = 0.63; p < 0.01)]. However, the MA was negatively correlated with CCR7 expression in all DCs (r = -0.46, p = 0.03.) and with CD83 [all DCs (r = -0.63; p = 0.01) and myeloid DCs (r = -0.75; p < 0.01)]. There were no relationships between the fat indexes and the DC phenotype. These results highlight a direct relationship between muscle depletion and changes in stimulatory, migratory and fatty acid-processing potential of DC in patients with CRC.

Compartment-specific immunity in the human gut: properties and functions of dendritic cells in the colon versus the ileum.

OBJECTIVE: Dendritic cells (DC) mediate intestinal immune tolerance. Despite striking differences between the colon and the ileum both in function and bacterial load, few studies distinguish between properties of immune cells in these compartments. Furthermore, information of gut DC in humans is scarce. We aimed to characterise human colonic versus ileal DC. DESIGN: Human DC from paired colonic and ileal samples were characterised by flow cytometry, electron microscopy or used to stimulate T cell responses in a mixed leucocyte reaction. RESULTS: A lower proportion of colonic DC produced pro-inflammatory cytokines (tumour necrosis factor-α and interleukin (IL)-1ß) compared with their ileal counterparts and exhibited an enhanced ability to generate CD4(+)FoxP3(+)IL-10(+) (regulatory) T cells. There were enhanced proportions of CD103(+)Sirpα(-) DC in the colon, with increased proportions of CD103(+)Sirpα(+) DC in the ileum. A greater proportion of colonic DC subsets analysed expressed the lymph-node-homing marker CCR7, alongside enhanced endocytic capacity, which was most striking in CD103(+)Sirpα(+) DC. Expression of the inhibitory receptor ILT3 was enhanced on colonic DC. Interestingly, endocytic capacity was associated with CD103(+) DC, in particular CD103(+)Sirpα(+) DC. However, expression of ILT3 was associated with CD103(-) DC. Colonic and ileal DC differentially expressed skin-homing marker CCR4 and small-bowel-homing marker CCR9, respectively, and this corresponded to their ability to imprint these homing markers on T cells. CONCLUSIONS: The regulatory properties of colonic DC may represent an evolutionary adaptation to the greater bacterial load in the colon. The colon and the ileum should be regarded as separate entities, each comprising DC with distinct roles in mucosal immunity and imprinting.

Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients.

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are important regulators of immune responses in cancer and have been directly implicated in promotion of tumor progression. However, the heterogeneity of these cells and lack of distinct markers hampers the progress in understanding of the biology and clinical importance of these cells. Using partial enrichment of PMN-MDSC with gradient centrifugation we determined that low density PMN-MDSC and high density neutrophils from the same cancer patients had a distinct gene profile. Most prominent changes were observed in the expression of genes associated with endoplasmic reticulum (ER) stress. Surprisingly, low-density lipoprotein (LDL) was one of the most increased regulators and its receptor oxidized LDL receptor 1 OLR1 was one of the most overexpressed genes in PMN-MDSC. Lectin-type oxidized LDL receptor 1 (LOX-1) encoded by OLR1 was practically undetectable in neutrophils in peripheral blood of healthy donors, whereas 5-15% of total neutrophils in cancer patients and 15-50% of neutrophils in tumor tissues were LOX-1+. In contrast to their LOX-1- counterparts, LOX-1+ neutrophils had gene signature, potent immune suppressive activity, up-regulation of ER stress, and other biochemical characteristics of PMN-MDSC. Moreover, induction of ER stress in neutrophils from healthy donors up-regulated LOX-1 expression and converted these cells to suppressive PMN-MDSC. Thus, we identified a specific marker of human PMN-MDSC associated with ER stress and lipid metabolism, which provides new insight to the biology and potential therapeutic targeting of these cells.