novoBreak: local assembly for breakpoint detection in cancer genomes.

We present novoBreak, a genome-wide local assembly algorithm that discovers somatic and germline structural variation breakpoints in whole-genome sequencing data. novoBreak consistently outperformed existing algorithms on real cancer genome data and on synthetic tumors in the ICGC-TCGA DREAM 8.5 Somatic Mutation Calling Challenge primarily because it more effectively utilized reads spanning breakpoints. novoBreak also demonstrated great sensitivity in identifying short insertions and deletions

Heterogeneous amplification of ERBB2 in primary lesions is responsible for the discordant ERBB2 status of primary and metastatic lesions in gastric carcinoma

Aims: To determine the extent of HER2 homogeneity/heterogeneity in primary versus metastatic gastric carcinoma ( GC). Materials and results: The human epidermal growth factor receptor 2 ( HER2) status in primary and metastatic lesions was evaluated by immunohistochemistry ( IHC) and fluorescence in-situ hybridization ( FISH). Four separate cohorts consisting of primary GC alone or primary GC paired with metastatic lesions were examined. In the FISH analysis of 325 primary GCs, eight cases ( 2.5%) showed amplification with a heterogeneous pattern, whereas 27 cases ( 8.3%) showed amplification with a homogeneous pattern, and in this cohort the discordant: concordant FISH ratio based on examination of three different areas in each primary lesion was 0.30: 1. FISH testing using 250 paired primary and metastatic lesions revealed seven cases (2.8%) with discordant amplification. In metastatic disease positive conversion occurred in six cases (2.4%), whereas negative conversion happened in one case (0.4%). The discordant: concordant ratio of primary versus secondary lesions was 0.23: 1. When the seven discordant cases were re-evaluated using whole sections of primary GCs, six showed a heterogeneous pattern of amplification. Conclusions: These findings suggest that the discordant HER2 amplification observed in metastatic lesions is explained substantially by heterogeneity within primary tumours

An Integrated Individual Environmental Exposure Assessment System for Real-Time Mobile Sensing in Environmental Health Studies

The effects of environmental exposure on human health have been widely explored by scholars in health geography for decades. However, recent advances in geospatial technologies, especially the development of mobile approaches to collecting real-time and high-resolution individual data, have enabled sophisticated methods for assessing people’s environmental exposure. This study proposes an individual environmental exposure assessment system (IEEAS) that integrates objective real-time monitoring devices and subjective sensing tools to provide a composite way for individual-based environmental exposure data collection. With field test data collected in Chicago and Beijing, we illustrate and discuss the advantages of the proposed IEEAS and the composite analysis that could be applied. Data collected with the proposed IEEAS yield relatively accurate measurements of individual exposure in a composite way, and offer new opportunities for developing more sophisticated ways to measure individual environmental exposure. With the capability to consider both the variations in environmental risks and human mobility in high spatial and temporal resolutions, the IEEAS also helps mitigate some uncertainties in environmental exposure assessment and thus enables a better understanding of the relationship between individual environmental exposure and health outcomes

TDP1 and TOP1 Modulation in Olaparib-Resistant Cancer Determines the Efficacy of Subsequent Chemotherapy

The aim of this study was to elucidate the carryover effect of olaparib to subsequent chemotherapy and its underlying mechanisms. We generated olaparib-resistant SNU-484, SNU-601, SNU-668, and KATO-III gastric cancer cell lines and confirmed their resistance by cell viability and colony forming assays. Notably, olaparib-resistant cell lines displayed cross-resistance to cisplatin except for KATO-III. Inversely, olaparib-resistant SNU-484, SNU-668, and KATO-III were more sensitive to irinotecan than their parental cells. However, sensitivity to paclitaxel remained unaltered. There were compensatory changes in the ATM/ATR axis and p-Chk1/2 protein expression. ERCC1 was also induced in olaparib-resistant SNU-484, SNU-601, and SNU-668, which showed cross-resistance to cisplatin. Olaparib-resistant cells showed tyrosyl-DNA phosphodiesterase 1 (TDP1) downregulation with higher topoisomerase 1 (TOP1) activity, which is a target of irinotecan. These changes of TOP1 and TDP1 in olaparib-resistant cells was confirmed as the underlying mechanism for increased irinotecan sensitivity through manipulated gene expression of TOP1 and TDP1 by specific plasmid transfection and siRNA. The patient-derived xenograft model established from the patient who acquired resistance to olaparib with BRCA2 mutation showed increased sensitivity in irinotecan. In conclusion, the carryover effects of olaparib to improve antitumor effect of subsequent irinotecan were demonstrated. These effects should be considered when determining the subsequent therapy with olaparib.

Surface-modified poly(lactide- co -glycolide) nanospheres for targeted bone imaging with enhanced labeling and delivery of radioisotope

Surface-modified nanospheres can be utilized for targeting drugs and diagnostic agents to the bone and bone marrow while extending their circulation time in the blood stream. The surface modification of poly(lactide- co -glycolide) (PLGA) nanospheres by radioisotope carrying poly(ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide) triblock copolymers (Poloxamer 407) has been assessed by in vitro characterization and in vivo biodistribution studies after intravenous administration of the nanospheres to the mouse. A hydroxyphenylpropionic acid, a ligand for 125 I and 131 I labeling, was conjugated to the hydroxyl group of the Poloxamer 407 by using dicyclohexyl carbodiimide. The ligand-conjugated Poloxamer 407 was adsorbed onto the surface of PLGA nanospheres. Surface coating was confirmed by measuring both size distribution and the surface charge of the nanospheres. Besides, 125 I-labeling efficiency, radiolabeling stability, whole body imaging, and biodistribution of the radioisotope-labeled nanospheres were examined. Ligand-labeled, surface-modified PLGA nanospheres were in 100-nm size ranges, which may be adequate for long-circulation and further bone imaging. 125 I-labeling efficiency was >90% and was more stable at human serum for 24 h. A noticeable decrease in liver or spleen uptake was obtained by the surface-modified nanospheres. 125 I-labeled nanospheres showed higher blood maintenance and bone uptake compared with stannous colloid with the same size distribution. Therefore, a fully biodegradable, radioisotope-carrying, surface-modified nanosphere system has been developed as a promising tool for targeting bone and bone marrows. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 67A: 751–760, 2003Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34431/1/10167_ftp.pd

Amniotic fluid embolism that took place during an emergent Cesarean section -A case report-

Amniotic fluid embolism (AFE) is a rare but fatal obstetric emergency, characterized by sudden cardiovascular collapse, dyspnea or respiratory arrest and altered mentality, disseminated intravascular coagulation (DIC). It can lead to severe maternal morbidity and mortality, but the prediction of its occurrence and treatment are very difficult. We experienced a case of AFE during emergent Cesarean section in a 40+6 weeks healthy pregnant woman, age 33. Sudden dyspnea, hypotension, signs of pulmonary edema and DIC were developed during Cesarean section, and cardiac arrest followed after these events. The course of these events was so rapid and catastrophic, which was consistent with AFE. Thus, we report this case precisely and review pathophysiology, diagnosis, treatment of AFE by referring to up-to-date literatures

Phase II Study of Low-dose Paclitaxel and Cisplatin as a Second-line Therapy after 5-Fluorouracil/Platinum Chemotherapy in Gastric Cancer

This study was performed to evaluate the efficacy and toxicity of low-dose paclitaxel/cisplatin chemotherapy in patients with metastatic or recurrent gastric cancer that had failed 5-fluorouracil/platinum-based chemotherapy. Thirty-two patients with documented progression on or within 6 months after discontinuing 5-fluorouracil/platinum-based chemotherapy were enrolled. As a second-line treatment, paclitaxel (145 mg/m2) and cisplatin (60 mg/m2) was administered on day 1 every 3 weeks. Among 32 patients enrolled, 8 (25%) responded partially to paclitaxel/cisplatin, 8 (25%) had stable disease, and 14 (44%) had progressive disease. Two patients (6%) were not evaluable. The median time to progression (TTP) and overall survival for all patients were 2.9 months and 9.1 months, respectively. The most common hematologic toxicity was anemia (47%). Grade 3 neutropenia developed in three patients (9%), but no other grade 3/4 hematologic toxicity occurred. The most common non-hematologic toxicities were emesis (31%) and peripheral neuropathy (38%). Three cases (9%) of grade 3/4 emesis and 2 cases (6%) of grade 3 peripheral neuropathy developed. In conclusion, low-dose paclitaxel and cisplatin chemotherapy showed moderate activity with favorable toxicity profiles. However, relatively short TTP of this regimen warrants the development of more effective paclitaxel-based regimens other than combination with cisplatin in these patients as second-line therapies

Short- and long-term outcomes of single bare metal stent versus drug eluting stent in nondiabetic patients with a simple de novo lesion in the middle and large vessel

<p>Abstract</p> <p>Objective</p> <p>This study was aimed to investigate the short- and long-term outcomes of percutaneous coronary intervention (PCI) between single bare metal stent (BMS) and single drug eluting stent (DES) in nondiabetic patients with a simple de novo lesion in the middle and large vessel.</p> <p>Methods</p> <p>Two hundred and thirty-five consecutive patients with a simple de novo lesion in the middle and large vessel were treated with BMS or DES in our hospital from Apr. 2004 to Dec. 2004.</p> <p>The inclusion criteria: a simple de novo lesion in the middle and large vessel, stent diameter ≥ 3.0 mm, stent length ≤ 18 mm, the exclusion criteria: diabetes mellitus, left main trunk disease and left ventricular ejection fraction ≤ 30%. Of them, there were 150 patients in BMS group and 85 patients in DES group, and the rates of lost to follow up were 6.7% and 1.2% respectively.</p> <p>Results</p> <p>BMS group had lower hypercholesteremia rate (22.0% vs 38.8%) and higher proportion of TIMI grade 0 (12% vs 1.2%) than DES group (all P < 0.05), but both groups had similar stent length (16.16 ± 2.81 mm vs 16.06 ± 2.46 mm) and stent diameter (3.85 ± 3.07 mm vs 3.19 ± 0.24 mm) after procedure, in-segment restenosis rate (0% vs 1.2%) and target lesion revascularization (TLR, 2.0% vs 2.4%) at 6-month follow-up (all P > 0.05). No difference was found in TLR (1.3% vs 1.2%, P = 1.00) and recurrent myocardial infarction (Re-MI) (0% vs 1.2%, P = 0.36), cardiac death (0.7% vs 1.2%, P = 1.00) between 1- and 3-year. So were TLR (6.0% vs 5.9%, P = 0.97), Re-MI (0% vs 2.4%, P = 0.06), cardiac death (2.0% vs 3.5%, P = 0.48) and major adverse cardiac events (MACE, 8.7% vs 10.6%, P = 0.63), cardiac death-free cumulative survival (98.7% vs 97.7%, P = 0.56), TLR-free cumulative survival (94.0% vs 94.1%, P = 0.98) and Re-MI-free cumulative survival (100% vs 97.7%, P = 0.06) at 3-year follow-up.</p> <p>Conclusion</p> <p>The single BMS has similar efficacy and safety to single DES in nondiabetic patients with a simple de novo lesion in the middle and large vessel at short- and long-term follow-up.</p

Modified FOLFOX-6 chemotherapy in advanced gastric cancer: Results of phase II study and comprehensive analysis of polymorphisms as a predictive and prognostic marker

<p>Abstract</p> <p>Background</p> <p>The objective of this study was to evaluate the efficacy and toxicity of infusional 5-fluorouracil (5-FU), folinic acid and oxaliplatin (modified FOLFOX-6) in patients with advanced gastric cancer (AGC), as first-line palliative combination chemotherapy. We also analyzed the predictive or prognostic value of germline polymorphisms of candidate genes associated with 5-FU and oxaliplatin.</p> <p>Methods</p> <p>Seventy-three patients were administered a 2 hour infusion of oxaliplatin (100 mg/m²) and folinic acid (100 mg/m²) followed by a 46 hour continuous infusion of 5-FU (2,400 mg/m²). Genomic DNA from the patients' peripheral blood mononuclear cells was extracted. Ten polymorphisms within five genes were investigated including TS, GSTP, ERCC, XPD and XRCC.</p> <p>Results</p> <p>The overall response rate (RR) was 43.8%. Median time to progression (TTP) and overall survival (OS) were 6.0 months and 12.6 months, respectively. Toxicities were generally tolerable and manageable. The RR was significantly higher in patients with a 6-bp deletion homozygote (-6 bp/-6 bp) in TS-3'UTR (55.0% <it>vs</it>. 30.3% in +6 bp/+6 bp or +6 bp/-6 bp, <it>p </it>= 0.034), and C/A or A/A in XPD156 (52.0% <it>vs</it>. 26.1% in C/C, <it>p </it>= 0.038). The -6 bp/-6 bp in TS-3'UTR was significantly associated with a prolonged TTP and OS. In a multivariate analysis, the 6-bp deletion in TS-3'UTR was identified as an independent prognostic marker of TTP (hazard ratio = 0.561, <it>p </it>= 0.032).</p> <p>Conclusion</p> <p>Modified FOLFOX-6 chemotherapy appears to be active and well tolerated as first line chemotherapy in AGC patients. The 6-bp deletion in TS-3'UTR might be a candidate to select patients who are likely to benefit from 5-FU based modified FOLFOX-6 in future large scale trial.</p