The genus Ranunculus L. (Ranunculus) in Asia: a review of its botany, traditional uses, phytochemistry, pharmacology, toxicity, and pharmaceutical preparations.

OBJECTIVES: Ranunculus L. genus contains 413 species, and it is the biggest genus in the family Ranunculaceae Juss. This review is to provide botanical characteristics, traditional uses, phytochemistry, pharmacology, toxicity, and pharmaceutical preparations of the genus Ranunculus. KEY FINDINGS: The genus Ranunculus contains flavonoids, organic acids, coumarins, lactones, glycosides, sterols, polysaccharides, and trace elements. These chemical constituents complement the pharmacological actions and work together to exert anti-inflammatory, anticancer, antitubercular, antibacterial, antimalarial, etc. Those traditional Chinese medicine characteristics, like clearing away heat and detoxification, make this genus significant in ethnic medicine. The progress in research and the development of various pharmaceutical preparations made it appear in epidemiological and clinical studies. SUMMARY: The genus Ranunculus has attracted the attention of experts and scholars in many fields due to its unique advantages. However, there are many species that are not scientifically investigated. The toxicity issues are also a huge concern. Fortunately, the toxicity can be overcome via special processes like drying or heating and by choosing a safe extraction solvent, such as water thus ensuring the safety of medication. Pharmaceutical preparations containing the plants from Ranunculus have gratifying clinical value, but they are not promoted sufficiently. Therefore, further research should be carried out to promote the genus for its health benefits to humans.

Spatial transcriptomics reveals prognosis-associated cellular heterogeneity in the papillary thyroid carcinoma microenvironment.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common malignant endocrine tumour, and its incidence and prevalence are increasing considerably. Cellular heterogeneity in the tumour microenvironment is important for PTC prognosis. Spatial transcriptomics is a powerful technique for cellular heterogeneity study. METHODS: In conjunction with a clinical pathologist identification method, spatial transcriptomics was employed to characterise the spatial location and RNA profiles of PTC-associated cells within the tissue sections. The spatial RNA-clinical signature genes for each cell type were extracted and applied to outlining the distribution regions of specific cells on the entire section. The cellular heterogeneity of each cell type was further revealed by ContourPlot analysis, monocle analysis, trajectory analysis, ligand-receptor analysis and Gene Ontology enrichment analysis. RESULTS: The spatial distribution region of tumour cells, typical and atypical follicular cells (FCs and AFCs) and immune cells were accurately and comprehensively identified in all five PTC tissue sections. AFCs were identified as a transitional state between FCs and tumour cells, exhibiting a higher resemblance to the latter. Three tumour foci were shared among all patients out of the 13 observed. Notably, tumour foci No. 2 displayed elevated expression levels of genes associated with lower relapse-free survival in PTC patients. We discovered key ligand-receptor interactions, including LAMB3-ITGA2, FN1-ITGA3 and FN1-SDC4, involved in the transition of PTC cells from FCs to AFCs and eventually to tumour cells. High expression of these patterns correlated with reduced relapse-free survival. In the tumour immune microenvironment, reduced interaction between myeloid-derived TGFB1 and TGFBR1 in tumour focus No. 2 contributed to tumourigenesis and increased heterogeneity. The spatial RNA-clinical analysis method developed here revealed prognosis-associated cellular heterogeneity in the PTC microenvironment. CONCLUSIONS: The occurrence of tumour foci No. 2 and three enhanced ligand-receptor interactions in the AFC area/tumour foci reduced the relapse-free survival of PTC patients, potentially leading to improved prognostic strategies and targeted therapies for PTC patients.

Pan-Cancer Drug Response Prediction Using Integrative Principal Component Regression.

The pursuit of precision oncology heavily relies on large-scale genomic and pharmacological data garnered from preclinical cancer model systems such as cell lines. While cell lines are instrumental in understanding the interplay between genomic programs and drug response, it well-established that they are not fully representative of patient tumors. Development of integrative methods that can systematically assess the commonalities between patient tumors and cell-lines can help bridge this gap. To this end, we introduce the Integrative Principal Component Regression (iPCR) model which uncovers both joint and model-specific structured variations in the genomic data of cell lines and patient tumors through matrix decompositions. The extracted joint variation is then used to predict patient drug responses based on the pharmacological data from preclinical models. Moreover, the interpretability of our model allows for the identification of key driver genes and pathways associated with the treatment-specific response in patients across multiple cancers. We demonstrate that the outputs of the iPCR model can assist in inferring both model-specific and shared co-expression networks between cell lines and patients. We show that iPCR performs favorably compared to competing approaches in predicting patient drug responses, in both simulation studies and real-world applications, in addition to identifying key genomic drivers of cancer drug responses.

Follicular helper T lymphocytes in the endometria of patients with reproductive failure: Association with pregnancy outcomes and inflammatory status of the endometria.

PROBLEM: The phenotypes and functions of B and CD4+ T-helper cell subsets during chronic inflammation of the endometria remain largely unexplored. This study aimed to investigate the characteristics and functions of follicular helper T (Tfh) cells to understand the pathological mechanisms of chronic endometritis (CE). METHOD OF STUDY: Eighty patients who underwent hysteroscopic and histopathological examinations for CE were divided into three groups-those with positive results for hysteroscopy and CD138 staining (DP), negative results for hysteroscopy but positive CD138 staining (SP), and negative results for hysteroscopy and CD138 staining (DN). The phenotypes of B cells and CD4+ T-cell subsets were analyzed using flow cytometry. RESULTS: CD38+ and CD138+ cells were mainly expressed in the non-leukocyte population of the endometria, and the endometrial CD19+ CD138+ B cells were fewer than the CD3+ CD138+ T cells. The percentage of Tfh cells increased with chronic inflammation in the endometria. Additionally, the elevated percentage of Tfh cells correlated with the number of miscarriages. CONCLUSIONS: CD4+ T cells, particularly Tfh cells, may be critical in chronic endometrial inflammation and affect its microenvironment, thereby regulating endometrial receptivity, compared to B cells.

Immune profiling identifies CD8+ T-cell subset signatures as prognostic markers for recurrence in papillary thyroid cancer.

Background: Thyroid tissue has a special immune microenvironment that is not well characterized. Whether immune cells have a prognostic value in the recurrence of papillary thyroid cancer (PTC) needs further investigation. Methods: Multinodular non-toxic goiter (MNG) was taken as normal tissue for the difficulty in obtaining completely normal thyroid tissue (normal thyroid function, no thyroiditis, and no nodules). We compared the composition of mononuclear cells (MNCs) in peripheral blood and thyroid tissues from MNG and PTC patients by high-dimensional flow cytometry profiling and verified the results by multiplex immunohistochemistry. The recurrence rates of PTC patients with different CD8+T cell subset signatures were compared using TCGA database. Results: We observed that the immune cell composition of MNG was different from that in peripheral blood. Thyroid tissue contains higher percentages of T cells and NK cells. Moreover, the percentages of memory T cells and Treg cells were higher in thyroid than in peripheral blood and increased in PTC tumors. We further focused on the antitumoral CD8+T cells and found that the expression patterns of PD-1, CD39, and CD103 on CD8+T cells were different between MNG and PTC. Importantly, we found higher percentages of PD-1+CD39+CD103+CD8+T and PD-1+CD39+CD103-CD8+T cells in PTC tumor tissues from recurrent patients than non-recurrent patients. By analyzing PTC data from TCGA database, we found that the expression patterns of these molecules were associated with different pathologic types and genders among PTC patients. Moreover, patients with PD-1hiCD39loCD103hiCD8hi, PD-1hiCD39hiCD103loCD8hi, and PD-1loCD39hiCD103hiCD8hi expression patterns have a higher 10-year recurrence-free survival. Conclusion: The immune microenvironment in MNG tissue is distinct from that in peripheral blood and paratumor tissue. More memory CD8+T cells were detected in PTC, and expression patterns of PD-1, CD39, and CD103 on CD8+T cells were significantly different in physiology and gender and associated with the recurrence rate of PTC. These observations indicate that CD8+T cell signatures may be useful prognostic markers for PTC recurrence.

Comparison of Geqingpi and Sihuaqingpi based on ultra-high-performance liquid chromatography-tandem mass spectrometry combined with multivariate statistics, network pharmacology analysis, and molecular docking.

Citri Reticulatae Pericarpium Viride is used in traditional Chinese medicine as Geqingpi and Sihuaqingpi varieties. We used the ultra-high-performance liquid chromatography-quadrupole-Exactive Orbitrap-mass spectrometry method and high-performance liquid chromatography-triple quadrupole-tandem mass spectrometry to analyze the chemical compounds in these varieties. Principal components analysis and orthogonal partial least squares discriminant analysis were used to analyze the quantitative results. Network pharmacology and molecular docking technology were used to forecast Citri Reticulatae Pericarpium Viride treatment mechanisms in irritable bowel syndrome. We identified 44 main compounds in Citri Reticulatae Pericarpium Viride. Compared to Sihuaqingpi, Geqingpi had higher narirutin, didymin, naringenin, and hesperetin, and lower hesperidin, isosinensetin, nobiletin, 3,5,6,7,8,3',4'-hexamethoxyflavone, tangeretin. Tangeretin, nobiletin, narirutin, didymin, and isosinensetin were the main compounds distinguishing Geqingpi from Sihuaqingpi. We found that the MAPK signaling pathway, which is closely related to irritable bowel syndrome, was an important target pathway. TP53, HRAS, MAPK1, AKT1, and EGFR were important targets in this pathway. Eriodictyol-7-O-rutinoside, narirutin, limonin, and hesperidin showed a good binding ability to the five targets. Orientin, unique to Sihuaqingpi, bound well to TP53, MAPK1, AKT1, and EGFR, while rhoifolin bound well to TP53, HRAS, MAPK1, AKT1, and EGFR. Hesperetin, unique to Geqingpi, bound well to TP53, HRAS, and MAPK1, while naringenin bound well to HRAS. Hesperidin and didymin bound well to TP53, MAPK1, AKT1, and EGFR.

[Chemical constituents and pharmacological effects of Dictamni Cortex: a review].

Dictamni Cortex, the dried root bark of Dictamnus dasycarpus, has many chemical constituents, such as alkaloids, limonoids, flavonoids, sesquiterpenoids, glycosides, and steroids.It has the effects of anti-inflammation, anti-fungi, anti-arteriosclerosis, stopping bleeding, anti-cancer, neuroprotection, and antioxidation.The chemical constituents of Dictamni Cortex are the important material basis for its medicinal effects.This paper reviewed the chemical constituents and pharmacological activities of Dictamni Cortex and analyzed the research trend and present research progress on this medicinal, with a view to its further development and utilization.

Tumor Mutation Burden Predicts Relapse in Papillary Thyroid Carcinoma With Changes in Genes and Immune Microenvironment.

Background: The risk factors of papillary thyroid carcinoma (PTC) recurrence are meaningful for patients and clinicians. Tumor mutation burden (TMB) has been a biomarker for the effectiveness of immune checkpoint inhibitor (ICI) and prognosis in cancer. However, the role of TMB and its latent significance with immune cell infiltration in PTC are still unclear. Herein, we aimed to explore the effect of TMB on PTC prognosis. Material and Methods: RNA-seq and DNA-seq datasets of PTC patients were downloaded from The Cancer Genome Atlas (TCGA) database. The Gene Ontology (GO) and gene set enrichment analysis (GSEA 4.0.1) were applied further to explore potential differences in PTC patients' biological functions. The differentially expressed genes (DEGs) and immune microenvironment between the high and low TMB groups were determined. Results: TMB had the highest AUC score than other clinical indicators in ROC analysis on recurrence-free survival, and a higher TMB score was related to a worse prognosis. Further, GSEA showed a higher level of oxidative phosphorylation (OXPHOS) in the high TMB group, and four genes correlated with recurrence-free survival rate were identified. The abundance of CD8+ T cells and M1 macrophages in the high TMB group was significantly lower than that in the low TMB group. Conclusions: Our study found that TMB was a better predictor variable at evaluating the risk of PTC recurrence. Moreover, TMB-related genes conferred dramatically correlated prognosis, which was worth exploring in guiding postoperative follow-up and predicting recurrence for PTC patients.

ICN: Extracting interconnected communities in gene Co-expression networks.

MOTIVATION: The analysis of gene co-expression network (GCN) is critical in examining the gene-gene interactions and learning the underlying complex yet highly organized gene regulatory mechanisms. Numerous clustering methods have been developed to detect communities of co-expressed genes in the large network. The assumed independent community structure, however, can be oversimplified and may not adequately characterize the complex biological processes. RESULTS: We develop a new computational package to extract interconnected communities from gene co-expression network. We consider a pair of communities be interconnected if a subset of genes from one community is correlated with a subset of genes from another community. The interconnected community structure is more flexible and provides a better fit to the empirical co-expression matrix. To overcome the computational challenges, we develop efficient algorithms by leveraging advanced graph norm shrinkage approach. We validate and show the advantage of our method by extensive simulation studies. We then apply our interconnected community detection method to an RNA-seq data from The Cancer Genome Atlas (TCGA) Acute Myeloid Leukemia (AML) study and identify essential interacting biological pathways related to the immune evasion mechanism of tumor cells. AVAILABILITY: The software is available at Github: https://github.com/qwu1221/ICN and Figshare: https://figshare.com/articles/software/ICN-package/13229093. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Two populations of self-maintaining monocyte-independent macrophages exist in adult epididymis and testis.

Macrophages are the principal immune cells of the epididymis and testis, but their origins, heterogeneity, development, and maintenance are not well understood. Here, we describe distinct populations of epididymal and testicular macrophages that display an organ-specific cellular identity. Combining in vivo fate-mapping, chimeric and parabiotic mouse models with in-depth cellular analyses, we found that CD64hiMHCIIlo and CD64loMHCIIhi macrophage populations of epididymis and testis arise sequentially from yolk sac erythro-myeloid progenitors, embryonic hematopoiesis, and nascent neonatal monocytes. While monocytes were the major developmental source of both epididymal and testicular macrophages, both populations self-maintain in the steady-state independent of bone marrow hematopoietic precursors. However, after radiation-induced macrophage ablation or during infection, bone marrow-derived circulating monocytes are recruited to the epididymis and testis, giving rise to inflammatory macrophages that promote tissue damage. These results define the layered ontogeny, maintenance and inflammatory response of macrophage populations in the male reproductive organs.

Multi-omics analysis identifies FoxO1 as a regulator of macrophage function through metabolic reprogramming.

Macrophages are plastic cells that can switch among different states according to bioenergetic or biosynthetic requirements. Our previous work demonstrated that the transcription factor Forkhead Box Protein 1 (FoxO1) plays a pivotal role in regulating the function of macrophages, but the underlying mechanisms are still unclear. Here we identify FoxO1 as a regulator of macrophage function through metabolic reprogramming. Transcriptomic and proteomic analyses showed that the deficiency of FoxO1 results in an alternatively activated (M2) phenotype of macrophages, with lower expression of inflammatory response- and migration-associated genes. Using the high content screening and analysis technology, we found that deletion of FoxO1 in macrophages slows their migration rate and impairs their function to limit tumor cell growth in vitro. Next, we demonstrated that glycolysis is inhibited in FoxO1-deficient macrophages, which leads to the observed functional changes and the reduced tumor suppression capability. This prospective study shows that FoxO1 serves as a bridge between metabolism and macrophage function.

Personalized Network Modeling of the Pan-Cancer Patient and Cell Line Interactome.

PURPOSE: Personalized network inference on diverse clinical and in vitro model systems across cancer types can be used to delineate specific regulatory mechanisms, uncover drug targets and pathways, and develop individualized predictive models in cancer. METHODS: We developed TransPRECISE (personalized cancer-specific integrated network estimation model), a multiscale Bayesian network modeling framework, to analyze the pan-cancer patient and cell line interactome to identify differential and conserved intrapathway activities, to globally assess cell lines as representative models for patients, and to develop drug sensitivity prediction models. We assessed pan-cancer pathway activities for a large cohort of patient samples (> 7,700) from the Cancer Proteome Atlas across ≥ 30 tumor types, a set of 640 cancer cell lines from the MD Anderson Cell Lines Project spanning 16 lineages, and ≥ 250 cell lines' response to > 400 drugs. RESULTS: TransPRECISE captured differential and conserved proteomic network topologies and pathway circuitry between multiple patient and cell line lineages: ovarian and kidney cancers shared high levels of connectivity in the hormone receptor and receptor tyrosine kinase pathways, respectively, between the two model systems. Our tumor stratification approach found distinct clinical subtypes of the patients represented by different sets of cell lines: patients with head and neck tumors were classified into two different subtypes that are represented by head and neck and esophagus cell lines and had different prognostic patterns (456 v 654 days of median overall survival; P = .02). High predictive accuracy was observed for drug sensitivities in cell lines across multiple drugs (median area under the receiver operating characteristic curve > 0.8) using Bayesian additive regression tree models with TransPRECISE pathway scores. CONCLUSION: Our study provides a generalizable analytic framework to assess the translational potential of preclinical model systems and to guide pathway-based personalized medical decision making, integrating genomic and molecular data across model systems.

Network-Based Matching of Patients and Targeted Therapies for Precision Oncology.

The extensive acquisition of high-throughput molecular profiling data across model systems (human tumors and cancer cell lines) and drug sensitivity data, makes precision oncology possible - allowing clinicians to match the right drug to the right patient. Current supervised models for drug sensitivity prediction, often use cell lines as exemplars of patient tumors and for model training. However, these models are limited in their ability to accurately predict drug sensitivity of individual cancer patients to a large set of drugs, given the paucity of patient drug sensitivity data used for testing and high variability across different drugs. To address these challenges, we developed a multilayer network-based approach to impute individual patients' responses to a large set of drugs. This approach considers the triplet of patients, cell lines and drugs as one inter-connected holistic system. We first use the omics profiles to construct a patient-cell line network and determine best matching cell lines for patient tumors based on robust measures of network similarity. Subsequently, these results are used to impute the "missing link" between each individual patient and each drug, called Personalized Imputed Drug Sensitivity Score (PIDS-Score), which can be construed as a measure of the therapeutic potential of a drug or therapy. We applied our method to two subtypes of lung cancer patients, matched these patients with cancer cell lines derived from 19 tissue types based on their functional proteomics profiles, and computed their PIDS-Scores to 251 drugs and experimental compounds. We identified the best representative cell lines that conserve lung cancer biology and molecular targets. The PIDS-Score based top sensitive drugs for the entire patient cohort as well as individual patients are highly related to lung cancer in terms of their targets, and their PIDS-Scores are significantly associated with patient clinical outcomes. These findings provide evidence that our method is useful to narrow the scope of possible effective patient-drug matchings for implementing evidence-based personalized medicine strategies.

Tip and Inner Wall Modification of 4.9 nm Diameter Multi-Walled Carbon Nanotubes and Its Nanocomposite Polyamide Reverse Osmosis Membrane.

The tip and inner surface of large diameter multi-walled carbon nanotubes (MWCNTs) (4.9 nm diameter) were functionalized on the tip and inner surface to improve the rate of desalination and maintain high water flux. The modified MWCNTs-doped reverse osmosis membranes were fabricated by interfacial polymerization using trimesoyl chloride (TMC) solution in n-hexane and aqueous solutions of m-phenylenediamine (MPD) containing functionalized MWCNTs. The functionalized MWCNTs were analyzed by X-ray photoelectron spectroscopy (XPS), thermal gravity analysis (TGA), high resolution transmission electron microscopy (HRTEM), UV-Vis spectroscopy and other techniques. The obtained results showed that changes occurred in the structure of the carbon nanotubes with the inner diameter becoming smaller, and the dispersibility and stability were improved. Carboxyl, acyl chloride, amide and amino groups were successfully grafted on the tip and interior of MWCNTs. The surface characteristics of the prepared membranes were studied by scanning electron microscopy (SEM) and contact angle analysis. The desalination performance of the membranes was investigated in terms of water flux and salt rejection. The experimental results revealed that the incorporation of the modified MWCNTs (especially containing hydrophilic groups such as carboxyl groups) into the polyamide layer of RO membranes led to a significantly increase of the water flux and salt rejection.

Tandem Enzymatic Self-Assembly and Slow Release of Dexamethasone Enhances Its Antihepatic Fibrosis Effect.

Many chronic liver diseases will advance to hepatic fibrosis and, if without timely intervention, liver cirrhosis or even hepatocellular carcinoma. Anti-inflammation could be a standard therapeutic strategy for hepatic fibrosis treatment, but a "smart" strategy of hepatic fibrosis-targeted, either self-assembly or slow release of an anti-inflammation drug ( e.g., dexamethasone, Dex), has not been reported. Herein, we rationally designed a hydrogelator precursor Nap-Phe-Phe-Lys(Dex)-Tyr(H2PO3)-OH (1-Dex-P) and proposed a tandem enzymatic strategy of self-assembly and slow release of Dex, with which the precursor exhibited much stronger antihepatic fibrosis effect than Dex both in vitro and in vivo. Enzymatic and cell experiments validated that 1-Dex-P was first dephosphorylated by alkaline phosphatase to yield Nap-Phe-Phe-Lys(Dex)-Tyr-OH (1-Dex), which self-assembled into nanofiber 1-Dex. The nanofiber was then hydrolyzed by esterase to transform into nanofiber 1, accompanied by slow release of Dex. We anticipate that our "smart" tandem enzymatic strategy could be widely employed to design more sophisticated drug delivery systems to achieve enhanced therapeutic efficacy than free drugs in the future.

Adaptive immune cells are necessary for the enhanced therapeutic effect of sorafenib-loaded nanoparticles.

Sorafenib is a kinase inhibitor approved for the treatment of primary kidney cancer, advanced primary liver cancer, and radioactive iodine resistant advanced thyroid carcinoma. However, sorafenib usually causes serious side effects, which limit its antitumor effect. Nanoparticle based drug delivery systems have been widely used to enhance the therapeutic effects and reduce the side effects of this drug by the enhanced permeability and retention (EPR) effect. Herein, to improve the therapeutic effect of sorafenib, we developed poly(ethylene glycol)-b-poly(lactic acid-co-glycolic acid) (PEG-PLGA) based nanoparticles by a dialysis method for sorafenib encapsulation. After intravenous injection of the sorafenib loaded nanoparticles (NPsorafenib), the tumor growth of mice bearing B16-F10, MC38 and LLC tumor was significantly inhibited. Meanwhile, the dose of sorafenib was reduced to one ninth and the side effects on the hematopoietic system and immune system were abrogated. More importantly, the tumor growth inhibition effect of NPsorafenib was dramatically reduced in B16-F10 bearing Rag1-/- mice which are adaptive immune cell defective, indicating that the antitumor effects of NPsorafenib are dependent on the adaptive immune cells. These results emphasize the indispensable role of the adaptive immune system in nano-drug mediated antitumor effects and the adaptive immune system should be considered as an important factor for clinical applications.

FoxO1 is a regulator of MHC-II expression and anti-tumor effect of tumor-associated macrophages.

Macrophages are a critical component in host immune responses against tumor. In this work we investigated the role of forkhead box O1 (FoxO1) in the transcriptional regulation in macrophages, which affects the anti-tumor functions of tumor-associated macrophages (TAMs). First, we showed that TAMs expressed reduced levels of FoxO1, which was associated with their protumoral M2 polarization state. The suppression of FoxO1 expression in TAM was induced by the hypoxic condition in the tumor microenviroment. Next, we confirmed that FoxO1 positively regulates MHC-II genes by binding to the promoter region of Ciita gene, the master activator of multiple MHC-II genes. Loss of FoxO1 in TAMs resulted in reduced MHC-II expression. Furthermore, we used FoxO1 conditional knockout mice to show that FoxO1 deficiency in myeloid cells exacerbates tumor growth. These results demonstrate that the protumoral property of TAMs is induced by the hypoxia-triggered FoxO1 deficiency, which could be a potential target of novel anti-tumor therapies.

Modulation of liver regeneration via myeloid PTEN deficiency.

Molecular mechanisms that modulate liver regeneration are of critical importance for a number of hepatic disorders. Kupffer cells and natural killer (NK) cells are two cell subsets indispensable for liver regeneration. We have focused on these two populations and, in particular, the interplay between them. Importantly, we demonstrate that deletion of the myeloid phosphatase and tensin homolog on chromosome 10 (PTEN) leading to an M2-like polarization of Kupffer cells, which results in decreased activation of NK cells. In addition, PTEN-deficient Kupffer cells secrete additional factors that facilitate the proliferation of hepatocytes. In conclusion, PTEN is critical for inhibiting M2-like polarization of Kupffer cells after partial hepatectomy, resulting in NK cell activation and thus the inhibition of liver regeneration. Furthermore, PTEN reduces growth factor secretion by Kupffer cells. Our results suggest that targeting PTEN on Kupffer cells may be useful in altering liver regeneration in patients undergoing liver resection.

Forkhead Box O1 Regulates Macrophage Polarization Following Staphylococcus aureus Infection: Experimental Murine Data and Review of the Literature.

The functions of macrophages that lead to effective host responses are critical for protection against Staphylococcus aureus. Deep tissue-invading S. aureus initially countered by macrophages trigger macrophage accumulation and induce inflammatory responses through surface receptors, especially toll-like receptor 2 (TLR2). Here, we found that macrophages formed sporadic aggregates in the liver during infection. Within those aggregates, macrophages co-localized with T cells and were indispensable for their infiltration. In addition, we have focused on the mechanisms underlying the polarization of macrophages in Forkhead box transcription factor O1 (FoxO1) conditional knockout Lys Cre/+ FoxO1 fl/fl mice following S. aureus infection and report herein that macrophage M1-M2 polarization via TLR2 is intrinsically regulated by FoxO1. Indeed, for effective FoxO1 activity, stimulation of TLR2 is essential. However, following S. aureus challenge, there was a decrease in macrophage FoxO1, with increased phosphorylation of FoxO1 because of TLR2-mediated activation of PI3K/Akt and c-Raf/MEK/ERK pathway. Following infection in Lys Cre/+ FoxO1 fl/fl mice, mice became more susceptible to S. aureus with reduced macrophage aggregation in the liver and attenuated Th1 and Th17 responses. FoxO1 abrogation reduced M1 pro-inflammatory responses triggered by S. aureus and enhanced M2 polarization in macrophages. In contrast, overexpression of FoxO1 in macrophages increased pro-inflammatory mediators and functional surface molecule expression. In conclusion, macrophage FoxO1 is critical to promote M1 polarization and maintain a competent T cell immune response against S. aureus infection in the liver. FoxO1 regulates macrophage M1-M2 polarization downstream of TLR2 dynamically through phosphorylation.

Dosimetric Evaluation of Different Intensity-Modulated Radiotherapy Techniques for Breast Cancer After Conservative Surgery.

Intensity-modulated radiotherapy (IMRT) potentially leads to a more favorite dose distribution compared to 3-dimensional or conventional tangential radiotherapy (RT) for breast cancer after conservative surgery or mastectomy. The aim of this study was to compare dosimetric parameters of the planning target volume (PTV) and organs at risk (OARs) among helical tomotherapy (HT), inverse-planned IMRT (IP-IMRT), and forward-planned field in field (FP-FIF) IMRT techniques after breast-conserving surgery. Computed tomography scans from 20 patients (12 left sided and 8 right sided) previously treated with T1N0 carcinoma were selected for this dosimetric planning study. We designed HT, IP-IMRT, and FP-FIF plans for each patient. Plans were compared according to dose-volume histogram analysis in terms of PTV homogeneity and conformity indices (HI and CI) as well as OARs dose and volume parameters. Both HI and CI of the PTV showed statistically significant difference among IP-IMRT, FP-FIF, and HT with those of HT were best (P < .05). Compared to FP-FIF, IP-IMRT showed smaller exposed volumes of ipsilateral lung, heart, contralateral lung, and breast, while HT indicated smaller exposed volumes of ipsilateral lung but larger exposed volumes of contralateral lung and breast as well as heart. In addition, HT demonstrated an increase in exposed volume of ipsilateral lung (except for fraction of lung volume receiving >30 Gy and 20 Gy), heart, contralateral lung, and breast compared with IP-IMRT. For breast cancer radiotherapy (RT) after conservative surgery, HT provides better dose homogeneity and conformity of PTV compared to IP-IMRT and FP-FIF techniques, especially for patients with supraclavicular lymph nodes involved. Meanwhile, HT decreases the OAR volumes receiving higher doses with an increase in the volumes receiving low doses, which is known to lead to an increased rate of radiation-induced secondary malignancies. Hence, composite factors including dosimetric advantage, clinical effect, and economic burden should be taken into comprehensive consideration when choosing an RT technique in clinical practice.