Complications and Reinterventions of Reverse Total Shoulder Arthroplasty in a Korean Population: 14-Year Experience in Reverse Shoulder Arthroplasty.

Background: There are few reports on the revision or reintervention of reverse total shoulder arthroplasty (RTSA) in South Korea. The purpose of this study was to evaluate the true incidence of complications and reintervention of RTSA and clinical and radiological outcomes based on our 14-year experience in RTSA in a Korean population. Methods: Between March 2008 and June 2022, 412 consecutive cases of RTSA were performed in 388 patients with an average age of 74.4 years at our institute. Excluding 23 patients lost to follow-up, 365 patients (373 shoulders including 8 bilateral cases) who underwent primary RTSA with more than 6 months of follow-up were enrolled in this study. We evaluated those who had complications or reintervention including revision RTSA for failed RTSA. Patient charts were reviewed, and clinical outcomes including clinical scores, complications, and reintervention and radiologic outcomes were evaluated at the last follow-up. Results: Among the 373 shoulders that underwent primary RTSA, complications were found in 50 patients (13.94%, 10 men and 40 women with a mean age of 75.9 ± 6.7 years [range, 51-87 years]). The causes of complications were as follows: 13 acromion, coracoid, or scapular spine fractures, 10 loosening (glenoid: 5, humeral stem: 5), 5 infections, 4 periprosthetic fractures, 2 instability, 2 neurologic complications, and 14 miscellaneous complications. Twenty patients (5.63%, 4 men and 16 women with a mean age of 74.2 ± 8.2 years [range, 51-87 years]) underwent reintervention. The interval to the first reintervention was 27.8 ± 23.1 months (range, 0.1-78 months). The causes of reintervention (20 cases) were 8 loosening (glenoid: 4, humeral stem: 4), 5 infections, 5 fractures, and 2 instability. Among them, 15 component revisions (4.02%) were performed. At the last follow-up, American Shoulder and Elbow Surgeons, University of California at Los Angeles, and Simple Shoulder Test scores were improved from 25.4, 12.4, and 1.6 preoperatively to 40.4, 16.2, and 3.2, respectively. Forward flexion (48° to 87°), abduction (52° to 79°), external rotation (18° to 22°), and internal rotation (buttock to L2) were improved. Conclusions: After primary RTSA in a Korean population, the complication, reintervention, and revision rates were 13.94%, 5.63%, and 4.02%, respectively. Careful evaluation of the complications and adequate treatments should be performed.

Comparative Analysis of Autophagy and Apoptosis in Disc Degeneration: Understanding the Dynamics of Temporary-Compression-Induced Early Autophagy and Sustained-Compression-Triggered Apoptosis.

The purpose of this study was to investigate the initiation of autophagy activation and apoptosis in nucleus pulposus cells under temporary compression (TC) and sustained compression (SC) to identify ideal research approaches in intervertebral disc degeneration. Various techniques were used: radiography (X-ray), magnetic resonance imaging (MRI), transmission electron microscope (TEM), H&E staining, Masson's trichrome staining, immunohistochemistry (IHC) (LC3, beclin-1, and cleaved caspase-3), and real-time polymerase chain reaction (RT-qPCR) for autophagy-related (beclin-1, LC3, and P62) and apoptosis-related (caspase-3 and PARP) gene expression analysis. X-ray and MRI revealed varying degrees of disc degeneration, ranging from moderate to severe in both groups. The severity was directly linked to compression duration, with SC resulting in notably severe central NP cell degeneration. Surprisingly, TC also caused similar, though less severe, degeneration. Elevated expression of LC3 and beclin-1 was identified after 6 weeks, but it notably declined after 12 weeks. Central NP cells in both groups exhibited increased expression of cleaved caspase-3 that was positively correlated with the duration of SC. TC showed fewer apoptotic markers compared to SC. LC3, beclin-1, and P62 mRNA expression peaked after 6 weeks and declined after 12 weeks in both groups. Cleaved caspase-3 and PARP expression peaked in SC, positively correlating with longer compression duration, while TC showed lower levels of apoptosis gene expression. Furthermore, TEM results revealed different events of the autophagic degradation process after 2 weeks of compression. TCmay be ideal for studying early triggered autophagy-mediated degeneration, while SC may be ideal for studying late or slower-triggered apoptosis-mediated degeneration.

Incidence and outcomes of intraoperative periprosthetic acetabular fractures during cementless total hip arthroplasty: a prospective three-dimensional computer tomography-based study.

PURPOSE: Unlike periprosthetic femoral fractures, periprosthetic acetabular fractures during total hip arthroplasty (THA) have not been evaluated in detail. We prospectively evaluated the incidence, patterns, risk factors, and clinical outcomes of intraoperative periprosthetic acetabular fractures using pre- and postoperative computer tomography (CT). METHODS: In this prospective single-centre study, we evaluated 234 consecutive patients (250 hips) who underwent THA and three-dimensional CT before and after the surgery. We assessed the incidence, pattern of fractures, outcomes for each fracture pattern, reoperation and revision rates, Harris hip score, and visual analog scale (VAS) for pain. Multivariate regression models were used to identify risk factors for periprosthetic acetabular fractures. RESULTS: In total, 43 periprosthetic acetabular fractures (17.2%) were identified via CT. Fractures occurred most frequently at the superolateral wall. Early cup migration occurred in three hips. None of the patients underwent revision surgery for acetabular loosening. Regression modeling showed that rheumatoid arthritis was a significant predictor of periprosthetic acetabular fractures. CONCLUSIONS: Periprosthetic acetabular fractures are not infrequent during cementless THA and are more common in patients with rheumatoid arthritis.

Role of Interleukin(IL)-6 in NK Activity to Hypoxic-Induced Highly Invasive Hepatocellular Carcinoma(HCC) Cells.

Natural killer (NK) cell dysfunctions against hepatocellular carcinoma (HCC) in a hypoxic environment. Many solid tumors are present in a hypoxic condition, which changes the effector function of various immune cells. The transcription of hypoxic-inducible factors (HIFs) in cancer cells make it possible to adapt to their hypoxic environment and to escape the immune surveillance of NK cells. Recently, the correlation between the transcription of HIF-1α and pro-inflammatory cytokines has been reported. Interleukin (IL)-6 is higher in cancers with a highly invasive ability, and is closely related to the metastasis of cancers. This study showed that the expression of HIF-1α in HCC cells was associated with the presence of IL-6 in the environment of HCC-NK cells. Blocking of IL-6 by antibody in the HCC-NK interaction changed the production of several cytokines including TGF-ß, IL-1, IL-18 and IL-21. Interestingly, in a co-culture of HIF-1α-expressed HCC cells and NK cells, blocking of IL-6 increased the production of IL-21 in their supernatants. In addition, the absence of IL-6 significantly enhanced the cytotoxic ability and the expression of the activating receptors (NKG2D, NKp44, and NKG2C) in NK cells to HIF-1α-expressed HCC cells. These effects might be made by the decreased expression of HIF-1α in HCC cells through the inhibited phosphorylation of STAT3. In conclusion, the absence of IL-6 in the interaction of HIF-1α-expressed HCC cells and NK cells could enhance the antitumor activity of NK cells to HCC cells.

Mid-term comparative study between the glenoid and humerus lateralization designs for reverse total shoulder arthroplasty: which lateralization design is better?

INTRODUCTION: The complications of the conventional medialized design for reverse total shoulder arthroplasty (RSA) are increased scapular notching, and decreased external rotation and deltoid wrapping. Currently, lateralization design RSA, which avoid scapular notching and improve impingement-free range of motion, is commonly used. Especially, humeral lateralization design was most commonly used and glenoid lateralization design was preferred for glenoid abnormities. We compared mid-term clinical and radiologic outcomes of glenoid and humeral lateralization RSA in an Asian population in this study. MATERIALS AND METHODS: We enrolled 124 shoulders of 122 consecutive patients (mean age 73.8 ± 6.8 years) who received glenoid or humeral lateralization RSA from May, 2012 to March, 2019. We divided these patients into two groups according to RSA using either glenoid or humeral lateralization design. These different designs were introduced consecutively in Korea. The clinical and radiological results of 60 glenoid lateralization RSA (Group I, 60 patients) and 64 humeral lateralization RSA (Group II, 62 patients) were retrospectively evaluated and also were compared between the two groups. All patients were followed for mean 3 years. RESULTS: The clinical and radiologic outcomes of the two groups did not differ significantly, including scapular notching (p = 0.134). However, humeral lateralization RSA showed a larger glenoid-tuberosity (GT) distance (p = 0.000) and less distalization shoulder angle (DSA) (p = 0.035). The complication rate did not differ significantly either. But, revision surgery was performed for 2 humeral loosening in the Group II. CONCLUSION: The clinical and radiologic outcomes of the two groups did not differ significantly, including scapular notching at mid-term follow-up. However, humeral lateralization design showed larger GT distance and less DSA. Humeral lateralization design RSA could preserve the normal shoulder contour due to a larger GT distance (more lateralization) and provide less deltoid tension due to less DSA (less distalization of COR).

Immune-Enhancing Effects of Limosilactobacillus fermentum in BALB/c Mice Immunosuppressed by Cyclophosphamide.

This study evaluates the immune-enhancing effects of Limosilactobacillus fermentum on cyclophosphamide (CP)-induced immunosuppression in BALB/c mice. In vitro, the expressions of pro-inflammatory cytokines and MAPK signaling molecules in Raw264.7 cells were analyzed by ELISA and Western blot analysis. Moreover, cell proliferation, surface receptor expression, and cytotoxicity of NK-92 cells were examined by Cell Counting Kit-8, CytoTox96 assay, and flow cytometry, respectively. To investigate the immune-enhancing effects of selected L. fermentum strains in vivo, these strains were orally administered to BALB/c mice for 2 weeks, and CP was intraperitoneally injected. Then, liver, spleen, and whole blood were isolated from each animal. Administration of single L. fermentum strains or their mixture sustained the spleen weight, the counts of white blood cells compared to non-fed group. Splenocyte proliferation and NK cytotoxicity were significantly increased in all L. fermentum-fed groups. The frequency of B220+ cells was also significantly enhanced in splenocytes isolated from L. fermentum groups. In addition, the production of cytokines (TNF-α, IFN-γ) and antibodies was recovered in splenocyte supernatants isolated from L. fermentum groups. In conclusion, L. fermentum could be a suitable functional food additive for immune-enhancing effect.

The incidence of focal osteonecrosis of the femoral head and its impact on conversion hip arthroplasty after screw fixation of femoral neck fractures: a multicenter retrospective study based on postoperative magnetic resonance imaging.

PURPOSE: Osteonecrosis of the femoral head (ONFH) and subsequent head collapse is a major concern after internal fixation of femoral neck fracture (FNF). Previous studies focused on ONFH incidence using plain radiography; postoperative magnetic resonance imaging (MRI) was rarely performed. We performed a multicenter retrospective study to investigate the incidence of ONFH and the need for conversion hip arthroplasty after FNF screw fixation. METHODS: We reviewed 195 patients who underwent screw fixation during closed FNF reduction between 2012 and 2017 at three institutions. Except for patients who did not consent to MRI, all patients underwent postoperative MRI either 1-3 years after screw fixation. The occurrence of ONFH was investigated through plain radiography and MRI. RESULTS: Thirty patients were diagnosed with ONFH through plain radiography, and an additional 33 patients were diagnosed with MRI, resulting in a total of 63 patients (32.3%) diagnosed with ONFH. The mean time to ONFH diagnosis was 18.9 months and the conversion rate to hip arthroplasty was 10.2%. Of the 33 patients who were normal on hip radiography but exhibited ONFH on MRI, all had small focal lesions not associated with head collapse at the last follow-up. The ONFH group diagnosed through plain radiography had more unstable FNFs than the group diagnosed through MRI. CONCLUSION: Although postoperative MRI revealed a higher incidence of ONFH after FNF screw fixation than reported previously, the small focal MRI lesions were not associated with increased risks of femoral head collapse or conversion to arthroplasty.

Concomitant tuberculosis of the iliotibial band mimicking a soft tissue tumor and tuberculous trochanteric bursitis: a case report emphasizing on magnetic resonance imaging findings.

The risk of tuberculosis (TB) increases in immunocompromised patients. Multiple myeloma is considered a risk factor for TB and myeloma patients with TB have a higher mortality rate than those without TB. Herein, we report a case of concomitant TB of the iliotibial band mimicking a soft tissue tumor and tuberculous trochanteric bursitis in a patient with multiple myeloma. In this article, the characteristic magnetic resonance imaging (MRI) findings were low T2 signals in the cystic fluid lesion, a dark T2 signal rim, and peripheral rim enhancement. These results could help differentiate TB of the iliotibial band and trochanteric bursitis from other pathologies. If the abovementioned findings were observed in immunocompromised patients, extrapulmonary TB may be expected even if chest radiographs are normal.

Osteoclast and Sclerostin Expression in Osteocytes in the Femoral Head with Risedronate Therapy in Patients with Hip Fractures: A Retrospective Comparative Study.

Background and Objectives: The majority of research on the effects of osteoporosis drugs has measured the bone mineral density (BMD) of the spine and femur through dual-energy X-ray absorptiometry (DEXA) and compared and analyzed the effects of the drugs through changes in the BMD values. This study aims to compare osteoclast and sclerostin expression in osteocytes after risedronate therapy by obtaining femoral heads from patients with hip fractures. Materials and Methods: We obtained the femoral heads of 10 female patients (age: ≥65 years) who received risedronate therapy for at least 1 year through hip arthroplasty during 2019−2021 (risedronate group). Meanwhile, 10 patients who had never received osteoporosis treatment were selected as controls using propensity scores with age, body mass index, and bone density as covariates (control group). While the osteoclast count was evaluated using tartrate-resistant acid phosphatase (TRAP) staining, the sclerostin expression in osteocytes was assessed using immunohistochemistry. Moreover, Western blotting and polymerase chain reaction (PCR) were performed for receptor activation of nuclear factor kappa-Β ligand (RANKL), RANK, osteoprotegerin (OPG), sclerostin, and bone morphogenetic protein-2 (BMP2). Results: TRAP staining revealed significantly more TRAP-positive cells in the control group (131.75 ± 27.16/mm2) than in the risedronate group (28.00 ± 8.12/mm2). Moreover, sclerostin-positive osteocytes were expressed more in the control group (364.12 ± 28.12/mm2) than in the risedronate group (106.93 ± 12.85/mm2). Western blotting revealed that the expressions of RANKL, RANK, sclerostin, and BMP2 were higher in the control group than in the risedronate group (p < 0.05). Furthermore, RANK, sclerostin, and OPG protein levels were higher in the control group than in the risedronate group. Conclusions: In this study, the risedronate group demonstrated lower osteoclast activity and sclerostin expression in osteocytes in the femoral head than the control group.

TonEBP in Myeloid Cells Promotes Obesity-Induced Insulin Resistance and Inflammation Through Adipose Tissue Remodeling.

The phenotypic and functional plasticity of adipose tissue macrophages (ATMs) during obesity plays a crucial role in orchestration of adipose and systemic inflammation. Tonicity-responsive enhancer binding protein (TonEBP) (also called NFAT5) is a stress protein that mediates cellular responses to a range of metabolic insults. Here, we show that myeloid cell-specific TonEBP depletion reduced inflammation and insulin resistance in mice with high-fat diet-induced obesity but did not affect adiposity. This phenotype was associated with a reduced accumulation and a reduced proinflammatory phenotype of metabolically activated macrophages, decreased expression of inflammatory factors related to insulin resistance, and enhanced insulin sensitivity. TonEBP expression was elevated in the ATMs of obese mice, and Sp1 was identified as a central regulator of TonEBP induction. TonEBP depletion in macrophages decreased induction of insulin resistance-related genes and promoted induction of insulin sensitivity-related genes under obesity-mimicking conditions and thereby improved insulin signaling and glucose uptake in adipocytes. mRNA expression of TonEBP in peripheral blood mononuclear cells was positively correlated with blood glucose levels in mice and humans. These findings suggest that TonEBP in macrophages promotes obesity-associated systemic insulin resistance and inflammation, and downregulation of TonEBP may induce a healthy metabolic state during obesity.

Anti-Tumor Effect of Heat-Killed Bifidobacterium bifidum on Human Gastric Cancer through Akt-p53-Dependent Mitochondrial Apoptosis in Xenograft Models.

Paraprobiotics, inactivated microbial cells, regulate immune system and exhibit antioxidant and anti-inflammatory activities in patients with weakened immunity or the elderly. This study evaluated the anti-tumor effects of heat-killed Bifidobacterium and Lactobacillus on human gastric cancer MKN1 cells in vitro and in vivo in xenograft animal models. First, cytotoxicity and apoptosis in MKN1 cells of 11 different heat-killed Bifidobacterium or Lactobacillus strains were examined using the MTT assay or flow cytometry, respectively. Then, BALB/c nude mice xenograft animal models were implanted with human gastric cancer MKN1 cells and orally administered a selected single or a mixture of heat-killed bacterial strains to investigate their inhibitory effect on tumor growth. In addition, the expression of p-Akt, p53, Bax, Bak, cleaved caspase-9, -3, and PARP in the tumor tissues was analyzed using Western blotting assay or immunohistochemistry staining. The results show that heat-killed B. bifidum MG731 (MG731), L. reuteri MG5346 (MG5346), and L. rhamnosus MG5200 (MG5200) induced relatively greater apoptosis than other strains in MKN1 cells. Oral administration of a single dose or a mixture of MG731, MG5346, or MG5200 significantly delayed tumor growth, and MG731 had the most effective anti-tumor effect in the xenograft model. Protein expression of p-Akt, p53, Bax, cleaved caspase-3 and -9, and PARP in tumors derived from the xenograft model correlated with the results of the immunohistochemistry staining.

Apigenin Increases Natural Killer Cytotoxicity to Human Hepatocellular Carcinoma Expressing HIF-1α through High Interaction of CD95/CD95L.

Natural killer (NK) cell activity is more attenuated in hepatocellular carcinoma (HCC) patients than normal. Hypoxic-inducible factor (HIF)-1α is highly expressed in tumors to maintain their metabolism in a hypoxic environment. The expression of HIF-1α in cancers can lead to cell growth, proliferation, invasion/metastasis and immune escape. Although apigenin, a flavonoid, is known to have various biological activities, it has not been demonstrated in NK cell immune activity in HCC cells. In this study, NK-92 cells were directly cocultured with HCC SK-Hep1 cells for 24 h to evaluate NK cell activity in HCC cells or HCC cells expressing HIF-1α by apigenin. NK cell cytotoxicity to HCC cells expressing HIF-1α was significantly increased, and NK cell-activating receptors, NKG2D, NKp30 and NKp44 were highly expressed. The activating effect of apigenin on NK cells substantially induced apoptosis in HCC cells expressing HIF-1α through high expression of CD95L on the surface of NK-92 cells. Moreover, apigenin excellently inhibited the level of TGF-ß1 in a coculture of NK cells and HCC cells. In conclusion, apigenin seems to be a good compound that increases NK cell cytotoxicity to HCC cells by controlling HIF-1α expression.

Impact of coronal plane fragments and anterior big neck fragments on the occurrence of perioperative lateral wall fractures in AO/OTA 31-A1,2 intertrochanteric fractures treated with cephalomedullary nailing.

PURPOSE: Cephalomedullary nails are used widely today for pertrochanteric fractures, and intraoperative lateral wall fractures can cause adverse effects. Recently, a high incidence of coronal fragments in pertrochanteric fractures was reported when analyzed with 3D CT reconstructions. In this study, we analyzed the association between the type of coronal fragments and perioperative lateral wall fractures. METHODS: Patients diagnosed with pertrochanteric fractures and treated by cephalomedullary nails at three university hospitals from September 2016 to December 2020 were examined. A total of 463 patients were included. We examined the coronal fragments and divided the patients into two groups according to the involvement of the posteromedial cortex. Postoperative X-rays were scanned for fracture lines at the blade entry site. RESULTS: Twenty-two patients among 463 patients had perioperative lateral wall fractures. The AO type A2 fractures, use of provisional pins, existence of coronal fragments, involvement of the posteromedial cortex, and the existence of anterior big neck fragments were significantly relevant to perioperative lateral wall fractures. 11 of 22 lateral wall fracture patients were delayed fracture patients, identified 4 weeks after surgery. A coronal fragment combined by anterior big neck fragments had a 9.24 times higher risk of lateral wall fractures compared to fractures with only coronal fragments. CONCLUSION: Pertrochanteric fractures with large coronal fragments and anterior big neck fragments have a high risk of perioperative lateral wall fractures when treated by cephalomedullary nails. Surgeons should examine the width of the intact lateral wall, and take caution to preserve its integrity.

NLRP3 Deficiency in Hepatocellular Carcinoma Enhances Surveillance of NK-92 through a Modulation of MICA/B.

Human hepatocellular carcinoma (HCC) is the most common and even worse at prognosis. The patients with HCC which accompanied by other diseases, such as cirrhosis, can be limited in various treatments, such as chemotherapy, not HCC patients without other diseases. NLRP3 inflammasome plays an important role in the innate immune response, but emerging evidence has indicated that the NLRP3 inflammasome is implicated in all stages of cancer development. Various cells express NLRP3 protein through the autocrine or paracrine signaling in their environment, but NK cells do not. The expanding evidence shows that patients who suffer from liver cancers have a low frequency of natural killer (NK) cells, and the function of these cells is also impaired. Thus, we examined how the expression of NLRP3 in HCC cells affects cancer surveillance by NK cells in a state of a co-culture of both cells. When the expression of NLRP3 in HCC cells was ablated, MICA/B on the surface of HCC cells was upregulated through the lowered expression of matrix metalloproteinase. The expression of MICA on the surface of HCC cells interacted with the NKG2D receptor on NK-92 cells, which led to NK cytotoxicity. Furthermore, in a xenograft mice model, NLRP3 KO HCC cells delayed tumor development and metastasis as well as increased the sensitivity to NK cell cytotoxicity. Taken together, NLRP3 KO in HCC could enhance NK immunosurveillance through an interaction of NKG2D-MICA.

Factors Affecting Periprosthetic Bone Loss after Hip Arthroplasty.

Periprosthetic bone loss may lead to major complications in hip arthroplasty, including aseptic loosening, implant migration, and even periprosthetic fracture. Such a complication leads to revision surgeries, which are expensive, technically demanding, and result in a low satisfaction rate. Therefore, a study was conducted of the factors affecting the periprosthetic bone loss around the stem that caused these complications. Factors influencing periprosthetic bone loss include demographic factors such as age, sex, obesity, smoking, and comorbidity including diabetes and osteoporosis. The implant design and fixation method are also factors that are determined before surgery. In addition, there are surgical factors, such as surgical approach and surgical technique, and we wish to investigate the factors affecting periprosthetic bone loss around the stem by comparing the effects of postoperative rehabilitation protocols and osteoporosis drugs.

Korean Red Ginseng Enhances Immunotherapeutic Effects of NK Cells via Eosinophils in Metastatic Liver Cancer Model.

Metastasis decreases the survival rate of patients with liver cancer. Therefore, novel anti-metastatic strategies are needed. Korean Red Ginseng (KRG) is often ingested as a functional food with an immune-boosting effect. We investigated a combination of KRG and natural killer (NK) cells as a novel immunotherapy approach. SK-Hep1 cells were injected into the tail vein of NRGA mice to establish an experimental metastasis model. KRG, NK cells, or a combination of KRG and NK cells were administered. Tumor growth was observed using an in vivo imaging system, and metastatic lesions were evaluated by histological analysis and immunohistochemistry. Bioluminescence intensity was lower in the KRG and NK cell combination group than in the other groups, indicating that the combination treatment suppressed the progression of metastasis. CD56 expression was used as a NK cell marker and hematological analysis was performed. The combination treatment also decreased the expression of matrix metalloproteinases and the area of metastatic lesions in liver and bone tissues, as well as increased the eosinophil count. Expression of cytokines-related eosinophils and NK cells was determined by Western blotting analysis. The expression of interleukin 33 (IL33) was induced by the combination of KRG and NK cells. High IL33 expression was associated with prolonged overall survival in the Kaplan-Meier plotter. Our results suggest that KRG enhances the immune activity of NK cells by IL-33 through eosinophils and suppresses metastatic liver cancer progression.

Natural killer cells inhibit breast cancer cell invasion through downregulation of urokinase­type plasminogen activator.

Triple­negative breast cancer (TNBC) is one of the most aggressive types of breast cancer, and there is no effective therapeutic target to date. Natural killer (NK) cells are functionally diverse lymphocytes that recognize and kill cancer cells. Although it is clear that NK cells exert antitumor activity in the tumor microenvironment, their role in the aggressive progression of TNBC has not been elucidated in detail. In the present study, we investigated the effect of NK cells on MDA­MB­231 TNBC cells using an indirect co­culture system. The invasive phenotype of MDA­MB­231 cells was significantly inhibited by co­culture with NK cells. Notably, the expression of urokinase­type plasminogen activator (uPA) was markedly reduced by NK cells. Cytokine array analysis showed that the levels of interleukin (IL)­10, IL­6, IL­8, C­C motif ligand (CCL)5, and CCL2 were increased in conditioned media from the co­cultured cells. Among these cytokines, IL­6 played a crucial role in the NK cell­induced uPA downregulation and inhibition of the invasive phenotype of MDA­MB­231 cells and Hs578T cells. We analyzed the Gene Expression Profiling Interactive Analysis database for correlations between IL­6 and uPA with the overall survival of breast cancer patients. The Kaplan­Meier survival analysis revealed that a low IL­6/uPA ratio was associated with the poor survival of breast cancer patients, suggesting it as an important factor for determining the overall survival of breast cancer patients. Taken together, our findings demonstrate that NK cells in the tumor microenvironment inhibit the invasiveness of TNBC cells through the IL­6­mediated inhibition of uPA.

Is there a correlation between fragility fractures of the pelvis (FFP) and the morphology of the true pelvis in geriatric patients?

PURPOSE: There has been no prior study to demonstrate the relationship between the occurrence of fragility fractures of the pelvis and its morphology. The aim of this study was to investigate the effect of pelvic morphology on fragility fractures of the pelvis caused by low-energy trauma in elderly female patients. MATERIALS AND METHODS: As a normal pelvis group, 643 female patients over 65 years of age who underwent pelvic CT were collected. Using three-dimensional multiplanar reconstruction (3D-MPR) function of RadiAnt software, the DT (diameter of transverse true pelvis)/DS (diameter of sagittal true pelvis) values of normal pelvis were measured. Sorted in ascending order, the mean DT/DS value of normal pelvis was 1.13 ± 0.09. The values corresponding to the 25th percentile and the 75th percentile were 1.06 and 1.18, respectively. We arbitrarily named DT/DS values of 1.06 or less corresponding to lower than 25th percentile as 'Circle types', and DT/DS values of 1.18 or higher corresponding to higher than 75th percentile as 'Ellipse types'. Total of 76 female patients over 65 years of age who underwent 3D reconstructions of pelvic CT scans with fragility fractures of the pelvis, who fell into the criteria corresponding to FFP classification type II, were studied separately. Of the 76 female FFPs, two were FFP type IIa, 32 were FFP type IIb, and 42 were FFP type IIc. Their DT/DS was measured. RESULTS: Based on the above mentioned criteria, we classified the pelvis shape of 76 patients with fragility fracture of the pelvis type II. 33 patients (43.4%) were classified as circle types and eight patients (10.5%) were classified as ellipse types. The odds ratio of "circle type" for fragility fractures of pelvis type II was 4.1. CONCLUSION: With digital reconstruction and 3D measurement of normal adult pelvic CT scans, this study obtained a series of DT/DS values describing the shape of true pelvises. Circle-type true pelvis was found to be more common in patients with fragility fracture of the pelvis type II.

Microglial TonEBP mediates LPS-induced inflammation and memory loss as transcriptional cofactor for NF-κB and AP-1.

BACKGROUND: Microglia are brain-resident myeloid cells involved in the innate immune response and a variety of neurodegenerative diseases. In macrophages, TonEBP is a transcriptional cofactor of NF-κB which stimulates the transcription of pro-inflammatory genes in response to LPS. Here, we examined the role of microglial TonEBP. METHODS: We used microglial cell line, BV2 cells. TonEBP was knocked down using lentiviral transduction of shRNA. In animals, TonEBP was deleted from myeloid cells using a line of mouse with floxed TonEBP. Cerulenin was used to block the NF-κB cofactor function of TonEBP. RESULTS: TonEBP deficiency blocked the LPS-induced expression of pro-inflammatory cytokines and enzymes in association with decreased activity of NF-κB in BV2 cells. We found that there was also a decreased activity of AP-1 and that TonEBP was a transcriptional cofactor of AP-1 as well as NF-κB. Interestingly, we found that myeloid-specific TonEBP deletion blocked the LPS-induced microglia activation and subsequent neuronal cell death and memory loss. Cerulenin disrupted the assembly of the TonEBP/NF-κB/AP-1/p300 complex and suppressed the LPS-induced microglial activation and the neuronal damages in animals. CONCLUSIONS: TonEBP is a key mediator of microglial activation and neuroinflammation relevant to neuronal damage. Cerulenin is an effective blocker of the TonEBP actions.

TonEBP Promotes ß-Cell Survival under ER Stress by Enhancing Autophagy.

The endoplasmic reticulum (ER) stress response and autophagy are important cellular responses that determine cell fate and whose dysregulation is implicated in the perturbation of homeostasis and diseases. Tonicity-responsive enhancer-binding protein (TonEBP, also called NFAT5) is a pleiotropic stress protein that mediates both protective and pathological cellular responses. Here, we examined the role of TonEBP in ß-cell survival under ER stress. We found that TonEBP increases ß-cell survival under ER stress by enhancing autophagy. The level of TonEBP protein increased under ER stress due to a reduction in its degradation via the ubiquitin-proteasome pathway. In response to ER stress, TonEBP increased autophagosome formations and suppressed the accumulation of protein aggregates and ß-cell death. The Rel-homology domain of TonEBP interacted with FIP200, which is essential for the initiation of autophagy, and was required for autophagy and cell survival upon exposure to ER stress. Mice in which TonEBP was specifically deleted in pancreatic endocrine progenitor cells exhibited defective glucose homeostasis and a loss of islet mass. Taken together, these findings demonstrate that TonEBP protects against ER stress-induced ß-cell death by enhancing autophagy.