Octyl gallate has potent anti-inflammasome activity by directly binding to NLRP3 LRR domain.

The NOD-, LRR-, and Pyrin domain-containing protein 3 (NLRP3) inflammasome plays key roles in regulating inflammation. Numerous studies show that the abnormal activation of NLRP3 associates with the initiation and progression of various diseases. Hence, the NLRP3 inflammasome may be a promising therapeutic target for these diseases. Octyl gallate (OG) is a small molecule with antioxidant, antimicrobial, antifungal, and anti-inflammatory activities; however, the mechanism underlying its anti-inflammatory activity is still unclear. Here, we developed a screening system for NLRP3-inflammasome inhibitors. A total of 3287 small molecules were screened for inhibitors of nigericin-induced NLRP3 oligomerization. OG was identified as a novel inhibitor. We show that OG directly targets the LRR domain of NLRP3 and thereby blocks the inflammatory cascade of the NLRP3 inflammasome. This contrasts with the mode-of-action of other direct NLRP3 inhibitors, which all bind to the NACHT domain of NLRP3. Interestingly, OG also inhibits the priming step by downregulating the Raf-MEK1/2-ERK1/2 axis. Thus, OG inhibits the NLRP3 inflammasome by two distinct mechanisms. Importantly, OG injection ameliorated the inflammation in mouse models of foot gout and sepsis. Our study identifies OG as a potential therapeutic agent for NLRP3-associated diseases.

Characteristics and risk factors of axillary lymph node metastasis of microinvasive breast cancer.

PURPOSE: To select patients who would benefit most from sentinel lymph node biopsy (SLNB) by investigating the characteristics and risk factors of axillary lymph node metastasis (ALNM) in microinvasive breast cancer (MIBC). METHODS: This retrospective study included 1688 patients with MIBC who underwent breast surgery with axillary staging at the Asan Medical Center from 1995 to 2020. RESULTS: Most patients underwent SLNB alone (83.5%). Seventy (4.1%) patients were node-positive, and the majority had positive lymph nodes < 10 mm, with micro-metastases occurring frequently (n = 37; 55%). Node-positive patients underwent total mastectomy and axillary lymph node dissection (ALND) more than breast-conserving surgery (BCS) and SLNB compared with node-negative patients (p < 0.001). In the multivariate analysis, independent predictors of ALNM included young age [odds ratio (OR) 0.959; 95% confidence interval (CI) 0.927-0.993; p = 0.019], ALND (OR 11.486; 95% CI 5.767-22.877; p < 0.001), number of lymph nodes harvested (≥ 5) (OR 3.184; 95% CI 1.555-6.522; p < 0.001), lymphovascular invasion (OR 6.831; 95% CI 2.386-19.557; p < 0.001), presence of multiple microinvasion foci (OR 2.771; 95% CI 1.329-5.779; p = 0.007), prominent lymph nodes in preoperative imaging (OR 2.675; 95% CI 1.362-5.253; p = 0.004), and hormone receptor positivity (OR 2.491; 95% CI 1.230-5.046; p = 0.011). CONCLUSION: Low ALNM rate (4.1%) suggests that routine SLNB for patients with MIBC is unnecessary but can be valuable for patients with specific risk factors. Ongoing trials for omitting SLNB in early breast cancer, and further subanalyses focusing on rare populations with MIBC are necessary.

Comparative analysis of organ preservation attempt and radical surgery in clinical T2N0 mid to low rectal cancer.

PURPOSE: Debate persists regarding the feasibility of adopting an organ-preserving strategy as the treatment modality for clinical T2N0 rectal cancer. This study aimed to compare the outcomes of attempting organ-preserving strategies versus radical surgery in patients with clinical T2N0 mid to low rectal cancer. METHODS: Patients diagnosed with clinical T2N0 rectal cancer, with lesions located within 8 cm from the anal verge as determined by pre-treatment magnetic resonance imaging between January 2010 and December 2020 were included. RESULTS: Of 119 patients, 91 and 28 were categorized into the organ-preserving attempt group and the radical surgery group, respectively. The median follow-up duration was 48.8 months (range, 0-134 months). The organ-preserving attempt group exhibited a reduced incidence of stoma formation (44.0% vs. 75.0%; p = 0.004) and a lower occurrence of grade 3 or higher surgical complications (5.8% vs. 21.4%; p = 0.025). Univariate analyses revealed no significant association between treatment strategy and 3-year local recurrence-free survival (organ-preserving attempt 87.9% vs. radical surgery 96.2%; p = 0.129), or 3-year disease-free survival (79.6% vs. 84.9%; p = 0.429). Multivariate analysis did not identify any independent prognostic factors associated with oncologic outcomes. CONCLUSION: Compared with radical surgery, attempted organ preservation resulted in lower incidences of stoma formation and severe surgical complications, whereas oncological outcomes were comparable. Attempting organ preservation may be a safe alternative to radical surgery for clinical T2N0 mid to low rectal cancer.

Impact of Preoperative Immunonutrition on the Outcomes of Colon Cancer Surgery: Results from a Randomized Controlled Trial.

OBJECTIVE: This study aimed to assess the impact of preoperative immunonutrition on the outcomes of colon cancer surgery. BACKGROUND: Although current guidelines recommend that immunonutrition should be prescribed for malnourished patients before major gastrointestinal surgery, the benefit of preoperative immunonutrition remains debatable. METHODS: Between April 2019 and October 2020, 176 patients with primary colon cancer were enrolled and randomly assigned (1:1) to receive preoperative immunonutrition plus a normal diet (n = 88) or a normal diet alone (n = 88). Patients in the immunonutrition group received oral nutritional supplementation (400 mL/d) with arginine and ω-3 fatty acids for 7 days before elective surgery. The primary endpoint was the rate of infectious complications, and the secondary endpoints were the postoperative complication rate, change in body weight, and length of hospital stay. RESULTS: The rates of infectious (17.7% vs 15.9%, P = 0.751) and total (31.6% vs 29.3%, P = 0.743) complications were not different between the two groups. Old age was the only significant predictive factor for the occurrence of infectious complications (odds ratio = 2.990, 95% confidence interval 1.179-7.586, P = 0.021). The length of hospital stay (7.6 ± 2.5 vs 7.4 ± 2.3 days, P = 0.635) and overall change in body weight ( P = 0.379) were similar between the two groups. However, only the immunonutrition group showed weight recovery after discharge (+0.4 ± 2.1 vs -0.7 ± 2.3 kg, P = 0.002). CONCLUSIONS: Preoperative immunonutrition was not associated with infectious complications in patients undergoing colon cancer surgery. Routine administration of immunonutrition before colon cancer surgery cannot be justified.

Clinical significance of microinvasive breast cancer across the different subtypes and human epidermal growth factor receptor 2 expression levels.

PURPOSE: The clinical behavior, prognosis, and management of microinvasive breast cancer (MiBC) is controversial. We aimed to clarify its significance across different subtypes and the role of human epidermal growth factor receptor 2 (HER2) expression in MiBC. METHODS: We analyzed 1530 patients with T1mi (tumor size ≤ 0.1 cm), node-negative breast cancer who underwent breast conserving surgery or total mastectomy between 2001 and 2020 at the Asan Medical Center (AMC). RESULTS: When divided into four subtypes, hormone receptor (HR)+/HER2-, HR+ /HER2+ , HR-/HER2+ , and HR-/HER2-, HR-/HER2+ had the highest prevalence rate of 38.5% in MiBC patients. In a median follow-up period of 74 months (0-271 months), 103 (6.7%) patients had recurrent tumor, and 95 (6.2%) had local recurrence. Disease-free survival (DFS) and local recurrence-free survival (LRFS) were worst in the HR-/HER2+ group. The five-year DFS for the HR-/HER2+ group was 92.2%, while it was 97.1% for the HR+/HER2- group (p = 0.024 The five-year LRFS for HER2- patients were better than that of HER2+ MiBC patients, which were 97.1 and 93.8%, respectively (p = 0.010). Univariate and multivariate Cox regression analyses showed that the HR-/HER2+ group had relatively higher risk of recurrence compared to the HR+/HER2- group (hazard ratio [HR] = 2.332, 95% confidence interval [CI] 1.412-3.852, p = 0.001 unadjusted; HR = 3.346, 95% CI 1.408-7.953, p = 0.006 adjusted). CONCLUSION: HER2 overexpression was significantly associated with adverse clinicopathologic parameters and increased local recurrence risk in MiBC. Therefore, more understanding of the clinical behavior of HER2 in MiBC will enable tailoring of adjuvant therapy for these patients.

The orphan nuclear receptor SHP acts as a negative regulator in inflammatory signaling triggered by Toll-like receptors.

The orphan nuclear receptor SHP (small heterodimer partner) is a transcriptional corepressor that regulates hepatic metabolic pathways. Here we identified a role for SHP as an intrinsic negative regulator of Toll-like receptor (TLR)-triggered inflammatory responses. SHP-deficient mice were more susceptible to endotoxin-induced sepsis. SHP had dual regulatory functions in a canonical transcription factor NF-κB signaling pathway, acting as both a repressor of transactivation of the NF-κB subunit p65 and an inhibitor of polyubiquitination of the adaptor TRAF6. SHP-mediated inhibition of signaling via the TLR was mimicked by macrophage-stimulating protein (MSP), a strong inducer of SHP expression, via an AMP-activated protein kinase-dependent signaling pathway. Our data identify a previously unrecognized role for SHP in the regulation of TLR signaling.

A booster administration of the OKA/SK strain causes fatal disseminated varicella in an immunocompetent child.

Live varicella vaccines are known to provide robust immunity against varicella zoster virus (VZV) infections. However, problems with viral attenuation have led to pathogenic VZV vaccine strains causing varicella-like rash and herpes zoster in immunocompetent children after immunization. We report the first fatal case of VZV infection caused by OKA/SK strain contained in the vaccine administrated as a booster shot in an immunocompetent child, which has been independently developed from any currently available varicella vaccines that are OKA strain or MAV/06 strain based. The patient died due to sudden pulmonary alveolar hemorrhage as a secondary complication of VZV pneumonitis. Sequencing of the four SNPs unique to the OKA/SK strain (SNP loci 14 035T; 32 626C; 58 777G; 70 319G) enabled discrimination of the strain responsible for the disseminated infection. OKA/SK strain does not have any SNPs in ORF62 postulated to be responsible for the attenuation of varicella vaccines which have been safely and effectively used world-wide or locally, and exclusively enriches a virulent factor in ORF31 identified in parental OKA strain, thus possibly resulting in disseminated VZV infection leading to mortality. Therefore, actions need to be taken to prevent vaccine related morbidity and mortality in children.

Core promoter activity contributes to chromatin-based regulation of internal cryptic promoters.

During RNA polymerase II (RNA Pol II) transcription, the chromatin structure undergoes dynamic changes, including opening and closing of the nucleosome to enhance transcription elongation and fidelity. These changes are mediated by transcription elongation factors, including Spt6, the FACT complex, and the Set2-Rpd3S HDAC pathway. These factors not only contribute to RNA Pol II elongation, reset the repressive chromatin structures after RNA Pol II has passed, thereby inhibiting aberrant transcription initiation from the internal cryptic promoters within gene bodies. Notably, the internal cryptic promoters of infrequently transcribed genes are sensitive to such chromatin-based regulation but those of hyperactive genes are not. To determine why, the weak core promoters of genes that generate cryptic transcripts in cells lacking transcription elongation factors (e.g. STE11) were replaced with those from more active genes. Interestingly, as core promoter activity increased, activation of internal cryptic promoter dropped. This associated with loss of active histone modifications at the internal cryptic promoter. Moreover, environmental changes and transcription elongation factor mutations that downregulated the core promoters of highly active genes concomitantly increased their cryptic transcription. We therefore propose that the chromatin-based regulation of internal cryptic promoters is mediated by core promoter strength as well as transcription elongation factors.

Tetraspanin 7 regulates osteoclast function through association with the RANK/αvß3 integrin complex.

Actin rings are unique structures that facilitate the attachment of osteoclasts to the bone matrix during bone resorption. Previous studies have shown that tetraspanin7 (TSPAN7) plays an important role in the reorganization of the cytoskeleton necessary for the bone-resorbing activity of osteoclasts. However, questions remain as to the mechanisms by which TSPAN7 regulates this cytoskeletal rearrangement. In this study, we investigated the roles of TSPAN7 in osteoclasts by deleting the Tm4sf2 gene in mice, which encodes TSPAN7. The Tm4sf2 global knockout model showed protective effects on pathological bone loss, but no discernible changes in bone phenotypes under physiological conditions. In vitro study revealed that ablation of Tm4sf2 caused significant defects in integrin-mediated actin ring formation, thereby leading to significantly decreased bone resorption. Additionally, we demonstrated an association between TSPAN7 and the receptor activator of nuclear factor-кB/αvß3 integrin. Overall, our findings suggest that TSPAN7 acts as a novel modulator regulating the bone-resorbing function of osteoclasts.

Periumbilical Transverse Incision for Reducing Incisional Hernia in Laparoscopic Colon Cancer Surgery.

BACKGROUND: Although off-midline incisions (unilateral low transverse or Pfannenstiel incision) have been reported to have a lower incidence of incisional hernia (IH) than periumbilical vertical incision for the purpose of specimen extraction, it is most commonly used in laparoscopic colon cancer surgery because off-midline incisions are associated with the limitation of colon exteriorization. This study aims to investigate the risk of IH after laparoscopic colectomy and compare midline vertical incision versus transverse incision focusing on the incidence of IH. METHODS: Patients who underwent elective laparoscopic colectomy due to colon malignancy from June 2015 to May 2017 were included. All patients had either vertical (n = 429) or muscle splitting periumbilical transverse incisions (n = 125). RESULTS: Median duration of the follow-up period was 23.6 months, during which IHs occurred in 12.1% patients. The incidence of hernia was significantly lower in the transverse group (3 vs. 64, 2.4% vs. 14.9%, p < 0.001). On multivariate analysis, BMI ≥ 23 [odds ratio (OR) 2.282, 95% confidence interval (CI) 1.245-4.182, p = 0.008], postoperative surgical site infection (OR 3.780, 95% CI 1.969-7.254, p < 0.001) and vertical incision (OR 7.113, 95% CI 2.173-23.287, p < 0.001) were independently related with increased incidence of IH. CONCLUSIONS: A muscle splitting periumbilical transverse incision could significantly reduce the rate of IH in minimally invasive colon cancer surgery.

Effect of the First Assistant on Anastomotic Leakage after Rectal Cancer Surgery with Double-Stapling Anastomosis: A Propensity Score Matching Analysis.

INTRODUCTION: Proper handling and firing of the circular stapler are important for secure anastomosis in rectal cancer surgery. This study aimed to investigate the association between the first assistant and anastomotic leakage (AL) after rectal cancer surgery with double-stapling anastomosis. METHODS: Patients with primary rectal cancer who underwent low anterior resection with double-stapling anastomosis between January 2015 and September 2019 were included. Data on clinicopathological characteristics, including the first assistant's sex and experience level, were retrospectively reviewed, and the risk factors for AL were analyzed using propensity score matching analysis. RESULTS: Among 758 rectal cancer surgeries, residents participated in 401 (52.9%) surgeries, and fellows participated in 357 (47.1%) surgeries as first assistants. After propensity score matching (n = 650), AL occurred in 5.4% (35/650). The first assistant's experience level (resident: 5.5% vs. fellow: 5.2%, p = 0.862) and sex (male: 5.4% vs. female: 4.9%, p = 0.849) were not associated with the occurrence of AL. Male sex in patients was the only significant predictive factor for AL (odds ratio = 2.804, 95% confidence interval 1.070-7.351, p = 0.036). DISCUSSION/CONCLUSION: The first assistant's sex and experience level were not associated with AL after rectal cancer surgery with double-stapling anastomosis. These findings may justify resident participation in rectal cancer surgeries in which circular staplers are used.

Anti-Obesity and Anti-Adipogenic Effects of Administration of Arginyl-Fructose-Enriched Jeju Barley (Hordeum vulgare L.) Extract in C57BL/6 Mice and in 3T3-L1 Preadipocytes Models.

In our previous study, we reported that arginyl-fructose (AF), one of the Amadori rearrangement compounds (ARCs) produced by the heat processing of Korean ginseng can reduce carbohydrate absorption by inhibiting intestinal carbohydrate hydrolyzing enzymes in both in vitro and in vivo animal models. This reduced absorption of carbohydrate might be helpful to control body weight gain due to excessive carbohydrate consumption and support induced calorie restriction. However, the weight management effect, except for the effect due to anti-hyperglycemic action, along with the potential mechanism of action have not yet been determined. Therefore, the efforts of this study are to investigate and understand the possible weight management effect and mechanism action of AF-enriched barley extracts (BEE). More specifically, the effect of BEE on lipid accumulation and adipogenic gene expression, body weight gain, body weight, plasma lipids, body fat mass, and lipid deposition were evaluated using C57BL/6 mice and 3T3-L1 preadipocytes models. The formation of lipid droplets in the 3T3-L1 treated with BEE (500 and 750 µg/mL) was significantly blocked (p < 0.05 and p < 0.01, respectively). Male C57BL/6 mice were fed a high-fat diet (30% fat) for 8 weeks with BEE (0.3 g/kg-body weight). Compared to the high fat diet control (HFD) group, the cells treated with BEE significantly decreased in intracellular lipid accumulation with concomitant decreases in the expression of key transcription factors, peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (CEBP/α), the mRNA expression of downstream lipogenic target genes such as fatty acid binding protein 4 (FABP4), fatty acid synthase (FAS), and sterol regulatory element-binding protein 1c (SREBP-1c). Supplementation of BEE effectively lowered the body weight gain, visceral fat accumulation, and plasma lipid concentrations. Compared to the HFD group, BEE significantly suppressed body weight gain (16.06 ± 2.44 g vs. 9.40 ± 1.39 g, p < 0.01) and increased serum adiponectin levels, significantly, 1.6-folder higher than the control group. These results indicate that AF-enriched barley extracts may prevent diet-induced weight gain and the anti-obesity effect is mediated in part by inhibiting adipogenesis and increasing adiponectin level.

Body Mapping and Story Circles in Sexual Health Research With Youth of Color: Methodological Insights and Study Findings From Adolescent X, an Art-Based Research Project.

We describe the implementation and select findings from Adolescent X, an arts-based research project that used story circles and body mapping to elucidate how young people understand the relationship between their social contexts and their sexual and reproductive health, with a particular focus on youth's understandings of gender, sexuality, and the body as sites of possibility and power. A community-based sample of N = 24 youth of color was recruited from the South and West Sides of Chicago to participate in 3-day workshops. In addition to story circles and body mapping, data were collected via brief surveys with N = 24 youth, debriefing groups (n = 10 youth), and focus groups (n = 14 youth). Study data consisted of (1) body map visuals, that is, legends, mini-, and full-body maps; (2) written body map narratives; and (3) audio recordings of the story circles, body mapping activities, debriefing groups, and focus groups. All audio recordings were transcribed, deidentified, and uploaded in Dedoose for qualitative thematic analysis. Data analysis was conducted by a team of independent coders. Across all sources of data, three major themes were identified: (1) strong feelings of unsafety related to how young people's bodies are gendered, sexualized, and racialized in different social settings; (2) the extent to which adults and institutions foster youth safety; and (3) sources of young people's coping and resilience. Implications for public health research, practice, and policy are discussed.

Proper surgical extent for clinical Stage I right colon cancer.

PURPOSE: Pre-operative evaluation identifying clinical-stage affects the decision regarding the extent of surgical resection in right colon cancer. This study was designed to predict a proper surgical resection through the prognosis of clinical Stage I right colon cancer. PATIENTS AND METHODS: We included patients who were diagnosed with clinical and pathological Stage I right-sided colon cancer, including appendiceal, caecal, ascending, hepatic flexure and proximal transverse colon cancer, between August 2010 and December 2016 in two tertiary teaching hospitals. Patients who underwent open surgeries were excluded because laparoscopic surgery is the initial approach for colorectal cancer in our institutions. RESULTS: Eighty patients with clinical Stage I and 104 patients with pathological Stage I were included in the study. The biopsy reports showed that the tumour size was larger in the clinical Stage I group than in the pathological Stage I group (3.4 vs. 2.3 cm, P < 0.001). Further, the clinical Stage I group had some pathological Stage III cases (positive lymph nodes, P = 0.023). The clinical Stage I group had a higher rate of distant metastases (P = 0.046) and a lower rate of overall (P = 0.031) and cancer-specific survival (P = 0.021) than the pathological Stage I group. Compared to pathological Stage II included in the period, some of the survival curves were located below the pathological Stage II, but there was no statistical difference. CONCLUSION: The study results show that even clinical Stage I cases, radical resection should be considered in accordance with T3 and T4 tumours.

Cinchonine inhibits osteoclast differentiation by regulating TAK1 and AKT, and promotes osteogenesis.

Cinchonine (CN) has been known to exert antimalarial, antiplatelet, and antiobesity effects. It was also recently reported to inhibit transforming growth factor ß-activated kinase 1 (TAK1) and protein kinase B (AKT) through binding to tumor necrosis factor receptor-associated factor 6 (TRAF6). However, its role in bone metabolism remains largely unknown. Here, we showed that CN inhibits osteoclast differentiation with decreased expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a key determinant of osteoclastogenesis. Immunoblot and quantitative real-time polymerase chain reaction analysis as well as the reporter assay revealed that CN inhibits nuclear factor-κB and activator protein-1 by regulating TAK1. CN also attenuated the activation of AKT, cyclic AMP response element-binding protein, and peroxisome proliferator-activated receptor-γ coactivator 1ß (PGC1ß), an essential regulator of mitochondrial biogenesis. Collectively, these results suggested that CN may inhibit TRAF6-mediated TAK1 and AKT activation, which leads to downregulation of NFATc1 and PGC1ß resulting in the suppression of osteoclast differentiation. Interestingly, CN not only inhibited the maturation and resorption function of differentiated osteoclasts but also promoted osteoblast differentiation. Furthermore, CN protected lipopolysaccharide- and ovariectomy-induced bone destruction in mouse models, suggesting its therapeutic potential for treating inflammation-induced bone diseases and postmenopausal osteoporosis.

Therapeutic effect of CT-P59 against SARS-CoV-2 South African variant.

The global circulation of newly emerging variants of SARS-CoV-2 is a new threat to public health due to their increased transmissibility and immune evasion. Moreover, currently available vaccines and therapeutic antibodies were shown to be less effective against new variants, in particular, the South African (SA) variant, termed 501Y.V2 or B.1.351. To assess the efficacy of the CT-P59 monoclonal antibody against the SA variant, we sought to perform as in vitro binding and neutralization assays, and in vivo animal studies. CT-P59 neutralized B.1.1.7 variant to a similar extent as to wild type virus. CT-P59 showed reduced binding affinity against a RBD (receptor binding domain) triple mutant containing mutations defining B.1.351 (K417N/E484K/N501Y) also showed reduced potency against the SA variant in live virus and pseudovirus neutralization assay systems. However, in vivo ferret challenge studies demonstrated that a therapeutic dosage of CT-P59 was able to decrease B.1.351 viral load in the upper and lower respiratory tracts, comparable to that observed for the wild type virus. Overall, although CT-P59 showed reduced in vitro neutralizing activity against the SA variant, sufficient antiviral effect in B.1.351-infected animals was confirmed with a clinical dosage of CT-P59, suggesting that CT-P59 has therapeutic potential for COVID-19 patients infected with SA variant.

The in vitro and in vivo efficacy of CT-P59 against Gamma, Delta and its associated variants of SARS-CoV-2.

The SARS-CoV-2 variant is rapidly spreading across the world and causes to resurge infections. We previously reported that CT-P59 presented its in vivo potency against Beta variants, despite its reduced activity in cell experiments. Yet, it remains uncertain to exert the antiviral effect of CT-P59 on Gamma, Delta and its associated variants (L452R). To tackle this question, we carried out cell tests and animal studies. CT-P59 showed neutralization against Gamma, Delta, Epsilon, and Kappa variants in cells, with reduced susceptibility. The mouse challenge experiments with Gamma and Delta variants substantiated in vivo potency of CT-P59 showing symptom remission and virus abrogation in the respiratory tract. Collectively, cell and animal studies showed that CT-P59 is effective against Gamma and Delta variants infection, hinting that CT-P59 has therapeutic potential for patients infected with Gamma, Delta and its associated variants.

Early estrogen-induced gene 1 facilitates osteoclast formation through the inhibition of interferon regulatory factor 8 expression.

Osteoclast-mediated inflammatory bone resorption is a major cause of many inflammatory bone disorders, including rheumatoid arthritis and periodontitis. However, the mechanisms regulating osteoclast differentiation in inflammatory settings are not well understood. We demonstrate here that early estrogen-induced gene 1 (EEIG1)-deficient mice are protected from inflammatory bone loss as determined with the use of models of lipopolysaccharide (LPS)-induced bone destruction. EEIG1-deficient macrophages markedly decreased RANKL- and TNFα-mediated osteoclastogenesis due to the downregulation of the nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), which is an essential transcription factor for osteoclast formation. In contrast, expression of interferon regulatory factor 8 (IRF8), a transcriptional repressor that blocks osteoclast differentiation, is elevated in EEIG1-deficient macrophages relative to wild-type cells. We found that reduced expression of B lymphocyte-induced maturation protein-1 (Blimp1) by siRNA downregulated RANKL-induced EEIG1 levels, whereas overexpression of Blimp1 potentiated EEIG1 levels. Mechanistic studies revealed that EEIG1 forms a complex with Blimp1 to negatively regulate the expression of the anti-osteoclastogenic gene, Irf8. We elucidated a novel mechanism by which EEIG1 restricts IRF8 expression and function, thereby enhancing the osteoclast formation by contributing to Blimp1-mediated IRF8 regulation. Together, these findings identify EEIG1 as a key regulator of osteoclastogenesis and a possible therapeutic target for pathological bone destruction.

Glycogen Synthase Kinase 3ß Regulates Antiviral Responses of TLR3 via TRAF2-Src Axis.

The protein tyrosine kinase Src regulates the synthesis of TLR3-mediated IFN-ß via the TBK1-IFN regulatory factor 3 axis. However, the molecular mechanisms regulating Src activity in TLR3 signaling remain unclear. In this study, we report that GSK3ß regulates Src phosphorylation via TNFR-associated factor 2 (TRAF2)-mediated Src ubiquitination. GSK3ß deficiency in mouse embryonic fibroblasts significantly reduces polyinosinic:polycytidylic acid-induced IFN-ß and IFN-stimulated gene expression, which is caused by diminished phosphorylation of Src at tyrosine 416. Src undergoes polyinosinic:polycytidylic acid-dependent lysine 63 chain ubiquitination, and TRAF2 is a direct E3 ligase for Src. Our study reveals novel mechanisms underlying TLR3-mediated antiviral responses mediated via the GSK3ß-TRAF2-Src axis.

Distribution of lymph node metastasis and oncological outcomes of mid-transverse colon cancer: extended versus transverse colectomy.

AIM: The optimal surgical method for cancer of the mid-transverse colon has not been well established. The present study aimed to explore the distribution of lymph node metastasis and compare the outcomes of extended and transverse colectomies for cancer of the mid-transverse colon. METHODS: We retrospectively analysed the data of patients with cancer of the mid-transverse colon treated with either an extended hemicolectomy (right or left) or a transverse colectomy. A propensity score matching analysis was performed to rule out selection bias, and short-term and survival outcomes were compared. The distribution of lymph node metastasis was also investigated. RESULTS: A total of 107 patients were included, 70 of whom underwent an extended colectomy while 37 underwent a transverse colectomy. There were no significant differences in the operation time, postoperative complications, hospital stay, 3-year disease-free survival (86.5% vs. 90.9%, P = 0.675) and 5-year overall survival (87.4% vs. 93.0%, P = 0.349) between the two groups after propensity score matching. However, metastases were observed in the lymph nodes along the right colic artery (pericolic [#211], 14.0%; intermediate [#212], 8.2%; apical [#213], 9.8%) in the extended colectomy group. CONCLUSION: Extended and transverse colectomies showed similar short-term and long-term outcomes for mid-transverse colon cancer. However, care should be taken to determine the extent of resection considering the possibility of metastatic lymph nodes along the right colic artery.