Mucosal Profiling of Pediatric-Onset Colitis and IBD Reveals Common Pathogenics and Therapeutic Pathways.

Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease subtypes remains incompletely understood. Here, we report single-cell clustering, immune phenotyping, and risk gene analysis for children with undifferentiated colitis, Crohn's disease, and ulcerative colitis. We demonstrate disease-specific characteristics, as well as common pathogenesis marked by impaired cyclic AMP (cAMP)-response signaling. Specifically, infiltration of PDE4B- and TNF-expressing macrophages, decreased abundance of CD39-expressing intraepithelial T cells, and platelet aggregation and release of 5-hydroxytryptamine at the colonic mucosae were common in colitis and IBD patients. Targeting these pathways by using the phosphodiesterase inhibitor dipyridamole restored immune homeostasis and improved colitis symptoms in a pilot study. In summary, comprehensive analysis of the colonic mucosae has uncovered common pathogenesis and therapeutic targets for children with colitis and IBD.

Integrating Genome-Wide Polygenic Risk Scores With Nongenetic Models to Predict Surgical Site Infection After Total Knee Arthroplasty Using United Kingdom Biobank Data.

BACKGROUND: Prediction of the risk of developing surgical site infection (SSI) in patients following total knee arthroplasty (TKA) is of clinical importance. Genetic susceptibility is involved in developing TKA-related SSI. Previously reported models for predicting SSI were constructed using nongenetic risk factors without incorporating genetic risk factors. To address this issue, we performed a genome-wide association study (GWAS) using the UK Biobank database. METHODS: Adult patients who underwent primary TKA (n = 19,767) were analyzed and divided into SSI (n = 269) and non-SSI (n = 19,498) cohorts. Nongenetic covariates, including demographic data and preoperative comorbidities, were recorded. Genetic variants associated with SSI were identified by GWAS and included to obtain standardized polygenic risk scores (zPRS, an estimate of genetic risk). Prediction models were established through analyses of multivariable logistic regression and the receiver operating characteristic curve. RESULTS: There were 4 variants (rs117896641, rs111686424, rs8101598, and rs74648298) achieving genome-wide significance that were identified. The logistic regression analysis revealed 7 significant risk factors: increasing zPRS, decreasing age, men, chronic obstructive pulmonary disease, diabetes mellitus, rheumatoid arthritis, and peripheral vascular disease. The areas under the receiver operating characteristic curve were 0.628 and 0.708 when zPRS (model 1) and nongenetic covariates (model 2) were used as predictors, respectively. The areas under the receiver operating characteristic curve increased to 0.76 when both zPRS and nongenetic covariates (model 3) were used as predictors. A risk-prediction nomogram was constructed based on model 3 to visualize the relative effect of statistically significant covariates on the risk of SSI and predict the probability of developing SSI. Age and zPRS were the top 2 covariates that contributed to the risk, with younger age and higher zPRS associated with higher risks. CONCLUSIONS: Our GWAS identified 4 novel variants that were significantly associated with susceptibility to SSI following TKA. Integrating genome-wide zPRS with nongenetic risk factors improved the performance of the model in predicting SSI.

New Degradable Semiconducting Polymers for Photoacoustic Imaging of λ-Carrageenan-Induced Arthritis Mouse Model.

Semiconducting polymer has a high extinction coefficient and a long band absorption and can be used as a photoacoustic imaging contrast agent. However, nonbiodegradable semiconducting polymers may cause biosafety issues due to being retained in the body. Therefore, developing degradable semiconducting polymers is necessary for in vivo imaging. Herein, we developed three degradable semiconducting polymers with unique optical properties. We adjusted the optical properties of semiconducting polymers by designing the molecular structure of semiconducting polymers. Polymers with a donor-π-acceptor structure could easily improve the optical properties through adjusting the donor or acceptor units. Through adjusting the electron-donor and -acceptor units, three diketopyrrolopyrrole derivative polymers (DPPTz, DPPQu, and DPPWu) were synthesized and converted into nanosize particles. By introducing the degradable chemical groups in the main chain structure of semiconducting polymers, diketopyrrolopyrrole polymers could be degraded by ClO-. Among these nanosize particles, DPPTz NPs and DPPQu NPs were used to achieve the in vivo photoacoustic imaging of λ-carrageenan-induced arthritis mouse model. This work provides a novel design idea for the designing of red-shifted semiconducting polymer with degradable properties.

Cytokine and epigenetic regulation of programmed death-ligand 1 in stem cell differentiation and cancer cell plasticity.

Programmed death-ligand 1 (PD-L1), an immune checkpoint ligand, is recognized as a potential target for cancer immunotherapy as well as for the induction of transplantation tolerance. However, how the crosstalk between stem cell programming and cytokine signaling regulates PD-L1 expression during stem cell differentiation and cancer cell plasticity remains unclear. Herein, we reported that PD-L1 expression was regulated by SOX2 during embryonic stem cell (ESC) differentiation and lung cancer cell plasticity. PD-L1 was induced during ESC differentiation to fibroblasts and was downregulated during SOX2-mediated reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs). Furthermore, SOX2 activation affected cancer cell plasticity and inhibited PD-L1 expression in lung cancer cells. We discovered that the H3K27ac signal at the PD-L1 locus was enhanced during ESC differentiation to fibroblasts as well as during cancer plasticity of SOX2-positive lung cancer cells to SOX2-negative counterparts. Romidepsin, an epigenetic modifier, induced PD-L1 expression in lung cancer cells, whereas TGF-ß stimulation downregulated SOX2 but upregulated PD-L1 expression in lung cancer cells. Furthermore, in addition to PD-L1, the expressions of EGFR and its ligand HBEGF were downregulated by activation of endogenous SOX2 expression during lung cancer cell plasticity and iPSC reprogramming, and the activation of EGFR signaling by HBEGF upregulated PD-L1 expression in lung cancer cells. Together, our results reveal the crosstalk between SOX2 programming and cytokine stimulation influences PD-L1 expression, and these findings may provide insights into PD-L1-mediated therapeutics.

A versatile method for dorsal-approach plantar plate repair using standard operative instruments.

BACKGROUND: The plantar plate is an important static stabilizer of the lesser metatarsophalangeal joints, and disruptions of the plantar plate can lead to significant instability and lesser toe deformities. In recent years, direct plantar plate repair has been proposed. Although direct repair via a dorsal approach is attractive, a torn plantar plate is small and difficult to access using regular instruments in a restricted operative field. METHODS: In this report, a unique method for plantar plate repairs was used to repair various configurations of plantar plate tears with standard operative instruments that are available in most operating rooms. RESULTS: Using this method, 10 patients underwent plantar plate repairs, and the mean follow-up period was 24 (range, 14-38) months. The mean visual analog scale score for pain preoperatively was 4.1 (range, 0-6) and decreased to 0.6 (range, 0-3) at last follow-up. Postoperatively, the mean visual analog scale score for satisfaction was 9.6 (range, 8-10) and the mean American Orthopedic Foot and Ankle Society forefoot score was 88.8 (range, 75-100). CONCLUSIONS: Our study proposes an inexpensive and versatile method for plantar plate repair via a dorsal approach that uses standard operative instruments. TRIAL REGISTRATION: ClinicalTrials.gov , NCT04949685 . July 2, 2021 - Retrospectively registered, LEVEL OF CLINICAL EVIDENCE: 4.

Excessive deubiquitination of NLRP3-R779C variant contributes to very-early-onset inflammatory bowel disease development.

BACKGROUND: Very-early-onset inflammatory bowel disease (VEOIBD) is a chronic inflammatory disease of the gastrointestinal tract occurring during infancy or early childhood. NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome has emerged as a crucial regulator of intestinal homeostasis; however, whether NLRP3 variants may modify VEOIBD risk is unknown. OBJECTIVE: We sought to investigate whether and how a rare NLRP3 variant, found in 3 patients with gastrointestinal symptoms, contributes to VEOIBD development. METHODS: Whole-exome sequencing and bioinformatic analysis were performed to screen disease-associated NLRP3 variants from a cohort of children with VEOIBD. Inflammasome activation was determined in reconstituted HEK293T human embryonic kidney cells with NLRP3 inflammasome components, doxycycline-inducible NLRP3 macrophages, as well as PBMCs and biopsies from patients with NLRP3 variants. Pathogenesis of the variants was determined using a dextran sulfate sodium-induced acute colitis model. RESULTS: We identified a dominant gain-of-function missense variant of NLRP3, encoded by rs772009059 (R779C), in 3 patients with gastrointestinal symptoms. Functional analysis revealed that R779C increased NLRP3 inflammasome activation and pyroptosis in macrophages. This was mediated by enhanced deubiquitination of NLRP3 via binding with deubiquitinases BRCC3 and JOSD2, which are highly expressed in myeloid cells. In a dextran sulfate sodium-induced acute colitis model, NLRP3-R779C in hematopoietic cells resulted in more severe colitis, which can be ameliorated via knockdown of BRCC3 or JOSD2. CONCLUSIONS: BRCC3 and JOSD2 mediate NLRP3-R779C deubiquitination, which promotes NLRP3 inflammasome activation and the risk of developing VEOIBD.

Predictive factors for glucocorticoid therapy in children with eosinophilic gastroenteritis. / å„¿ç«¥å—œé ¸æ€§ç²’ç»†èƒžæ€§èƒƒè‚ ç‚Žç³–çš®è´¨æ¿€ç´ æ²»ç–—çš„é¢„æµ‹å› ç´ åˆ†æž.

OBJECTIVES: To study the predictive factors for glucocorticoid therapy by analyzing the association between the clinical features and treatment regimens in children with eosinophilic gastroenteritis. METHODS: A retrospective analysis was performed on the medical data of 182 children with eosinophilic gastroenteritis who were admitted to Guangzhou Women and Children's Medical Center from January 2012 to December 2020. According to whether glucocorticoids were used, these children were divided into a glucocorticoid treatment group and a control group. The two groups were compared in terms of age, history of allergy, clinical symptoms, laboratory examination results, endoscopic findings, and pathological results of gastrointestinal mucosa. A multivariate logistic regression analysis was performed for the results with statistical significance. RESULTS: Of the 182 children, 36 (19.8%) received glucocorticoid therapy. The rates of hematochezia, anemia, and mucosal ulceration/luminal stenosis under endoscopy and the mucosal eosinophil infiltration count were significantly higher in the glucocorticoid treatment group than those in the control group (P<0.05). The serum albumin level in the glucocorticoid treatment group was significantly lower than that in the control group (P<0.05). The multivariate logistic regression analysis showed that mucosal ulceration/luminal stenosis under endoscopy (OR=10.830, 95%CI: 3.090-37.961, P<0.001) and the increased mucosal eosinophil infiltration count (OR=0.967, 95%CI: 0.941-0.993, P=0.015) were predictive factors for glucocorticoid therapy in children with eosinophil gastroenteritis. CONCLUSIONS: Mucosal ulceration/luminal stenosis under endoscopy or a significant increase in the mucosal eosinophil infiltration count based on pathology suggests that glucocorticoid therapy can be considered in children with eosinophil gastroenteritis.

Storage lipid studies in tuberculosis reveal that foam cell biogenesis is disease-specific.

Foam cells are lipid-laden macrophages that contribute to the inflammation and tissue damage associated with many chronic inflammatory disorders. Although foam cell biogenesis has been extensively studied in atherosclerosis, how these cells form during a chronic infectious disease such as tuberculosis is unknown. Here we report that, unlike the cholesterol-laden cells of atherosclerosis, foam cells in tuberculous lung lesions accumulate triglycerides. Consequently, the biogenesis of foam cells varies with the underlying disease. In vitro mechanistic studies showed that triglyceride accumulation in human macrophages infected with Mycobacterium tuberculosis is mediated by TNF receptor signaling through downstream activation of the caspase cascade and the mammalian target of rapamycin complex 1 (mTORC1). These features are distinct from the known biogenesis of atherogenic foam cells and establish a new paradigm for non-atherogenic foam cell formation. Moreover, they reveal novel targets for disease-specific pharmacological interventions against maladaptive macrophage responses.

YAP1 regulates chondrogenic differentiation of ATDC5 promoted by temporary TNF-α stimulation through AMPK signaling pathway.

Local injection of tumor necrosis factor-alpha (TNF-α) at bone fracture sites during the early stage of the inflammatory response is reported to improve fracture repair in a murine model. However, the underlying mechanism is unclear. Endochondral bone formation, a process that is highly related to fracture repair, requires a certain amount of chondrocyte hypertrophy. This study aimed to investigate the effect of TNF-α on the differentiation of murine chondrogenic ATDC5 cells and the underlying mechanism. In this study, improved chondrogenic differentiation of ATDC5 cells was achieved by brief TNF-α stimulation. Moreover, the expression of Yes-associated protein 1 (YAP1) was suppressed after brief TNF-α stimulation. The expressions of inflammatory mediators and chondrogenic and hypertrophic-associated genes in ATDC5 cells triggered by TNF-α were suppressed in the YAP1 overexpression group but enhanced in the YAP1 knockdown group. Mechanistically, TNF-α-induced activation of the 5' AMP-activated protein kinase (AMPK) signaling pathway was regulated by YAP1, as revealed by the phosphorylated-AMPK/AMPK change ratios in the YAP1 overexpression and knockdown groups, respectively. Moreover, the potential for TNF-α to enhance chondrogenic differentiation could be partially reversed with an AMPK inhibitor. Taken together, we demonstrate, for the first time, that YAP1 modulates the ability of TNF-α to enhance chondrocyte differentiation partly through AMPK signaling.

Shapes of epitaxial gold nanocrystals on SrTiO3 substrates.

Morphological control of gold nanocrystals is important as their catalytic and optical properties are highly shape dependent. In this paper we report the shapes of gold nanocrystals which deviate from the equilibrium Wulff shape due to the influence of the SrTiO3 single crystal substrates. The gold crystals are characterized by scanning tunneling microscopy (STM) and scanning electron microscopy (SEM). The nanocrystals have an equilibrium shape of a truncated octahedron with {111} and {001} facets. On all three substrate surfaces, i.e., SrTiO3(001)-(2 × 1), SrTiO3(001)-c(4 × 2), and SrTiO3(111)-(4 × 4) + (6 × 6), the height-to-width ratio of the gold crystals is not a constant as would be expected for equilibrium crystals, but instead it increases with crystal height. We propose that as the crystals increase in size, their aspect ratio heightens to relax the interfacial strain. The ratio between the {111} and {001} surface areas of our gold crystals is found to differ on the three substrates, which we speculate is due to the selective adsorption of surfactants on the {111} and {001} gold facets resulting from the different substrate surfaces. Reentrant facets of gold crystals that should be present according to their Wulff shape are not observed because these concave sites typically grow out due to kinetic considerations. This study demonstrates the significant effect of the crystal facet termination and surface reconstruction of an oxide substrate on the shape of supported gold nanocrystals.

YAP1 influences differentiation of osteoblastic MC3T3-E1 cells through the regulation of ID1.

Yes-associated protein 1 (YAP1) transcriptional coactivator has recently been identified to regulate skeletal lineage cell differentiation and bone development. However, the role and molecular mechanisms of YAP1 in the regulation of osteoblastic differentiation remains to be elucidated. In this study, we demonstrated that YAP1 expression was increased during osteogenic differentiation of rat bone mesenchymal stem cells and MC3T3-E1. YAP1 overexpression MC3T3-E1 showed increased expression of osteogenesis markers, such as runt-related transcription factor 2, osteocalcin, and osteopontin, as well as alkaline phosphatase and alizarin red staining. Conversely, YAP1 knockdown significantly suppressed MC3T3-E1 osteoblastic differentiation. Mechanistically, we found that YAP1 overexpression upregulated the mRNA and protein expression of the inhibitor of differentiation/DNA binding 1 (ID1), which was contrary to the results of YAP1-knockdown group. Moreover, the early osteogenic differentiation of MC3T3-E1 cells was enhanced by ID1 overexpression. Furthermore, transient transfection with exogenous ID1 overexpression plasmid completely recaptured the decreased effects of YAP1 knockdown on MC3T3-E1 cell differentiation. In addition, ß-catenin and AMP-activated protein kinase signaling pathways participated in YAP1 regulation processes. Taken together, our study suggests that YAP1 is a crucial modulator of osteoblast differentiation in vitro, and provides insight into the mechanism by which YAP1 regulates osteoblast differentiation.

Use of graphene coated with ZnO nanocomposites for microextraction in packed syringe of carbamate pesticides from juice samples.

In this work, nanocomposites of reduced graphene oxide coated with ZnO were synthesized using a hydrothermal reduction strategy. Nanocomposite was then used as a sorbent for microextraction in a packed syringe, and its application to the extraction of carbamate pesticides from juice samples prior to high-performance liquid chromatography detection was demonstrated. Factors affecting the enrichment efficiency of the microextraction in a packed syringe procedure were optimized, which included desorption conditions, sample pH, salting-out effect, washing solution, and sample cycles. Under optimal conditions, the prepared materials exhibited excellent enrichment efficiency for carbamate pesticides. Good linearity existed in the concentration range of 0.5-200 ng/mL, with correlation coefficients of 0.9991-0.9997. The limits of detection of these carbamate pesticides were in the range of 0.23-1.21 ng/mL, and the average recoveries of the analytes at two spiked levels for real-sample analysis ranged from 90.5 to 104.2% with relative standard deviations of 3.6-5.9%.

Acute and Long-Term Effects of Mechanotherapy on the Outcome After an Achilles Repair: A Prospective Cohort Study With Historical Controls.

OBJECTIVES: To evaluate the effects of vibration on Achilles' tendon microcirculation and characteristics following surgical repair of Achilles' tendon rupture. DESIGN: Cohort study with historical controls. SETTING: A university institute. PARTICIPANTS: Participants (N=32), including 19 (16 men, 3 women; median [range] age: 43.0 [25.0-57.0] years) and 13 (10 men, 3 women; 44.00 [29.0-60.0] years) in the vibration (application to the ball of the foot, 30Hz, 2mm amplitude, 4kg pressure, and self-administration) and control groups, respectively, who underwent unilateral Achilles' tendon repairs were recruited. INTERVENTION: A 4-week vibration intervention in the vibration group. MAIN OUTCOME MEASUREMENTS: The tendon microcirculation was measured after the first session of vibration. The participants were evaluated repeatedly with bilateral follow-up measurements of tendon stiffness, 3 functional outcome tests, and a questionnaire survey. RESULTS: Acute effects of the vibration were observed immediately after the 5-minute vibration (P≤.001). Lower total hemoglobin and oxygen saturation were respectively observed (P=.043) in the repaired legs 3 and 6 months postsurgery in the vibration group as compared with the control group. The vibration group also showed greater tendon stiffness, heel raising height and hopping distance 3 or 6 months postoperation in both the repaired and noninjured legs (all P<.05). The microcirculatory characteristics 2 months postoperation were correlated with the outcomes at 6 months postoperation. CONCLUSIONS: Differences in microcirculatory characteristics and better rehabilitation outcomes were observed in the legs with an Achilles repair that underwent the early vibration intervention.

IMU Consensus Exception Detection with Dynamic Time Warping-A Comparative Approach.

A dynamic time warping (DTW) algorithm has been suggested for the purpose of devising a motion-sensitive microelectronic system for the realization of remote motion abnormality detection. In combination with an inertial measurement unit (IMU), the algorithm is potentially applicable for remotely monitoring patients who are at risk of certain exceptional motions. The fixed interval signal sampling mechanism has normally been adopted when devising motion detection systems; however, dynamically capturing the particular motion patterns from the IMU motion sensor can be difficult. To this end, the DTW algorithm, as a kind of nonlinear pattern-matching approach, is able to optimally align motion signal sequences tending towards time-varying or speed-varying expressions, which is especially suitable to capturing exceptional motions. Thus, this paper evaluated this kind of abnormality detection using the proposed DTW algorithm on the basis of its theoretical fundamentals to significantly enhance the viability of the methodology. To validate the methodological viability, an artificial neural network (ANN) framework was intentionally introduced for performance comparison. By incorporating two types of designated preprocessors, i.e., a DFT interpolation preprocessor and a convolutional preprocessor, to equalize the unequal lengths of the matching sequences, two kinds of ANN frameworks were enumerated to compare the potential applicability. The comparison eventually confirmed that the direct template-matching DTW is excellent in practical application for the detection of time-varying or speed-varying abnormality, and reliably captures the consensus exceptions.

Light Bulb Procedure for the Treatment of Tarsal Navicular Osteonecrosis After Failed Percutaneous Decompression: A Case Report.

Tarsal navicular osteonecrosis in adults is a rare condition with unclear etiology, and the optimal treatment has not been established. Here we report a case of tarsal navicular osteonecrosis with a complete course of treatment and comprehensive imaging studies starting at an early stage. A 37-year-old female diagnosed with tarsal navicular osteonecrosis was first treated with percutaneous decompression, but her symptoms persisted postoperatively. The tarsal navicular showed no further collapse, but follow-up magnetic resonance imaging (MRI) at 6 months postoperatively revealed persistent osteonecrotic changes. Debridement of the necrotic bone with preservation of the cortical shell and bone substitute packing for the defect (light bulb procedure) were performed. The symptoms resolved by 3 months postoperatively, and the patient could return to work. At a 6-year follow-up visit, the patient was free of symptoms, and MRI showed remodeling of the tarsal navicular without further collapse.

Ultrasound-Guided Minimally Invasive Surgical Resection of Retrocalcaneal Bursitis: A Preliminary Comparison With Traditional Open Surgery.

Posterior heel pain is a common complaint that is often caused by overuse injuries. In such cases, the retrocalcaneal bursa is compressed and chafed repeatedly, leading to local inflammation. Sonography is a popular imaging tool used to study the pathology of soft tissues, and it can be used to assist in diagnosing bursitis because of its accuracy. Herein, we report an innovative method to treat retrocalcaneal bursitis under ultrasound guidance. Ten patients with posterior heel pain for >6 months who failed conservative treatment received this ultrasound-guided minimally invasive surgery. An endoscopic puncher and burr were inserted under ultrasound guidance via a stabbing wound, and the swollen retrocalcaneal bursa and bony prominence were resected. The patients were able to ambulate and undergo a rehabilitation program 2 weeks postoperatively. In the patients who underwent this ultrasound-guided minimally invasive surgery, both the average surgical time and average hospital stay were shorter than in those (n = 12) who underwent open surgery. In outcome rating assessment, the American Orthopaedic Foot & Ankle Society (AOFAS) pain score and total AOFAS ankle-hindfoot score were improved in the ultrasound-guided minimally invasive surgery group compared to the open surgery group at 2 months postoperatively. Other advantages included lesser wound pain, shorter hospital stay, faster recovery time, and minimal blood loss. Accordingly, ultrasound-guided surgery appears to be a good option for the treatment of retrocalcaneal bursitis.

Fibroblast growth factor-transforming growth factor beta dialogues, endothelial cell to mesenchymal transition, and atherosclerosis.

PURPOSE OF REVIEW: Despite much effort, atherosclerosis remains an important public health problem, leading to substantial morbidity and mortality worldwide. The purpose of this review is to provide an understanding of the role of endothelial cell fate change in atherosclerosis process. RECENT FINDINGS: Recent studies indicate that a process known as endothelial-to-mesenchymal transition (EndMT) may play an important role in atherosclerosis development. Transforming growth factor beta (TGFß) has been shown to be an important driver of the endothelial cell phenotype transition. SUMMARY: The current review deals with the current state of knowledge regarding EndMT's role in atherosclerosis and its regulation by fibroblast growth factor (FGF)-TGFß cross-talk. A better understanding of FGF-TGFß signaling in the regulation of endothelial cell phenotypes is key to the development of novel therapeutic agents.

PKN2 in colon cancer cells inhibits M2 phenotype polarization of tumor-associated macrophages via regulating DUSP6-Erk1/2 pathway.

BACKGROUND: Protein kinase N2 (PKN2) is a PKC-related serine/threonine-protein kinase. PKN2 is required for tumor cell migration, invasion and apoptosis. However, the functional role of PKN2 in regulating tumor associated macrophages (TAMs) polarization in colon cancer has never been reported. METHODS: PKN2 expression in human colon cancer tissues was examined with immunohistochemistry (IHC). M1/M2 macrophage signatures were evaluated by RT-PCR, IHC and flow cytometry. The effects of PKN2 on tumor growth and TAM polarization were investigated both in vitro and in vivo. PKN2 targeted cytokines/pathway were analyzed by gene expression analysis and further confirmed by PCR, luciferase assay or western blot. Correlations between PKN2 and transcriptional factors for IL4 and IL10 were confirmed by ChIP-qPCR. The catalytic activities of PKN2 and DUSP6 were determined by kinase activity assay. Interactions between PKN2 and DUSP6 were confirmed by Co-IP. RESULTS: The expression of PKN2 in colon cancer cells predicted a favorable prognosis and was associated with low M2 macrophage content in human colon cancer tissues. PKN2 inhibited tumor growth in mice xenograft model and inhibited M2 phenotype polarization both in vitro and in vivo. Mechanistically, PKN2 suppresses the expression of IL4 and IL10 from colon cancer cells by inhibiting Erk1/2 phosphorylation, which is required for phosphorylation and binding of CREB and Elk-1 to the promoters of IL4 and IL10. DUSP6, which is phosphorylated and activated through direct association with PKN2, suppresses Erk1/2 activation. CONCLUSIONS: The expression of PKN2 in colon cancer cells suppresses tumor associated M2 macrophage polarization and tumor growth. Targeting PKN2 signaling pathway may provide a potential therapeutic strategy for colon cancer.

Prognostic Value of the Glasgow Prognostic Score or Modified Glasgow Prognostic Score for Patients with Colorectal Cancer Receiving Various Treatments: a Systematic Review and Meta-Analysis.

BACKGROUND/AIMS: Increasing evidence indicates that the systemic inflammatory response plays a vital role in carcinogenesis. The Glasgow Prognostic Score or modified Glasgow Prognostic Score (GPS/mGPS) is a novel inflammatory indicator which consists of CRP and albumin. Here, we performed a meta-analysis to evaluate the prognostic value of the GPS/ mGPS in patients with colorectal cancer (CRC) and to assess its consistency in different CRC therapies. METHODS: The electronic databases PubMed, Embase, Scopus, Web of Science, and Cochrane Library were searched from inception through December 2017 for the association between the GPS/mGPS and clinical outcomes. Study characteristics and prognostic data were extracted from each relevant study. Overall survival (OS) and cancer-specific survival (CSS) were considered the primary outcomes, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. The quality of each study was pooled using the random-effects Mantel-Haenszel model. Finally, subgroup analyses were performed to detect the heterogeneity of different CRC treatments. RESULTS: Thirty-four studies, with a combined total of 8834 patients, were eligible for this meta-analysis. Data on OS and CSS were available in 23 and 22 studies, respectively. By comparing the prognostic values of different levels of the GPS in CRC patients, the summary HRs for OS and CSS were 2.18 (95% CI 1.83-2.60) and 1.82 (95% CI 1.57-2.11), respectively. According to the different tumor stages, the subgroup analyses were stratified by different treatments, including curative or palliative therapy. The results robustly confirmed the prognostic role of the GPS/mGPS. CONCLUSION: Our results suggest that the GPS/mGPS is a novel and effective prognostic indicator for the OS and CSS of patients with CRC.

PKCα in colon cancer cells promotes M1 macrophage polarization via MKK3/6-P38 MAPK pathway.

Tumor associated macrophages are potential targets of the immune therapy for patients with colon cancer. PKCα acts as a tumor suppressor in the intestine. However, the correlation between PKCα expressed in colon cancer cells and tumor associated macrophages polarization has never been detected. In the present study, the correlation between PKCα expression and level of M1 macrophages was evaluated in human colon cancer tissues. A xenograft mouse model of colon cancer cells with different PKCα expression level was constructed to evaluate the effect of PKCα on M1 macrophages polarization in vivo. Co-culture of colon cancer cells and differentiated macrophages was used to detect the potential interplay in vitro. PKCα regulated production of cytokines which correlated with macrophage polarization and the underlying mechanism was further explored. Our study showed that high PKCα expression in human colon cancer tissues correlated with better prognosis and high M1 macrophage content. PKCα expressed in colon cancer cells inhibited the growth of colon cancer in mice model. PKCα induced macrophages polarized to the M1-like phenotype both in vitro and in vivo. Mechanistically, PKCα targeted P38 via MKK3/6 to promote IL12 and GM-CSF expression which further enhanced M1-like macrophages polarization. In conclusion, this study provided evidence for the first time that PKCα in colon cancer cells play an anticancer action by inducing the polarization of tumor associated macrophages to M1-like phenotype in the tumor microenvironment. PKCα promoted IL12/GM-CSF-mediated M1 polarization through MKK3/6-P38 signaling pathway. Our investigation suggested that modulation of the PKCα signaling pathway might serve as a novel strategy for colon cancer therapy.