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.

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.

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).

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.

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.

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.

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.

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.

Characteristics of medial condyle sagittal fracture of distal femur involving intercondylar notch in geriatric patients.

INTRODUCTION: Unicondylar femoral fractures are uncommon injuries, known to occur primarily in young people, with high energy trauma. However, according to our experiences, unicondylar femoral fractures in geriatric patients generally involved the medial femoral condyle, unlike previously reported. In addition, the fractures of medial femoral condyle (FMFC) showed a characteristic fracture pattern. To date, there has been no published article focusing on the FMFC in geriatric patients. Thus, the aim of this study was to determine the characteristics of FMFC in geriatric patients and to present their outcomes. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 13 patients over age of 65 who underwent surgery for FMFC (AO-OTA 33B2). Of the 13, 10 patients were treated with Tomofix medial distal femoral plate (MDF) (Synthes GmbH, Switzerland) and additional screws fixation; the other three were treated with screw fixation and cast application. RESULTS: The mean age of patients was 76.8 years, and 10 patients were females. The fracture was due to low-energy trauma in all of the cases. Eight patients had medial knee osteoarthritis, and 2 patients were on osteoporosis treatment. A characteristic fracture pattern was observed. The fracture line extended from the lateral aspect of the intercondylar notch to the posteromedial column of the distal femur, with a characteristic medial beak. All fractures belonged to AO classification 33B2.1; there were no cases of AO classification 33B2.2 or 33B2.3. The postoperative joint function was graded according to the Kolmert functional criteria: ten cases were excellent, one case was good, one case was fair, and one case was poor. CONCLUSION: FMFC caused by low-energy trauma in geriatric patients tend to have a characteristic pattern. We believe that anatomic reduction and firm fixation with Tomofix MDF plate and cannulated screw for low-energy trauma FMFC in geriatric patients would yield good outcomes.

Trans-tendon suture bridge rotator cuff repair with tenotomized pathologic biceps tendon augmentation in high-grade PASTA lesions.

PURPOSE: The purpose of this study was to evaluate whether trans-tendon suture bridge repair with tenotomized pathologic biceps tendon augmentation improves mid-term clinical outcomes for high-grade partial articular-sided supraspinatus tendon avulsion (PASTA) lesions or not. METHODS: A retrospective review of a consecutive series of arthroscopic trans-tendon suture bridge repair with tenotomized pathologic biceps tendon augmentation was conducted. Total 115 patients (44 men and 71 women) with minimum 2 years follow-up were enrolled in our study. Their mean age was 59.7 ± 7.6 (38-77) years and mean follow-up were 6.9 ± 2.5 (2 ~ 10) years. Clinical assessment and radiological outcomes using post-operative MRI were evaluated at last follow-up. RESULTS: All these tears were high-grade PASTA lesions in which mean cuff tear size (exposed footprint) was anteroposterior length 15.7 ± 6.3 mm (5-25 mm) and mediolateral width 10.1 ± 3.6 mm 6.4 mm (5-16 mm). At last follow-up, mean pain VAS, ASES, UCLA, and SST scores were improved from pre-operative values of 5, 59, 21, and 7 to post-operative values of 1, 84.4, 29.5, and 9.4, respectively (p value < 0.001). ROM such as forward flexion, abduction, and internal rotation to the back were improved from a pre-operative mean of 148° (±24), 144° (±24), L2 (Buttock-T7) to a post-operative mean of 161° (±10), 160.0° (±12), and T12 (L3-T5), respectively (p value < 0.001). Follow-up MRI showed Sugaya classification type I in 24 patients (20.9%), type II in 78 patients (67.8%), type III in 11 patients (9.6%) and type 4 in 2 patients (1.7%) were found. As complications, shoulder stiffness was found in five patients, Popeye deformity in two patients and retear in two patients. Revision surgery of the retear was performed in 2 patients. At the last follow-up, 17% (20/115 patients) reported occasional discomfort at the extremes of range of motion during a heavy work or sports activities. CONCLUSIONS: In high-grade PASTA lesions, arthroscopic trans-tendon suture bridge repair with tenotomized pathologic biceps tendon augmentation could be a useful treatment modality capable of preserving rotator cuff footprint, providing simultaneous biceps tenodesis, inducing better tendon healing and possibly preventing tendon buckling and residual pain of the conventional trans-tendon repair methods. These specific methods showed satisfactory outcomes and decreased residual shoulder discomfort (17%) at mid-term follow-up. LEVEL OF EVIDENCE: Level IV, Retrospective case study.

Tonicity-responsive enhancer-binding protein promotes hepatocellular carcinogenesis, recurrence and metastasis.

OBJECTIVES: Hepatocellular carcinoma (HCC) is a common cancer with high rate of recurrence and mortality. Diverse aetiological agents and wide heterogeneity in individual tumours impede effective and personalised treatment. Tonicity-responsive enhancer-binding protein (TonEBP) is a transcriptional cofactor for the expression of proinflammatory genes. Although inflammation is intimately associated with the pathogenesis of HCC, the role of TonEBP is unknown. We aimed to identify function of TonEBP in HCC. DESIGN: Tumours with surrounding hepatic tissues were obtained from 296 patients with HCC who received completion resection. TonEBP expression was analysed by quantitative reverse transcription-quantitative real-time PCR (RT-PCR) and immunohfistochemical analyses of tissue microarrays. Mice with TonEBP haplodeficiency, and hepatocyte-specific and myeloid-specific TonEBP deletion were used along with HCC and hepatocyte cell lines. RESULTS: TonEBP expression is higher in tumours than in adjacent non-tumour tissues in 92.6% of patients with HCC regardless of aetiology associated. The TonEBP expression in tumours and adjacent non-tumour tissues predicts recurrence, metastasis and death in multivariate analyses. TonEBP drives the expression of cyclo-oxygenase-2 (COX-2) by stimulating the promoter. In mouse models of HCC, three common sites of TonEBP action in response to diverse aetiological agents leading to tumourigenesis and tumour growth were found: cell injury and inflammation, induction by oxidative stress and stimulation of the COX-2 promoter. CONCLUSIONS: TonEBP is a key component of the common pathway in tumourigenesis and tumour progression of HCC in response to diverse aetiological insults. TonEBP is involved in multiple steps along the pathway, rendering it an attractive therapeutic target as well as a prognostic biomarker.

Efficacy and safety of a novel topical agent for gallstone dissolution: 2-methoxy-6-methylpyridine.

BACKGROUND: Although methyl-tertiary butyl ether (MTBE) is the only clinical topical agent for gallstone dissolution, its use is limited by its side effects mostly arising from a relatively low boiling point (55 °C). In this study, we developed the gallstone-dissolving compound containing an aromatic moiety, named 2-methoxy-6-methylpyridine (MMP) with higher boiling point (156 °C), and compared its effectiveness and toxicities with MTBE. METHODS: The dissolubility of MTBE and MMP in vitro was determined by placing human gallstones in glass containers with either solvent and, then, measuring their dry weights. Their dissolubility in vivo was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after directly injecting each solvent into the gallbladder in hamster models with cholesterol and pigmented gallstones. RESULTS: In the in vitro dissolution test, MMP demonstrated statistically higher dissolubility than did MTBE for cholesterol and pigmented gallstones (88.2% vs. 65.7%, 50.8% vs. 29.0%, respectively; P < 0.05). In the in vivo experiments, MMP exhibited 59.0% and 54.3% dissolubility for cholesterol and pigmented gallstones, respectively, which were significantly higher than those of MTBE (50.0% and 32.0%, respectively; P < 0.05). The immunohistochemical stains of gallbladder specimens obtained from the MMP-treated hamsters demonstrated that MMP did not significantly increase the expression of cleaved caspase 9 or significantly decrease the expression of proliferation cell nuclear antigen. CONCLUSIONS: This study demonstrated that MMP has better potential than does MTBE in dissolving gallstones, especially pigmented gallstones, while resulting in lesser toxicities.

Narrow locking compression plate vs long philos plate for minimally invasive plate osteosynthesis of spiral humerus shaft fractures.

BACKGROUND: Our hypothesis was that minimally invasive plate osteosynthesis (MIPO) using long philos plate (LPP) would show better clinical and radiological outcomes and less complications than narrow locking compression plate (NLCP) for spiral humerus shaft fractures with or without metaphyseal fracture extension. METHODS: From January 2009 to May 2016, we retrospectively studied 35 patients who underwent MIPO for spiral humerus shaft fractures with or without metaphyseal fracture extension (AO classification 12 A, B, C except A3). Eighteen patients underwent MIPO with a 4.5 mm NLCP (group I) in the early period of this study, while 17 patients underwent MIPO with LPP (group II) in the later period. Range of motion (ROM), pre- and post-operative anteroposterior (AP) and lateral angulation of the fracture, operation time, amount of bleeding, and functional outcomes including American Shoulder and Elbow Surgeons score, University of California at Los Angeles score, and Simple Shoulder Test score were analyzed at the final follow up. RESULTS: All patients had complete bony union and achieved satisfactory functional outcomes except 2 patients. In LPP group, better outcomes in postoperative fracture angulation on X-ray and operation time (p < 0.05) were shown. But, two revision surgery with NLCP and bone graft was performed owing to 2 metal failures. CONCLUSIONS: In spiral humeral shaft fractures, LPP group showed better fracture reduction on X-ray and shorter operation time except metal failure owing to weak fixation. Even though MIPO technique using LPP is easier and more accurate reduction method, rigid fixation should be considered.

Tonicity-Responsive Enhancer-Binding Protein Mediates Hyperglycemia-Induced Inflammation and Vascular and Renal Injury.

Diabetic nephropathy (DN) has become the single leading cause of ESRD in developed nations. Bearing in mind the paucity of effective treatment for DN and progressive CKD, novel targets for treatment are sorely needed. We previously reported that increased activity of tonicity-responsive enhancer-binding protein (TonEBP) in monocytes was associated with early DN in humans. We now extend these findings by testing the hypotheses that TonEBP in macrophages promotes hyperglycemia-mediated proinflammatory activation and chronic renal inflammation leading to DN and CKD, and TonEBP genetic variability in humans is associated with inflammatory, renal, and vascular function-related phenotypes. In a mouse model of DN, compared with the wild-type phenotype, TonEBP haplodeficiency associated with reduced activation of macrophages by hyperglycemia, fewer macrophages in the kidney, lower renal expression of proinflammatory genes, and attenuated DN. Furthermore, in a cohort of healthy humans, genetic variants within TonEBP associated with renal function, BP, and systemic inflammation. One of the genetic variants associated with renal function was replicated in a large population-based cohort. These findings suggest that TonEBP is a promising target for minimizing diabetes- and stress-induced inflammation and renovascular injury.

Antitumor and Anti-Invasive Effect of Apigenin on Human Breast Carcinoma through Suppression of IL-6 Expression.

Interleukin (IL)-6 plays a crucial role in the progression, invasion, and metastasis of breast cancer. Triple-negative breast cancer (TNBC) cell line MDA-MB-231 is known for its aggressive metastasis. Epithelial to mesenchymal transition (EMT) is a critical process in cancer metastasis. The positive correlation between IL-6 and EMT in tumor microenvironment is reported. We found significantly upregulated IL-6 expression in MDA-MB-231 cells. A blockade of IL-6 expression decreased levels of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), phosphorylated protein kinase B (pAkt), and cell cycle-related molecules, including cyclin-dependent kinases (CDKs) and cyclins in MDA-MB-231 cells. A short-hairpin RNA (shRNA)-mediated blockade of IL-6 expression inhibited migration and N-cadherin expression and induced E-cadherin expression in MDA-MB-231 cells. Growth rate was slower for the tumors derived from IL-6 shRNA-treated MDA-MB-231 cells than for those derived from control shRNA-treated MDA-MB-231 cells. The expression of pSTAT3, phosphorylated extracellular signal-regulated kinase (pERK), PI3K, pAkt, snail, vimentin, and N-cadherin was significantly lower in tumors from IL-6 shRNA-treated MDA-MB cells. In addition, apigenin treatment significantly inhibited the growth of MDA-MB-231-derived xenograft tumors along with the protein expressions of pSTAT3, pERK, IL-6, PI3K, pAkt, and N-cadherin. Our results demonstrate that the anti-invasive effect of apigenin in MDA-MB-231-derived xenograft tumors is mediated by the inhibition of IL-6-linked downstream signaling pathway.

Cytokine-Modulated Natural Killer Cells Differentially Regulate the Activity of the Hepatitis C Virus.

HCV genotype 2a strain JFH-1 replicates and produces viral particles efficiently in human hepatocellular carcinoma (huh) 7.5 cells, which provide a stable in vitro cell infection system for the hepatitis C virus (HCVcc system). Natural killer (NK) cells are large lymphoid cells that recognize and kill virus-infected cells. In this study, we investigated the interaction between NK cells and the HCVcc system. IL-10 is a typical immune regulatory cytokine that is produced mostly by NK cells and macrophages. IL-21 is one of the main cytokines that stimulate the activation of NK cells. First, we used anti-IL-10 to neutralize IL-10 in a coculture of NK cells and HCVcc. Anti-IL-10 treatment increased the maturation of NK cells by enhancing the frequency of the CD56+dim population in NK-92 cells. However, with anti-IL-10 treatment of NK cells in coculture with J6/JFH-1-huh 7.5 cells, there was a significant decrease in the expression of STAT1 and STAT5 proteins in NK-92 cells and an increase in the HCV Core and NS3 proteins. In addition, rIL-21 treatment increased the frequency of the CD56+dim population in NK-92 cells, Also, there was a dramatic increase in the expression of STAT1 and STAT5 proteins in rIL-21 pre-stimulated NK cells and a decrease in the expression of HCV Core protein in coculture with J6/JFH-1-huh 7.5 cells. In summary, we found that the functional activation of NK cells can be modulated by anti-IL-10 or rIL-21, which controls the expression of HCV proteins as well as HCV RNA replication.

Synthesis and biological evaluation of thiazole derivatives as GPR119 agonists.

A series of 4-(phenoxymethyl)thiazole derivatives was synthesized and evaluated for their GPR119 agonistic effect. Several 4-(phenoxymethyl)thiazoles with pyrrolidine-2,5-dione moieties showed potent GPR119 agonistic activities. Among them, compound 27 and 32d showed good in vitro activity with an EC50 value of 49 nM and 18 nM, respectively with improved human and rat liver microsomal stability compare with MBX-2982. Compound 27 &32d did not exhibit significant CYP inhibition, hERG binding, and cytotoxicity. Moreover, these compounds lowered the glucose excursion in mice in an oral glucose-tolerance test.

Programmed Cell Death 1 (PD-1) and Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) in Viral Hepatitis.

Virus-specific cluster of differentiation 8 (CD8+) cytotoxic T cells (CTL) recognize viral antigens presented on major histocompatibility complex (MHC) class I chains on infected hepatocytes, with help from CD4+ T cells. However, this CTL response is frequently weak or undetectable in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are receptors in the CD28 family of costimulatory molecules, providing inhibitory signals to T cells. The overexpressions of PD-1 and CTLA-4 in patients with viral infection have been shown to associate with functional impairment of virus-specific T cells. In acute viral hepatitis, PD-1 and CTLA-4 are up-regulated during the symptomatic phase, and then down-regulated after recovery. These findings suggest that PD-1 and CTLA-4 have protective effects as inhibitory molecules to suppress cytotoxic T cells which induce harmful destruction of viral infected hepatocytes in self-limited viral hepatitis. In chronic viral hepatitis, the extended upregulations of PD-1 and CTLA-4 are associated with T cell exhaustion and persistent viral infection, suggesting positive correlations between expression of immune inhibitory factors and the chronicity of viral disease. In this review, we summarize recent literature relating to PD-1, CTLA-4, and other inhibitory receptors in antigen-specific T cell exhaustion in viral hepatitis, including hepatitis A, B, C, and others.

Anti-Cancer Effect of Quercetin in Xenograft Models with EBV-Associated Human Gastric Carcinoma.

Licorice extracts have been widely used in herbal and folk medications. Glycyrrhiza contains diverse range of biological compounds including triterpenes (glycyrrhizin, glycyrrhizic acid) and flavonoids (quercetin, liquiritin, liquiritigenin, glabridin, licoricidin, isoliquiritigenin). The flavonoids in licorice are known to have strong anti-cancer activities. Quercetin, the most abundant flavonoid, has been shown to have anti-ulcer, anti-cancer, antioxidant, and anti-inflammatory properties. Latent Epstein-Barr virus (EBV) infection can lead to serious malignancies, such as, Burkitt's lymphoma, Hodgkin's disease and gastric carcinoma(GC), and (Epstein-Barr virus associated gastric carcinoma) EBVaGC is one of the most common EBV-associated cancers. In this study, the authors first examined the anti-cancer effects of quercetin and isoliquiritigenin in vivo xenograft animal models implanted with EBV(+) human gastric carcinoma (SNU719) or EBV(-) human gastric carcinoma (MKN74), and then explored the molecular mechanisms responsible for their anti-cancer activities. The results obtained showed that anti-cancer effect of quercetin was greater than isoliquiritigenin in mice injected with EBV(+) human gastric carcinoma (SNU719) cells. On the other hand, quercetin and isoliquiritigenin had similar anti-cancer effects in mice injected with EBV(-) human gastric carcinoma (MKN74) cells. Interestingly, quercetin inhibited EBV viral protein expressions, including EBNA-1 and LMP-2 proteins in tumor tissues from mice injected with EBV(+) human gastric carcinoma. Quercetin more effectively induced p53-dependent apoptosis than isoliquiritigenin in EBV(+) human gastric carcinoma, and this induction was correlated with increased expressions of the cleaved forms of caspase-3, -9, and Parp. In EBV(-)human gastric carcinoma (MKN74), both quercetin and isoliquiritigenin induced the expressions of p53, Bax, and Puma and the cleaved forms of caspase-3 and -9 and Parp at similar levels.

Step Detection Robust against the Dynamics of Smartphones.

A novel algorithm is proposed for robust step detection irrespective of step mode and device pose in smartphone usage environments. The dynamics of smartphones are decoupled into a peak-valley relationship with adaptive magnitude and temporal thresholds. For extracted peaks and valleys in the magnitude of acceleration, a step is defined as consisting of a peak and its adjacent valley. Adaptive magnitude thresholds consisting of step average and step deviation are applied to suppress pseudo peaks or valleys that mostly occur during the transition among step modes or device poses. Adaptive temporal thresholds are applied to time intervals between peaks or valleys to consider the time-varying pace of human walking or running for the correct selection of peaks or valleys. From the experimental results, it can be seen that the proposed step detection algorithm shows more than 98.6% average accuracy for any combination of step mode and device pose and outperforms state-of-the-art algorithms.