Differences in brain functional connectivity between tinnitus with or without hearing loss.

To explore the differences in brain imaging in tinnitus with or without hearing loss (HL). We acquired functional MRI scans from 26 tinnitus patients with HL (tinnitus-HL), 24 tinnitus patients with no HL (tinnitus-NHL), and 26 healthy controls (HCs) matched by age and sex. The left and right thalamus were selected as seeds to study the endogenous functional connectivity (FC) of the whole brain, and its correlation with clinical indices was analyzed. Brain regions showing FC differences among the three groups included the Heschl gyrus (HES), right Hippocampus (HIP), right Amygdala (AMYG), left Calcarine fissure and surrounding cortex (CAL). Post hoc analysis showed that the thalamus-HIP connection and thalamus-lingual gyrus (LING) connection were enhanced in the tinnitus-NHL group, as compared to tinnitus-HL. Compared with HCs, the tinnitus-NHL group showed an enhanced connection between the thalamus and the left Inferior occipital gyrus, left CAL and LING. While in the tinnitus-HL group, the connection between the thalamus and several brain regions (right HES, right AMYG, etc) was weakened. In the tinnitus-HL group, the tinnitus handicap inventory scores were positively correlated with the FC of the left thalamus and right HES, right thalamus and right Rolandic operculum. The duration of tinnitus was negatively correlated with the FC of the right thalamus and right HIP. Abnormal FC in the thalamus may play an important role in the pathogenesis of tinnitus. Tinnitus-NHL and tinnitus-HL show different connection patterns, indicating that there are some differences in their pathogenesis.

Cold storage alters the fat-trehalose trade-off, decreases the flight ability, and maintains the high survival rate and flight speed of Osmia excavata (Hymenoptera: Megachilidae).

Osmia solitary bees are important pollinators of various crops worldwide. Refrigeration has been widely used to synchronize the emergence time of Osmia species from cocoons with the blooming time of different crops, but the fitness of Osmia after refrigeration remains unknown. Here, the effects of long-term refrigeration at 0 °C on the vitality, flight ability, and metabolism of Osmia excavata, which is known as the "king of pollination" in China, were studied. The survival rate (>90% before 120 d), weight loss rate (<15% after 170 d), and mean flight speed of O. excavata were not greatly affected after long-term refrigeration. The content of fats, which have antifreeze and energy storage properties, was not significantly altered in O. excavata before 130 d of refrigeration, which might explain why the survival rates and flight speed of O. excavata remained high after long-term refrigeration. However, the flight duration and distance decreased significantly (P < 0.05), and both were positively correlated with the reduced trehalose levels in O. excavata (r = [+0.69] - [+0.71]; P < 0.05). Overall, these findings indicate that the pollination potential of O. excavata for various crops with different flowering periods is high after long-term refrigeration; however, long-term refrigeration may decrease pollination efficiency. Our findings highlight new research directions that could improve the ecological service function of refrigerated O. excavata.

Reassessment of oxidative stress in idiopathic sudden hearing loss and preliminary exploration of the effect of physiological concentration of melatonin on prognosis.

Background and purpose: The pathogenesis of idiopathic sudden sensorineural hearing loss (ISSNHL) is still unclear, and there is no targeted treatment. This research aimed to verify the role of oxidative stress in ISSNHL and explore whether melatonin has a protective effect on hearing. Materials and methods: A total of 43 patients with ISSNHL and 15 healthy controls were recruited to detect the level of melatonin, reactive oxygen species (ROS), and total antioxidant capacity (TAC) in the blood and compared before and after treatment. Multivariate logistic regression models were performed to assess the factors relevant to the occurrence and improvement of ISSNHL. Results: The patients with ISSNHL showed significantly higher ROS levels than controls (4.42 ± 4.40 vs. 2.30 ± 0.59; p = 0.031). The levels of basal melatonin were higher (1400.83 ± 784.89 vs. 1095.97 ± 689.08; p = 0.046) and ROS levels were lower (3.05 ± 1.81 vs. 5.62 ± 5.56; p = 0.042) in the effective group as compared with the ineffective group. Logistic regression analysis showed that melatonin (OR = 0.999, 95% CI 0.997-1.000, p = 0.049), ROS (OR = 1.154, 95% CI 1.025-2.236, p = 0.037), and vertigo (OR = 3.011, 95% CI 1.339-26.983, p = 0.019) were independent factors associated with hearing improvement. Besides, the level of melatonin (OR = 0.999, 95% CI 0.998-1.000, p = 0.023) and ROS (OR = 3.248, 95% CI 1.109-9.516, p = 0.032) were associated with the occurrence of ISSNHL. Conclusion: Our findings may suggest oxidative stress involvement in ISSNHL etiopathogenesis. The level of melatonin and ROS, and vertigo appear to be predictive of the effectiveness of hearing improvement following ISSNHL treatment.

Cnidium monnieri (L.) Cusson Flower as a Supplementary Food Promoting the Development and Reproduction of Ladybeetles Harmonia axyridis (Pallas) (Coleoptera: Coccinellidae).

Predaceous ladybeetles are highly polyphagous predators that ingest supplementary food from flowering plants. Flowering plants widely grown in agroecosystems can sustain multiple natural enemies of agricultural pests, and the pollen and nectar resources from flowering plants may have a positive role in natural enemies. Cnidium monnieri (L.) Cusson, an annual herb with many flowers, blooms from May to July. C. monnieri can support several predatory natural enemies, and the addition of C. monnieri strips increases the density of Harmonia axyridis (Pallas) and improves the biological control of apple aphids in an apple orchard. H. axyridis is also the most important natural enemy in wheat aphid biocontrol and is attracted to healthy and aphid-infested C. monnieri plants. In addition, adult Propylaea japonica Thunberg survives significantly longer on C. monnieri flowers than on a water-only diet. In this study, a laboratory experiment was conducted to assess (i) the effect of nutritional supplements derived from C. monnieri flowers on the development and reproduction of H. axyridis under a wheat aphids-only diet; (ii) the effect of C. monnieri flowers on H. axyridis adult reproduction performance. We compared the larval durations, survival, weight, adult longevity, and reproduction of H. axyridis reared on wheat aphids-only and aphids plus C. monnieri flower diets. The results showed that H. axyridis larvae reared on aphids plus flowers had significantly greater weights and survival rates, shorter larval durations, and produced 1.62 times more eggs than those reared on wheat aphids-only diets. H. axyridis adults ingesting a C. monnieri flowers plus an aphid diet increased egg production 1.44 times compared to the aphids-only diet. Our study demonstrates that C. monnieri flowers as a supplementary food positively affect the survival, development, and reproduction performance of H. axyridis.

A minireview of the medicinal and edible insects from the traditional Chinese medicine (TCM).

Entomoceuticals define a subset of pharmaceuticals derived from insects. The therapeutic effect of insect-derived drugs has been empirically validated by the direct use of various folk medicines originating from three sources in particular: the glandular secretions of insects (e.g., silk, honey, venom), the body parts of the insect or the whole used live or by various processing (e.g., cooked, toasted, ground), and active ingredients extracted from insects or insect-microbe symbiosis. Insects have been widely exploited in traditional Chinese medicine (TCM) relative to other ethnomedicines, especially in the prospect of insect species for medicinal uses. It is noticeable that most of these entomoceuticals are also exploited as health food for improving immune function. In addition, some edible insects are rich in animal protein and have high nutritional value, which are used in the food field, such as insect wine, health supplements and so on. In this review, we focused on 12 insect species that have been widely used in traditional Chinese herbal formulae but have remained less investigated for their biological properties in previous studies. We also combined the entomoceutical knowledge with recent advances in insect omics. This review specifies the underexplored medicinal insects from ethnomedicine and shows their specific medicinal and nutritional roles in traditional medicine.

Coincidence rate of adjustable and non adjustable desks and chairs in primary and secondary schools in Shanghai / 中国学校卫生

Objective@#To understand the coincidence rate of adjustable and non adjustable desks and chairs in primary and secondary schools in Shanghai, so as to provide a reference for the effective management of desks and chairs in schools.@*Methods@#Stratified random cluster sampling was applied to measure 1 091 sets of desks and chairs in 33 classrooms of 7 primary and secondary schools in 4 districts of Shanghai including Huangpu, Hongkou, Yangpu and Jiading districts. The height examination data of seated students in the same semester were also collected to evaluate the matching type of functional size of desks and chairs and students height according to Functional Sizes and Technical Requirements of Chairs and Tables for Educational Institutions.@*Results@#The matching coincidence rate of desk and chair distribution in primary and secondary schools was 22.5%, and the matching coincidence rates of primary, middle and high schools were 11.7%, 27.1% and 40.9% respectively ( χ 2=83.23, P <0.01); the matching coincidence rate of adjustable desks and chairs (28.2%) was significantly higher than that of fixed (18.2%) ( χ 2=14.49, P <0.01). The type of distribution of desks and chairs that do not correspond to national standards, from elementary school to high school, showing a trend of high desks with high chairs, low desks with high chairs to high desks with low chairs.@*Conclusion@#The coincidence rate of desk and chair distribution in primary and secondary schools is low, and the adjustable desks and chairs has improved the problems to a certain extent, but has not significantly improved the coincidence rate. It is necessary to further explore the effective management mode in the use of adjustable desks and chairs and improve the current situation of the use of desks and chairs in schools.

The Supercooling Responses of the Solitary Bee Osmia excavata (Hymenoptera: Megachilidae) under the Biological Stress of Its Brood Parasite, Sapyga coma (Hymenoptera: Sapygidae).

(1) Background: Many insects have evolved different strategies to adapt to subzero temperatures and parasites, but the supercooling response of pollinator populations under the brood parasitism pressure has not been sufficiently investigated. (2) Methods: This study assessed the supercooling traits (supercooling points, fresh weight and fat content) of the solitary bee Osmia excavata Alfken and its brood parasite, Sapyga coma Yasumatsu & Sugihara. We measured 4035 samples (3025 O. excavata and 1010 S. coma, one individual as one sample) and discovered the supercooling traits relations between solitary bee and brood parasite. (3) Results: Significant differences in the supercooling points were found between O. excavata (females: −24.18 (−26.02~−20.07) vs. males: −23.21 (−25.15~−18.65) °C) and S. coma (females: −22.19 (−25.46~−18.38) vs. males: −20.65 (−23.85~−16.15) °C, p < 0.0001) in the same sex, and also between sexes of same species. The two species' supercooling traits (supercooling points, fresh weight, and fat content) were significantly positively correlated. The supercooling points of the solitary bee varies regularly under brood parasitism pressure. (4) Conclusions: Our study indicates the supercooling traits relationships between a solitary bee and its brood parasite and suggests that the supercooling points of the solitary bee increase under the biological stress of its brood parasite in a certain level.

Evaluating the Effect of Pesticides on the Larvae of the Solitary Bees.

Current ecological risk assessments of pesticides on pollinators have primarily considered only laboratory conditions. For the larvae of solitary bees, ingestion of provisions contaminated with pesticides may increase the mortality rate of the larvae, decrease the collection rate and the population of adult solitary bees in the next year from a demographic perspective. But there are limited studies on the effects of pesticides on the larvae of solitary bees. Therefore, understanding how pesticides influence the larvae of solitary bees should be considered an integral part of pesticide ecological risk assessment. This study presents a method to expose the larvae of solitary bee, Osmia excavata, to lethal or sublethal doses of pesticide, tracking larval weight gain, developmental duration, eclosion ability, and food consumption efficiency conversion of ingested food. To demonstrate the effectiveness of this method, the larvae of O. excavata were fed with provisions containing acute lethal and sublethal doses of chlorpyrifos. Then, the above indexes of the treated larvae were investigated. This technique helps to predict and mitigate the risk of pesticides to pollinators.

Comprehensive analysis of pivotal biomarkers, immune cell infiltration and therapeutic drugs for steroid-induced osteonecrosis of the femoral head.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a progressive disease that leads to an increased disability rate. This study aimed to ascertain biomarkers, infiltrating immune cells, and therapeutic drugs for SONFH. The gene expression profile of the GSE123568 dataset was downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using the NetworkAnalyst platform. Functional enrichment, protein-protein interaction network (PPI), and module analyses were performed using Metascape tools. An immune cell abundance identifier was used to explore immune cell infiltration. Furthermore, hub genes were identified based on maximal clique centrality (MCC) evaluation using cytoHubba application and confirmed by qRT-PCR using clinical samples. Finally, the L1000 platform was used to determine potential drugs for SONFH treatment. The SONFH mouse model was used to determine the therapeutic effects of aspirin. In total, 429 DEGs were identified in SONFH samples. Functional enrichment analysis showed that these DEGs were enriched in myeloid leukocyte activation and osteoclast differentiation processes. A set of nine immune cell types was confirmed to be markedly different between the SONFH and control samples. All 10 hub genes were significantly highly expressed in the serum of SONFH patients, as shown by qRT-PCR. Finally, the therapeutic effect of aspirin on SONFH was examined in animal experiments. Taken together, our data revealed the hub genes and infiltrating immune cells in SONFH, and we also screened potential drugs for use in SONFH treatment.

Biological Control of Aphis spiraecola (Hemiptera: Aphididae) Using Three Different Flowering Plants in Apple Orchards.

Increasing the biodiversity of agroecosystems can increase populations of natural enemies that are useful for pest control. Orchards often have a low diversity of plant species, which is not conducive to maintaining ecosystem functions and services. However, additional flowering plants could provide natural enemies with beneficial resources. To assess the ability of flowering plants to attract predators and increase the biological control of Aphis spiraecola Patch, we established individual plots of three different flowering plant species with sequential bloom periods between the rows of apple orchard. These plants attracted predators such as Coccinellidae, Syrphidae, and Chrysopidae when flowering. The density of predators on trees in the three flowering plant plots was significantly higher than that in the control, whereas the density of aphids on trees in Orychophragmus violaceus (L.) O. E. Schulz (Rhoeadales: Brassicaceae) and Cnidium monnieri (Linn.) Cuss. (Apiales: Apiaceae) plots were significantly lower than that in control. The density of aphids on trees in Calendula officinalis L. (Asterales: Asteraceae) plots was significantly lower than in other plots at second peak period. There was a significant negative correlation between the population of aphids and predators on trees at peak of aphids. Cage exclusion tests showed that the biocontrol services index (BSI) of O. violaceus was highest (32.7%) on 24 May, and the BSI of C. monnieri was highest (47.6%) on 7 June. Our results suggest that the temporal combination of different flowering plants could provide useful effective biocontrol to management pest in orchard.

Comparative ecotoxicity of insecticides with different modes of action to Osmia excavata (Hymenoptera: Megachilidae).

Osmia excavata is an important pollinator in commercial fruit orchards. Little information has been published about ecotoxicity to O. excavata, especially the larvae. To clarify the risk of commonly used insecticides with different modes of action to the larvae of O. excavata, six insecticides (clothianidin, acetamiprid, sulfoxaflor, lambda-cyhalothrin, chlorfenapyr and abamectin) were selected for evaluation of their acute lethal toxicity and sublethal effects. Clothianidin and abamectin were the two most toxic insecticides to the larvae of O. excavata with LD50 values of 0.007 (0.006-0.008) and 0.0004 (0.0003-0.0006) µg active ingredient (a.i.) bee-1, respectively. And their ecological risks were high according to the hazard quotient values (HQ > 2500). Sulfoxaflor was identified as the only safe insecticide for O. excavata (HQ < 50) under field conditions. Sublethal toxicity tests showed that larval weight was significantly decreased by ingesting food treated with clothianidin, lambda-cyhalothrin and abamectin (less than the maximum field registered concentrations on fruit trees) due to interference with consumption per larva and reduction of the efficiency of conversion of ingested food. Additionally, above three insecticides significantly prolonged larval developmental duration before cocooning and decreased eclosion rate. Overall, there results suggested that clothianidin and abamectin should not be applied, especially during the flowering phase, the application frequency of lambda-cyhalothrin should be minimized for the purpose of conserving O. excavata. Our results provided important evidences for selecting appropriate insecticides for use in fruit orchards.

Moderately decreasing fertilizer in fields does not reduce populations of cereal aphids but maximizes fitness of parasitoids.

Examination of the tradeoff between the extent of decreasing nitrogen input and pest suppression is crucial for maintaining the balance between essential yield and an efficient, sustainable pest control strategy. In this study, an experiment with four manipulated nitrogen fertilizer levels (70, 140, 210, and 280 kg N ha-1 = conventional level) was conducted to explore the effects of decreasing nitrogen on cereal aphids (Sitobion avenae and Rhopalosiphum padi) (Hemiptera: Aphididae), Aphidiinae parasitoids (Hymenoptera: Braconidae: Aphidiinae), and body sizes of parasitoids. The results indicated that nitrogen application, in the range of 70-280 kg N ha-1, has the potential to impact the populations of cereal aphids and their parasitoids. However, both differences between densities of cereal aphids and their parasitoids in moderate (140-210 kg N ha-1) and those in high nitrogen input (280 kg N ha-1) were not significant, and the parasitism rate was also unaffected. A higher parasitism rate reduced population growth of the cereal aphid (S. avenae). Additionally, a moderate decrease of nitrogen fertilizer from 280 to 140-210 kg N ha-1 maximized the body sizes of Aphidiinae parasitoids, indicating that a moderate decrease of nitrogen fertilizer could facilitate biocontrol of cereal aphid by parasitoids in the near future. We conclude that a moderate decrease in nitrogen application, from 280 to 140-210 kg N ha-1, does not quantitatively impact the densities of cereal aphids or the parasitism rate but can qualitatively maximize the fitness of the parasitoids.

Landscape genetic analyses reveal host association of mitochondrial haplotypes in the Asian corn borer, Ostrinia furnacalis.

Crop expansion often leads to high pest pressure. These pests may have fitness trade-offs related to host use, and some host-associated genotypes may benefit and increase in frequency. However, evidence concerning the effect of host availability on spatial distribution and frequency of mitochondrial haplotypes is scarce. We studied genetic variation of the Asian corn borer, Ostrinia furnacalis (Guenée), across a large area during 2 years (2016 and 2017). Mitochondrial sequence data were obtained from 530 individuals collected from 79 locations in Shandong Province, China. In total, 155 haplotypes were found based on the combined cytochrome oxidase subunit 1 (COI) and COII genes. Three haplotypes (H2, H12, and H23) were dominant, whereas most of the other haplotypes occurred in low frequency. A haplotype network showed that the 155 haplotypes can be grouped into three clusters. Haplotype clusters seemed to be randomly distributed. The frequency of H12 (in Cluster 1) was positively correlated with maize crop proportion, but negatively correlated with other crops (primarily vegetables, oilseed crops, and cotton) at all spatial scales (1-, 3-, and 5-km radius). Cluster 2 had haplotype H23, and this cluster was negatively correlated with semi-natural habitats. Cluster 3 had no dominant haplotype and was not affected by landscape factors. We conclude that H12 may be a maize-associated haplotype. Further study is needed to verify the possibility that the carriers of this haplotype may possess some fitness trade-offs. Our study highlights the importance of host availability in O. furnacalis haplotype distribution and frequency.

Flower strips as a bridge habitat facilitate the movement of predatory beetles from wheat to maize crops.

BACKGROUND: Generalist predators play a key role in the biocontrol of insect pests in agricultural systems. However, predators are subject to frequent mortality events due to periodic disturbance regimes such as crop planting and harvest, which inevitably affect the population development of predators. Conservation of predators in this critical period is important for double-cropping systems such as winter wheat and summer maize, the most widely used cropping system in North China. RESULTS: Planting Cnidium monnieri flower strips at field borders could not only serve as a bridge habitat to conserve the dominant predator Propylaea japonica in wheat fields during harvest but also help the predator immigrate to adjacent maize fields. The predator abundance was 7-fold higher on flower strips than that on natural vegetation strips during the wheat postharvest period and before the maize plant emergence for about a month, and its abundance in maize fields planted with flower strips was nearly 2-fold higher than that in maize fields planted with natural vegetation strips. Moreover, 77.56% of predators that entered maize fields were proven to originate from flower strips. CONCLUSION: Our findings provided evidence that manipulating flower strips as a bridge habitat in wheat-maize rotation fields could conserve P. japonica during crop phenophase changes, and we quantitatively testified that the proportion of this predator in maize fields derived from flower strips. In practice, such a strategy may also be applied in other double-cropping and triple-cropping systems. © 2020 Society of Chemical Industry.

Landscape agricultural simplification correlates positively with the spatial distribution of a specialist yet negatively with a generalist pest.

Agricultural expansion at the cost of natural or semi-natural habitats is simplifying human-dominated landscapes. As croplands provide a large resource of food to herbivores, pest damage may increase, but such large-scale patterns across regions are little known. Here, we used two years of maize field data from 102 counties (each 1318 km2 on average) across Shandong Province in China to study the spatial distribution of two major co-occurring maize pests: the putative habitat specialist the Asian Corn Borer (Ostrinia furnacalis) (ACB) and the generalist Yellow Peach Moth (Conogethes punctiferalis) (YPM). We used Spatial Analysis by Distance Indices (SADIE) to assess the spatial distribution patterns of these pests and their relation to landscape factors. In both 2016 and 2017, the aggregation and abundance of the ACB was positively correlated with the proportion of maize on the county level, whereas the YPM exhibited the opposite pattern, i.e., a negative correlation with maize proportion. The ACB abundance was below the economic threshold level when maize was <31% in 2017, whereas the YPM abundance was below the threshold when maize was >27% (in 2016) or 23% (in 2017). Maize plant presence was the main determinant of the abundance of the ACB, while the YPM appeared to benefit from further resources in non-crop habitats. These contrasting distribution patterns suggest that the two pests are driven by their different resource requirements. In more diversified landscapes, pest control may need to focus primarily on the generalist consumer, the YPM, whereas in maize-dominated landscapes, the specialist consumer, the ACB, is dominant and needs attention.

Effect of coupled reduced irrigation and nitrogen fertilizer on soil mite community composition in a wheat field.

Groundwater and nitrogen fertilizer overuse severely threatens crop productions; thus, current ecological agriculture requires low irrigation and nitrogen fertilizer inputs. The effects of combined reduced irrigation and nitrogen fertilizer addition on soil organism (e.g., mite) community and biodiversity remain poorly understood. We analyzed soil mite community composition, wheat grain yield, and soil characteristics in a 10-year manipulation experiment with two levels of irrigation (reduced and conventional irrigation) and five nitrogen fertilizer levels (0, 70, 140, 210, and 280 kg N/ha). Reduced irrigation (20% reduction, from 280 to 220 mm) and nitrogen fertilizer (25% reduction, from 280 to 210 kg N/ha) addition did not significantly influence soil mite community and wheat yield. The relative abundances of fungivores and predators showed negative quadratic relationships with wheat yield, while that of plant parasites showed a positive relationship. The relationships between soil mite trophic groups and wheat yield revealed that we can evaluate the impacts of reduced irrigation and nitrogen fertilizer addition from the perspective of soil fauna. Soil mite community composition was altered by soil abiotic factors prior to reduced irrigation and nitrogen fertilizer addition. Overall, moderate reductions of irrigation and nitrogen fertilizer may not threaten to soil mite community and diversity or decrease crop production; in contrast, such reductions will benefit mite community development and the sustainable agriculture.

Adaptation of Defensive Strategies by the Pea Aphid Mediates Predation Risk from the Predatory Lady Beetle.

Within a species, individual animals adopt various defensive strategies to resist natural enemies, but the defensive strategies that are adopted in response to variations in predation risk are poorly understood. Here, we assessed consecutive foraging processes on cohorts of two biotypes (green and red) of the pea aphid, Acyrthosiphon pisum, by the predatory lady beetle Propylea japonica, to investigate the adaptive mechanism underlying the defensive strategy. We observed the behavioral responses of individuals (continue feeding or escape, i.e., walk away or drop off from initial feeding site), simultaneously quantified the amount of alarm pheromone, (E)-ß-farnesene (EßF) released from cohorts using gas chromatography-mass spectrometry (GC-MS), and recorded the foraging times of predators in intervals. The results indicated that: (1) the anti-predator responses differed markedly between biotypes and among the stages of the consecutive foraging processes. (2) Few green cohorts tended to release EßF during the first foraging; those that did released only a low dose that did not increase the number of escapes. However, the amount of EßF rose rapidly following the second foraging process, which caused an intense escape response. In contrast, more red cohorts released greater amounts of EßF, which caused more individuals to escape from their innate feeding sites during the first foraging. During the second foraging, more red individuals tended to escape without releasing EßF in greater quantities. (3) The foraging time was effectively shortened in each biotype cohort that adopted diverse defensive strategies. This study of the defensive strategies of the pea aphid may contribute to understanding the intraspecific differences in aphid defense mechanisms.

Dendritic cell-elicited B-cell activation fosters immune privilege via IL-10 signals in hepatocellular carcinoma.

B cells are prominent components of human solid tumours, but activation status and functions of these cells in human cancers remain elusive. Here we establish that over 50% B cells in hepatocellular carcinoma (HCC) exhibit an FcγRIIlow/- activated phenotype, and high infiltration of these cells positively correlates with cancer progression. Environmental semimature dendritic cells, but not macrophages, can operate in a CD95L-dependent pathway to generate FcγRIIlow/- activated B cells. Early activation of monocytes in cancer environments is critical for the generation of semimature dendritic cells and subsequent FcγRIIlow/- activated B cells. More importantly, the activated FcγRIIlow/- B cells from HCC tumours, but not the resting FcγRIIhigh B cells, without external stimulation suppress autologous tumour-specific cytotoxic T-cell immunity via IL-10 signals. Collectively, generation of FcγRIIlow/- activated B cells may represent a mechanism by which the immune activation is linked to immune tolerance in the tumour milieu.

Polarization of Tissue-Resident TFH-Like Cells in Human Hepatoma Bridges Innate Monocyte Inflammation and M2b Macrophage Polarization.

The existence, regulation, and functions of IL21+ immune cells are poorly defined in human cancers. Here, we identified a subset of protumorigenic IL21+ TFH-like cells in human hepatocellular carcinoma. These cells were the major source of IL21 in tumors and represented about 10% of the CD4+ T-cell population at levels comparable with the TFH cells present in lymph nodes. However, these TFH-like cells displayed a unique CXCR5-PD-1lo/-BTLA-CD69hi tissue-resident phenotype with substantial IFNγ production, which differed from the phenotype of TFH cells. Toll-like receptor 4 (TLR4)-elicited innate monocyte inflammation was important for IL21+ TFH-like cell induction in tumors, and activation of STAT1 and STAT3 was critical for TFH-like cell polarization in this process. Importantly, the TFH-like cells operated in IL21-IFNγ-dependent pathways to induce plasma cell differentiation and thereby create conditions for protumorigenic M2b macrophage polarization and cancer progression. Thus, induction of TFH-like cells links innate inflammation to immune privilege in tumors. SIGNIFICANCE: We identified a novel protumorigenic IL21+ TFH-like cell subset with a CXCR5-PD-1- BTLA-CD69hi tissue-resident phenotype in hepatoma. TLR4-mediated monocyte inflammation and subsequent T-cell STAT1 and STAT3 activation are critical for TFH-like cell induction. TFH-like cells operate via IL21-IFNγ pathways to induce plasma cells and create conditions for M2b macrophage polarization. Cancer Discov; 6(10); 1182-95. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1069.

PD-1hi Identifies a Novel Regulatory B-cell Population in Human Hepatoma That Promotes Disease Progression.

UNLABELLED: B cells often constitute abundant cellular components in human tumors. Regulatory B cells that are functionally defined by their ability to produce IL10 downregulate inflammation and control T-cell immunity. Here, we identified a protumorigenic subset of B cells that constitutively expressed higher levels of programmed cell death-1 (PD-1) and constituted ∼10% of all B cells in advanced-stage hepatocellular carcinoma (HCC). These PD-1(hi) B cells exhibited a unique CD5(hi)CD24(-/+)CD27(hi/+)CD38(dim) phenotype different from the phenotype of conventional CD24(hi)CD38(hi) peripheral regulatory B cells. TLR4-mediated BCL6 upregulation was crucial for PD-1(hi) B-cell induction by HCC environmental factors, and that effect was abolished by IL4-elicited STAT6 phosphorylation. Importantly, upon encountering PD-L1(+) cells or undergoing PD-1 triggering, PD-1(hi) B cells acquired regulatory functions that suppressed tumor-specific T-cell immunity and promoted cancer growth via IL10 signals. Our findings provide significant new insights for human cancer immunosuppression and anticancer therapies regarding PD-1/PD-L1. SIGNIFICANCE: We identify a novel protumorigenic PD-1(hi) B-cell subset in human HCC that exhibits a phenotype distinct from that of peripheral regulatory B cells. TLR4-mediated BCL6 upregulation is critical for induction of PD-1(hi) B cells, which operate via IL10-dependent pathways upon interacting with PD-L1 to cause T-cell dysfunction and foster disease progression. Cancer Discov; 6(5); 546-59. ©2016 AACR.See related commentary by Ren et al., p. 477This article is highlighted in the In This Issue feature, p. 461.