[Show abstract][Hide abstract] ABSTRACT: Peritoneal carcinomatosis accompanied by malignant ascites is a major cause of death of advanced gastric cancer (GC). To comprehensively characterize the underlying genomic events involved in GC peritoneal carcinomatosis, we analyzed whole-exome sequences of normal gastric tissues, primary tumors, and malignant ascites from eight GC patients. We identified a unique mutational signature biased toward C-to-A substitutions in malignant ascites. In contrast, the patients who received treatment of adjuvant chemotherapy showed a high rate of C-to-T substitutions along with hypermutation in malignant ascites. Comparative analysis revealed several candidate mutations for GC peritoneal carcinomatosis: recurrent mutations in COL4A6, INTS2, and PTPN13; mutations in druggable genes including TEP1, PRKCD, BRAF, ERBB4, PIK3CA, HDAC9, FYN, FASN, BIRC2, FLT3, ROCK1, CD22, and PIK3C2B; and mutations in metastasis-associated genes including TNFSF12, L1CAM, DIAPH3, ROCK1, TGFBR1, MYO9B, NR4A1, and RHOA. Notably, gene ontology analysis revealed the significant enrichment of mutations in the Rho-ROCK signaling pathway-associated biological processes in malignant ascites. At least four of the eight patients acquired somatic mutations in the Rho-ROCK pathway components, suggesting the possible relevance of this pathway to GC peritoneal carcinomatosis. These results provide a genome-wide molecular understanding of GC peritoneal carcinomatosis and its clinical implications, thereby facilitating the development of effective therapeutics.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
The purpose was to assess the effects of chlorhexidine gluconate (CHG) bathing on health care-associated infections among critically ill patients.
This meta-analysis evaluated English-language studies from the PubMed, Embase, and Cochrane databases. The Cochrane Collaboration methodology was used to evaluate all publications regarding daily CHG bathing and the risks of acquiring central line-associated bloodstream infection (CLABSI), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE). Risk ratios (RRs) and the ratio of the log RRs (RRR) were estimated with 95% confidence intervals (CIs).
Eighteen studies were included. Compared with conventional care, the RRs (95% CIs) for CLABSI, MRSA, and VRE with CHG bathing were 0.45 (0.37-0.55), 0.67 (0.59-0.77), and 0.60 (0.42-0.85), respectively (all, P < .05). For MRSA acquisition, CHG bathing with concomitant nasal antibiotics provided a lower incidence compared with only CHG bathing (RRR: 0.81, 95% CI: 0.66-0.98, P = .035). Greater risk reduction was also observed in studies with prolonged interventions (RRR per 1-month extension: -0.02, P = .027).
Daily CHG bathing was associated with reduced risks of acquiring CLABSI, MRSA, and VRE. A prolonged intervention period and concomitant nasal antibiotic use were associated with lower risks of MRSA acquisition.
No preview · Article · Dec 2015 · Journal of critical care
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Early diagnosis and timely treatment are essential to improve the outcomes of pulmonary embolism (PE), but no study has investigated the impact of anticoagulation timing on clinical outcomes in high-risk acute PE patients. We analyzed the relationship between early anticoagulation initiation and in-hospital mortality in high-risk acute PE patients at the intensive care unit (ICU) of a teaching hospital.
Materials and methods:
Seventy-three PE patients admitted to the ICU were included in this retrospective study. Demographic, clinical, radiological, and therapeutic data were collected on ICU admission, and the timings of diagnosis and anticoagulation initiation were analyzed.
The number of survivors was 67. The median time from hospital arrival to the start of anticoagulation therapy was significantly lower in survivors (3.6 [2.6-5.0] hours) than nonsurvivors (5.7 [4.5-14.9] hours; P = .03). However, the median time required to achieve a therapeutic anticoagulation level was comparable between survivors and nonsurvivors (12.0 [9.5-19.5] vs 16.4 [10.7-27.4] hours; P = .488). Ventilatory support and vasopressor use were found to be associated with higher in-hospital mortality.
Delayed anticoagulation is an important prognostic factor of poor outcomes in high-risk acute PE patients.
No preview · Article · Dec 2015 · Journal of critical care
[Show abstract][Hide abstract] ABSTRACT: Copy number variation is a well‑known genetic variation. microRNAs (miRNAs/miRs) are non‑coding RNAs that mediate gene expression by regulating target mRNAs. In the present study, copy number deletions encompassing miRNA coding regions were investigated to determine the association between the deletion of miRNA and its phenotypic effects. A total of 38 human miRNAs in copy number variants were identified and miR‑650, which is functional in the human osteosarcoma MG‑63 cell line, was selected. Overexpression of miR‑650 decreased the expression of inhibitor of growth family member 4 (ING4) in the MG‑63 cells and increased interleukin (IL)6 transcription, as well as IL6 secretion in IL1B‑stimulated cells. Furthermore, miR‑650 downregulated the amount of nuclear factor of κ light polypeptide gene enhancer in B cells inhibitor α and increased the transcriptional activity of nuclear factor (NF)κB. Downregulation of ING4 also increased the production of IL6, similar to miR‑650 overexpression. Taken together, these data indicate that miR‑650 plays a significant role in the production of IL6 by regulating ING4 expression and NFκB signaling in IL1B‑stimulated MG‑63 osteosarcoma cells.
[Show abstract][Hide abstract] ABSTRACT: Hemangioma is the most common type of benign tumor that arises in the liver. Although rupture and hemorrhage of hepatic hemangioma are rare complications, they can be the cause of mortality. The authors report a case of hemorrhagic hepatic hemangioma: in a 54-year-old woman who was admitted with epigastric pain. She had taken oral contraceptives several weeks prior. The results of a blood examination were normal. An abdominal computed tomography scan revealed a tumor in hepatic segment 4, and a hemorrhage inside the cystic mass was suspected. The mass was removed laparoscopically to confirm the tumor properties and control the hemorrhage. The pathologic findings of the resected mass were consistent with hepatic hemangioma with intratumoral hemorrhage. The patient was discharged 8 d after the surgery, without further complications or complaints, and the patient's condition was found to have improved during follow-up.
[Show abstract][Hide abstract] ABSTRACT: In the previous study, we observed agmatine (AGM) posttreatment immediately after 30 minutes of suture occlusion of the middle cerebral artery (MCAO) reduced the infarct size and neurological deficit in diabetic rats. The aim of the present study was to investigate the anti-inflammatory effect of AGM to reduce cerebral ischemic damage in diabetic rats.
Normoglycemic (n=20) and streptozotocin-induced diabetic rats (n=40) were subjected to 30 minutes of MCAO followed by reperfusion. Twenty diabetic rats were treated with AGM (100 mg/kg, intraperitoneal) immediately after 30 minutes of MCAO. Modified neurological examinations and rotarod exercises were performed to evaluate motor function. Western blot and immunohistochemical analysis were performed to determine the expression of inflammatory cytokines in ischemic brain tissue. Real-time polymerase chain reaction was performed to measure the mRNA expression of high-mobility group box 1, receptor for advanced glycation end products (RAGE), Toll-like receptor (TLR)2, and TLR4 RESULTS AND CONCLUSIONS:: AGM posttreatment improved the neurobehavioral activity and motor function of diabetic MCAO rats at 24 and 72 hours after reperfusion. Immunohistochemical analysis showed that AGM treatment significantly decreased the expression of inflammatory cytokines in diabetic MCAO rats at 24 and 72 hours after reperfusion (P<0.01). Western blotting and real-time polymerase chain reaction results indicated that AGM treatment significantly decreased the expression of high-mobility group box 1, RAGE, TLR2, and TLR4 in diabetic rats at 24 hours after reperfusion (P<0.05). This neuroprotective effect of AGM after MCAO was associated with modulation of the postischemic neuronal inflammation cascade.
No preview · Article · Jun 2015 · Journal of neurosurgical anesthesiology
[Show abstract][Hide abstract] ABSTRACT: Intravenous tissue-type plasminogen activator (tPA) is recognized as the standard treatment for ischemic stroke. However, its narrow therapeutic window and association with an increased risk of intracranial hemorrhage have required caution when used. In this context, several approaches are required to deal with the shortcomings of such a double-edged drug. Anesthetics are known to protect against ischemic reperfusion injury, and their protective role in ischemic post-conditioning is crucial for reducing ischemia-related injury. The aim of this study was to assess the effect of isoflurane post-treatment on intracranial hemorrhage and cerebral infarction after tPA treatment for transient cerebral ischemia.
Cerebral ischemia was modeled in male Sprague-Dawley rats (n = 32) by occluding the right middle cerebral artery for 1 h, followed by intravenous tPA administration. Rats were randomly divided into control and isoflurane post-treatment group, and isoflurane post-treatment group was post-treated by administering 1.5% isoflurane for 1 h from the start of reperfusion. Twenty-four h after reperfusion, neurobehavioral changes were assessed. The extent of cerebral infarction and intracranial hemorrhage were also assessed by quantification of infarction volume and cerebral hemoglobin concentration from brain tissue, respectively.
Neurobehavioral testing showed better functional outcomes in the isoflurane post-treatment group than the control group. The extent of cerebral infarction and intracranial hemorrhage were both reduced in isoflurane post-treatment group compared to control group.
Isoflurane post-treatment may mitigate infarction volume and intracranial hemorrhage in tPA-exaggerated brain injury. Our findings provide an encouraging novel approach for enhancing clinical outcomes in tPA-exaggerated brain injury.
Preview · Article · Jun 2015 · Korean journal of anesthesiology
[Show abstract][Hide abstract] ABSTRACT: We aimed to determine whether KRAS and BRAF mutant colorectal cancer (CRC) cells exhibit distinct sensitivities to the multi-target angiokinase inhibitor, TKI258 (dovitinib).
We screened 10 CRC cell lines by using receptor tyrosine kinase (RTK) array to identify activated RTKs. MTT assays, anchorage-independent colony-formation assays, and immunoblotting assays were performed to evaluate the in vitro anti-tumor effects of TKI258. In vivo efficacy study followed by pharmacodynamic evaluation was done.
Fibroblast Growth Factor Receptor 1 (FGFR1) and FGFR3 were among the most highly activated RTKs in CRC cell lines. In in vitro assays, the BRAF mutant HT-29 cells were more resistant to the TKI258 than the KRAS mutant LoVo cells. However, in xenograft assays, TKI258 equally delayed the growth of tumors induced by both cell lines. TUNEL assays showed that the apoptotic index was unchanged following TKI258 treatment, but staining for Ki-67 and CD31 was substantially reduced in both xenografts, implying an anti-angiogenic effect of the drug. TKI258 treatment was effective in delaying CRC tumor growth in vivo regardless of the KRAS and BRAF mutation status.
Our results identify FGFRs as potential targets in CRC treatment and suggest that combined targeting of multiple RTKs with TKI258 might serve as a novel approach to improve outcome of patients with CRC.
No preview · Article · Jan 2015 · American Journal of Cancer Research
[Show abstract][Hide abstract] ABSTRACT: Although the incidence is not high in the general surgical population, pulmonary aspiration of gastric contents can result in serious long-term morbidity and mortality. We report a case of early use of extracorporeal membrane oxygenation (ECMO) to correct severe hypoxemia refractory to conventional mechanical ventilation in a patient with massive aspiration of gastric contents immediately followed by acute lung injury during general anesthesia induction.
[Show abstract][Hide abstract] ABSTRACT: Bronchiectasis and asthma are different in many respects, but some patients have both conditions. Studies assessing the effect of bronchiectasis on asthma exacerbation are rare. The aim of this study is to investigate the effect of bronchiectasis on asthma exacerbation.
We enrolled 2,270 asthma patients who were followed up in our hospital. Fifty patients had bronchiectasis and asthma. We selected fifty age- and sex-matched controls from the 2,220 asthma patients without bronchiectasis, and assessed asthma exacerbation and its severity based on the annual incidence of total asthma exacerbation, annual prevalence of steroid use, and frequency of emergency room visits and hospitalizations due to asthma exacerbation in each group.
Fifty patients (2.2%) had bronchiectasis and asthma. The annual incidence of asthma exacerbation was higher in patients with asthma and bronchiectasis than in patients with asthma alone (1.08±1.68 vs. 0.35±0.42, p=0.004). The annual prevalence of steroid use (0.9±1.54 vs. 0.26±0.36, p=0.006) and the frequency of emergency room visits (0.46±0.84 vs. 0.02±0.13, p=0.001) due to asthma exacerbation were also higher in patients with asthma and bronchiectasis than in patients with asthma alone.
Bronchiectasis is associated with difficult asthma control.
Full-text · Article · Nov 2014 · Tuberculosis and Respiratory Diseases
[Show abstract][Hide abstract] ABSTRACT: Advanced gastric cancer (GC) is one of the most aggressive gastrointestinal malignancies, ADAM (A Disintegrin and Metalloproteinase)-9 is a cell-surface membrane glycoprotein with oncogenic properties that is overexpressed in several cancers. Herein, we investigated the biological mechanism of ADAM9 in the progression, proliferation and invasion of GC. First, we detected ADAM's expression, processing and protease activity in GC cells. Protease activity was moderately correlated with ADAM9 protein expression, but was better related to a processed smaller molecular weight (84 kDa) form of ADAM9. Knockdown of ADAM9 or specifically targeted monoclonal antibody (RAV-18) suppressed cancer cell proliferation and invasion in high ADAM9 expressing cells, not in low expressing cells. RAV-18 showed in vivo antitumor activity in a GC xenograft model. Hypoxia (1% oxygen) induced ADAM9 expression and functional activity in low expressing GC cells that was inhibited by siRNA knockdown or RAV-18 antibody to levels in normoxic cells. Overall, our studies show that ADAM9 plays an important role in GC proliferation and invasion, and that while expressed in some GC cells at high levels that are responsive to functional inhibition and antitumor activity of a catalytic site directed antibody, other GC cells have low levels of expression and only when exposed to hypoxia do ADAM9 levels increase and the cells become responsive to ADAM9 antibody inhibition. Therefore, our findings suggest that ADAM9 could be an effective therapeutic target for advanced GC.
Full-text · Article · Oct 2014 · Molecular Cancer Therapeutics
[Show abstract][Hide abstract] ABSTRACT: Irisin is a recently found myokine that aids obesity control and improves glucose homeostasis by acting on white adipose tissue cells and increases total energy consumption. The aim of this study was to evaluate serum irisin levels in patients with non-alcoholic fatty liver disease (NAFLD) and to compare these levels with those of normal controls. Among 595 health screen examinees who had visited our institute between January 2013 to March 2013, 355 patients (84 NAFLD patients and 271 normal controls) were enrolled depending on whether they gave written informed consents and their history of alcohol intake, blood tests, and abdominal ultrasonographic findings. Age; sex; laboratory test parameters; homeostasis model assessment-insulin resistance; and levels of leptin, adiponectin, and irisin were assessed. Serum irisin levels (ng/ml) were significantly higher in the NAFLD group than in normal controls (63.4±32.6 vs. 43.0±29.7, p<0.001) and higher in the mild fatty liver group than in the moderate-to-severe fatty liver group (68.3±38.2 vs. 56.6±21.2, p<0.001). Additionally, serum irisin levels were not different between the non-obese and obese groups (48.4±34.2 vs. 45.8±22.9, p = 0.492); however, the levels were significantly lowest in normal controls and highest in the mild fatty liver group in the non-obese (44.9±31.7 vs. 73.1±48.5 vs 59.7±18.0, p<0.001) and obese groups (35.0±17.0 vs. 62.9±21.2 vs. 54.6±23.3, p<0.001). Serum irisin levels were significantly higher in NAFLD patients, which is not consistent with the results of previously published studies. Therefore, more studies are needed to confirm the role of irisin in NAFLD.
[Show abstract][Hide abstract] ABSTRACT: Primary lung adenoid cystic carcinoma (ACC) is extremely rare and accounts for approximately 0.1%-0.2% of all lung cancers. ACC of the head and neck has generally been regarded as a slow-growing, low-grade malignancy which has a tendency for local recurrence and frequent distant metastasis. When ACC of the lung is identified, physicians must determine whether it represents distant metastasis or a primary lung cancer. Thyroid transcription factor-1 staining is one of the most useful methods to differentiate primary from metastatic lesions in lung cancer. Herein we report a case of metachronous, not synchronous, ACC at the peripheral lung followed by ACC presentation at the base of the tongue, and review of relevant literatures.