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Evidence has shown that interleukin-18 (IL-18) has both antitumor and pro-tumor effects in various types of leukemia. The current study aimed at investigating the contribution of IL-18 polymorphisms to the risk of childhood acute lymphocytic leukemia (ALL) in Taiwan.IL-18 promoter -656 (rs1946519), -607 (rs1946518), and -137 (rs187238) genotypes of 266 childhood ALL cases and 266 controls were determined by polymerase chain reaction-restriction fragment length polymorphism methodology.The distributions of genotypic and allelic frequencies of IL-18 rs1946519, rs1946518 or rs187238, were not significantly different between childhood ALL cases and controls (all p0.05). However, in the stratification analysis among the cases, IL-18 rs187238 GC and CC genotypes were associated with increased childhood ALL risk and shorter survival (OR=4.19 and 2.93, 95%CI=2.04-8.64 and 1.19-7.23, p=0.0001 and 0.0250, respectively). No association was found with rs1946519 and rs1946518 (all p0.05).IL-18 rs187238 GC and CC genotypes can serve as predictors for childhood ALL prognosis among Taiwanese. Validation in larger and various populations can greatly extend the feasibility of this novel predictor.

Sleep disorder (SD), especially sleep apnea, and its effect on atrial fibrillation (AF) are gathering attention. However, other SDs may also play an essential role in AF. The aim of the study is to investigate the effects of other SDs on the risk of atrial fibrillation development.This study investigated the risk of AF in people diagnosed with SD compared with that in age and sex-matched unaffected individuals. This longitudinal, nationwide, population-based cohort study was conducted using data from the Taiwan National Health Insurance Research Database (NHIRD) of individuals diagnosed with SD from January 1, 2001, to December 31, 2012.The sample consisted of 193,288 people with the SD, which include of 4406 people with sleep apnea, 73,704 people with insomnia, 107,395 people with sleep disturbance, 7,783 people with other SD, and 193,288 matched controls. A Cox proportional hazard regression was used to compute the risk of AF in people with SD and subgroup of SD, relative to that in people without SD. The AF incidences were 1.21-fold higher (95% CI 1.15-1.27) in the SD cohort, 1.19-fold higher (95% CI 0.91-1.56) in the sleep apnea cohort, 1.26-fold higher (95% CI 1.19-1.34) in the insomnia cohort, 1.15-fold higher (95% CI 1.08-1.22) in the sleep disturbance cohort, and 1.30-fold higher (95% CI 1.11-1.53) in other SDs, than in the control cohort, after age, sex, and comorbidities were adjusted.This nationwide population-based cohort study indicates a strong relationship between SD and incident AF, and insomnia has a higher impact on AF compared with other SD.

Additional file 1: Supplementary Table S1. ICD-10 codes used to assess HFRS. Supplementary Table S2. ICD-10 codes used to identify CML, comorbidities and treatments. Supplementary Table S3. ICD-10 codes used to define CCI. Supplementary Table S4. Quartile ranges of household income (USD).

Background: The effects of Nerve growth factor (NGF) in chondrosarcoma are not confirmed, although NGF is capable of promoting the progression and metastasis of several different types of tumors. Here we aim to explore the role of NGF in chondrosarcoma and elucidate how NGF acts.Methods: Immunohistochemistry (IHC)-stained tissue samples from chondrosarcoma patients were stained with NGF and LOX antibodies. Cell migration was examined by Transwell migration and invasion assays. The expression levels of LOX, microRNA-149-5p (miR-149-5p) were measured by quantitative real-time polymerase chain reaction. LOX, PI3K, Akt, and mTOR protein expression were examined by Western blot assays. The interaction between LOX 3’-UTRs and miR-149-5p binding site was explored by luciferase assay. We established the orthotopic in vivo model of chondrosarcoma lung metastasis to further investigate the promoting effects of NGF in metastatic chondrosarcoma. Results: Here, we found that the levels of NGF and lysyl oxidase (LOX) correlated with tumor stage in patients with chondrosarcoma. NGF facilitated LOX-dependent cellular migration in human chondrosarcoma JJ012 cells, while overexpression of NGF enhanced lung metastasis in a mouse model of chondrosarcoma. NGF promoted LOX synthesis and cell migration by inhibiting miR-149-5p expression through the PI3K, Akt and mTOR signaling cascades. NGF appears to be a worthwhile therapeutic target in the treatment of metastatic chondrosarcoma.Conclusions: Our study has identified that NGF promotes LOX-dependent cell migration in human chondrosarcoma tissue by inhibiting miR-149-5p synthesis via the PI3K, Akt and mTOR signaling cascades

Since patients with acute myeloid leukemia (AML) in the real world have a much different clinical picture than patients recruited in the clinical trials, obtaining real-world evidence of medication adoption is important for therapeutic efficiency and safety. This study used three population-based data in Taiwan, the National Health Insurance Research Database, Taiwan Cancer Registry, and National Death Registry, between 2001 and 2015, to investigate the effect of conventional chemotherapy (CCT) versus non-conventional chemotherapy (NCCT) on the overall survival (OS) of patients with AML (n = 7,763). Cox proportional hazard regression was used to estimate the hazard ratios (HR) of different treatments on the risk of mortality. To reduce the potential selection bias, we used the inverse probability of treatment weighting based on the propensity score to balance the baseline characteristics between patients receiving CCT and NCCT. The median survival time for CCT and NCCT arms was 10.2 months (95% confidence interval (95% CI): 9.7-10.9) and 4.1 months (95% CI: 3.8-4.5), respectively. Compared to the patients received NCCT, those receiving CCT had a lower risk of mortality (HR 0.63 (95% CI: 0.59-0.67, P

Huey-En Tzeng,1– 3 Chih-Hsin Tang,4– 7 Chun-Hao Tsai,8 Chih-Hui Chiu,9 Min-Huan Wu,10,11 Yun Yen12,13 1Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan; 2PhD Program & Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; 3Division of Hematology/Oncology, Department of Medicine, Taipei Medical University Hospital, Taipei, Taiwan; 4Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; 5School of Medicine, China Medical University, Taichung, Taiwan; 6Chinese Medicine Research Center, China Medical University, Taichung, Taiwan; 7Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan; 8Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan; 9Graduate Program in Department of Exercise Health Science, National Taiwan University of Sport, Taichung, Taiwan; 10Sports Recreation and Health Management Continuing Studies, Tunghai University, Taichung, Taiwan; 11Bachelor of Science in Senior Wellness and Sport Science, Tunghai University, Taichung, Taiwan; 12TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; 13Graduate Institute of Medical Informatics, Taipei Medical University, Taipei, TaiwanCorrespondence: Min-Huan Wu Tel +886 4-23590121 Ext. 30703Email mhwu@thu.edu.twYun Yen Email yyen@tmu.edu.twObjective: Oral squamous cell carcinoma (OSCC) constitutes almost 90% of head and neck malignancies and has a poor prognosis. To improve the efficacy of OSCC therapy, it is of great significance to explore other therapy for OSCC. Endothelin-1 (ET-1), a potent vasoconstrictor peptide, is implicated in cancer pathogenesis. Moreover, ET-1 promotes epithelial-mesenchymal transition (EMT) during the development of human cancers. We further to found that ET-1 exposure induced EMT in human squamous cell carcinoma cell lines SCC4 and SAS, by enhancing the expression of EMT biomarkers N-cadherin and vimentin and reducing E-cadherin expression via upregulation of the transcription factor TWIST.Materials and Methods: Cell motility was examined by migration, invasion and wound-healing assays. Quantitative real time polymerase chain reaction (q-PCR), and promoter assays confirmed the inhibitory effects of ET-1 on miRNAs expression in oral cancer cells. We demonstrate an intravenous injection model of lung metastasis followed by an advanced method for quantifying metastatic tumor using image analysis software.Results: In addition, ET-1/ETAR reduced levels of microRNA-489-3p (miR-489-3p), a transcriptional repressor of TWIST. We have identified a novel bypass mechanism through which ET-1/ETAR are involved in TWIST signaling and downregulate miR-489-3p expression, enabling OSCC cells to acquire the EMT phenotype. Notably, ET-1 knockdown dramatically decreased levels of EMT markers and cell migration potential.Conclusion: The role of ET-1 in OSCC progression is supported by our findings from an in vivo murine model of OSCC. ET-1 may therefore represent a novel molecular therapeutic target in OSCC metastasis.Keywords: oral squamous cell carcinoma, endothelin-1, TWIST, microRNA-489-3p, epithelial–mesenchymal transition

Oral squamous cell carcinoma (OSCC) is an extremely common head and neck cancer with a poor 5-year survival rate, especially in cases of metastatic disease. Interleukin (IL)-11 reportedly promotes cell growth and the epithelial-mesenchymal transition process in metastasis. However, the molecular mechanisms of IL-11 in OSCC metastasis are unclear. This study found that IL-11 upregulates matrix metalloproteinase 13 (MMP-13) expression in OSCC via the IL-11 receptor alpha subunit/glycoprotein 130 receptors that activate phosphatidyl-inositol 3-kinase, Ak strain transforming, and activator protein 1 signaling, which subsequently enhance MMP-13-induced tumor metastasis. TIMER2.0 analysis revealed a positive correlation between MMP-13 and IL-11 levels (r = 0.454). Moreover, a strong positive association was observed between higher levels of IL-11 expression in OSCC tissue (p 0.01), lymph node metastasis (p = 0.0154), and clinical disease stage (p = 0.0337). IL-11 knockdown suppressed the migration of OSCC cells (p 0.05). The evidence indicates that IL-11 can serve as a new molecular therapeutic target in OSCC metastasis.

The adipokine resistin is linked with obesity, inflammation and various cancers, including breast cancer. This study sought to determine whether certain polymorphisms in the gene encoding resistin, RETN, increase the risk of breast cancer susceptibility. We analyzed levels of resistin expression in breast cancer tissue and samples from The Cancer Genome Atlas database. We also examined associations between four RETN single nucleotide polymorphisms (SNPs; rs3745367, rs7408174, rs1862513 and rs3219175) and breast cancer susceptibility in 515 patients with breast cancer and 541 healthy women without cancer. Compared with wild-type (GG) carriers, those carrying the AG genotype of the RETN SNP rs3219175 and those carrying at least one A allele in the SNP rs3219175 had a higher chance of developing breast cancer (adjusted odds ratio, AOR: 1.295, 95% confidence intervals, CI: 1.065-1.575 and 2.202, 1.701-2.243, respectively). When clinical aspects and the RETN SNP rs7408174 were examined in the breast cancer cohort, the CT genotype was linked to late-stage disease, while women with luminal A disease and at least one C allele were likely to progress to stage III/IV disease and to develop highly pathological grade III disease. Moreover, resistin-positive individuals were at greater risk than resistin-negative individuals for developing pathological grade III disease (OR: 5.020; 95% CI: 1.380-18.259). This study details risk associations between resistin and RETN SNPs in breast cancer susceptibility in Chinese Han women.

BACKGROUND/AIM Matrix metalloproteinase-9 (MMP-9) is responsible for modifying extracellular components and plays a crucial role in the metastatic behavior of cancer. This study aimed at examining the role of MMP-9 rs3918242 genotypes on colorectal cancer (CRC) risk. MATERIALS AND METHODS A total of 362 CRC patients and 362 healthy subjects in Taiwan, were examined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. RESULTS The MMP-9 rs3918242 TT genotype carriers had a slightly increased risk of CRC compared to CC carriers (p=0.1642, OR=1.88, 95% CI=0.84-4.16). Patients of CT/TT genotypes were on significantly higher risk of metastasis (p=0.0027) than those of CC genotype. No obvious association was found between MMP-9 genotype and CRC risk among ever-smokers, non-smokers, non-alcohol drinkers or alcohol drinkers. No significant correlation was observed between MMP-9 genotypic distributions with age, gender, tumor size or location. CONCLUSION MMP-9 rs3918242 genotypes may interact with BMI to serve as a predictor for higher CRC risk, and independently as a predictor for metastasis.

(1) Although emerging evidence suggests that proton pump inhibitor (PPI)-induced dysbiosis negatively alters treatment response to immune checkpoint inhibitors (ICIs) in cancer patients, no study systematically investigates the association between PPIs, ICIs, and chemotherapy; (2) Cochrane Library, Embase, Medline, and PubMed were searched from inception to 20 May 2022, to identify relevant studies involving patients receiving ICIs or chemotherapy and reporting survival outcome between PPI users and non-users. Survival outcomes included overall survival (OS) and progression-free survival (PFS). Network meta-analyses were performed using random-effects models. p-scores, with a value between 0 and 1, were calculated to quantify the treatment ranking, with a higher score suggesting a higher probability of greater effectiveness. We also conducted pairwise meta-analyses of observational studies to complement our network meta-analysis; (3) We identified 62 studies involving 26,484 patients (PPI = 8834; non-PPI = 17,650), including non-small cell lung cancer (NSCLC), urothelial carcinoma (UC), melanoma, renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and squamous cell carcinoma (SCC) of the neck and head. Eight post-hoc analyses from 18 randomized–controlled trials were included in our network, which demonstrated that, in advanced NSCLC and UC, patients under ICI treatment with concomitant PPI (p-score: 0.2016) are associated with both poorer OS (HR, 1.49; 95% CI, 1.37 to 1.67) and poorer PFS (HR, 1.41; 95% CI, 1.25 to 1.61) than those without PPIs (p-score: 1.000). Patients under ICI treatment with concomitant PPI also had poorer OS (HR, 1.18; 95% CI, 1.07 to 1.31) and poorer PFS (HR, 1.30; 95% CI, 1.14 to 1.48) in comparison with those receiving chemotherapy (p-score: 0.6664), implying that PPIs may compromise ICI’s effectiveness, making it less effective than chemotherapy. Our pairwise meta-analyses also supported this association. Conversely, PPI has little effect on patients with advanced melanoma, RCC, HCC, and SCC of the neck and head who were treated with ICIs; (4) “PPI-induced dysbiosis” serves as a significant modifier of treatment response in both advanced NSCLC and UC that are treated with ICIs, compromising the effectiveness of ICIs to be less than that of chemotherapy. Thus, clinicians should avoid unnecessary PPI prescription in these patients. “PPI-induced dysbiosis”, on the other hand, does not alter the treatment response to ICIs in advanced melanoma, RCC, HCC, and SCC of the head and neck.

Background:Approximately 25% of patients with early-stage breast cancer experience cancer progression throughout the disease course. Alterations in TMEM240 in breast cancer were identified and investigated to monitor treatment response and disease progression.Methods:Circulating methylated TMEM240 in the plasma of breast cancer patients was used to monitor treatment response and relapse events. Illumina methylation arrays were used to identify novel hypermethylated CpG sites and genes related to poor hormone therapy response. Quantitative methylation-specific real-time polymerase chain reaction (QMSP), quantitative real-time reverse transcription PCR, and immunohistochemical analyses were performed to measure DNA methylation, mRNA and protein expression levels in 335 breast samples from Taiwanese and Korean patients. Kaplan–Meier curves, Cox proportional hazards regression and receiver operating characteristic curves were used to analyze 10-year survival and disease progression. The Cancer Genome Atlas (TCGA) dataset was used to investigate TMEM240 alterations in Western countries. Transient transfection and knockdown of TMEM240 were performed to determine its biological functions and its relationship to hormone drug treatment response in breast cancer cells.Results: Aberrant methylated TMEM240 was identified in breast cancer patients with poor hormone therapy response using genome-wide methylation analysis in the Taiwan and TCGA breast cancer cohorts. A cell model showed that TMEM240, which is localized to the cell membrane and cytoplasm, represses breast cancer cell proliferation and cell migration. TMEM240 protein expression was observed in normal breast tissues, but not detected in 88.2% (67/76) of breast tumors and in 90.0% (9/10) of metastatic tumors from breast cancer patients. Almost all triple-negative breast cancer patients (95.7%, 22/23) had deficient TMEM240 protein expression. QMSP revealed that in 54.5% (55/101) of Taiwanese breast cancer patients, the methylation level of TMEM240 was at least 2-fold higher in tumor tissues than in the matched normal breast tissues. Patients with hypermethylation of TMEM240 had poor 10-year overall survival (p = 0.003) and poor treatment response, especially hormone therapy response (p < 0.001). Prediction of disease progression based on circulating methylated TMEM240 was found to have 87.5% sensitivity, 93.1% specificity, and 90.2% accuracy, better than the currently used biomarkers CEA and CA-153.Conclusions: Circulating methylated TMEM240 is a potential biomarker for treatment response and disease progression monitoring in breast cancer.

Simple Summary A chondrosarcoma is a common tumor of the bone that has a high propensity to metastasize to distant organs. The effects of NGF in a chondrosarcoma are not confirmed although NGF is capable of promoting the progression and metastasis of several different types of tumors. Here, we found that NGF promotes the chondrosarcoma migration and metastasis in vitro and in vivo. The levels of NGF and MMP-2 in human chondrosarcoma tumor tissues correlated strongly with the tumor stage. We identified that NGF induces the MMP-2 synthesis and chondrosarcoma cell motility by inhibiting miR-423-5p expression through the FAK and c-Src pathways. We suggest that NGF is a worthwhile therapeutic target in the treatment of a metastatic chondrosarcoma. Abstract A chondrosarcoma is a common tumor of the soft tissue and bone that has a high propensity to metastasize to distant organs. Nerve growth factor (NGF) is capable of promoting the progression and metastasis of several different types of tumors although the effects of NGF in a chondrosarcoma are not confirmed. Here, we found that the levels of NGF and matrix metalloproteinase-2 (MMP-2) correlated with the tumor stage in patients with a chondrosarcoma. NGF facilitated the MMP-2-dependent cellular migration in human chondrosarcoma JJ012 cells while the overexpression of NGF enhanced the lung metastasis in a mouse model of a chondrosarcoma. NGF promoted the MMP-2 synthesis and cell migration by inhibiting miR-423-5p expression through the FAK and c-Src signaling cascades. NGF appears to be a worthwhile therapeutic target in the treatment of a metastatic chondrosarcoma.

Background: The effects of Nerve growth factor (NGF) in chondrosarcoma are not confirmed, although NGF is capable of promoting the progression and metastasis of several different types of tumors. Here we aim to explore the role of NGF in chondrosarcoma and elucidate how NGF acts.Methods: Immunohistochemistry (IHC)-stained tissue samples from chondrosarcoma patients were stained with NGF and MMP-2 antibodies. Cell migration was examined by Transwell and wound healing assays. The expression levels of MMP-2, microRNA-423-5p (miR-423-5p) were measured by quantitative real-time polymerase chain reaction. MMP-2, FAK, and c-Src protein expression were examined by Western blot assays. The interaction between MMP-2 3’-UTRs and miR-423-5p binding site was explored by luciferase assay. We established the orthotopic in vivo model of chondrosarcoma lung metastasis to further investigate the promoting effects of NGF in metastatic chondrosarcoma.Results: Here, we found that the levels of NGF and matrix metalloproteinase-2 (MMP-2) correlated with tumor stage in patients with chondrosarcoma. NGF facilitated MMP-2-dependent cellular migration in human chondrosarcoma JJ012 cells, while overexpression of NGF enhanced lung metastasis in a mouse model of chondrosarcoma. NGF promoted MMP-2 synthesis and cell migration by inhibiting miR-423-5p expression through the FAK and c-Src signaling cascades. NGF appears to be a worthwhile therapeutic target in the treatment of metastatic chondrosarcoma.Conclusions: Our study has identified that NGF promotes MMP-2-dependent cell migration in human chondrosarcoma tissue by inhibiting miR-423-5p synthesis via the FAK and c-Src signaling cascades

Since patients with acute myeloid leukemia (AML) in the real world have a much different clinical picture than patients recruited in the clinical trials, obtaining real-world evidence of medication adoption is important for therapeutic efficiency and safety. This study used three population-based data in Taiwan, the National Health Insurance Research Database, Taiwan Cancer Registry, and National Death Registry, between 2001 and 2015, to investigate the effect of conventional chemotherapy (CCT) versus non-conventional chemotherapy (NCCT) on the overall survival (OS) of patients with AML (n = 7,763). Cox proportional hazard regression was used to estimate the hazard ratios (HR) of different treatments on the risk of mortality. To reduce the potential selection bias, we used the inverse probability of treatment weighting based on the propensity score to balance the baseline characteristics between patients receiving CCT and NCCT. The median survival time for CCT and NCCT arms was 10.2 months (95% confidence interval (95% CI): 9.7-10.9) and 4.1 months (95% CI: 3.8-4.5), respectively. Compared to the patients received NCCT, those receiving CCT had a lower risk of mortality (HR 0.63 (95% CI: 0.59-0.67, P 0.001). Subgroup analysis showed that CCT did benefit patients in different gender, age, comorbidity, and socioeconomic status (SES) groups. In conclusion, the real-world population-based data exhibited CCT were more likely to be prescribed for patients with AML of younger age, fewer comorbidities, diagnosed recently (2011-2015), and higher SES. In fact, CCT had better treatment outcomes than NCCT in terms of OS for adult patients diagnosed with AML.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with high mortality. To date, there is no comprehensive population-based analysis of patients with AML in Asia, including Taiwan.This is a retrospective cohort study using three population-based databases, namely, the Taiwan Cancer Registry, Taiwanese National Health Insurance Research Database, and Taiwan Death Registry, between 2001 and 2015 to provide detailed information on patients with AML and relevant clinical variables, such as sex, age, year of diagnosis, socioeconomic status (SES) level, hospital level, treatment location, and Deyo-Charlson Comorbidity Index (Deyo-CCI) score.Patients with newly diagnosed AML (n = 9949) were included in the study. The median age was 60 years, and the overall age-adjusted AML incidence over 15 years was 2.44 per 100,000 person-years. The median overall survival (OS) of patients younger than 65 years was 18 months, whereas the OS of patients older than age 65 was only 5 months. AML patients with a prior cancer history had the worst outcomes, and the acute promyelocytic leukemia subtype predicted better survival. Patients who were older, male and a higher Deyo-CCI score had a significantly higher risk of death. In contrast, patients with a higher SES level and receiving treatment in a medical center had a lower risk of mortality than their respective counterparts.Our study results could enable clinicians to obtain a comprehensive picture of the epidemiology, survival outcomes and unmet medical needs of AML patients in Taiwan.

Simple Summary This study highlights the epidemiological, cytogenetic and clinical difference between patients with multiple hit diffuse large B-cell lymphoma in Taiwan and those from western countries. Unlike in the West, the majority of patients with multiple hit lymphoma in Taiwan harbor a BCL6 rearrangement. Almost three in every five BCL6-rearranged double hit lymphoma cases in Taiwan are non-GCB phenotype, indicating, at least in part, that the preferential screening for double hit with BCL6 rearrangement may be a clinically-informative modality for patients with non-GCB phenotype DLBCL in Taiwan. This also suggests the need for a different treatment approach than is obtained in the West where BCL6 double hit lymphomas are seemingly GCB. Consistent with our present findings, mandatory screening for BCL6-rearrangement in suspected DLBCL cases in Taiwan may aid early diagnosis, therapy decision, and clinical outcome forecast. Abstract This study investigated the epidemiological and clinical peculiarities of BCL2 and BCL6 rearrangement in patients with high grade B-cell lymphoma (HGBL) from Taiwan, compared with data from Western countries. Two hundred and eighty-two DLBCL cases from Taipei Medical University-affiliated hospitals (n = 179) and Tri-Service General Hospital (n = 103) were enrolled for this study. From the 282, 47 (16.7%) had MYC translocation; 24 of these harbored concurrent BCL2 and/or BCL6 translocation (double-hit, DH or triple-hit, TH). Twelve DH-HGBL cases had simultaneous MYC and BCL6 translocations, 8 harbored MYC and BCL2 rearrangement, while the remaining 4 patients exhibited TH. Together, 66.7% of DH/TH-HGBL patients were BCL6 rearrangement positive. Among these BCL6-rearranged DH/TH-HGBL patients, only 6 (37.5%) overexpressed MYC and BCL6 proteins simultaneously, indicating that MYC-BCL6 co-overexpression may not be plausible surrogate biomarker for screening BCL6-rearranged DH-HGBL. By the end of year 5, all patients with TH-HGBL, BCL2 DH-HGBL and all but one BCL6 DH-HGBL cases had expired or were lost to follow-up. Progression-free survival (PFS) was longer for the non-DH/TH-HGBL group compared with the DH/TH-HGBL group. While the patients with BCL2 DH-HGBL were lost to follow-up by day 800, their remaining TH-HGBL and BCL6 DH-HGBL peers exhibited very poor PFS, regardless of age strata. More so, patients with BCL6 rearrangement were 5.5-fold more likely associated with extranodal involvement compared with their BCL2-rearranged peers. Moreover, ~60.0% of the BCL6-rearranged DH-HGBL cases were non-GCB, suggesting that including screening for BCL6 rearrangement in patients with the non-GCB phenotype may aid medical decision-making and therapeutic strategy. Contrary to contemporary data from western countries, 2 in every 3 patients with DH/TH-HGBL in Taiwan harbor BCL6 rearrangement. Consistent with present findings, we recommend mandatory screening for BCL6 rearrangement in patients with aggressive HGBL in Taiwan.

Controversy remains regarding the relationship between bone health and sleep. In the literature, the effect of sleep on bone density in the clinical setting varies depending on the definition of normal sleep duration, sleep quality, selected population, and diagnostic tools for bone density. The aim of this study was to examine the association between bone mineral density (BMD)assessed by dual-energy X-ray absorptiometry and sleep duration/quality in the defined adult population from the National Health and Nutrition Examination Survey (NHANES) (a national household survey) within a 6-year period (2005–2010) and explore age differences. The basic variables, metabolic diseases, and bone density in the femoral neck as determined through dual-energy X-ray absorptiometry, were segregated, and analyzed according to different sleep durations (1–4, 5–6,7–8, and > 9 h/day) and sleep quality using multinomial regression models. A total of 12,793 subjects were analyzed. Our results reveal that women aged > 50 years with sleep duration

Background/aim A single study has shown positive association and genotype-phenotype correlation between metalloproteinase-9 (MMP-9) promoter genotypes and adult acute lymphocytic leukemia (ALL). However, there is no report about childhood ALL. Thus, this study aimed at examining the role of MMP-9 rs3918242 genotypes in childhood ALL risk. Patients and methods A total of 266 childhood ALL cases and 266 healthy controls in Taiwan were examined for their MMP-9 rs3918242 genotypes via polymerase chain reaction-restriction fragment length polymorphism methodology. Results The MMP-9 rs3918242 CT or TT genotype carriers only had a slightly increased risk compared with CC carriers (p=0.6386 and 0.6005, respectively). The allelic frequency analysis also supported the idea that the variant T allele at MMP-9 rs3918242 is not differentially distributed between the case and control groups (p=0.4834). Conclusion MMP-9 rs3918242 genotypes may indirectly influence the risk of childhood ALL. Further validations in other populations and analysis of the detail mechanisms are needed.

Chronic myelogenous leukemia (CML) is the most common type of leukemia in adults, and more than 90% of CML patients harbor the abnormal Philadelphia chromosome (Ph) that encodes the BCR-ABL oncoprotein. Although the ABL kinase inhibitor (imatinib) has proven to be very effective in achieving high remission rates and improving prognosis, up to 33% of CML patients still cannot achieve an optimal response. Here, we used CRISPR/Cas9 to specifically target the BCR-ABL junction region in K562 cells, resulting in the inhibition of cancer cell growth and oncogenesis. Due to the variety of BCR-ABL junctions in CML patients, we utilized gene editing of the human ABL gene for clinical applications. Using the ABL gene-edited virus in K562 cells, we detected 41.2% indels in ABL sgRNA_2-infected cells. The ABL-edited cells reveled significant suppression of BCR-ABL protein expression and downstream signals, inhibiting cell growth and increasing cell apoptosis. Next, we introduced the ABL gene-edited virus into a systemic K562 leukemia xenograft mouse model, and bioluminescence imaging of the mice showed a significant reduction in the leukemia cell population in ABL-targeted mice, compared to the scramble sgRNA virus-injected mice. In CML cells from clinical samples, infection with the ABL gene-edited virus resulted in more than 30.9% indels and significant cancer cell death. Notably, no off-target effects or bone marrow cell suppression was found using the ABL gene-edited virus, ensuring both user safety and treatment efficacy. This study demonstrated the critical role of the ABL gene in maintaining CML cell survival and tumorigenicity in vitro and in vivo. ABL gene editing-based therapy might provide a potential strategy for imatinib-insensitive or resistant CML patients.

Chondrosarcomas are primary malignant bone tumors that have a poor prognosis. WNT1-inducible signaling pathway protein-3 (WISP-3, also termed CCN6) belongs to the CCN family of proteins and is implicated in the regulation of various cellular functions, such as cell proliferation, differentiation, and migration. It is unknown as to whether CCN6 affects human chondrosarcoma metastasis. We show how CCN6 promotes chondrosarcoma cell migration and invasion via matrix metallopeptidase-9 (MMP)-9 expression. These effects were abolished by pretreatment of chondrosarcoma cells with PI3K, Akt, mTOR, and NF-κB inhibitors or short interfering (si)RNAs. Our investigations indicate that CCN6 facilitates metastasis through the PI3K/Akt/mTOR/NF-κB signaling pathway. CCN6 and MMP-9 expression was markedly increased in the highly migratory JJ012(S10) cell line compared with the primordial cell line (JJ012) in both in vitro and in vivo experiments. CCN6 knockdown suppressed MMP-9 production in JJ012(S10) cells and attenuated cell migration and invasion ability. Importantly, CCN6 knockdown profoundly inhibited chondrosarcoma cell metastasis to lung. Our findings reveal an important mechanism underlying CCN6-induced metastasis and they highlight the clinical significance between CCN6 and MMP-9 in regard to human chondrosarcoma. CCN6 appears to be a promising therapeutic target in chondrosarcoma metastasis.

Breast cancer is a major cause of cancer mortality amongst women. Chemokine (C-C motif) ligand 4 is encoded by the CCL4 gene; specific CCL4 gene polymorphisms are related to the risks and prognoses of various diseases. In this study, we examined whether CCL4 gene single nucleotide polymorphisms (SNPs) predict the risk and progression of breast cancer. Between 2014 and 2016, we recruited 314 patients diagnosed with breast cancer and a cohort of 209 healthy participants (controls) without a history of cancer. Genotyping of the CCL4 rs1634507, rs10491121 and rs1719153 SNPs revealed no significant between-group differences for these polymorphisms. However, amongst luminal A and luminal B subtypes, compared with patients with the AA genotype, those carrying the AG genotype at SNP rs10491121 were less likely to develop lymph node metastasis. In addition, compared with AA carriers, those carrying the AG + GG genotype at SNP rs10491121 were at lower risk of developing distant metastasis, while the presence of the AT genotype at SNP rs1719153 increased the likelihood of pathologic grade (G3 or G4) disease. Variations in the CCL4 gene may help to predict breast cancer progression and metastasis.

Breast cancer is a major cause of cancer mortality worldwide. High-mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein found in all mammal eukaryotic cells that participates in tumor progression, migration and metastasis. HMGB1 overexpression has been indicated in breast cancer patients. However, scant information is available regarding the association between HMGB1 single nucleotide polymorphisms (SNPs) and the risk or prognosis of breast cancer. We report on the association between 4 SNPs of the HMGB1 gene (rs1360485, rs1045411, rs2249825 and rs1412125) and breast cancer susceptibility as well as clinical outcomes in 313 patients with breast cancer and in 217 healthy controls. Patients with one G allele in the rs1360485 or rs2249825 domains are likely to progress to T2 tumor and lymph node metastasis. In addition, the presence of one G allele in SNPs rs1360485 or rs2249825 was associated with a higher risk of progressing to T2 tumor and distant metastasis amongst HER2-enriched and triple-negative breast cancer (TNBC) tumors compared with luminal A and luminal B tumors. Furthermore, having one C allele in the rs1412125 domain increased the risk of pathologic grade 3 disease in HER2-enriched and TNBC tumors. Our results indicate that genetic variations in the HMGB1 gene may serve as an important predictor of breast cancer progression and metastasis.

In thalassemia major or transfusion-dependent thalassemia patients, osteoporosis-related bone complications such as fracture events are common. However, no studies have investigated the risk of fracture in transfusion-naïve thalassemia population. Therefore, we conducted a longitudinal nationwide cohort study to determine whether this population has an increased risk of fracture. This nationwide, population-based cohort study analyzed data from 1998 to 2010 obtained from the Taiwanese National Health Insurance Research Database, with a follow-up period extending until the end of 2011. We identified cases with transfusion-naïve thalassemia and selected a comparison cohort that was frequency-matched according to age and year of diagnosis of thalassemia at a ratio of one subject with thalassemia to four subjects in the control group. We analyzed the risk of fracture events to occur in transfusion-naïve thalassemia cases by using Cox proportional hazards regression models. Totally, the study recruited 1369 transfusion-naïve thalassemia subjects and 5416 controls. We identified a total of 71 cases with fracture events within the thalassemia group and 204 within the control group. The overall risks for developing fracture events were 1.35-fold higher in transfusion-naïve thalassemia individuals than the comparison cohort after adjusting for age, sex and comorbidities. Most fracture events were observed in male transfusion-naïve thalassemia individuals rather than the normal population. In subgroup analysis, there was a 1.46-fold higher risk to develop upper-limb fracture in the thalassemia group than in the control groups. In conclusion, our long-term, cohort study results showed that there was a higher risk for the development of fractures in transfusion-naïve thalassemia individuals, particularly in male cases.

Chondrosarcoma is the second most prevalent general primary tumor of bone following osteosarcoma. Chondrosarcoma development may be linked to angiogenesis, which is principally elicited by vascular endothelial growth factor-A (VEGF-A). VEGF-A level has been recognized as a prognostic marker in angiogenesis. WNT1-inducible signaling pathway protein-3 (WISP)-3/CCN6 belongs to the CCN family and is involved in regulating several cellular functions, including cell proliferation, differentiation, and migration. Nevertheless, the effect of WISP-3 on VEGF-A production and angiogenesis in human chondrosarcoma remains largely unknown. This current study shows that WISP-3 promoted VEGF-A production and induced angiogenesis of human endothelial progenitor cells. Moreover, WISP-3-enhanced VEGF-A expression and angiogenesis involved the c-Src and p38 signaling pathways, while miR-452 expression was negatively affected by WISP-3 via the c-Src and p38 pathways. Our results illustrate the clinical significance of WISP-3, VEGF-A and miR-452 in human chondrosarcoma patients. WISP-3 may illustrate a novel therapeutic target in the metastasis and angiogenesis of chondrosarcoma.

Background/aim Cells suffer from oxidative DNA damage which leads to the accumulation of 8-oxoguanine (8-oxoG) adducts in our genome that can become carcinogenic. The human 8-oxoG DNA glycosylase 1 (hOGG1) plays a central role in repairing these 8-oxoGs via the base excision repair pathway. Mounting evidence has suggested that hOGG1 polymorphisms may affect the activity of hOGG1 and serve as genomic markers for the prediction of personal susceptibility to several cancers. To determine whether the commonly examined hOGG1 rs1052133 (Ser326Cys) polymorphism is associated with the risk of childhood acute lymphoblastic leukemia (ALL) among Taiwanese children, we genotyped the hOGG1 rs1052133 (Ser326Cys) in 266 cases and 266 controls. Results The distributions of the GG, CG and CC genotypes at the hOGG1 rs1052133 were 49.2, 39.1 and 11.7% in the control group and 48.1, 36.1 and 15.8% in the case group (p=0.3656). The combined genotypes CG+CC were not associated with increased risk of childhood ALL (odds ratio [OR]=1.05, 95% confidence interval [CI]=0.74-1.47, p=0.7947). Conclusion The hOGG1 rs1052133 polymorphism is not associated with susceptibility to childhood ALL in the Taiwanese population.

// Chia-Lin Lee 1, 2, 3, 4 , Chun-Hao Tsai 5, 6 , Dah-Cherng Yeh 7 , Chi-Shy Lin 8 , Yu-Fen Li 4 , Huey-En Tzeng 6, 9, 10 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taiwan 2 Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan 3 Department of Medical Research, Taichung Veterans General Hospital, Taiwan 4 Graduate Institute of Biostatistics, China Medical University, Taichung, Taiwan 5 Department of Orthopedics, China Medical University Hospital, Taichung, Taiwan 6 School of Medicine, China Medical University, Taichung, Taiwan 7 Department of Surgery, Taichung Tzu Chi General Hospital, Taichung, Taiwan 8 Department of Family Medicine, Taichung Veterans General Hospital, Taiwan 9 Division of Hematology/Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan 10 Breast Cancer Center, Taichung Veterans General Hospital, Taiwan Correspondence to: Yu-Fen Li, email: yufenli@mail.cmu.edu.tw Huey-En Tzeng, email: tzenghueyen@gmail.com Keywords: breast cancer, hemoglobin, survival, trajectory Received: October 06, 2016 Accepted: November 08, 2016 Published: November 29, 2016 ABSTRACT Hemoglobin (Hb) levels are reportedly related with treatment outcomes and survival in patients of breast cancer. However, the long-term change in Hb levels after treatment and the effects of Hb on survival remain unknown. This retrospective cohort study enrolled 1931 breast cancer patients with pathological stage I-IV between 1/1/2003 and 12/31/2013. Latent class modeling was used to identify trajectories in monthly Hb levels over time. The primary endpoint was 10-year cancer-related death. We identified 5 distinct Hb trajectories: persistent anemia (5.6 %; n = 109), improved anemia (4.8 %, n = 93), mild anemia (21.0%; n = 406), low normal Hb (46.6 %; n = 899), and normal Hb (21.9%; n = 424). Compared with the normal-Hb group, trajectories with low Hb levels had worst 10-year survival. The adjusted hazard ratios were 1.79(95% CI, 0.91-3.53) for the improved anemia group, 1.09(95% CI, 0.68-1.74) for the mild anemia group, 1.06 (95% CI, 0.71-1.60) for the low normal Hb group, and 2.19(95% CI 1.28-3.75) for the persistent anemia group. Our findings show there are five Hb level trajectories during breast cancer treatment. The anemia Hb level trajectory during the first 12 months after treatment reflect the worst cancer-related 10-year survival in breast cancer patients.

// Huey-En Tzeng 1, 2, * , An-Chen Chang 3, * , Chun-Hao Tsai 1, 4 , Shih-Wei Wang 5 , Chih-Hsin Tang 6, 7, 8 1 Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan 2 Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan 3 Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan 4 Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan 5 Department of Medicine, Mackay Medical College, New Taipei City, Taiwan 6 Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan 7 Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan 8 Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan * These authors contributed equally to this work Correspondence to: Chih-Hsin Tang, email: chtang@mail.cmu.edu.tw Keywords: bFGF, chondrosarcoma, lymphangiogenesis, VEGF-C, miR-381 Received: March 22, 2016 Accepted: May 10, 2016 Published: May 24, 2016 ABSTRACT A chondrosarcoma is a common, primary malignant bone tumor that can grow to destroy the bone, produce fractures and develop soft tissue masses. Left untreated, chondrosarcomas metastasize through the vascular system to the lungs and ultimately lead to large metastatic deposits of the malignant cartilage taking over lung volume and function. Vascular endothelial growth factor (VEGF)-C has been implicated in tumor-induced lymphangiogenesis and elevated expression of VEGF-C has been found to correlate with cancer metastasis. bFGF (basic fibroblast growth factor), a secreted cytokine, regulates biological activity, including angiogenesis and metastasis. We have previously reported on the important role of bFGF in angiogenesis in chondrosarcomas. However, the effect of bFGF in VEGF-C regulation and lymphangiogenesis in chondrosarcomas is poorly understood. In this investigation, we demonstrate a correlation exists between bFGF and VEGF-C in tissue specimens from patients with chondrosarcomas. To examine the lymphangiogenic effect of bFGF, we used human lymphatic endothelial cells (LECs) to mimic lymphatic vessel formation. We found that bFGF-treated chondrosarcomas promoted LEC tube formation and cell migration. In addition, bFGF knockdown inhibited lymphangiogenesis in vitro and in vivo . We also found that bFGF-induced VEGF-C is mediated by the platelet-derived growth factor receptor (PDGFR) and c-Src signaling pathway. Furthermore, bFGF inhibited microRNA-381 expression via the PDGFR and c-Src cascade. Our study is the first to describe the mechanism of bFGF-promoted lymphangiogenesis by upregulating VEGF-C expression in chondrosarcomas. Thus, bFGF could serve as a therapeutic target in chondrosarcoma metastasis and lymphangiogenesis.

Multiple myeloma (MM) is a hematological malignancy that presents with infection, anemia, bone lesions, renal function impairment, and hypercalcemia. The survival of MM patients has improved in recent decades; however, early mortality remains a critical problem. The aim of this study was to identify the etiologies and clinical variables associated with early mortality in MM. In addition, the effects of bortezomib on reducing early mortality incidence were investigated.Medical records from 122 MM patients diagnosed between November 2007 and December 2013 were retrospectively reviewed. Early mortality was defined as death by any cause within the first 180 days after pathological diagnosis.In newly diagnosed MM patients, early mortality occurred in 22.95% of patients. Infection accounted for 67.86% of early deaths. Multivariate analyses by Cox proportional-hazards regression showed that higher β2-microglobulin (P 0.001) and serum lactate dehydrogenase (P 0.001) levels, and lower serum albumin levels (P 0.001) were associated with early mortality. Both first-line and greater than or equal to second-line bortezomib treatments were not associated with superior 180-day overall survival (P = 0.546 for first-line bortezomib treatment; P = 0.066 for greater than or equal to second-line bortezomib treatment).Our results suggest that infection is the leading cause of early death in MM. High β2-microglobulin, high serum lactate dehydrogenase, and low serum albumin levels are poor prognostic factors for early mortality. Bortezomib therapy does not appear to reduce the incidence of early mortality in MM patients.

NC-8 (ent-16-oxobeyeran-19-N-methylureido) is an isosteviol-derived analogue with multiple biological effects, including anti-inflammation and anti-bacterial activities and inhibition of HBV viral surface antigen gene expression. In this study, we explored the effects of NC-8 on the formation of osteoclasts from RAW 264.7 cells. We found that NC-8 exerts the novel effect of inhibiting osteoclast-like cell formation. Our experiments showed that RANKL-induced ERK, p38, and JNK phosphorylation were inhibited by NC-8. An ovariectomy-induced osteoporosis animal model was used to examine the protective effects of oral treatment with NC-8. Serum analysis was used to examine markers of osteoblasts, osteoclasts, and renal and hepatic function in rats. Micro CT scanning and histological analysis were used to measure bone loss in ovariectomized rats. Oral administration of NC-8 effectively decreased excess bone resorption and significantly antagonized trabecular bone loss in ovariectomized rats. Serum analysis of C-terminal telopeptide of type-I collagen, an osteoclast marker, also showed that NC-8 administration inhibited excess bone resorption. Furthermore, serum analysis showed that renal and liver function were not affected by these doses of NC-8 during long-term treatment. Our results demonstrate that NC-8 inhibits osteoclast differentiation and effectively ameliorates ovariectomy-induced osteoporosis.

Background Radix Paeoniae Rubra (RPR), a traditional Chinese herb, has anti-inflammatory and immuno-regulatory properties. This study explored the effects of RPR on stimulation of osteoclast differentiation in RAW264.7 cells and peripheral blood mononuclear cells (PBMC)s. Methods The mature osteoclasts were measured by bone resorption assays and TRAP staining. JNK, ERK, p38 and NF-κB inhibitors were used applied in order to verify their contribution in RPR-induced osteoclast differentiation. The NF-κB and MAPK pathways were evaluated by western blotting, RT-PCR and luciferase assay. Results RPR induced osteoclast differentiation in a dose-dependent manner and induced the resorption activity of osteoclasts differentiation of RAW264.7 cells and PBMCs. Western blotting showed that RPR treatment induced phosphorylation of JNK, ERK, and p38 in RAW 264.7 cells. Treatment of JNK, ERK, and p38 MAP kinase inhibitors verified the contribution of JNK, ERK and p38. RPR treatment induced c-Fos and NFATc1 protein expression; NF-κB inhibitor treatment and luciferase assay verified the contribution of the NF-κB pathway. Conclusions This study demonstrated the interesting effect, in which RPR stimulated osteoclast differentiation in murine RAW264.7 cells and human monocytes. Electronic supplementary material The online version of this article (10.1186/s12906-018-2196-7) contains supplementary material, which is available to authorized users.