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Background/aims Nilotinib is used for treating patients with imatinib-sensitive or -resistant chronic myeloid leukemia (CML); however, nilotinib-resistant cases have been observed in recent years. In addition, a considerable number of patients receiving nilotinib developed diabetes. Metformin is a front-line drug for the treatment of type 2 diabetes, and several studies have shown that diabetes patients treated with metformin have reduced incidence of cancer. This study aimed to define the effect of metformin on CML cells to determine whether metformin overcomes nilotinib resistance, and to identify novel targets for the treatment of nilotinib resistance. Methods We observed the effects of metformin and nilotinib on K562 and KU812 human CML cell lines. Nilotinib-resistant CML cell lines were generated by exposing cells to gradually increasing doses of nilotinib. Then, we investigated the driving force that makes resistance to nilotinib and the effect of metformin on the driving force. Results Sub-toxic doses of metformin enhanced nilotinib efficacy by reducing Bcl-xL expression, which induces apoptosis in CML cells. Next, we generated nilotinib-resistant K562 and KU812 cell lines that overexpressed the c-Jun N-terminal kinase (JNK) gene. JNK silencing by a JNK inhibitor restored sensitivity to nilotinib. Furthermore, metformin was effective in decreasing phosphorylated JNK levels, restoring nilotinib sensitivity. Combined treatment with nilotinib and metformin was more effective than combined treatment with nilotinib and a JNK inhibitor in terms of cell proliferation inhibition. Conclusion This study suggested that combination therapy with metformin and nilotinib may have clinical benefits of enhancing antileukemia efficacy and overcoming resistance to nilotinib.

Considering the occurrence of gait impairment following stroke, walk-ing recovery is an important goal of rehabilitation. Ground reaction force (GRF) is used for gait assessment of rehabilitation progress during exercise in stroke patients. The aim of this study was to compare the GRF during gait of the nonparetic side in hemiparetic patients and the dominant side in healthy subjects. Twenty hemiparetic patients and 20 healthy subjects were enrolled in the study. Force plate was used to evaluate GRF during gait. Additionally, with the patients and subjects in supine position, we measured their range of motion (ROM) in ankle dor-siflexion using a digital goniometer. The force values of stance phase on the nonparetic side of hemiparetic patients were significantly less than on the dominant side of healthy subjects (P

Theoretically, proprioceptive acuity could decrease in patients with knee osteoarthritis. However, there have been conflicting results in terms of proprioceptive deficit in osteoarthritic knees. The purpose of this systematic review and meta-analysis was to compare knee proprioception between osteoarthritic and healthy control knees. Studies comparing proprioception in osteoarthritic and healthy knees of age-matched control group using thresholds to detect passive motion (TTDPM) or joint position sense (JPS) tests were identified. JPS was assessed by measuring the reproduction of passive positioning (RPP) or active positioning (RAP) of the knees. Seventeen studies were finally included in this meta-analysis. The pooled results of the analyses of the TTDPM for both 30° and 45° knee flexion showed that the mean angle of error was 0.83° greater (95% confidence interval: 0.44 to 1.23°; p

Severe open tibia fractures are disastrous injuries associated with a high incidence of complications. Negative pressure wound therapy (NPWT) is a novel treatment for open tibia fractures; however, its efficacy remains unclear. This is a systematic review and meta-analysis performed to evaluate the effect of NPWT on decreasing the infection rate, amputation rate, nonunion rate, and flap-related complications in open tibia fractures.The MEDLINE, EMBASE, and Cochrane Library databases were systematically searched. Complications were evaluated in terms of the rates of infection, amputation, nonunion, and flap-related complications.Twelve studies were included. In the meta-analysis, NPWT showed significantly lower soft-tissue infection rate (odds ratio [OR] 0.48, 95% confidence interval [CI] 0.34-0.68, P 0.0001), nonunion rate (OR 0.61, 95% CI 0.39-0.95, P = 0.03), flap necrosis rate (OR 0.37, 95% CI 0.21-0.63, P = 0.0003), and flap revision rate (OR 0.44, 95% CI 0.22-0.89, P = 0.02) than conventional wound management. However, no significant difference was found in osteomyelitis rate (OR 0.54, 95% CI 0.09-3.28, P = 0.50) and amputation rate (OR 0.89, 95% CI 0.36-2.22, P = 0.80) between the 2 groups.Lower rates of soft-tissue infection, nonunion, flap necrosis, and flap revision were observed in the NPWT group than in the conventional dressing group. However, additional high-quality studies are warranted to verify the efficacy of NPWT in the treatment of severe open tibia fractures. We could not make a definitive conclusion about the comparative efficacy of the 2 methods in terms of complications because of insufficient data.

Simple Summary Cannabidiol (CBD), one of the compounds present in the marijuana plant, has antitumor properties. However, the effect of CBD on breast cancer remains unclear. The aim of this study was to assess the effects of CBD for the angiogenesis and stemness of breast cancer cells by decreasing the expression of hypoxia-induced factor-1α (HIF-1α) through the Src/von Hippel–Lindau tumor suppressor protein (VHL) interaction. CBD can suppress angiogenesis and stem cell-like properties of breast cancer through Src/VHL/HIF-1α signaling. Abstract To assess the effect of Cannabidiol (CBD) on the angiogenesis and stemness of breast cancer cells as well as proliferation. Methods: mRNA level and the amount of protein of vascular endothelial growth factor (VEGF) were determined by qRT-PCR and ELISA. The angiogenic potential of breast cancer cells under hypoxic conditions was identified by the HUVEC tube formation assay. The degradation of HIF-1α by CBD and the Src/von Hippel–Lindau tumor suppressor protein (VHL) interaction were assessed by a co-immunoprecipitation assay and Western blotting. To identify the stemness of mamospheres, they were evaluated by the sphere-forming assay and flow cytometry. Results: CBD can suppress angiogenesis and stem cell-like properties of breast cancer through Src/VHL/HIF-1α signaling. CBD may potentially be utilized in the treatment of refractory or recurrent breast cancer.

The distribution of differential extracellular matrix (ECM) in the lateral and medial menisci can contribute to knee instability, and changes in the meniscus tissue can lead to joint disease. Thus, deep proteomic identification of the lateral and medial meniscus cartilage is expected to provide important information for treatment and diagnosis of various knee joint diseases. We investigated the proteomic profiles of 12 lateral/medial meniscus pairs obtained from excess tissue of osteoarthritis patients who underwent knee arthroscopy surgery using mass spectrometry-based techniques and measured 75 ECM protein levels in the lesions using a multiple reaction monitoring (MRM) assay we developed. A total of 906 meniscus proteins with a 1% false discovery rate (FDR) was identified through a tandem mass tag (TMT) analysis showing that the lateral and medial menisci had similar protein expression profiles. A total of 131 ECM-related proteins was included in meniscus tissues such as collagen, fibronectin, and laminin. Our data showed that 14 ECM protein levels were differentially expressed in lateral and medial lesions (p < 0.05). We present the proteomic characterization of meniscal tissue with mass spectrometry-based comparative proteomic analysis and developed an MRM-based assay of ECM proteins correlated with tissue regeneration. The mass spectrometry dataset has been deposited to the MassIVE repository with the dataset identifier MSV000087753.

Hypoxia, or the deficiency of oxygen, in solid tumors is majorly responsible for the progression of cancer and remains unaffected by chemotherapy, but still requires definitive definition of the hypoxia signaling. Hypoxia disrupts the complete folding of mitochondrial proteins, leading to several diseases. The present study confirms that hypoxia activates the Hedgehog pathway in colorectal cancer (CRC), considering its role in cancer epithelial to mesenchymal transition, migration, and invasion. The activity of hypoxia-mediated Gli-1, a Hedgehog signaling factor in hypoxia, was confirmed by in vitro western blotting, immunofluorescence staining, wound-healing assay, and matrigel invasion assay, as well as by in vivo xenograft models (n = 5 per group). The Gli-1 mechanism in hypoxia was analyzed via mass spectrometry. Hypoxia enhanced the interaction of Gli-1 and T-complex protein 1 subunit beta (CCT2), as observed in the mass spectrometric analysis. We observed that reduction in CCT2 inhibits tumor induction by Gli-1. Ubiquitination-mediated Gli-1 degradation by β-TrCP occurs during incomplete folding of Gli-1 in hypoxia. The human CRC tissues revealed greater CCT2 expression than did the normal colon tissues, indicating that higher CCT2 expression in tumor tissues from CRC patients reduced their survival rate. Moreover, we suggest that CCT2 correlates with Gli-1 expression and is an important determinant of survival in the CRC patients. The results reveal that CCT2 can regulate the folding of Gli-1 in relation to hypoxia in CRC.

A major problem of colorectal cancer (CRC) targeted therapies is relapse caused by drug resistance. In most cases of CRC, patients develop resistance to anticancer drugs. Cetuximab does not show many of the side effects of other anticancer drugs and improves the survival of patients with metastatic CRC. However, the molecular mechanism of cetuximab resistance is not fully understood. Methods: EPHB3-mediated cetuximab resistance was confirmed by in vitro western blotting, colony-forming assays, WST-1 colorimetric assay, and in vivo xenograft models (n = 7 per group). RNA-seq analysis and receptor tyrosine kinase assays were performed to identify the cetuximab resistance mechanism of EPHB3. All statistical tests were two-sided. Results: The expression of EFNB3, which upregulates the EPHB3 receptor, was shown to be increased via microarray analysis. When resistance to cetuximab was acquired, EPHB3 protein levels increased. Hedgehog signaling, cancer stemness, and epithelial-mesenchymal transition signaling proteins were also increased in the cetuximab-resistant human colon cancer cell line SW48R. Despite cells acquiring resistance to cetuximab, STAT3 was still responsive to EGF and cetuximab treatment. Moreover, inhibition of EPHB3 was associated with decreased STAT3 activity. Co-immunoprecipitation confirmed that EGFR and EPHB3 bind to each other and this binding increases upon resistance acquisition, suggesting that STAT3 is activated by the binding between EGFR and EPHB3. Protein levels of GLI-1, SOX2, and Vimentin, which are affected by STAT3, also increased. Similar results were obtained in samples from patients with CRC. Conclusion: EPHB3 expression is associated with anticancer drug resistance.

Cannabidiol (CBD), one of the compounds present in the marijuana plant, has anti-tumor properties, but its mechanism is not well known. This study aimed to evaluate the apoptotic action of CBD in colorectal cancer (CRC) cells, and focused on its effects on the novel pro-apoptotic Noxa-reactive oxygen species (ROS) signaling pathway. CBD experiments were performed using the CRC cell lines HCT116 and DLD-1. CBD induced apoptosis by regulating many pro- and anti-apoptotic proteins, of which Noxa showed significantly higher expression. To understand the relationship between Noxa and CBD-induced apoptosis, Noxa levels were downregulated using siRNA, and the expression of apoptosis markers decreased. After ROS production was blocked, the level of Noxa also decreased, suggesting that ROS is involved in the regulation of Noxa, which along with ROS is a well-known pro-apoptotic signaling agents. As a result, CBD induced apoptosis in a Noxa-and-ROS-dependent manner. Taken together, the results obtained in this study re-demonstrated the effects of CBD treatment in vivo, thus confirming its role as a novel, reliable anticancer drug.

Background Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signalling pathway and are attractive targets for cancer therapy. These agents continue to be investigated in KRAS mutant colon cancer but are met with significant resistance. Clinical investigations have demonstrated that these strategies are not well tolerated by patients. Methods We investigated a biomarker of response for MEK inhibition in KRAS mutant colon cancers by LC-MS/MS analysis. We tested the MEK inhibitor in PIK3CA wild(wt) and mutant(mt) colon cancer cells. In addition, we tested the combinational effects of MEK and TNKS inhibitor in vitro and in vivo. Results We identified β-catenin, a key mediator of the WNT pathway, in response to MEK inhibitor. MEK inhibition led to a decrease in β-catenin in PIK3CA wt colon cancer cells but not in mt. Tumour regression was promoted by combination of MEK inhibition and NVP-TNS656, which targets the WNT pathway. Furthermore, inhibition of MEK promoted tumour regression in colon cancer patient-derived xenograft models expressing PIK3CA wt. Conclusions We propose that inhibition of the WNT pathway, particularly β-catenin, may bypass resistance to MEK inhibition in human PIK3CA mt colon cancer. Therefore, we suggest that β-catenin is a potential predictive marker of MEK inhibitor resistance.

Previously, we demonstrated that IR triggers the invasion/migration of A549 cells via activation of an EGFR–p38/ERK–STAT3/CREB-1–EMT pathway. Here, we have demonstrated the involvement of a novel intracellular signaling mechanism in γ-ionizing radiation (IR)-induced migration/invasion. Expression of receptor-interacting protein (RIP) 1 was initially increased upon exposure of A549, a non-small cell lung cancer (NSCLC) cell line, to IR. IR-induced RIP1 is located downstream of EGFR and involved in the expression/activity of matrix metalloproteases (MMP-2 and MMP-9) and vimentin, suggesting a role in epithelial-mesenchymal transition (EMT). Our experiments showed that IR-induced RIP1 sequentially induces Src-STAT3-EMT to promote invasion/migration. Inhibition of RIP1 kinase activity and expression blocked induction of EMT by IR and suppressed the levels and activities of MMP-2, MMP-9, and vimentin. IR-induced RIP1 activation was additionally associated with stimulation of the transcriptional factor NF-κB. Specifically, exposure to IR triggered NF-κB activation and inhibition of NF-κB suppressed IR-induced RIP1 expression followed by a decrease in invasion/migration as well as EMT. Based on the collective results, we propose that IR concomitantly activates EGFR and NF-κB and subsequently triggers the RIP1–Src/STAT3–EMT pathway, ultimately promoting metastasis.

According to recent studies, Cannabidiol (CBD), one of the main components of Cannabis sativa, has anticancer effects in several cancers. However, the exact mechanism of CBD action is not currently understood. Here, CBD promoted cell death in gastric cancer. We suggest that CBD induced apoptosis by suppressing X-linked inhibitor apoptosis (XIAP), a member of the IAP protein family. CBD reduced XIAP protein levels while increasing ubiquitination of XIAP. The expression of Smac, a known inhibitor of XIAP, was found to be elevated during CBD treatment. Moreover, CBD treatment increased the interaction between XIAP and Smac by increasing Smac release from mitochondria to the cytosol. CBD has also been shown to affect mitochondrial dysfunction. Taken together, these results suggest that CBD may have potential as a new therapeutic target in gastric cancer.

Despite the importance of radiation therapy, there are few radiation-related markers available for use in clinical practice. A larger catalog of such biomarkers is required to help clinicians decide when radiotherapy should be replaced with a patient-specific treatment. Arachidonate 15-lipoxygenase (15-LOX-1) enzyme is involved in polyunsaturated fatty acid metabolism. When colorectal cancer (CRC) cells were exposed to radiation, 15-LOX-1 was upregulated. To verify whether 15-LOX-1 protects against or induces DNA damage, we irradiated sh15-LOX-1 stable cells. We found that low 15-LOX-1 is correlated with radioresistance in CRC cells. These data suggest that the presence of 15-LOX-1 can be used as a marker for radiation-induced DNA damage. Consistent with this observation, gene-set-enrichment analysis based on microarray experiments showed that UV_RESPONSE was decreased in sh15-LOX-1 cells compared to shCon cells. Moreover, we discovered that the expression of the histone H2A variant macroH2A2 was sevenfold lower in sh15-LOX-1 cells. Overall, our findings present mechanistic evidence that macroH2A2 is transcriptionally regulated by 15-LOX-1 and suppresses the DNA damage response in irradiated cells by delaying H2AX activation.

Hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) play important roles in cancer progression in various cancer cell lines. Although genipin, a constituent of Gardenia fruit, has been shown to have anti-tumor activity, its role in the suppression of HIF-1 and its downstream target genes is not well understood. We examined the effect of genipin on the intracellular level of HIF-1α and extracellular level of VEGF using the colon cancer cell line HCT116. We observed that genipin suppressed the accumulation of HIF-1α under hypoxia in various cancer cell lines, including HCT116, via the modulation of protein degradation. Genipin also suppressed the expression of VEGF and the invasion of colon cancer cells by blocking the extracellular signal-regulated kinase signaling pathway. Taken together, our results provide new insights into the potential role of genipin in suppressing colon cancer progression.

Background Implant survivorship is reported to be lower and complications, particularly bearing dislocation, are reported to be more frequent in Asian than in Western patients with medial knee osteoarthritis (OA) undergoing Oxford® Phase III unicompartmental knee arthroplasty (UKA). To date, however, these complications have not been compared between these groups of patients. Questions/purposes The purpose of this study was to perform a meta-analysis comparing the standardized incidence rates of (1) all-cause reoperation; (2) reoperation related to bearing dislocation; and (3) reoperation related to progression of lateral compartment arthritis in Asian and Western patients with medial knee OA who underwent Oxford Phase III UKA. Methods We searched MEDLINE® (January 1, 1976, to May 31, 2017), EMBASE® (January 1, 1985, to May 31, 2017), and the Cochrane Library (January 1, 1987, to May 31, 2017) for studies that reported complications of Oxford Phase III UKAs. Studies were included if they reported reoperation rates attributable to bearing dislocation and/or progression of lateral knee OA after surgery with this implant. Twenty-seven studies were included in this systematic review and 16 studies with followups > 5 years were included in the meta-analysis. These rates were converted to standardized incidence rate (that is, reoperations per 100 observed component years) based on mean followup and number of involved knees in each study. After applying prespecified inclusion and exclusion criteria, the studies were categorized into two groups, Asian and Western, based on hospital location. Twenty-five studies, containing 3152 Asian patients and 5455 Western patients, were evaluated. Study quality was assessed by the modified Coleman Methodology score (MCMS). Although all studies were Level IV, their mean MCMS score was 66.92 (SD, 8.7; 95% confidence interval [CI], 63.5-70.3), indicating fair quality. Because the heterogeneity of all subgroup meta-analyses was high, a random-effects model was used with estimations using the restricted maximum likelihood method. Results There was no difference in the proportion of Asian patients versus Western patients undergoing reoperation for any cause calculated as 100 component observed years (1.022 of 3152 Asian patients; 95% CI, 0.810-1.235 versus 1.300 of 5455 Western patients; 95% CI, 1.067-1.534; odds ratio, 0.7839; 95% CI, 0.5323-1.1545; p = 0.178). The mean reoperation rate attributable to bearing dislocation per 100 observed years was higher in Asian than in Western patients (0.525; 95% CI, 0.407-0.643 versus 0.141; 95% CI, 0.116-0.166; odds ratio, 3.7378; 95% CI, 1.694-8.248; p = 0.001) Conversely, the mean reoperation rate attributable to lateral knee OA per 100 observed years was lower in Asian than in Western patients (0.093; 95% CI, 0.070-0.115 versus 0.298; 95% CI, 0.217-0.379; odds ratio, 0.3114; 95% CI, 0.0986-0.9840; p Conclusions Although total reoperation rates did not differ in the two populations, reoperation for bearing dislocation was more likely to occur in Asian than in Western patients, whereas reoperation for lateral knee OA progression was more likely to occur in Western than in Asian patients after Oxford Phase III UKA. Although possible explanations for these findings may be hypothesized, additional randomized, prospective comparative studies are needed. However, better survival outcomes after UKA may require consideration of ethnicity and lifestyle choices in addition to traditional surgical technique and perioperative care. Level of evidence Level III, therapeutic study.

Background:Previous studies on the link between female reproductive factors and osteoarthritis (OA) have shown conflicting results.Objectives:This study attempted to explore the association between reproductive factors and joint replacement arthroplasty of knee (TKRA) and hip (THRA) in a large nationwide population-based cohort of postmenopausal women.Methods:1,218,257 subjects who participated in national health examination in 2009 were included in the study. The study outcomes is incident THRA or TKRA due to severe hip or knee OA. The association of reproductive factors and THRA or TKRA was evaluated using a multivariate-adjusted proportional hazards model.Results:During the mean follow-up duration of 8.2 years, 1,733 incident THRA cases and 65,108 incident TKRA cases were observed. Later age at menarche (aHR 1.12 in 13-14 years; aHR 1.24 in 15-16 years; aHR 1.32 in ≥ 17 years), longer breastfeeding (aHR 1.24 in < 6 months; aHR 1.24 in 6-12 months; aHR 1.50 in ≥ 12 months), HRT (aHR 1.06 in < 2 years; aHR 1.11 in 2-5 years; aHR 1.21 ≥ 5 years) and OC use (aHR 1.11 in < 1 year; aHR 1.17 ≥ 1 year) was associated with increased risk of TKRA for severe knee OA, while later age at menopause (aHR 0.93 in 45-49 years; aHR 0.89 in 50-54 years), longer reproductive span (aHR 0.91 in 30-34 years; aHR 0.87 in 35-39 years; aHR 0.91 in ≥ 40 years) was associated with decreased risk. With regard to THRA for severe hip OA, later menarche (aHR 1.21 ≥ 17 years), longer breastfeeding (aHR 1.39 in < 6 months; aHR 1.31 in ≥ 12 months), and HRT more than 5 years (aHR 1.49) were associated with higher risk. The association between reproductive factors and severe OA was more pronounced in underweight and younger subjects.Conclusion:Our study found that shorter estrogen exposure was associated with higher risk of joint replacement therapy due to severe OA, and such association was more pronounced in underweight and younger subjects.Disclosure of Interests:None declared

Posterior drooling, which can lead to substantial respiratory morbidity, including unexplained lung diseases and recurrent pneumonia, is an important issue in the rehabilitation unit. There are various treatment options for posterior drooling, including pharmacologic therapy, oral motor or behavioral therapy, biofeedback, local glandular injection of botulinum toxin, irradiation, and surgery. Among them, nebulized glycopyrrolate has the following advantages: It is noninvasive and is relatively free of central adverse effects because it does not cross the blood-brain barrier unlike other anticholinergics. Although there has been one case report regarding the effectiveness of nebulized glycopyrrolate for drooling in a motor neuron patient, there have not been any reports on its effectiveness for posterior drooling. Herein, we report two cases (an 82-year-old male bilateral hemiplegic stroke patient and a 1-year-old female cerebral palsy infant with bilaterally spastic hemiplegia of posterior drooling treated with nebulized glycopyrrolate) and identify salivary aspiration and the effect of nebulized glycopyrrolate using radionuclide salivagram. Considering its advantages and effectiveness, nebulized glycopyrrolate should be considered as one of the reliable methods to manage posterior drooling in patients with impaired cognition or swallowing difficulties, such as severe brain injury.

Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is a promising anticancer reagent for antitumor therapy. However, many cancer cells, including malignant glioma cells, tend to be resistant to TRAIL, due to repeat treat to cancer cells, highlighting the need for strategies to overcome TRAIL resistance. Here we present that in combination with diallyl trisulfide (DATS), exposure to TRAIL induced apoptosis in TRAIL-resistant glioma cells. Surprisingly, we found that subtoxic concentrations of DATS significantly potentiated TRAIL-induced cytotoxicity and apoptosis in glioma cells. DATS dramatically upregulated DR5 receptor expression but had no effects on DR4 receptor. In addition, DATS enhances TRAIL-induced apoptosis through the downregulation of anti-apoptotic protein (Mcl-1) and the upregulation of DR5 receptors through actions on the ROS- induced-p53.

Implantation of polyurethane (PU) meniscal scaffolds has become a popular procedure to provide a scaffold for vessel ingrowth and meniscal tissue regeneration in patients with partial meniscal defects. However, it is unclear whether PU meniscal scaffolds lead to better clinical and magnetic resonance imaging (MRI) outcomes post-operatively. This meta-analysis compared the clinical and MRI outcomes in patients with partial meniscal defects treated with PU meniscal scaffolds. This meta-analysis reviewed all studies that assessed Lysholm score, International Knee Documentation Committee (IKDC) score, visual analogue scale (VAS) for pain, Tegner score, Knee Injury and Osteoarthritis Outcomes Score (KOOS), articular cartilage (AC), absolute meniscal extrusion (AME), morphology and size (MS), signal intensity (SI) of meniscal implant, and interface of the implant–residual meniscus complex (IIRMC) in patients with partial meniscal defects treated with PU meniscal scaffolds. Eighteen studies were included in the meta-analysis. The proportion of patients who evaluated MS (OR 0.71, 95% CI 0.38–1.33; n.s.), SI (OR 1.07, 95% CI 0.53–2.18; n.s.), and IIRMC (OR 1.00, 95% CI 0.33–3.06; n.s.) did not differ significantly between baseline and final follow-up. However, AC (OR 0.31, 95% CI 0.11–0.84; P = 0.02) and AME (OR 0.05, 95% CI 0.01–0.18; P

There is a greater incidence of discoid meniscus in Asian countries than in Western countries, and bilateral discoid menisci are also common. The discoid meniscus may be a congenital anomaly, and genetics or family history may play a role in the development of discoid menisci. Because the histology of discoid meniscus is different from that of normal meniscus, it is prone to tearing. Individuals with a discoid meniscus can be asymptomatic or symptomatic. Asymptomatic discoid menisci do not require treatment. However, operative treatment is necessary if there are symptoms. Total meniscectomy leads to an increased risk of osteoarthritis. Therefore, total meniscectomy is generally reserved for rare unsalvageable cases. Partial meniscectomy (saucerization) with preservation of a stable peripheral rim combined with or without peripheral repair is effective, and good short-, mid-, and long-term clinical results have been reported.

Background: Although the anticancer activity of Korean Red Ginseng (KRG) has been known in various cancers, the mechanism of KRG-induced apoptosis is unknown in colorectal cancer (CRC). In our study, we examined whether KRG induces apoptosis in CRC cells. Methods: In the cell viability assay, the concentration of the appropriate KRG extracts was fixed at 2.5 mg/mL in numerous CRC cells. This fixed concentration was in other experiments, and it was confirmed that the KRG extracts induce apoptosis in CRC cells. Results: We found that KRG induced Noxa activation and apoptosis and increased endoplasmic reticulum stress via reactive oxygen species production. This indicated that KRG efficiently enhanced cell death in CRC cells. Conclusion: Our results show that KRG can be used as a possible anticancer drug for patients with CRC

Oxaliplatin is an anticancer drug administered to colorectal cancer (CRC) patients in combination with 5-fluorouracil and antibodies (bevacizumab and cetuximab), thereby significantly improving the survival rate of CRC. However, due to various side effects associated with the above treatment strategy, the need for combinatorial therapeutic strategies has emerged. Based on the demand for new combinatorial therapies and the known antitumor effects of the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), we investigated the Oxaliplatin and DHA combination for its effect. Our results indicated that DHA further enhanced Oxaliplatin-induced cell viability and autophagic cell death, in vitro and in vivo. Oxaliplatin and DHA also increased the expression of Sestrin 2 (SESN2) and endoplasmic reticulum (ER) stress related C/EBP homologous protein (CHOP). Additionally, treatment with Oxaliplatin and DHA enhanced the binding of CHOP to the promotor region of SESN2, increasing SESN2 expression. These results suggested that DHA enhanced Oxaliplatin-induced reduction in cell viability and increase in autophagy via activating SESN2 and increasing ER stress. Thus, SESN2 may be an effective preclinical target for CRC treatment.

Shigella, which infects primates, can be transmitted via fresh vegetables; however, its molecular interactions with plants have not been elucidated. Here, we show that four Shigella strains, Shigella boydii, Shigella sonnei, Shigella flexneri 2a, and S. flexneri 5a, proliferate at different levels in Arabidopsis thaliana. Microscopic studies revealed that these bacteria were present inside leaves and damaged plant cells. Green fluorescent protein (GFP)-tagged S. boydii and S. flexneri 5a colonized leaves only, whereas S. flexneri 2a colonized both leaves and roots. Using Shigella mutants lacking type III secretion systems (T3SSs), we found that T3SSs that regulate the pathogenesis of shigellosis in humans also play a central role in bacterial proliferation in Arabidopsis. Strikingly, the immunosuppressive activity of two T3S effectors, OspF and OspG, was required for proliferation of Shigella in Arabidopsis. Of note, delivery of OspF or OspG effectors inside plant cells upon Shigella inoculation was confirmed using a split GFP system. These findings demonstrate that the human pathogen Shigella can proliferate in plants by adapting immunosuppressive machinery used in the original host human.

Oxaliplatin is used for treatment in combination with many drugs. However, the survival rate is still low due to side effects and drug resistance. Therefore, the combination with natural products was required for increasing efficacy and reducing side effects. Genipin, a natural product derived from the Gardenia jasminoides, associated with anti-angiogenic, anti-proliferative, hypertension, inflammatory, and the Hedgehog pathway. It is not known that genipin increases the therapeutic effect of oxaliplatin in gastric cancer. In this study, we found that genipin sensitizes oxaliplatin-induced apoptosis for the first time using colony forming assay, FACS analysis, and western blotting in gastric cancer. Additionally, genipin induced p53 expression in AGS, MKN45, and MKN28 cells. Also, genipin induced autophagy and LC3 expression. Knockdown of LC3 decreased cell death enhanced by the combination of oxaliplatin and genipin. In summary, we showed that genipin increases the oxaliplatin-induced cell death via p53-DRAM autophagy. Based on this, we suggest that genipin is a sensitizer of oxaliplatin.

Imatinib is a powerful tyrosine kinase inhibitor that specifically targets BCR‑ABL, c‑KIT, and PDGFR kinases, and is used in the treatment of chronic myelogenous leukemia, gastrointestinal stromal tumors, and other types of cancers. However, the possible anticancer effects of imatinib in gastric cancer have not yet been explored. The present study evaluated the in vitro effects of imatinib on gastric cancer cells and determined the molecular mechanism underlying these effects. We determined that imatinib induced mitochondria‑mediated apoptosis of gastric cancer cells by involving endoplasmic reticulum (ER) stress‑associated activation of c‑Jun NH2‑terminal kinase (JNK). We also found that imatinib suppressed cell proliferation in a time‑ and dose‑dependent manner. Cell cycle analysis revealed that imatinib‑treated AGS cells were arrested in the G2/M phase of the cell cycle. Moreover, imatinib‑treated cells exhibited increased levels of phosphorylated JNK, and of the transcription factor C/EBP homologous protein, an ER stress‑associated apoptotic molecule. Results of cell viability assays revealed that treatment with a combination of imatinib and chemotherapy agents irinotecan or 5‑Fu synergistically inhibited cell growth, compared with treatment with any of these drugs alone. These data indicated that imatinib exerted cytotoxic effects on gastric cancer cells by inducing apoptosis mediated by reactive oxygen species generation and ER stress‑associated JNK activation. Furthermore, we revealed that imatinib induced the apoptosis of gastric cancer cells by inhibiting platelet‑derived growth factor receptor signaling. Collectively, our results strongly support the use of imatinib in the treatment of treating gastric cancer.

Ever since several targeted agents were introduced a decade ago, progress in new therapeutic strategies for colorectal cancer (CRC) has been much slower than that for other cancers. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is widely known to induce cellular apoptosis in numerous cancer cell types. However, many cancer cells are resistant to the effects of TRAIL, and thus, approaches are needed to overcome TRAIL resistance. We demonstrated that non-cytotoxic doses of diallyl disulfide (DADS) increased TRAIL-associated cell death in CRC cell lines. Additionally, synergistic effects between DADS and TRAIL were validated in vivo in nude mice. One process involved in these effects includes down-regulation of the anti-apoptotic protein Bcl-2, and the synergistic effect of DADS with TRAIL was attenuated in Bcl-2-over-expressing cells. Taken together, the results of this study give new insights into the role of DADS in TRAIL-related repression of CRC progression by inhibition of Bcl-2.

// Seong Hye Park 1, * , Dae-Hee Lee 1, 2, * , Jung Lim Kim 2 , Bo Ram Kim 1 , Yoo Jin Na 1 , Min Jee Jo 1 , Yoon A. Jeong 2 , Suk-Young Lee 2 , Sun Il Lee 3 , Yong Yook Lee 4 , Sang Cheul Oh 1, 2 1 Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul, Republic of Korea 2 Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea 3 Department of Surgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea 4 The Korean Ginseng Research Institute, Daejeon, Republic of Korea * These authors contributed equally to this work Correspondence to: Sang Cheul Oh, email: sachoh@korea.ac.kr Keywords: metformin, TRAIL, CRC, Mcl-1, Noxa Received: December 20, 2015 Accepted: July 06, 2016 Published: August 09, 2016 ABSTRACT Metformin is an anti-diabetic drug with a promising anti-cancer potential. In this study, we show that subtoxic doses of metformin effectively sensitize human colorectal cancer (CRC) cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which induces apoptosis. Metformin alone did not induce apoptosis, but significantly potentiated TRAIL-induced apoptosis in CRC cells. CRC cells treated with metformin and TRAIL showed activation of the intrinsic and extrinsic pathways of caspase activation. We attempted to elucidate the underlying mechanism, and found that metformin significantly reduced the protein levels of myeloid cell leukemia 1 (Mcl-1) in CRC cells and, the overexpression of Mcl-1 inhibited cell death induced by metformin and/or TRAIL. Further experiments revealed that metformin did not affect mRNA levels, but increased proteasomal degradation and protein stability of Mcl-1. Knockdown of Mule triggered a significant decrease of Mcl-1 polyubiquitination. Metformin caused the dissociation of Noxa from Mcl-1, which allowed the binding of the BH3-containing ubiquitin ligase Mule followed by Mcl-1ubiquitination and degradation. The metformin-induced degradation of Mcl-1 required E3 ligase Mule, which is responsible for the polyubiquitination of Mcl-1. Our study is the first report indicating that metformin enhances TRAIL-induced apoptosis through Noxa and favors the interaction between Mcl-1 and Mule, which consequently affects Mcl-1 ubiquitination.

This meta-analysis was designed to compare the effectiveness and safety of intravenous (IV) versus topical administration of tranexamic acid (TXA) in patients undergoing primary total knee arthroplasty (TKA) by evaluating the need for allogenic blood transfusion, incidence of postoperative complications, volume of postoperative blood loss, and change in haemoglobin levels. Studies were included in this meta-analysis to check whether they assessed the allogenic blood transfusion rate, postoperative complications including pulmonary thromboembolism (PTE) or deep vein thrombosis (DVT), volume of postoperative blood loss via drainage, estimated blood loss, total blood loss, and change in haemoglobin levels before and after surgery in primary TKA with TXA administered through both the IV and topical routes. Ten studies were included in this meta-analysis. The proportion of patients requiring allogenic blood transfusion (OR 1.34, 95 % CI 0.63–2.81; n.s.) and the proportion of patients who developed postoperative complications including PTE or DVT (OR 0.85, 95 % CI 0.41 to 1.77; n.s.) did not significantly differ between the two groups. There was 52.3 mL less blood loss via drainage (95 % CI −50.74 to 185.66 mL; n.s.), 52.1 mL greater estimated blood loss (95 % CI −155.27 to 51.03 mL; n.s.), and 51.4 mL greater total blood loss (95 % CI −208.16 to 105.31 mL; n.s.) in the topical TXA group as compared to the IV TXA group. The two groups were also similar in terms of the change in haemoglobin levels (0.02 g/dL, 95 % CI −0.36 to 0.39 g/dL; n.s.). In primary TKA, there are no significant differences in the transfusion requirement, postoperative complications, blood loss, and change in haemoglobin levels between the IV and topical administration of TXA. In addition, results from subgroup analysis evaluating the effect of the times of TXA administration through the IV route suggested that double IV dose of TXA is more effective than single dose in terms of the transfusion requirements and blood loss via drainage. The current meta-analysis indicates that IV administration of 10 mg/kg of TXA 20 min before inflation of the tourniquet followed by 10 mg/kg of TXA 15 min before deflation of the tourniquet is effective and safe. The topical administration of 2 g of TXA mixed with 100 mL of normal saline after wound closure could be an alternative option in patients at greater risk of thromboembolic complications. Meta-analysis, Level III.

Osteomyelitis originating in the epiphysis of the long bones is quite rare and is usually found at either the distal femur or the proximal tibia. We report the case of a 12-year-old male with epiphyseal osteomyelitis that had developed in the distal tibia. To the best of our knowledge, this is the first published case report. The patient's history of a trauma that resembled an ankle sprain had delayed the diagnosis and subsequently led him to develop septic arthritis. The ankle is a common site of simple trauma; however, epiphyseal osteomyelitis is rare at this site. Therefore, if the symptoms continue or worsen after trauma, the clinician should check the affected site and take a more aggressive approach to make an early diagnosis.

Background To determine a new classification system for medial meniscus root tears (MMRT) based on arthroscopic findings. Methods 24 knees (55%) belonged to the nondisplaced or overlapped group, and 20 knees (45%) to the widely displaced group. Absolute meniscal extrusion was defined as distance between outer edge of the articular cartilage of tibial plateau and meniscal outer edge. Relative extrusion was defined as extruded meniscus width divided by entire meniscal width, multiplied by 100. The proportion of knees with major (>3mm) extrusion were compared in two groups, as were the severity of chondral wear and osteoarthritic change. Results Absolute (4.6mm vs. 3.7mm, P=0.006) and relative (46% vs. 39%, P=0.042) extrusion of the medial meniscus were greater in widely displaced than in nondisplaced or overlapped group. Medial joint space width was significantly narrower in the widely displaced than in the nondisplaced or overlapped group (3.0mm vs. 4.0mm, P=0.007). The widely displaced group had a 4° greater varus deformity, and higher rates of major extrusion (>3mm), grade III or IV chondral wear in the medial femoral condyle (60% vs. 29%, P=0.039) and medial compartment osteoarthritis (75% vs. 21%, P=0.001) than did the nondisplaced or overlapped group. Conclusions Widely displaced MMRT had greater meniscal extrusion and more severe chondral wear and osteoarthritis than did nondisplaced or overlapped MMRT. In this novel classification system, the stage of MMRT severity was associated with tear site displacement. Level of evidence Case series (level IV).

This meta-analysis was designed to compare clinical outcomes, including knee scale score and nonunion rate, of patients with periprosthetic supracondylar fractures of the distal femur after total knee arthroplasty (TKA) who were treated using locking compression plates and retrograde intramedullary nails. Studies were included in this meta-analysis if they compared clinical outcomes, including operation time, Knee Society Score (KSS), time to union, nonunion rate, and revision rate due to nonunion, in patients who underwent locking compression plate or retrograde intramedullary nail for periprosthetic distal femur fractures following TKA. Eight studies were included in this meta-analysis. Mean operation time was 11 min shorter (95 % CI −9.56 to 31.33 min; n.s.) and KSS one point higher (95 % CI −8.88 to 11.10; n.s.) with retrograde intramedullary nail than with locking compression plate, but these differences were not statistically significant. The two groups were also similar in mean time to union (0.46 weeks 95 % CI −1.17 to 2.08 weeks; n.s.), the proportion of subjects with nonunion (OR 0.83, 95 % CI 0.26–2.60; n.s.) and the proportion that underwent revision surgery (OR 0.88, 95 % CI 0.32–2.40; n.s.). Clinical outcomes, including nonunion and revision rates, were similar in patients who underwent locking compression plate and retrograde intramedullary nail fixation for periprosthetic supracondylar femoral fracture following TKA. Orthopaedic surgeons must train to master both the retrograde intramedullary nail and locking compression plate techniques because both approaches can be considered for periprosthetic distal femur fracture after TKA as they have similar clinicoradiologic outcomes. II.

Genipin is known as a compound derived from gardenia fruit extract. Although Genipin is known to have an anti-tumor effects in various cancers, its effect and mechanism are unknown in gastric cancer. In our studies, Genipin induced apoptosis in gastric cancer cells including AGS and MKN45 cells. Genipin reduced Mcl-1 mRNA levels and confirmed with transfection of Mcl-1 siRNA. Furthermore, We found that phospho Stat3 is regulated by Genipin through proteome profiler phosphor-kinase array. In addition, protein level of phosphor JAK2 decreased in Genipin treatment. The results elucidate that Stat3/JAK2/Mcl-1 signaling pathway was suppressed with Genipin treatment in gastric cancer cells. Mcl-1 is known to be closely related to the function of mitochondria. Genipin has been shown to result in the collapse of mitochondrial function such as mitochondrial membrane potential. In conclusion, Genipin induced apoptosis by suppressing Stat3/JAK2/Mcl-1 pathway and led to mitochondrial dysfunction. Our finding implies that a novel mechanism of anti-cancer effect of Genipin in gastric cancer can be identified. Citation Format: Min Jee Jo, Soyeon Jeong, Hye Kyeong Yun, Dae Yeong Kim, Bo Ram Kim, Jung Lim Kim, Yoo Jin Na, Seong Hye Park, Yoon A Jeong, Bu Gyeom Kim, Hassan Ashktorab, Duane T Smoot, Jun Young Heo, Jeongsu Han, Dae-Hee Lee, Sang Cheul Oh. Genipin enhanced apoptosis of gastric cancer by mitochondrial dysfunction and downregulation of Stat3/JAK2/Mcl-1 signaling pathway [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A021. doi:10.1158/1535-7163.TARG-19-A021

Multifunctional, antiproliferative small molecules are deemed to offer pharmacodynamic and pharmacokinetic benefits over combination therapy, in addition to reducing toxicity, cancer resistance, and therapy costs. In this study, we conducted an in vitro cellular screen of our recently reported series of EGFR/HER2 inhibitors. Due to its preferentially apoptosis triggering in colorectal cancer (CRC) cells compared to normal colon cells, the compound AF8c was selected for further evaluation. Analysis of the AF8c mode of action in CRC cells revealed that it mediates apoptosis via the generation of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS), as well as selective activation of nuclear respiratory factor 2 alpha subunit (Nrf2) and death receptor 5 (DR5), but not DR4. Silencing of DR5 attenuated the expression levels of Nrf2 and partially inhibited AF8c-induced apoptosis. Additionally, upregulation of Nrf2 by AF8c evoked apoptosis through a decrease in antioxidant levels. Treatment of mice with AF8c also resulted in the upregulation of DR5, Nrf2, and CHOP proteins, subsequently leading to a significant decrease in tumor burden. Overall, our results suggest that AF8c-induced apoptosis may be associated with DR5/Nrf2 activation through ER stress and ROS generation in CRC. These findings indicate that AF8c represents a promising polypharmacological molecule for the treatment of human CRC. Moreover, it could also be a potential starting point for the understanding of the structural features of quinazoline-based ErbB family inhibitors targeting the TRAIL cascade. Citation Format: Soyeon Jeong, Ahmed Karam Farag, Hye Kyeong Yun, Yoon A Jeong, Dae Yeong Kim, Min Jee Jo, Seong Hye Park, Bo Ram Kim, Jung Lim Kim, Dae-Hee Lee, Eun Joo Roh, Sang Cheul Oh. AF8c, a pan-ErbB family inhibitor induces apoptotic cell death by stimulating DR5/Nrf2 via ROS in colorectal cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A111. doi:10.1158/1535-7163.TARG-19-A111

Despite the possibility that the methodological difference of this salivagram may influence the results for detection rate, there has been no study on the effect of the solution volume on detection rate. Moreover, to date, since the introduction of the nucleotide salivagram, there has been a tendency that a constant solution volume and nucleotide dose is not used in studies. Therefore, the aim of this study is to investigate the effect of solution volume on the detection rate of a salivagram in patients with brain lesion, and to determine the optimal solution volume of salivagram. We retrospectively reviewed clinical data and solution volume of radionuclide used in the salivagram of 77 patients with dysphagia, and the patients were divided into 2 groups according to the solution volume of the radionuclide (Group A-0.1 mL vs Group B-0.5 mL). Although, there was no significant difference between 2 groups in clinical data, there was a statistically significant difference in the detection rate of salivary aspiration between the 2 groups (3.3% vs 19.1%). Even a small difference of the solution volume of radionuclide in salivagram can affect the detection rate of salivary aspiration in patients with brain lesion. Further study with various solution volumes of radionuclide is warranted to determine the optimal solution volume of the radionuclide salivagram.

Hong Jun Kim,1 Min Jee Jo,2 Bo Ram Kim,2 Jung Lim Kim,2 Yoon A Jeong,2 Yoo Jin Na,2 Seong Hye Park,2 Suk-young Lee,1 Dae-Hee Lee,1,2 Baek-hui Kim,3 Young Do Yoo,4 Sang Cheul Oh1,2 1Division of Oncology and Hematology, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea; 2Laboratory of Oncology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea; 3Department of Pathology, College of Medicine, Korea University, Seoul, Republic of Korea; 4Laboratory of Molecular Cell Biology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea Introduction: Reactive oxygen species modulator-1 (Romo1) is a protein that modulates levels of reactive oxygen species (ROS) and has been reported to affect cancer cell invasion and proliferation via persistent inflammation. Several studies have demonstrated the clinical application of Romo1 as a prognostic marker in non-small cell lung cancer (NSCLC); however, there have been no studies investigating the mechanism by which Romo1 adversely affects the prognosis of these patients. Methods: We examined Romo1, ROS, and vascular endothelial growth factor (VEGF) in tumor tissues immunohistochemically. We conducted survival analyses of patients who had curative resection (n=30) in accordance with clinical parameters including levels of Romo1 expression. Results: Romo1 levels were associated with serologic inflammatory markers and high lymphatic metastatic tendencies. Significantly longer disease-free survival (68.7 vs 24.2 months, P=0.031) and overall survival (92.7 vs 51.6 months) were observed in the group with low Romo1 compared with high Romo1. Survival outcomes were also significantly associated with serologic inflammatory markers. Spearman’s correlation analyses demonstrated significant positive correlations of Romo1 expression with VEGF-C (P=0.008, R=0.478) and ROS (P=0.016, R=0.436) in tumor samples. Conclusion: The current study demonstrates that Romo1 induces lymphatic metastasis of NSCLC by modulating persistent inflammation and oxidative stress (ROS)/VEGF signaling. Lymphatic metastasis associated with elevated Romo1 was shown to be a key reason for unfavorable survival rates. Keywords: non–small cell lung carcinoma, inflammation, reactive oxygen species modulator-1, vascular endothelial growth factor A, reactive oxygen species

Human enteropathogenic bacteria has been reported to be transmitted by fresh vegitables.Shigella, which infects primates, is reportedly transmitted by fresh vegetables; however, its molecular interactions with plants have not been elucidated. Here, we show that fourShigellastrains,S. boydii(S. b),S. sonnei,S. flexneri2a (S. f2a), andS. flexneri5a (S. f5a), proliferated at different levels inArabidopsis thaliana. Microscopic studies revealed that these bacteria were present inside leaves and damaged plant cells. Green fluorescent protein (GFP)-taggedS. bandS. f5a colonized in leaves only, andS. f2a colonized both leaves and roots. Using mutants lacking type III secretion systems (T3SS), we found that T3SS ofShigellathat regulate the pathogenesis of Shigellosis in humans also play a central role in proliferation inArabidopsis.Strikingly, the immunosuppressive activity of two T3S effectors, OspF and OspG, were needed for the proliferation ofShigellainArabidopsis. Of note, delivery of OspF or OspG effectors inside of plant cells uponShigellainoculation was confirmed by using a split GFP system, respectively. These findings demonstrate that the human pathogenShigellacan proliferate in plants by adoption of immunosuppressive machinery for its original host human.

Despite an increase in the survival rate of patients with cancer owing to the use of current chemotherapeutic agents, adverse effects of cancer therapies remain a concern. Combination therapies have been developed to increase efficacy, reduce adverse effects, and overcome drug resistance. Genipin is a natural product derived from Gardenia jasminoides, which has been associated with anti-inflammatory, anti-angiogenic, and anti-proliferative effects; hypertension; and anti-ischemic brain injuries. However, the enhancement of oxaliplatin sensitivity by genipin remains unexplored. Our study showed that a combination of genipin and oxaliplatin exerts synergistic antitumor effects in vitro and in vivo in colorectal cancer cell lines through the reactive oxygen species (ROS)/endoplasmic reticulum (ER) stress/BIM pathway. Importantly, the combination did not affect normal colon cells. BIM knockdown markedly inhibited apoptosis induced by the combination. In addition, genipin induced ROS by inhibiting superoxide dismutase 3 activity. These findings suggest that genipin may be a novel agent for increasing the sensitivity of oxaliplatin against colorectal cancer. The combination of oxaliplatin and genipin hold significant therapeutic potential with minimal adverse effects.

Background Achieving proper rotational alignment of the femoral component in total knee arthroplasty (TKA) for valgus knee is challenging because of lateral condylar hypoplasia and lateral cartilage erosion. Gap-based navigation-assisted TKA enables surgeons to determine the angle of femoral component rotation (FCR) based on the posterior condylar axis. This study evaluated the possible factors that affect the rotational alignment of the femoral component based on the posterior condylar axis. Materials and methods Between 2008 and 2016, 28 knees were enrolled. The dependent variable for this study was FCR based on the posterior condylar axis, which was obtained from the navigation system archives. Multiple regression analysis was conducted to identify factors that might predict FCR, including body mass index (BMI), Kellgren-Lawrence grade (K-L grade), lateral distal femoral angles obtained from the navigation system and radiographs (NaviLDFA, XrayLDFA), hip-knee-ankle (HKA) axis, lateral gap under varus stress (LGVS), medial gap under valgus stress (MGVS), and side-to-side difference (STSD, MGVS − LGVS). Results The mean FCR was 6.1° ± 2.0°. Of all the potentially predictive factors evaluated in this study, only NaviLDFA (β = −0.668) and XrayLDFA (β = −0.714) predicted significantly FCR. Conclusions The LDFAs, as determined using radiographs and the navigation system, were both predictive of the rotational alignment of the femoral component based on the posterior condylar axis in gap-based TKA for valgus knee. A 1° increment with NaviLDFA led to a 0.668° decrement in FCR, and a 1° increment with XrayLDFA led to a 0.714° decrement. This suggests that symmetrical lateral condylar hypoplasia of the posterior and distal side occurs in lateral compartment end-stage osteoarthritis with valgus deformity.

Restoration of correct coronal alignment is one of the main goals of total knee arthroplasty (TKA). Traditionally, TKA has been considered successful when a neutral mechanical hip–knee–ankle (HKA) axis within 3° is achieved. Recent studies have reported no differences or improved clinical outcomes following a slight under-correction of the HKA axis for a varus knee. However, the influence of under-correction of a valgus knee has not been reported. This study investigated the influence of post-operative HKA alignment in TKA patients with valgus deformity on clinical outcomes. Ninety-three knees (93 patients) with pre-operative valgus alignment were evaluated with a mean follow-up period of 60 months. All patients were classified into three groups based on post-operative HKA alignment: neutral (0 ± 3°), mild valgus (3°–6°), and severe valgus (> 6°). These groups were compared using the Western Ontario and McMaster Universities osteoarthritis (WOMAC) index, the Knee Society (KS) knee score, KS function score, α-angle, β-angle, patella tilt angle, and the congruence angle. Sixty-nine knees were included in the neutral group, seventeen knees in the mild valgus group, and seven knees in the severe valgus group. In all cases, post-operative clinical and functional scores significantly improved compared to pre-operative scores. There were no differences between the three groups in post-operative clinical and functional scores. More post-operative patellar tilt angle outliers (> 10°) and congruence angle outliers (> 16°) were apparent in the severe valgus group (patellar tilt angle, 13 vs. 17 vs. 57.1%, p = 0.022; congruence angle, 32 vs. 47 vs. 71%, p = 0.035). Slight under-correction following TKA for a valgus knee resulted in similar clinical outcomes. A residual valgus angle of more than 6° can induce patellar maltracking. III, Retrospective comparative study.

This study was designed to analyze the relationship between changes in posterior tibial slope and the absence or presence of lateral hinge fracture, diagnosed in the sagittal and axial planes, as well as the coronal plane, by computed tomography (CT) following opening wedge high tibial osteotomy (HTO). This study involved 55 patients (55 knees) undergoing opening wedge HTO for primary medial osteoarthritis. Lateral hinge fractures were evaluated on CT scans according to the Takeuchi classification and were also classified as subtypes A, B, and C, depending on anterior, posterior, and both anterior and posterior cortical disruptions, respectively, as determined by the sagittal and axial planes of CT scans which corresponded to the fracture line visible on coronal CT scans. Of the 55 knees, 23 were found on postoperative CT scans to have lateral hinge fractures. All 23 were classified as Type I, with 11, 12, and 0 being subtypes A, B, and C, respectively. Mean change in posterior tibial slope from 3 weeks postoperatively to last follow up in subtype B was significantly greater than in subtype A (2.5° vs 0.2°, P = 0.008) and in knees without hinge fracture (2.5° vs 0.1°, P = 0.002). Type I lateral hinge fractures encroached either the anterior or posterior cortex of the proximal tibia, but not both. In addition, posterior tibial slope increased over time following surgery in knees with Type I lateral hinge fracture and posterior cortex breakage, suggesting that caution should be exercised when deciding the starting time for weight bearing in such patients. Case series, Level IV.

Open-wedge high tibial osteotomy (HTO) cannot always accurately correct limb alignment, resulting in under- or over-correction. This study assessed the relationship between soft tissue laxity of the knee joint and alignment correction in open-wedge HTO. This prospective study involved 85 patients (86 knees) undergoing open-wedge HTO for primary medial osteoarthritis. The mechanical axis (MA), weight-bearing line (WBL) ratio, and joint line convergence angle (JLCA) were measured on radiographs preoperatively and after 6 months, and the differences between the pre- and post-surgery values were calculated. Post-operative WBL ratios of 57–67 % were classified as acceptable correction. WBL ratios 67 % were classified as under- and over-corrections, respectively. Preoperative JLCA correlated positively with differences in MA (r = 0.358, P = 0.001) and WBL ratio (P = 0.003). Difference in JLCA showed a stronger correlation than preoperative JLCA with differences in MA (P

Bone morphogenetic proteins (BMPs) have been involved in metastatic progression and tumorigenesis of many cancer types. However, it remains unclear how BMP-2 contributes to the initiation and development of these cancers. Here, we investigated the role of BMP-2 in colon cancer stem cell (CSC) development from colon cancer cells. We also determined the effects of BMP-2 on CSC development and epithelial-mesenchymal transition (EMT) in human colon cancer cell lines HCT-116 and SW620. We found that BMP-2 enhanced sphere formation of colon cancer cells without serum. Also, BMP-2-induced spheres displayed up-regulation of stemness markers (CD133+ and EpCAM+) and increased drug resistance, hallmarks of CSCs. Importantly, expression of EMT activators p-Smad1/5 and Snail and N-cadherin was increased in the spheres' cells, indicating that BMP-2 signaling might result in CSC self-renewal and EMT. Furthermore, siRNA-mediated knockdown of signal transducer and activator of transcription 3 (STAT3) in HCT-116 cells reversed BMP-2-induced EMT and stem cell formation. Taken together, our results suggest that the BMP-2 induced STAT3-mediated induction of colon cancer cell metastasis requires an EMT and/or changes in CSC markers.

Purpose To compare the incidence of overhang between two distinct femoral components and whether there is clinical and radiological benefit of gender-specific implants in short-term follow-up. Materials and Methods One hundred and four knees in consecutive 66 female patients who underwent primary total knee arthroplasty due to primary osteoarthritis were included in this study. Overhang was measured and recorded in every cut surface of femur with both gender-specific and traditional trial femoral components respectively in every patient. Then, the knees were divided into two groups according to the type of the permanent femoral component they received. Clinical and radiological outcomes were compared between 2 groups at minimum 3 years after operation. Results Mean follow-up duration was 41.3 months (range, 36 to 50 months). Sixty two knees (59.6%) showed femoral overhang at least in one area with a traditional trial component, while 26 knees (25.0%) did with a gender-specific trial component (p

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is one of the most effective cancer treatments owing to its ability to selectively kill cancer cells, without affecting normal cells. However, it has been reported that several gastric cancer cells show resistance to TRAIL because of a scarcity of death receptor 5 (DR5) expressed on the cell surface. In this study, we show that cyclopamine sensitizes gastric cancer cells to TRAIL-induced apoptosis by elevating the expression of DR5. Interestingly, survivin hampers the existence of DR5 protein under normal conditions and cyclopamine decreases the expression of survivin, thus acting as a TRAIL sensitizer. Mechanistically, cyclopamine induces endoplasmic reticulum (ER) stress via reactive oxygen species (ROS) and CHOP, the last protein of the ER stress pathway and it regulates the proteasome degradation of survivin. Taken together, our results indicate that cyclopamine can be used for combination therapy in TRAIL-resistant gastric cancer cells.

ABT-263 (navitoclax), a Bcl-2 family protein inhibitor, was clinically tested as an anti-cancer agent. However, the clinical trials were limited given the occurrence of resistance to monotherapy in breast cancer cells. Our study investigates the mechanisms for overcoming navitoclax resistance by combining it with an mTOR inhibitor to indirectly target survivin. The apoptotic effects of navitoclax occurred in MDA-MB-231 breast cancer cells in a time- and dose-dependent fashion, but MCF-7 cells were resistant to navitoclax treatment. The expression of Bcl-2 family genes was not altered by navitoclax, but the expression of survivin, a member of the inhibitors of apoptosis proteins (IAP) family, was downregulated, which increased death signaling in MDA-MB-231 cells. In MCF-7 cells, a navitoclax-resistant cell line, combined treatment with navitoclax and everolimus synergistically reduced survivin expression and induced cell death. These data indicate that navitoclax induces cell death in MDA-MB-231 cells but not in MCF-7 cells. Decreased survivin expression in MDA-MB-231 cells may be a primary pathway for death signaling. Combined navitoclax and everolimus treatment induces cell death by reducing the stability of survivin in MCF-7 cells. Given that survivin-targeted therapy overcomes resistance to navitoclax, this strategy could be used to treat breast cancer patients.

Background Reactive oxygen species modulator-1 (Romo1) is a novel protein that has been reported to be crucial for cancer cell proliferation and invasion. However, its clinical implications in colorectal cancer patients are not well-known. For the first time, we investigated the association between Romo1 and the clinical outcomes of colorectal cancer patients. Study We examined Romo1 expression in resected tumor tissues immunohistochemically and assessed it with histological scores. We conducted survival analyses for patients who had curative resection (n = 190) in accordance with clinical parameters including level of Romo1 expression, and we examined the association between Romo1 expression and cell invasion using Matrigel invasion assay in colorectal cancer cells. Results We observed significantly longer mean disease-free survival in the low Romo1 group compared with the high Romo1 group (161 vs 127.6 months, p = 0.035), and the median overall survival of the low Romo1 group was significantly longer than that of the high Romo1 group (196.9 vs 171.3 months, p = 0.036). Cell invasiveness decreased in the Romo1 knockdown colorectal cancer cells in contrast to the controlled cells. Romo1 overexpression in tumor tissue was associated with a high lymph node ratio between the metastatic and examined lymph nodes (p = 0.025). Conclusions Romo1 overexpression in tumor tissue was significantly associated with survival in curatively resected colorectal cancer patients, suggesting Romo1 expression as a potential adverse prognostic marker. Increased Romo1 expression was found to be associated with high lymph node ratio. Cancer invasiveness appeared to be a key reason for the poor survival related to highly expressed Romo1.

Deregulation of the PI3K-AKT/mTOR pathway due to mutation of the tumor suppressor gene PTEN frequently occurs in human prostate cancer and is therefore considered to be an attractive therapeutic target. Here, we investigated how the PTEN genotype affected the antitumor effect of NVP-BEZ235 in human prostate cancer cells. In this setting, NVP-BEZ235 induced cell death in a PTEN-independent manner. NVP-BEZ235 selectively induced apoptotic cell death in the prostate cancer cell line DU145, which harbors wild-type PTEN; however, in the PC3 cell line, which is PTEN-null, treatment with NVP-BEZ235 resulted in autophagic cell death. Consistently, NVP-BEZ235 treatment did not result in the cleavage of caspase-3; instead, it resulted in the conversion of LC3-I to LC3-II, indicating autophagic cell death; these results suggest that an alternate mechanism of cell death is induced by NVP-BEZ235 in PTEN-null prostate cancer cells. Based on our findings, we conclude that the PTEN/PI3K/Akt pathway is critical for prostate cancer survival, and targeting PI3K signaling by NVP-BEZ235 may be beneficial in the treatment of prostate cancer, independent of the PTEN genotype.

Although proteasome inhibitors (PIs) are used as anticancer drugs to treat various cancers, their relative therapeutic efficacy on stem cells vs. bulk cancers remains unknown. Here, we show that stem cells derived from gliomas, GSCs, are up to 1,000‐fold more sensitive to PIs (IC 50, 27–70 nM) compared with their differentiated controls (IC 50, 47 to »100 μM). The stemness of GSCs correlates to increased ubiquitination, whose misregulation readily triggers apoptosis. PI‐induced apoptosis of GSCs is independent of NF‐κB but involves the phosphorylation of c‐Jun N‐terminal kinase as well as the transcriptional activation of endoplasmic reticulum (ER) stress‐associated proapoptotic mediators. In contrast to the general notion that ER stress‐associated apoptosis is signaled by prolonged unfolded protein response (UPR), GSC‐selective apoptosis is instead counteracted by the UPR. ATF3 is a key mediator in GSC‐selective apoptosis. Pharmaceutical uncoupling of the UPR from its downstream apoptosis sensitizes GSCs to PIs in vitro and during tumorigenesis in mice. Thus, a combinational treatment of a PI with an inhibitor of UPR‐coupled apoptosis may enhance targeting of stem cells in gliomas.