A phase II study of tepotinib in patients with advanced solid cancers harboring MET exon 14 skipping mutations or amplification (KCSG AL19-17).

BACKGROUND: We evaluated the efficacy and safety of tepotinib in patients with various solid cancers harboring MET exon 14 skipping mutation (METex14) or MET gene amplification. PATIENTS AND METHODS: A phase II, multicenter study was conducted in patients with advanced or metastatic solid cancers who progressed after standard treatment, harboring either METex14 or MET amplification detected in tissue-based next-generation sequencing (NGS). The primary endpoint was objective response rate (ORR). For exploratory analyses, we analyzed the gene profiles using plasma NGS test. RESULTS: Thirty-five patients were enrolled. The ORR was 57.6% for all patients, 52.2% for those with METex14, and 70% for those with MET amplification. Median progression-free survival (PFS) was 8 months [95% confidence interval (CI) 4.5-11.5 months] and median overall survival (OS) was 14 months (95% CI 7.8-20.2 months) in all patients. For patients with non-small-cell lung cancer with METex14, the median PFS was 9 months (95% CI 4.7-13.4 months) and the median OS was 17 months [95% CI not applicable (NA)-NA]. For patients with MET amplification, the median PFS was 7 months (95% CI 1.5-12.5 months) and the median OS was 10 months (95% CI 5.8-14.2 months). The ORR of patients with MET dysregulation detected by plasma NGS was 72.2%, whereas the ORR was 30% in those without detection. The most common adverse events were peripheral edema, asthenia, transaminase elevation, and anorexia, mostly grade 1 or 2. CONCLUSIONS: Tepotinib demonstrated consistent antitumor activity in patients with METex14, and promising antitumor activity in various cancers with MET amplification. Detection of MET dysregulation by plasma NGS may predict the response to tepotinib.

Phase II study of a trastuzumab biosimilar in combination with paclitaxel for HER2-positive recurrent or metastatic urothelial carcinoma: KCSG GU18-18.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is a widely explored therapeutic target in solid tumors. We evaluated the efficacy and safety of trastuzumab-pkrb, a biosimilar of trastuzumab, in combination with paclitaxel, in HER2-positive recurrent or metastatic urothelial carcinoma (UC). PATIENTS AND METHODS: We enrolled 27 patients; they were administered a loading dose of 8 mg/kg trastuzumab-pkrb on day 1, followed by 6 mg/kg and 175 mg/m2 paclitaxel on day 1 every 3 weeks, intravenously. All patients received six cycles of the combination treatment and continued to receive trastuzumab-pkrb maintenance until disease progression, unacceptable toxicity, or for up to 2 years. HER2 positivity (based on immunohistochemistry analysis) was determined according to the 2013 American Society of Clinical Oncology /College of American Pathologists HER2 testing guidelines. The primary endpoint was objective response rate (ORR); the secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. RESULTS: Twenty-six patients were evaluated via primary endpoint analysis. The ORR was 48.1% (1 complete and 12 partial responses) and the duration of response was 6.9 months [95% confidence interval (CI) 4.4-9.3 months]. With a median follow-up of 10.5 months, the median PFS and OS were 8.4 months (95% CI 6.2-8.8 months) and 13.5 months (95% CI 9.8 months-not reached), respectively. The most common treatment-related adverse event (TRAE) of any grade was peripheral neuropathy (88.9%). The most common grade 3/4 TRAEs were neutropenia (25.9%), thrombocytopenia (7.4%), and anemia (7.4%). CONCLUSIONS: Trastuzumab-pkrb plus paclitaxel demonstrates promising efficacy with manageable toxicity profiles in patients with HER2-positive recurrent or metastatic UC.

Liposomal irinotecan plus fluorouracil/leucovorin versus FOLFIRINOX as the second-line chemotherapy for patients with metastatic pancreatic cancer: a multicenter retrospective study of the Korean Cancer Study Group (KCSG).

BACKGROUND: There is no clear consensus on the recommended second-line treatment for patients with metastatic pancreatic cancer who have disease progression following gemcitabine-based therapy. We retrospectively evaluated the clinical outcomes of liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (FL) and FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) in patients who had failed on the first-line gemcitabine-based therapy. PATIENTS AND METHODS: From January 2015 to August 2019, 378 patients with MPC who had received nal-IRI/FL (n = 104) or FOLFIRINOX (n = 274) as second-line treatment across 11 institutions were included in this retrospective study. RESULTS: There were no significant differences in baseline characteristics between groups, except age and first-line regimens. With a median follow-up of 6 months, the median progression-free survival (PFS) was 3.7 months with nal-IRI/FL versus 4.6 months with FOLFIRINOX (P = 0.44). Median overall survival (OS) was 7.7 months with nal-IRI/FL versus 9.7 months with FOLFRINOX (P = 0.13). There was no significant difference in PFS and OS between the two regimens in the univariate and multivariate analyses. The subgroup analysis revealed that younger age (<70 years) was associated with better OS with FOLFIRINOX. In contrast, older age (≥70 years) was associated with better survival outcomes with nal-IRI/FL. Adverse events were manageable with both regimens; however, the incidence of grade 3 or higher neutropenia and peripheral neuropathy was higher in patients treated with FOLFIRINOX than with nal-IRI/FL. CONCLUSIONS: Second-line nal-IRI/FL and FOLFIRINOX showed similar effectiveness outcomes after progression following first-line gemcitabine-based therapy. Age could be the determining factor for choosing the appropriate second-line therapy.

Lysyl oxidase-mediated VEGF-induced differentiation and angiogenesis in human dental pulp cells.

AIM: To investigate the effects of recombinant human vascular endothelial growth factor (rhVEGF) on odontoblastic differentiation, in vitro angiogenesis, and expression and activity of lysyl oxidase (LOX) in human dental pulp cells (HDPCs), compared with rhFGF-2. To identify the underlying molecular mechanisms, the study focused on whether LOX was responsible for the actions of rhVEGF. METHODOLOGY: Recombinant human vascular endothelial growth factor (rhVEGF) was constructed using the pBAD-HisA plasmid in Escherichia coli. HDPCs were treated with 1-50 µg mL-1 rhVEGF for 14 days. Alkaline phosphatase (ALP) activity was measured, and the formation of calcified nodules was assessed using alizarin red staining after the induction of odontogenic differentiation of HDPCs. The expression level of the odontogenic differentiation markers was detected by reverse transcription polymerase chain reaction. Signal pathways were assessed by Western blot and immunocytochemistry. The data were analysed by anova with Bonferroni's test (α = 0.05). RESULTS: Recombinant human vascular endothelial growth factor significantly increased cell growth (P < 0.05), ALP activity (P < 0.05) and mineralization nodule formation and upregulated the mRNA expression levels of the osteogenic/odontogenic markers that were lower with rhFGF-2. rhVEGF significantly increased amine oxidase activity (P < 0.05) and upregulated LOX and LOXL mRNA expression in HDPCs. Additionally, rhVEGF dose-dependently upregulated angiogenic gene mRNAs and capillary tube formation to a greater degree than rhFGF-2. Inhibition of LOX using ß-aminopropionitrile (BAPN) and LOX or LOXL gene silencing by RNA interference attenuated rhVEGF-induced growth, ALP activity, mineralization, the expression of marker mRNAs and in vitro angiogenesis. Furthermore, treatment with rhVEGF resulted in phosphorylation of Akt, ERK, JNK and p38, and activation of NF-κB, which was inhibited by LOX or LOXL silencing and BAPN. CONCLUSION: Recombinant human vascular endothelial growth factor promoted cell growth, odontogenic potential and in vitro angiogenesis via modulation of LOX expression. These results support the concept that rhVEGF may offer therapeutic benefits in regenerative endodontics.

Ureteral Complications in Kidney Transplantation: Analysis and Management of 853 Consecutive Laparoscopic Living-Donor Nephrectomies in a Single Center.

BACKGROUND: We report the incidence and nature of ureteral and surgical complications in our series of 853 consecutive living-donor renal transplants after laparoscopic living-donor nephrectomy. The aim of this study was to analyze the therapeutic approaches to ureteral complications in kidney transplantations and their relationship with recipient outcome. METHODS: The medical records of patients who underwent kidney transplantation from 2000 to 2014 were reviewed retrospectively. After the donor nephrectomies were performed with the use of laparoscopic, hand-assisted laparoscopic, and vesico-ureteral anastomosis, the recipient's ureteral complications were classified according to the mechanism and site of urinary tract involvement: anastomosis stricture, anastomosis leakage, vesico-ureteral reflux, and urolithiasis. RESULTS: Among the 853 cases of kidney transplantation, ureteral complications occurred in 66 patients (7.73%). The most common complication was urinary tract infection caused by vesico-ureteral reflux (n = 24, 2.81%), which was managed with by means of sub-ureteral polydimethylsiloxane injection. The second most common complication was the anastomosis site stricture (n = 23, 2.69%), which was treated by means of ureteral re-implantation or percutaneous nephrostomy. Anastomosis site leakage occurred in 11 patients (1.28%) and was managed by percutaneous nephrostomy with double-J stenting and drainage or ureteral re-implantation. Urolithiasis occurred in 8 patients (0.93%). CONCLUSIONS: There was an 8% rate of recipient ureteral complications at our institution. Of the 66 patients, 46 (5.4%) required surgical repair. The remaining 20 patients with ureteral complications were treated with conservative care or minimally invasive procedures. The keys to successful management of these problems are early diagnosis and prompt reconstruction whenever possible. Most ureteral complications are easily managed with a successful outcome with early intervention.

PIN1 Suppresses the Hepatic Differentiation of Pulp Stem Cells via Wnt3a.

This study aimed to investigate the role of PIN1 on the hepatic differentiation of human dental pulp stem cells (hDPSCs) and its signaling pathway, as well as the potential therapeutic effects of hDPSC transplantation and PIN1 inhibition on CCl4 (carbon tetrachloride)-induced liver fibrosis in mice. The in vitro results showed that hepatic differentiation was suppressed by infection with adenovirus-PIN1 and promoted by PIN1 inhibitor juglone via the downregulation of Wnt3a and ß-catenin. Compared with treatment with either hDPSC transplantation or juglone alone, the combination of hDPSCs and juglone into CCl4-injured mice significantly suppressed liver fibrosis and restored serum levels of alanine transaminase, aspartate transaminase, and ammonia. Collectively, the present study shows for the first time that PIN1 inhibition promotes hepatic differentiation of hDPSCs through the Wnt/ß-catenin pathway. Furthermore, juglone in combination with hDPSC transplantation effectively treats liver fibrosis, suggesting that hDPSC transplantation with PIN1 inhibition may be a novel therapeutic candidate for the treatment of liver injury.

Anti-inflammatory and anti-osteoclastogenic effects of zinc finger protein A20 overexpression in human periodontal ligament cells.

BACKGROUND AND OBJECTIVE: Although overexpression of the nuclear factor κB inhibitory and ubiquitin-editing enzyme A20 is thought to be involved in the pathogenesis of inflammatory diseases, its function in periodontal disease remains unknown. The aims of the present study were to evaluate A20 expression in patients with periodontitis and to study the effects of A20 overexpression, using a recombinant adenovirus encoding A20 (Ad-A20), on the inflammatory response and on osteoclastic differentiation in lipopolysaccharide (LPS)- and nicotine-stimulated human periodontal ligament cells (hPDLCs). MATERIAL AND METHODS: The concentration of prostaglandin E2 was measured by radioimmunoassay. Reverse transcription-polymerase chain reactions and western blot analyses were used to measure mRNA and protein levels, respectively. Osteoclastic differentiation was assessed in mouse bone marrow-derived macrophages using conditioned medium from LPS- and nicotine-treated hPDLCs. RESULTS: A20 was upregulated in the gingival tissues and neutrophils from patients with periodontitis and in LPS- and nicotine-exposed hPDLCs. Pretreatment with A20 overexpression by Ad-A20 markedly attenuated LPS- and nicotine-induced production of prostaglandin E2 , as well as expression of cyclooxygenase-2 and proinflammatory cytokines. Moreover, A20 overexpression inhibited the number and size of tartrate-resistant acid phosphatase-stained osteoclasts, and downregulated osteoclast-specific gene expression. LPS- and nicotine-induced p38 phosphorylation and nuclear factor κB activation were blocked by Ad-A20. Ad-A20 inhibited the effects of nicotine and LPS on the activation of pan-protein kinase C, Akt, GSK-3ß and protein kinase Cα. CONCLUSIONS: This study is the first to demonstrate that A20 overexpression has anti-inflammatory effects and blocks osteoclastic differentiation in a nicotine- and LPS-stimulated hPDLC model. Thus, A20 overexpression may be a potential therapeutic target in inflammatory bone loss diseases, such as periodontal disease.

UTE bi-component analysis of T2* relaxation in articular cartilage.

OBJECTIVES: To determine T2* relaxation in articular cartilage using ultrashort echo time (UTE) imaging and bi-component analysis, with an emphasis on the deep radial and calcified cartilage. METHODS: Ten patellar samples were imaged using two-dimensional (2D) UTE and Car-Purcell-Meiboom-Gill (CPMG) sequences. UTE images were fitted with a bi-component model to calculate T2* and relative fractions. CPMG images were fitted with a single-component model to calculate T2. The high signal line above the subchondral bone was regarded as the deep radial and calcified cartilage. Depth and orientation dependence of T2*, fraction and T2 were analyzed with histopathology and polarized light microscopy (PLM), confirming normal regions of articular cartilage. An interleaved multi-echo UTE acquisition scheme was proposed for in vivo applications (n = 5). RESULTS: The short T2* values remained relatively constant across the cartilage depth while the long T2* values and long T2* fractions tended to increase from subchondral bone to the superficial cartilage. Long T2*s and T2s showed significant magic angle effect for all layers of cartilage from the medial to lateral facets, while the short T2* values and T2* fractions are insensitive to the magic angle effect. The deep radial and calcified cartilage showed a mean short T2* of 0.80 ± 0.05 ms and short T2* fraction of 39.93 ± 3.05% in vitro, and a mean short T2* of 0.93 ± 0.58 ms and short T2* fraction of 35.03 ± 4.09% in vivo. CONCLUSION: UTE bi-component analysis can characterize the short and long T2* values and fractions across the cartilage depth, including the deep radial and calcified cartilage. The short T2* values and T2* fractions are magic angle insensitive.

PIN1 inhibition suppresses osteoclast differentiation and inflammatory responses.

Inflammatory responses and osteoclast differentiation play pivotal roles in the pathogenesis of osteolytic bone diseases such as periodontitis. Although overexpression or inhibition of peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1) offers a possible therapeutic strategy for chronic inflammatory diseases, the role of PIN1 in periodontal disease is unclear. The aim of the present study was to evaluate PIN1 expression in periodontitis patients as well as the effects of PIN1 inhibition by juglone or PIN1 small-interfering RNA (siRNA) and of PIN1 overexpression using a recombinant adenovirus encoding PIN1 (Ad-PIN1) on the inflammatory response and osteoclastic differentiation in lipopolysaccharide (LPS)- and nicotine-stimulated human periodontal ligament cells (PDLCs). PIN1 was up-regulated in chronically inflamed PDLCs from periodontitis patients and in LPS- and nicotine-exposed PDLCs. Inhibition of PIN1 by juglone or knockdown of PIN1 gene expression by siRNA markedly attenuated LPS- and nicotine-stimulated prostaglandin E2 (PGE2) and nitric oxide (NO) production, as well as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, whereas PIN1 overexpression by Ad-PIN1 increased it. LPS- and nicotine-induced nuclear factor (NF)-κB activation was blocked by juglone and PIN1 siRNA but increased by Ad-PIN1. Conditioned medium prepared from LPS- and nicotine-treated PDLCs increased the number of tartrate-resistant acid phosphatase-stained osteoclasts and osteoclast-specific gene expression. These responses were blocked by PIN1 inhibition and silencing but stimulated by Ad-PIN1. Furthermore, juglone and PIN1 siRNA inhibited LPS- and nicotine-induced osteoclastogenic cytokine expression in PDLCs. This study is the first to demonstrate that PIN1 inhibition exhibits anti-inflammatory effects and blocks osteoclastic differentiation in LPS- and nicotine-treated PDLCs. PIN1 inhibition may be a therapeutic strategy for inflammatory osteolysis in periodontal disease.

Oct4 is a critical regulator of stemness in head and neck squamous carcinoma cells.

Cancer stem cells (CSCs) have been suggested as responsible for the initiation and progression of cancers. Octamer-binding transcription factor 4 (Oct4) is an important regulator of embryonic stem cell fate. Here, we investigated whether Oct4 regulates stemness of head and neck squamous carcinoma (HNSC) CSCs. Our study showed that ectopic expression of Oct4 promotes tumor growth through cyclin E activation, increases chemoresistance through ABCC6 expression and enhances tumor invasion through slug expression. Also, Oct4 dedifferentiates differentiated HNSC cells to CSC-like cells. Furthermore, Oct4(high) HNSC CSCs have more stem cell-like traits compared with Oct4(low) cells, such as self-renewal, stem cell markers' expression, chemoresistance, invasion capacity and xenograft tumorigeneity in vitro and in vivo. In addition, knockdown of Oct4 led to markedly lower HNSC CSC stemness. Finally, there was a significant correlation between Oct4 expression and survival of 119 HNSC patients. Collectively, these data suggest that Oct4 may be a critical regulator of HNSC CSCs and its targeting may be potentially valuable in the treatment of HNSC CSCs.

SOX2 regulates self-renewal and tumorigenicity of stem-like cells of head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) display cellular heterogeneity and contain cancer stem cells (CSCs). Sex-determining region Y [SRY]-box (SOX)2 is an important regulator of embryonic stem cell fate and is aberrantly expressed in several types of human tumours. Nonetheless, the role of SOX2 in HNSCC remains unclear. METHODS: We created cells ectopically expressing SOX2 from previously established HNSCC cells and examined the cell proliferation, self-renewal capacity, and chemoresistance of these cells compared with control cells. In addition, we knocked down SOX2 in primary spheres obtained from HNSCC tumour tissue and assessed the attenuation of stemness-associated traits in these cells in vitro and in vivo. Furthermore, we examined the clinical relevance of SOX2 expression in HNSCC patients. RESULTS: SOX2 is aberrantly expressed in primary tissue of HNSCC patients but not in healthy tissue. SOX2 expression correlated with tumour recurrence and poor prognosis of HNSCC patients. Ectopic expression of SOX2 induced cell proliferation via cyclin B1 expression and stemness-associated features, such as self-renewal and chemoresistance. In addition, a knockdown of SOX2 in HNSCC CSCs attenuated their self-renewal capacity, chemoresistance (through ABCG2 suppression), invasion capacity (via snail downregulation), and in vivo tumorigenicity. CONCLUSIONS: These results suggest that SOX2 may have important roles in the 'stemness' and progression of HNSCC. Targeting SOX2-positive tumour cells (CSCs) could be a new therapeutic strategy in HNSCCs.

Replication of results of genome-wide association studies on esophageal squamous cell carcinoma susceptibility loci in a Korean population.

Two recent genome-wide association studies have identified that the rs2274223 single-nucleotide polymorphism inphospholipase C epsilon 1 and the single-nucleotide polymorphism rs13042395 in C20orf54 are involved in esophageal squamous cell carcinoma (ESCC) in Chinese populations. We hypothesized that genetic polymorphisms of phospholipase C epsilon 1 and C20orf54 are also associated with ESCC in a Korean population. The rs2274223 and rs13042395 genotyping was performed using high-resolution melting analysis. The rs2274223 GG genotype was significantly associated with an increased risk of ESCC (odds ratio [OR]=1.86, 95% confidence interval [CI]=1.08-3.25) compared with the rs2274223 AA genotype. The rs13042395 G allele showed a significantly decreased risk of ESCC in the younger age group (OR=0.71, 95% CI=0.52-0.97) and no significant association in the older group (OR=1.19, 95% CI=0.87-1.62). We observed that the rs2274223 polymorphism was associated with an increased risk of ESCC in this Korean case-control study and that age may modify the association between the rs13042395 polymorphism and the risk of ESCC.

Nicotine and lipopolysaccharide stimulate the production of MMPs and prostaglandin E2 by hypoxia-inducible factor-1α up-regulation in human periodontal ligament cells.

BACKGROUND AND OBJECTIVE: Although hypoxia-inducible factor 1α (HIF-1α) is up-regulated in the periodontal pockets of periodontitis patients, the expression and precise molecular mechanisms of HIF-1α remain unknown in human periodontal ligament cells (PDLCs). The aim of this study was to explore the effects, as well as the signaling pathway, of nicotine and lipopolysaccharide (LPS) on the expression of HIF-1α and on the production of its target genes, including cyclooxygenase-2 (COX-2)-derived prostaglandin E(2) (PGE(2) ), MMP-2 and MMP-9 in PDLCs. MATERIAL AND METHODS: The expression of COX-2 and HIF-1α proteins was evaluated using western blotting. The production of PGE(2) and MMPs was evaluated using enzyme immunoassays and zymography, respectively. RESULTS: LPS and nicotine synergistically induced the production of PGE(2) , MMP-2 and MMP-9, and increased the expression of MMP-2, MMP-9, COX-2 and HIF-1α proteins. Inhibition of HIF-1α activity by chetomin or knockdown of HIF1α gene expression by small interfering RNA markedly attenuated the production of LPS- and nicotine-stimulated PGE(2) and MMPs, as well as the expression of COX-2 and HIF-1α. Furthermore, pretreatment with inhibitors of COX-2, p38, extracellular signal-regulated kinase, Jun N-terminal kinase, protein kinase C, phosphatidylinositol 3-kinase and nuclear factor-kappaB decreased the expression of nicotine- and LPS-induced HIF-1α and COX-2, as well as the activity of PGE(2) and MMPs. CONCLUSION: These data demonstrate novel mechanisms by which nicotine and LPS promote periodontal tissue destruction, and provide further evidence that HIF-1α is a potential target in periodontal disease associated with smoking and dental plaque.

Heme oxygenase-1 protects human periodontal ligament cells against substance P-induced RANKL expression.

BACKGROUND AND OBJECTIVE: Although substance P (SP) stimulates bone resorption activity and this is reported to be correlated with the degree of periodontal inflammation, it is unclear how human periodontal ligament cells regulate neuropeptide-induced osteoclastogenesis or the possible involvement of heme oxygenase-1 (HO-1) might be. This study examines how SP affects osteoprotegerin (OPG) and RANKL expression via HO-1. MATERIAL AND METHODS: Using immortalized human periodontal ligament cells, the effects of SP on the expression of HO-1, RANKL and OPG mRNA and proteins were determined by RT-PCR and western blotting, respectively. Various concentrations of SP (10(-7), 10(-8), 10(-9) and 10(-10) m) were added to the medium, and the cells were treated for 0, 0.25, 0.5, 1, 2 and 3 d. RESULTS: Substance P upregulated RANKL and HO-1 and downregulated OPG mRNA and protein expression in periodontal ligament cells, in a concentration- and time-dependent manner. A HO-1 inducer inhibited both the upregulation of RANKL expression and downregulation of OPG expression by SP in periodontal ligament cells. By contrast, treatment with a HO-1 inhibitor or HO-1 small interferring RNA (siRNA) enhanced SP-stimulated RANKL expression. Inhibitors of ERK and p38 MAP kinases, phosphoinositide 3-kinase and nuclear factor-kappaB blocked the effects of SP on RANKL expression in periodontal ligament cells. CONCLUSION: These results suggest that SP stimulates osteoclastic differentiation by increasing the expression of RANKL vs. OPG via the HO-1 pathway in periodontal ligament cells. The HO-1 pathway may be an effective therapeutic target for inhibiting chronic periodontitis involving alveolar bone resorption.

Effects of antioxidant supplements on cancer prevention: meta-analysis of randomized controlled trials.

BACKGROUND: This meta-analysis aimed to investigate the effect of antioxidant supplements on the primary and secondary prevention of cancer as reported by randomized controlled trials. METHODS: We searched Medline (PubMed), Excerpta Medica database, and the Cochrane Review in October 2007. RESULTS: Among 3327 articles searched, 31 articles on 22 randomized controlled trials, which included 161 045 total subjects, 88 610 in antioxidant supplement groups and 72 435 in placebo or no-intervention groups, were included in the final analyses. In a fixed-effects meta-analysis of all 22 trials, antioxidant supplements were found to have no preventive effect on cancer [relative risk (RR) 0.99; 95% confidence interval (CI) 0.96-1.03). Similar findings were observed in 12 studies on primary prevention trials (RR 1.00; 95% CI 0.97-1.04) and in nine studies on secondary prevention trials (RR 0.97; 95% CI 0.83-1.13). Further, subgroup analyses revealed no preventive effect on cancer according to type of antioxidant, type of cancer, or the methodological quality of the studies. On the other hand, the use of antioxidant supplements significantly increased the risk of bladder cancer (RR 1.52; 95% CI 1.06-2.17) in a subgroup meta-analysis of four trials. CONCLUSIONS: The meta-analysis of randomized controlled trials indicated that there is no clinical evidence to support an overall primary and secondary preventive effect of antioxidant supplements on cancer. The effects of antioxidant supplements on human health, particularly in relation to cancer, should not be overemphasized because the use of those might be harmful for some cancer.

N(1)-guanyl-1,7,-diamineoheptane, an inhibitor of deoxyhypusine synthase, suppresses differentiation and induces apoptosis via mitochondrial and AMPK pathways in immortalized and malignant human oral keratinocytes.

BACKGROUND: Although N(1)-guanyl-1,7,-diamineoheptane (GC7), an inhibitor of deoxyhypusine synthase, has been shown to inhibit cell growth, the mechanism of its action is not completely understood. In this study, we investigated the mechanisms of the effects of GC7 on cell growth, differentiation and apoptosis in relation to adenosine monophosphate-activated protein kinase (AMPK) activation, as AMPK is known to be a possible target for cancer treatment. METHODS: The effects of GC7 on the growth of immortalized human oral keratinocytes (IHOK) and primary oral cancer cells (HN4), was investigated using MTT assay, Western blotting, cell cycle analysis, DNA fragmentation and expression of apoptotic pathway proteins. RESULTS: N(1)-guanyl-1,7,-diamineoheptane inhibited cell proliferation in a time- and dose-dependent manner in IHOK and HN4 cells. GC7 treatment decreased the expression of differentiation markers, such as involucrin, CK13 and CK19. The major mechanism of growth inhibition by GC7 treatment was induction of apoptosis, which is supported by sub-G(1) phase arrest, annexin V-FITC staining and DNA fragmentation analysis. GC7 treatment increased the cytosolic level of cytochrome c and resulted in caspase-3 activation. GC7 treatment also resulted in a strong activation of AMPK. Furthermore, specific AMPK activator blocked the GC7-induced growth inhibition effect, as well as apoptosis. CONCLUSION: These results demonstrate that GC7 blocks immortalized and malignant keratinocyte cell proliferation and differentiation by inducing apoptosis through the mitochondrial and AMPK pathways. On the basis of these observations, we propose that a strategy combining GC7 and AMPK inhibition could be developed into a novel chemotherapeutic modality in oral cancer.

Indentation probing of human articular cartilage: Effect on chondrocyte viability.

BACKGROUND: Clinical arthroscopic probes based on indentation testing are being developed. However, the biological effects of certain design parameters (i.e., tip geometry and size) and loading protocols (i.e., indentation depth, rate, and repetition) on human articular cartilage are unclear. OBJECTIVE: Determine if indenter design and indentation protocol modulate mechanical injury of probed cartilage samples. METHODS: The objectives of this study were to determine the effects of indentation testing using clinically applicable tips (0.4mm radius, plane- or sphere-ended) and protocols (indentation depths of 100, 200, or 300 microm, applied at a rate of 50 or 500 microm/s) on the extent and the pattern of chondrocyte death, should it occur. Grossly normal osteochondral blocks were harvested from human talar dome, indented, stained with live/dead dyes, and imaged en face on a fluorescence microscope. RESULTS: The occurrence and the extent of cell death generally increased with indentation depth, being undetected at an indentation depth of 100 microm but marked at 300 microm. In addition, tip geometry affected the pattern of cell death: ring- and solid circle-shaped areas of cell deaths were apparent when compressed to 300 microm using plane- and sphere-ended indenters. CONCLUSION: Indenter design and indentation protocol modulated the extent and the pattern of chondrocyte death. These results have implications for designing indentation probes and protocols, as well as clinicians performing arthroscopic probing.

Schwannoma of the breast showing massive exophytic growth: a case report.

Schwannoma is a slow-growing tumor that frequently occurs in the extremities, the trunk and the head region. Its occurrence in the breast is rare with only a few cases being reported. We present here the case of breast schwannoma in a 41-year-old woman who presented with a palpable mass in her right breast. This is the first report of breast schwannoma that showed massive exophytic growth with invasion of the skin, and it was initially presumed to be a breast cancer on preoperative mammography, ultrasonography and breast MRI examinations. Complete excision of the mass was done and pathology revealed a plexiform schwannoma.

Pancreatic carcinoid tumor with obstructive pancreatitis: multislice helical CT appearance: case report.

Carcinoid tumor of the pancreas is rare. Moreover, obstructive pancreatitis secondary to a pancreatic carcinoid tumor is extremely rare. We report a case of pancreatic carcinoid tumor in a 50-year-old male who presented with pancreatitis. On multislice helical computed tomography, the main pancreatic duct was obstructed by a small round tumor, and the main pancreatic duct proximal to the tumor was dilated. The correlation between the main pancreatic duct and the tumor was well depicted on minimum intensity projection image. This is the first report of multislice helical computed tomorgraphic and minimum intensity projection image findings of a pancreatic carcinoid tumor presenting with pancreatitis.