Gaining new understanding of sarcomere length non-uniformities in skeletal muscles.

Sarcomere lengths are non-uniform on all structural levels of mammalian skeletal muscle. These non-uniformities have been associated with a variety of mechanical properties, including residual force enhancement and depression, creep, increased force capacity, and extension of the plateau of the force-length relationship. However, the nature of sarcomere length non-uniformities has not been explored systematically. The purpose of this study was to determine the properties of sarcomere length non-uniformities in active and passive muscle. Single myofibrils of rabbit psoas (n = 20; with 412 individual sarcomeres) were subjected to three activation/deactivation cycles and individual sarcomere lengths were measured at 4 passive and 3 active points during the activation/deactivation cycles. The myofibrils were divided into three groups based on their initial average sarcomere lengths: short, intermediate, and long average sarcomere lengths of 2.7, 3.2, and 3.6 µm. The primary results were that sarcomere length non-uniformities did not occur randomly but were governed by some structural and/or contractile properties of the sarcomeres and that sarcomere length non-uniformities increased when myofibrils went from the passive to the active state. We propose that the mechanisms that govern the systematic sarcomere lengths non-uniformities observed in active and passive myofibrils may be associated with the variable number of contractile proteins and the variable number and the adjustable stiffness of titin filaments in individual sarcomeres.

Utility of a palatal speech appliance combined with the five-point eight-line segment technique in total tongue reconstruction.

The aim of this study was to explore a new total tongue reconstruction strategy based on the five-point eight-line segment (FIPELS) technique and a palatal speech appliance, and to evaluate the functional and aesthetic outcomes. Twenty patients with tongue squamous cell carcinoma were included in this study. All patients underwent total tongue resection followed by tongue reconstruction with an anterolateral thigh flap. The patients were divided randomly into two groups according to the reconstruction strategy: FIPELS group (10 patients) and traditional flap design group (10 patients). All 10 patients in the FIPELS group received a palatal speech appliance 1 month after the surgery. A Likert scale was used to assess swallowing function, speech articulation, and the aesthetic outcome of the reconstructed tongue in the traditional and FIPELS (with and without the palatal speech appliance) groups. Compared with the traditional group, swallowing function (1 month, P = 0.016; 3 months, P = 0.021) and the aesthetic outcome (1 month, P = 0.016; 3 months, P = 0.020) were significantly better in the FIPELS group (without the palatal speech appliance); however, there was no significant difference in speech articulation (1 month, P = 0.549; 3 months, P = 0.513). Within the FIPELS group, significantly better speech articulation was obtained with the palatal speech appliance than without it (1 month, P = 0.031; 3 months, P = 0.015).

Shear-wave velocity for colorectal cancer liver metastases as a potential prognostic factor after chemotherapy: a preliminary study.

AIM: To evaluate whether shear-wave velocity (SWV) can be used for predicting the prognoses of patients with colorectal cancer liver metastases (CRLMs) after chemotherapy. MATERIALS AND METHODS: Our institutional review board approved this prospective study, and written informed consent was obtained. SWV of CRLMs were obtained using point shear-wave elastography using acoustic radiation force impulse from 25 patients prior to and 2, 7, and 14 days after chemotherapy. Progression-free survival (PFS) after chemotherapy was estimated using the Kaplan-Meier method. The Cox proportional hazard regression model was used to determine significant predictive factors for PFS. For measurement reproducibility, an additional 37 patients with CRLMs were enrolled and assessed using intraclass correlation coefficients (ICCs). RESULTS: After chemotherapy, 10 and 15 patients were classified into responder and non-responder groups, respectively. The estimated 1- and 3-year PFS values in the whole cohort were 36% and 8%, respectively. A decrease in the SWV value on day 2 relative to the initial value was a significant predictive factor for better PFS outcome (hazard ratio = 0.20, 95% confidence interval = 0.07-0.57, p=0.003). The estimated 1 and 3-year PFS rates were 66.7% and 22.2%, respectively, in nine patients with decreased SWV values on day 2 and significantly higher than 18.8% and 0% of 16 patients with increased SWV values on day 2. The ICC value of SWV of CRLMs in the additional 37 patients was 0.823 (95% CI = 0.685-0.905), indicating good agreement. CONCLUSION: SWV values of CRLMs could provide prognostic information in patients with CRLMs treated with chemotherapy, as decreased SWV values on day 2 after chemotherapy was a significant predictive factor for better PFS.

Postpartum haemorrhage requiring transfusion and risk of cardiovascular disease later in life: a retrospective cohort study.

OBJECTIVE: To determine whether postpartum haemorrhage (PPH) is associated with cardiovascular disease (CVD), including cerebrovascular and ischaemic heart disease beyond the peripartum period. DESIGN: Population-based cohort study. SETTING: Merged databases of the Korea National Health Insurance (KNHI) claims, National Health Screening Examination and National Health Screening Program for Infants and Children. POPULATION: Women who gave birth in 2007 in the Republic of Korea and who were tracked through to 2015 for the occurrence of CVD. METHODS: Patients were identified and the occurrences of PPH and transfusion were determined using the KNHI claims database. The occurrence of CVD was tracked through 2015 using codes from the International Classification of Diseases, tenth revision (ICD-10). MAIN OUTCOME MEASURES: The risk of CVD after PPH. RESULTS: Among 150 381 women who gave birth during the study period, 9107 were diagnosed with PPH and 899 were treated with transfusion. The risk of CVD in women with PPH was no different than in women without PPH, after adjustment (HR 1.03, 95% CI 0.93-1.13). The risk of CVD in women with PPH requiring transfusion was significantly increased compared with women without PPH, after adjustment (HR 1.60, 95% CI 1.25-2.06). The risk of CVD in women with PPH without transfusion was not significantly different compared with women without PPH (HR 0.96, 95% CI 0.86-1.07). CONCLUSIONS: Postpartum haemorrhage (PPH) requiring transfusion is associated with an increased risk of CVD. Guidelines for management should be established, and further studies on the mechanisms involved should be conducted. TWEETABLE ABSTRACT: PPH requiring transfusion is associated with an increased risk of CVD.

Association between body mass index and stroke severity in acute ischaemic stroke with non-valvular atrial fibrillation.

BACKGROUND AND PURPOSE: The objective of this study was to investigate the association between body mass index (BMI) and both initial stroke severity at presentation and functional outcomes after acute ischaemic stroke (AIS) in patients with non-valvular atrial fibrillation (NVAF). METHODS: Patients were categorized on the basis of their BMI into underweight (BMI <18.5, n = 111), normal (18.5 ≤ BMI <25, n = 1036) and overweight to obese (BMI ≥25, n = 472) groups. Initial stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) score and functional outcomes were assessed using the modified Rankin Scale score at discharge. The differences in stroke severity and functional outcomes were compared between groups using robust log-linear regression with a Poisson distribution and binary logistic regression analysis. RESULTS: A total of 1619 AIS patients with NVAF from six hospitals were included. Compared with the NIHSS scores [median 5, interquartile range (IQR) 2-14] of normal-weight patients, the NIHSS scores (median 9, IQR 4-19) of underweight patients were more likely to be higher, whereas those of overweight to obese patients were lower (median 4, IQR 1-12) (P < 0.001). In terms of functional outcomes after stroke, underweight patients had a higher risk of poor functional outcomes (odds ratio 1.78, 95% confidence interval 1.09-2.56, P = 0.01) but overweight to obese patients had no significant difference in functional outcomes compared with normal-weight patients. CONCLUSION: An inverse association was found between BMI and stroke severity in AIS patients with NVAF. This suggests the presence of an obesity paradox for short-term outcomes in patients with NVAF.

Women with threatened preterm labour followed by term delivery have an increased risk of spontaneous preterm birth in subsequent pregnancies: a population-based cohort study.

OBJECTIVES: To evaluate the association of a history of threatened preterm labour (TPL) followed by term delivery with the risk of spontaneous preterm delivery (PTD) in subsequent pregnancy. DESIGN: Population-based cohort study. SETTING: Data of the National Health Insurance Claims Database and a national health-screening programme for infants and children in South Korea. POPULATION: Women who had their first singleton delivery in 2010 and a subsequent second singleton delivery between 2011 and 2015. METHODS: Multivariable analysis adjusting for maternal age and interval between first and second deliveries was used to assess the risk of PTD based on PTD, TPL followed by term delivery, and term delivery in the first pregnancy. MAIN OUTCOME MEASURES: The risk of PTD during the second pregnancy. RESULTS: This study included 115 629 women with two consecutive deliveries during the study period. Spontaneous PTD rates in the second pregnancy were 7.71, 2.22 and 1.02% in women with PTD, TPL followed by term delivery, and term delivery in the first pregnancy, respectively. Threatened preterm labour followed by term delivery in the first pregnancy was associated with increased risk of PTD in the subsequent pregnancy after adjustment for potential confounding factors (adjusted odds ratio 2.21; 95% CI 1.76-2.78). CONCLUSION: Although women with a history of TPL followed by term delivery had a lower risk of PTD during a subsequent pregnancy compared with those with history of previous PTD, they still had a significantly increased risk of PTD compared with those who delivered at term without TPL. TWEETABLE ABSTRACT: The history of threatened preterm labour followed by term delivery is related to increased risk of subsequent spontaneous preterm delivery.

Aberrant GATA2 epigenetic dysregulation induces a GATA2/GATA6 switch in human gastric cancer.

Six GATA transcription factors play important roles in eukaryotic development. Among these, GATA2, an essential factor for the hematopoietic cell lineage, exhibits low expression in human gastric tissues, whereas GATA6, which is crucial for gastrointestinal development and differentiation, is frequently amplified and/or overexpressed in human gastric cancer. Interestingly, we found that GATA6 was overexpressed in human gastric cancer cells only when GATA2 expression was completely absent, thereby showing an inverse correlation between GATA2 and GATA6. In gastric cancer cells that express high GATA6 levels, a GATA2 CpG island is hypermethylated, repressing expression in these cells. In contrast, GATA6 expression is undetectable in GATA2-overexpressing gastric cancer cells, which lack GATA2 DNA methylation. Furthermore, PRC2 complex-mediated transcriptional silencing of GATA6 was observed in the GATA2-overexpressing cells. We also show that the GATA2 and PRC2 complexes are enriched within the GATA6 locus, and that the recruitment of the PRC2 complex is impaired by disrupting GATA2 expression, resulting in GATA6 upregulation. In addition, ectopic GATA2 expression significantly downregulates GATA6 expression, suggesting GATA2 directly represses GATA6. Furthermore, GATA6 downregulation showed antitumor activity by inducing growth arrest. Finally, we show that aberrant GATA2 methylation occurs early during the multistep process of gastric carcinogenesis regardless of Helicobacter pylori infection. Taken together, GATA2 dysregulation by epigenetic modification is associated with unfavorable phenotypes in human gastric cancer cells by allowing GATA6 expression.

Quantitative proteomic analysis of HER2 expression in the selection of gastric cancer patients for trastuzumab treatment.

Background: A wide range of response rates have been reported in HER2-positive gastric cancer (GC) patients treated with trastuzumab. Other HER2-targeted therapies for GC have yet to show efficacy in clinical trials. These findings raise question about the ability of standard HER2 diagnostics to accurately distinguish between GC patients who would and would not benefit from anti-HER2 therapies. Patients and methods: GC patients (n = 237), including a subset from the Trastuzumab in GC (ToGA) trial were divided into three groups based on HER2 status and history of treatment with standard chemotherapy or chemotherapy plus trastuzumab. We applied mass spectrometry-based proteomic analysis to quantify HER2 protein expression in formalin-fixed tumor samples. Using HER2 expression as a continuous variable, we defined a predictive protein level cutoff to identify which patients would benefit from trastuzumab. We compared quantitated protein level with clinical outcome and HER2 status as determined by conventional HER2 diagnostics. Results: Quantitative proteomics detected a 115-fold range of HER2 protein expression among patients diagnosed as HER2 positive by standard methods. A protein level of 1825 amol/µg was predicted to determine benefit from the addition of trastuzumab to chemotherapy. Trastuzumab treated patients with HER2 protein levels above this cutoff had twice the median overall survival (OS) of their counterparts below the cutoff (35.0 versus 17.5 months, P = 0.011). Conversely, trastuzumab-treated patients with HER2 levels below the cutoff had outcomes similar to HER2-positive patients treated with chemotherapy. (Progression-free survival = 7.0 versus 6.5 months: P = 0.504; OS = 17.5 versus 12.6 months: P = 0.520). HER2 levels were not prognostic for response to chemotherapy. Conclusions: Proteomic analysis of HER2 expression demonstrated a quantitative cutoff that improves selection of GC patients for trastuzumab as compared with current diagnostic methods.

Circulating DNA for detection of gastric cancer.

OBJECTIVE: Gastric cancer (GC) is one of the most common malignant tumors worldwide, particularly, prevalent in China. Despite the decreasing incidence of GC in China, the 5-year survival rate is still not over 30% yet. Therefore, early diagnosis and therapeutic outcome evaluation of GC remains as the issue to be resolved in a clinical setting. MATERIALS AND METHODS: Recent studies have found the presence of a certain amount of circulating DNA in the peripheral blood of patients with malignant tumor and shown that these free DNA bear tumor-specific genetic information. The circulating DNA detection includes quantitative and qualitative methods and analysis. Combined monitoring of changes in circulating DNA levels and aberrant alteration of relevant tumor genes is likely to provide comprehensive real-time information to patients. RESULTS: Under normal conditions, oncogene presents in the form of proto-oncogene such as K-ras, which is in non-carcinogenic status under the influence of tumor suppressor gene. When tumor suppressor gene is damaged or mutated of oncogene itself is induced for instance P53, oncogene is then activated and induces tumorigenesis. However, compared to gene mutation detection, the detection of DNA methylation is relatively more well-developed and stable. CONCLUSIONS: This article reviews the current status of the research on circulating DNA in the diagnosis, assessment of response to therapy and prognostic evaluation in GC. In addition, the advantage, current issue and prospect of using circulating DNA as tumor marker are also analyzed.

Impact of caudal block on postoperative complications in children undergoing tubularised incised plate urethroplasty for hypospadias repair: a retrospective cohort study.

This study aimed to assess the association between caudal block and postoperative complications after tubularised incised plate urethroplasty. The medical records of 388 paediatric patients who underwent urethroplasty at a tertiary medical centre were analysed retrospectively. Among the 342 patients included, 216 patients received a caudal block and 72 (21.1%) patients suffered surgical complications. The number of patients having surgical complications was significantly greater among patients who received a caudal block than among patients who did not receive a caudal block (53 (24.5%) versus 19 (15.1%), respectively, p = 0.04). Based on multivariate logistic regression analysis, duration of surgery, caudal block and hypospadias types were independent risk factors for the surgical complications. Patients with caudal block had an odds ratio of 2.1 (95% CI, 1.14-3.81, p = 0.018) for the development of postoperative complications compared with patients without caudal block. This analysis demonstrates that caudal block is associated with surgical complications after tubularised incised plate urethroplasty.

Is c-Met oncoprotein expression an adverse prognosticator in extrahepatic bile duct cancer treated with curative resection followed by adjuvant chemoradiotherapy?

PURPOSE: To analyze the expression of c-Met, and to investigate correlations between the expression of c-Met, clinicopathologic variables, and survival in patients undergoing curative surgery followed by adjuvant chemoradiotherapy for extrahepatic bile duct (EHBD) cancer. METHODS: Ninety EHBD cancer patients who underwent curative resection followed by adjuvant chemoradiotherapy were enrolled. Expression of c-Met was assessed with immunohistochemical staining on tissue microarray. The correlation between clinicopathologic variables and survival outcomes was evaluated using Kaplan-Meier method and Cox proportional hazard model. RESULTS: On univariate analysis, 66 patients (76.7 %) showed c-Met expression. c-Met expression had a significant impact on 5-year overall survival (OS) (43.0 % in c-Met(+) vs. 25.0 % in c-Met(-), p = 0.0324), but not on loco-regional relapse-free survival or distant metastasis-free survival (DMFS). However, on multivariate analysis incorporating tumor location and nodal involvement, survival difference was not maintained (p = 0.2940). Tumor location was the only independent prognostic factor predicting OS (p = 0.0089). Hilar location tumors, nodal involvement, and poorly differentiated tumors were all identified as independent prognostic factors predicting inferior DMFS (p = 0.0030, 0.0013, and 0.0037, respectively). CONCLUSIONS: This study showed that c-Met expression was not associated with survival outcomes in EHBD cancer patients undergoing curative resection followed by adjuvant chemoradiotherapy. Further studies are needed to fully elucidate the prognostic value of c-Met expression in these patients.

A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer.

BACKGROUND: The purpose of this randomised phase III trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3methyglutaryl coenzyme A reductase inhibitor, to XELIRI/FOLFIRI chemotherapy regimens confers a clinical benefit to patients with previously treated metastatic colorectal cancer. METHODS: We undertook a double-blind, placebo-controlled phase III trial of 269 patients previously treated for metastatic colorectal cancer and enrolled in 5 centres in South Korea. Patients were randomly assigned (1:1) to one of the following groups: FOLFIRI/XELIRI plus simvastatin (40 mg) or FOLFIRI/XELIRI plus placebo. The FOLFIRI regimen consisted of irinotecan at 180 mg m(-2) as a 90-min infusion, leucovorin at 200 mg m(-2) as a 2-h infusion, and a bolus injection of 5-FU 400 mg m(-2) followed by a 46-h continuous infusion of 5-FU at 2400 mg m(-2). The XELIRI regimen consisted of irinotecan at 250 mg m(-2) as a 90-min infusion with capecitabine 1000 mg m(-2) twice daily for 14 days. The primary end point was progression-free survival (PFS). Secondary end points included response rate, duration of response, overall survival (OS), time to progression, and toxicity. RESULTS: Between April 2010 and July 2013, 269 patients were enrolled and assigned to treatment groups (134 simvastatin, 135 placebo). The median PFS was 5.9 months (95% CI, 4.5-7.3) in the XELIRI/FOLFIRI plus simvastatin group and 7.0 months (95% CI, 5.4-8.6) in the XELIRI/FOLFIRI plus placebo group (P=0.937). No significant difference was observed between the two groups with respect to OS (median, 15.9 months (simvastatin) vs 19.9 months (placebo), P=0.826). Grade⩾3 nausea and anorexia were noted slightly more often in patients in the simvastatin arm compared with with the placebo arm (4.5% vs 0.7%, 3.0% vs 0%, respectively). CONCLUSIONS: The addition of 40 mg simvastatin to the XELIRI/FOLFIRI regimens did not improve PFS in patients with previously treated metastatic colorectal cancer nor did it increase toxicity.

Micro-Structural Properties of YBa2Cu3O(7-x)/ZnO Nanorods on SrTiO3.

We examined the local structural and the interfacial properties of YBa2Cu3O(7-x) (YBCO)/ZnO nanorods on SrTiO3 (STO) substrates using various measurements. Vertically aligned ZnO nanorods were synthesized on STO substrates using a catalyst-free metal-organic chemical vapor deposition. YBCO films were deposited ex-situ on the ZnO nanorods/STO templates using a DC magnetron sputtering deposition. X-ray diffraction revealed that the YBCO films were crystallized along their c-axes on the ZnO nanorods/STO templates. Transmission electron microscopy measurements demonstrated that YBCO filled the space between ZnO nanorods and that both interfaces of YBCO/ZnO nanorods and ZnO nanorods/STO were quite clean with no disorder. Polarization-dependent extended X-ray absorption fine structure measurements at the Cu K edge showed extra disorder in the CuO2 planes of YBCO/ZnO nanorods/STO, compared with that of YBCO/STO. The superconductivity transition temperature (T(c)) of YBCO/ZnO nanorods/STO was approximately 50 K whereas that of YBCO/STO was 93 K. The decrease of T(c) of YBCO/ZnO nanorods/STO was ascribed to the structural disorder of CuO2 planes as well as grain boundaries in the YBCO films.

CXC chemokine ligand 12a enhances chondrocyte proliferation and maturation during endochondral bone formation.

OBJECTIVE: We investigated the roles of CXC chemokine ligand 12a (CXCL12a), also known as stromal cell-derived factor-1α (SDF-1α), in endochondral bone growth, which can give us important clues to understand the role of CXCL12a in osteoarthritis (OA). METHODS: Primary chondrocytes and tibial explants from embryonic 15.5 day-old mice were cultured with recombinant mouse CXCL12a. To assess the role of CXCL12a in chondrogenic differentiation, we conducted mesenchymal cell micromass culture. RESULTS: In tibia organ cultures, CXCL12a increased total bone length in a dose-dependent manner through proportional effects on cartilage and bone. In accordance with increased length, CXCL12a increased the protein level of proliferation markers, such as cyclin D1 and proliferating cell nuclear antigen (PCNA), in primary chondrocytes as well as in tibia organ culture. In addition, CXCL12a increased the expression of Runx2, Col10 and MMP13 in primary chondrocytes and tibia organ culture system, implying a role of CXCL12a in chondrocyte maturation. Micromass cultures of limb-bud mesenchymal progenitor cells (MPCs) revealed that CXCL12a has a limited effect on early chondrogenesis, but significantly promoted maturation of chondrocytes. CXCL12a induced the phosphorylation of p38 and Erk1/2 MAP kinases and IκB. The increased expression of cyclin D1 by CXCL12a was significantly attenuated by inhibitors of MEK1 and NF-κB. On the other hand, p38 and Erk1/2 MAP kinase and NF-κB signaling were associated with CXCL12a-induced expression of Runx2 and MMP13, the marker of chondrocyte maturation. CONCLUSION: CXCL12a promoted the proliferation and maturation of chondrocytes, which strongly suggest that CXCL12a may have a negative effect on articular cartilage and contribute to OA progression.

Disruption of CTCF/cohesin-mediated high-order chromatin structures by DNA methylation downregulates PTGS2 expression.

The CCCTC-binding factor (CTCF)/cohesin complex regulates gene transcription via high-order chromatin organization of the genome. De novo methylation of CpG islands in the promoter region is an epigenetic hallmark of gene silencing in cancer. Although the CTCF/cohesin complex preferentially targets hypomethylated DNA, it remains unclear whether the CTCF/cohesin-mediated high-order chromatin structure is affected by DNA methylation during tumorigenesis. We found that DNA methylation downregulates the expression of prostaglandin-endoperoxide synthase 2 (PTGS2), which is an inducible, rate-limiting enzyme for prostaglandin synthesis, by disrupting CTCF/cohesin-mediated chromatin looping. We show that the CTCF/cohesin complex is enriched near a CpG island associated with PTGS2 and that the PTGS2 locus forms chromatin loops through methylation-sensitive binding of the CTCF/cohesin complex. DNA methylation abolishes the association of the CTCF/cohesin complex with the PTGS2 CpG island. Disruption of chromatin looping by DNA methylation abrogates the enrichment of transcriptional components, such as positive elongation factor b, at the transcriptional start site of the PTGS2 locus. These alterations result in the downregulation of PTGS2. Our results provide evidence that CTCF/cohesin-mediated chromatin looping of the PTGS2 locus is dynamically influenced by the DNA methylation status.

Long-term outcome of transanal irrigation for children with spina bifida.

STUDY DESIGN: Experimental, prospective study. OBJECTIVES: We evaluated the long-term clinical efficacy of transanal irrigation (TAI) and its effect on the quality of life of spina bifida children and their caregivers. SETTING: Republic of Korea. METHOD: Forty-four spina bifida pediatric patients with constipation, fecal incontinence or both, underwent a TAI program at our spina bifida clinic between December 2010 and October 2013. The children and their caregivers were evaluated using a self-administered questionnaire before TAI and at 3 months and 3 years after initiation of the program. RESULTS: Successful treatment outcome was achieved in 38 (86.4%) children after a mean follow-up duration of 33 months (range, 30-36). The mean number of fecal incontinence episodes per week, the number of diaper changes and the total time for bowel care per day before the program decreased at the latest follow-up examination from 7.3 to 0.4 (P<0.001), 1.6 to 0.2 (P<0.001) and 29.2 to 19.4 min (P=0.038), respectively. These results remained constant from short-term follow-up at 3 months to 3 years. Caregivers and children could go out more often (P=0.002), and the emotional impact of bowel care on caregivers decreased (P<0.001). The reported mean overall satisfaction with TAI was 8/10. The common adverse effect during TAI was abdominal discomfort (60.5%). CONCLUSION: We observed a sustained significant improvement in defecation symptoms and quality of life for 3 years in spina bifida children who underwent continuous TAI.

Apparent treatment-resistant hypertension among elderly Korean hypertensives: an insight from the HIT registry.

The aim of this study was to determine the clinical characteristics of patients with resistant hypertension (RH) and predictors among elderly Korean hypertensives. This prospective, multi-center, observational study evaluated 2439 elderly hypertensive patients between December 2008 and November 2011, who visited secondary hypertension clinics for high blood pressure (BP). Patients were categorized as resistant if their BP was ≥140/90 mm Hg and if they reported using antihypertensive medications from three different drug classes, including a diuretic or drugs from ≥4 antihypertensive drug classes, regardless of BP. Characteristics of patients with RH were compared with those of patients who were controlled with one or two antihypertensive medications after 6-month antihypertensive treatment. In comparison with 837 patients with non-RH, 404 patients with RH were more likely to be aware of their status of high BP before enrollment and have a high baseline systolic BP ≥160 mm Hg, microalbuminuria, high body mass index (BMI) ≥24 kg m(-2) and diabetes mellitus (DM). In drug-naive patients, awareness of hypertension at baseline was the only independent predictor for RH. In elderly Korean hypertensives, BMI (≥24 kg m(-2)), baseline systolic BP (≥160 mm Hg), microalbuminuria, DM and awareness of hypertension showed an association with RH.

Testican-1-mediated epithelial-mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer.

Human epidermal growth factor receptor 2 (HER2)-directed treatment using trastuzumab has shown clinical benefit in HER2-positive gastric cancer. Clinical trials using lapatinib in HER2-positive gastric cancer are also currently underway. As with other molecularly targeted agents, the emergence of acquired resistance to HER2-directed treatment is an imminent therapeutic problem for HER2-positive gastric cancer. In order to investigate the mechanisms of acquired resistance to HER2-directed treatment in gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (SNU216 LR) in vitro by chronic exposure of a HER2-positive gastric cancer cell line (SNU216) to lapatinib. The resultant SNU216 LR cells were also resistant to gefitinib, cetuximab, trastuzumab, afatinib and dacomitinib. Interestingly, SNU216 LR cells displayed an epithelial-mesenchymal transition (EMT) phenotype and maintained the activation of MET, HER3, Stat3, Akt and mitogen-activated protein kinase signaling in the presence of lapatinib. Using gene expression arrays, we identified the upregulation of a variety of EMT-related genes and extracellular matrix molecules, such as Testican-1, in SNU216 LR cells. We showed that the inhibition of Testican-1 by small interfering RNA decreased Testican-1-induced, MET-dependent, downstream signaling, and restored sensitivity to lapatinib in these cells. Furthermore, treatment with XAV939 selectively inhibited ß-catenin-mediated transcription and Testican-1-induced EMT signaling, leading to G1 arrest. Taken together, these data support the potential role of EMT in acquired resistance to HER2-directed treatment in HER2-positive gastric cancer, and provide insights into strategies for preventing and/or overcoming this resistance in patients.

Novel fusion transcripts in human gastric cancer revealed by transcriptome analysis.

Gene fusion is involved in the development of various types of malignancies. Recent advances in sequencing technology have facilitated identification of gene fusions and have stimulated the research of this field in cancer. In the present study, we performed next-generation transcriptome sequencing in order to discover novel gene fusions in gastric cancer. A total of 282 fusion transcript candidates were detected from 12 gastric cancer cell lines by bioinformatic filtering. Among the candidates, we have validated 19 fusion transcripts, which are 7 inter-chromosomal and 12 intra-chromosomal fusions. A novel DUS4L-BCAP29 fusion transcript was found in 2 out of 12 cell lines and 10 out of 13 gastric cancer tissues. Knockdown of DUS4L-BCAP29 transcript using siRNA inhibited cell proliferation. Soft agar assay further confirmed that this novel fusion transcript has tumorigenic potential. We also identified that microRNA-coding gene PVT1, which is amplified in double minute chromosomes in SNU-16 cells, is recurrently involved in gene fusion. PVT1 produced six different fusion transcripts involving four different genes as fusion partners. Our findings provide better insight into transcriptional and genetic alterations of gastric cancer: namely, the tumorigenic effects of transcriptional read-through and a candidate region for genetic instability.

X-ray absorption fine structure study of cobalt ion distribution in ferromagnetic Zn(1-x)Co(x)O films.

We examined the distribution of Co ions in ferromagnetic n-type Zn(1-x)Co(x)O semiconducting films with Co concentrations of 0.0-0.07 using x-ray absorption fine structure (XAFS) measurements at the Co and Zn K edges. Extended XAFS (EXAFS) revealed that Co ions mainly occupied the zinc sites in the films. X-ray absorption near edge structure (XANES) spectra demonstrated that the pre-edge peak of the Co K edge was substantially affected by the second neighboring Co ions in the zinc sites due to their environmental potential distortion. From the pre-edge peak and EXAFS analysis using ab initio calculations, we found that Co ions uniformly occupied the zinc sites of the Zn0.93Co0.07O film, whereas the Co ions of the Zn0.97Co0.03O and Zn0.95Co0.05O films were substituted at the zinc sites with a non-uniform distribution. The ferromagnetic properties of the Zn0.93Co0.07O film may be induced by direct interaction between the magnetic dipoles of the Co ions with a mean distance of 4.3 Å, or by the Co conduction-electron mediation.