Cancers, like other diseases, arise from gene mutations and/or altered gene expression, which eventually cause dysregulation of numerous proteins and noncoding RNAs. Changes in gene expression, i.e., upregulation of oncogenes and/or downregulation of tumor suppressor genes, can be generated not only by genetic and environmental factors but also by epigenetic factors, which are inheritable but nongenetic modifications of cellular chromosome components. Identification of the factors that contribute to individual cancers is a prerequisite to a full understanding of cancer mechanisms and the development of customized cancer therapies. The search for genetic and environmental factors has a long history in cancer research, but epigenetic factors only recently began to be associated with cancer formation, progression, and metastasis. Epigenetic alterations of chromatin include DNA methylation and histone modifications, which can affect gene-expression profiles. Recent studies have revealed diverse mechanisms by which chromatin modifiers, including writers, erasers and readers of the aforementioned modifications, contribute to the formation and progression of cancer. Furthermore, functional RNAs, such as microRNAs and long noncoding RNAs, have also been identified as key players in these processes. This review highlights recent findings concerning the epigenetic alterations associated with cancers, especially gastric cancer.
Gastric cancer; Epigenetics; DNA methylation; Histone modification; Gene expression
Endoscopic resection has been an optimal treatment for selected patients with early gastric cancer (EGC) based on advances in endoscopic instruments and techniques. As endoscopic submucosal dissection (ESD) has been widely used for treatment of EGC along with expanding ESD indication, concerns have been asked to achieve curative resection for EGC while guaranteeing precise prediction of lymph node metastasis (LNM). Recently, new techniques including ESD or endoscopic full-thickness resection combined with sentinel node navigation enable minimal tumor resection and a laparoscopic lymphadenectomy in cases of EGC with high risk of LNM. This review covers the development and challenges of endoscopic treatment for EGC. Moreover, a new microscopic imaging and endoscopic techniques for precise endoscopic diagnosis and minimally invasive treatment of EGC are introduced.
Endoscopic resection; Early gastric cancer; Confocal laser endomicroscopy; Sentinel node navigation; Hybrid natural orifice transluminal endoscopic surgery
Interactions between proteins and genes are considered essential in
the description of biomolecular phenomena, and networks of interactions
are applied in a system's biology approach. Recently, many studies have
sought to extract information from biomolecular text using natural language
processing technology. Previous studies have asserted that linguistic
information is useful for improving the detection of gene interactions.
In particular, syntactic relations among linguistic information are good
for detecting gene interactions. However, previous systems give a reasonably
good precision but poor recall. To improve recall without sacrificing
precision, this paper proposes a three-phase method for detecting gene
interactions based on syntactic relations. In the first phase, we retrieve
syntactic encapsulation categories for each candidate agent and target.
In the second phase, we construct a verb list that indicates the nature of
the interaction between pairs of genes. In the last phase, we determine
direction rules to detect which of two genes is the agent or target. Even
without biomolecular knowledge, our method performs reasonably well using
a small training dataset. While the first phase contributes to improve
recall, the second and third phases contribute to improve precision. In
the experimental results using ICML 05 Workshop on Learning Language
in Logic (LLL05) data, our proposed method gave an F-measure of 67.2% for the test data, significantly outperforming previous methods. We also
describe the contribution of each phase to the performance.
To investigate CT and 18F-flurodeoxyglucose (18F-FDG) positron-emission tomography/CT findings of primary endobronchial marginal zone B-cell lymphoma of the bronchus-associated lymphoid tissue (BALT).
Materials and Methods
From June 2006 through April 2012, seven patients (six female, one male; age range, 21-61 years; mean age, 49 years) were examined who were pathologically diagnosed with the primary endobronchial marginal zone B-cell lymphoma of BALT. We evaluated the locations and characteristics of the lesions on CT and 18F-FDG-PET/CT scans. The lesions were classified into the following three patterns: 1) solitary intraluminal nodule; 2) several tiny nodular protrusions; and 3) diffuse wall thickening.
A solitary intraluminal nodule was observed in four patients (57.1%), several tiny nodular protrusion in two patients (28.6%), and diffuse wall thickening in one patient (14.3%). The lesions were categorized into 3 major locations: confined to the trachea (n = 3), confined to the lobar bronchus (n = 2), and diffuse involvement of the trachea and both main bronchi (n = 2). All lesions demonstrated homogeneous iso-attenuation as compared with muscle on pre- and post-enhancement scans. Secondary findings in the lungs (n = 3; 42.9%) included postobstructive lobar atelectasis (n = 1), air trapping (n = 1), and pneumonia (n = 1). On 18F-FDG-PET/CT (n = 5), 4 lesions showed homogeneous uptake with maximum standardized uptake values (mSUV), ranging 2.3-5.7 (mean mSUV: 3.3). One lesion showed little FDG uptake.
Primary endobronchial marginal zone B-cell lymphoma of the BALT manifests as three distinct patterns on CT, with the solitary intraluminal nodule presenting as the main pattern. Most lesions demonstrate homogeneous but weak FDG uptake on 18F-FDG-PET/CT.
Bronchial neoplasms; Lymphoma, non-Hodgkin/diagnosis; Lymphoma, non-Hodgkin/radiotherapy; Bronchus-associated lymphoid tissue; Tomography, X-ray computed; Positron-emission tomography
Primary malignant melanoma of the anterior mediastinum is extremely rare, accounting for 0.1-0.5% of all primary malignant neoplasms. These tumors may be mistakenly diagnosed as lymphomas, thymic carcinomas and malignant germ-cell tumors of the mediastinum. We describe two cases of primary malignant melanomas of the anterior mediastinum and report their CT and pathology findings.
Mediastinal neoplasm; Mediastinal melanoma; Malignant melanoma; Anterior mediastinum; CT
Non-alcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in the liver not due to alcohol abuse. NAFLD is accompanied by variety of symptoms related to metabolic syndrome. Although the metabolic link between NAFLD and insulin resistance is not fully understood, it is clear that NAFLD is one of the main cause of insulin resistance. NAFLD is shown to affect the functions of other organs, including pancreas, adipose tissue, muscle and inflammatory systems. Currently efforts are being made to understand molecular mechanism of interrelationship between NAFLD and insulin resistance at the transcriptional level with specific focus on post-translational modification (PTM) of transcription factors. PTM of transcription factors plays a key role in controlling numerous biological events, including cellular energy metabolism, cell-cycle progression, and organ development. Cell type- and tissue-specific reversible modifications include lysine acetylation, methylation, ubiquitination, and SUMOylation. Moreover, phosphorylation and O-GlcNAcylation on serine and threonine residues have been shown to affect protein stability, subcellular distribution, DNA-binding affinity, and transcriptional activity. PTMs of transcription factors involved in insulin-sensitive tissues confer specific adaptive mechanisms in response to internal or external stimuli. Our understanding of the interplay between these modifications and their effects on transcriptional regulation is growing. Here, we summarize the diverse roles of PTMs in insulin-sensitive tissues and their involvement in the pathogenesis of insulin resistance.
We investigated the clinical outcomes according to the method of treatment in synchronous esophageal and gastric cancer.
Synchronous esophageal squamous cell carcinoma and gastric adenocarcinoma were diagnosed in 79 patients between 1996 and 2010. We divided the patients into four groups according to treatment; Group 1 received surgical resection for both cancers or surgery for gastric cancer with chemoradiotherapy for esophageal cancer (n=27); Group 2 was treated by endoscopic resection with or without additional treatment (n=14); Group 3 received chemoradiotherapy only (n=18); and Group 4 received supportive care only (n=20).
The median survival times in groups 1 and 2 were 86 and 60 months, respectively. The recurrence rate and mortality were 23% and 48%, respectively, in group 1 and 21% and 4%, respectively, in group 2. The median survival time was 12 months in group 3 and 9 months in group 4. Multivariate analysis showed that age (p<0.001) and treatment group (p=0.019) were significantly associated with death. Compared with group 1, treatment in the intensive care unit (p=0.003), loss of body weight (p=0.042), and decrease in hemoglobin (p=0.033) were worse in group 1.
Endoscopic resection for synchronous esophageal and gastric cancer could be considered as a possible alternative to surgery for early-stage cancer.
Synchronous; Esophageal neoplasms; Stomach neoplasms
Solitary fibrous tumors (SFTs) are unique soft-tissue tumors of submesothelial origin. These tumors are mainly located in the pleural space but they can be originated within a variety of sites, including the abdomen, the pelvis, the soft tissues and the retroperitoneum. SFTs from all sites are usually benign, and the surgical resection is curative in almost all cases. According to the review of literatures, during the surgical resection, massive hemorrhage could occur due to the hypervascular nature of SFTs. This is a case report on SFT in the pelvis presenting great vessel injury, which resulted in life threatening hemorrhage during the resection of tumor. We wish this paper alerts gynecologists about the risk of massive bleeding during the resection of tumor located at adjacent to great vessels in the pelvis.
Hemorrhage; Pelvis; Solitary fibrous tumor
Standardized questionnaire is one of key instruments for general population surveys.
The present study aimed to develop and validate the Korean version of the European Community Respiratory Health Survey (ECRHS) screening questionnaire for adult asthma surveys.
The ECRHS screening questionnaire was translated into Korean language according to the international criteria. Study participants were prospectively recruited from six referral hospitals and one health check-up center. Comprehensibility of the translation was tested in a pilot study of 10 patients. The reliability was evaluated by internal consistency and test-retest repeatability. Validity was assess with regard to physician-diagnosed asthma.
A total of 100 adult asthma patients and 134 volunteers were recruited. Reliability was examined for 10 items in 100 asthmatics; Cronbach α coefficients were 0.84, and test-retest repeatability was good (Cohen κ coefficient, 0.71-1.00). Validity was assessed for 8 items in 234 participants; in particular, 'recent wheeze' showed a high sensitivity (0.89) for physician-diagnosed asthma. 'Recent asthma attack' and 'current asthma medication' showed high specificity (0.96-0.98).
The present study demonstrated that the Korean version of the ECRHS screening questionnaire was comprehensible, reliable and valid. We suggest the questionnaire to be utilized in further epidemiological studies for asthma in Korean adult populations.
Asthma; Epidemiology; Questionnaires
Myeloid cell leukemia-1 (Mcl-1) is a highly expressed anti-apoptotic Bcl-2 protein in cancer. Therefore, inhibition of its expression induces apoptosis in cancer cells and enhances sensitivity to cancer treatment. The aims of this study were to evaluate whether Mcl-1 affects the oncogenic behaviors of colorectal cancer cells, and to document the relationship of its expression with various clinicopathological parameters in colorectal cancer. Mcl-1 knockdown induced apoptosis by activating cleaved caspase-3 and -9, and increasing the expression of the pro-apoptotic protein, PUMA. Mcl-1 knockdown induced cell cycle arrest by decreasing cyclin D1, CDK4 and 6, and by increasing p27 expression. Mcl-1 knockdown decreased both endothelial cell invasion and tube formation, and decreased the expression of VEGF. The phosphorylation level of STAT3 was decreased by Mcl-1 knockdown. The mean apoptotic index value of Mcl-1 positive tumors was significantly lower than that of Mcl-1 negative tumors. The mean microvessel density value of Mcl-1 positive tumors was significantly higher than that of negative tumors. Mcl-1 expression was significantly increased in colorectal cancer, also associated with tumor stage, lymph node metastasis, and poor survival. These results indicate Mcl-1 is associated with tumor progression through its inhibition of apoptosis and enhancement of angiogenesis in colorectal cancer.
Myeloid cell leukemia-1; apoptosis; angiogenesis; prognosis; colorectal neoplasm
This study evaluated the efficacy of extended field irradiation (EFI) in patients with locally advanced cervical cancer without para-aortic nodal involvement.
Materials and Methods
A total of 203 patients with locally advanced cervical cancer (International Federation of Gynecology and Obstetrics [FIGO] stage, IB2-IIIB) treated with radiotherapy at Keimyung University Dongsan Medical Center from 1996 to 2010 were retrospectively analyzed. The median patient age was 59 years (range, 29 to 83 years). None of the patients had para-aortic node metastases. Of the 203 patients, 88 underwent EFI and 115 underwent irradiation of the pelvis only. Concurrent chemoradiotherapy (CCRT) was administered to 133 patients. EFI field was used for treatment of 26 patients who received radiotherapy alone and 62 who received CCRT.
The median follow-up period was 60 months. The 2- and 5-year overall survival (OS) rates were 87.8% and 73.5%, respectively, and the 2- and 5-year disease-free survival rates were 81.7% and 75.0%, respectively, however, no survival differences were observed between the two treatment field groups. EFI tended to increase OS in the radiotherapy alone group, but not in the CCRT group.
These findings suggest that EFI does not have a significant effect in patients with locally advanced cervical cancer, especially in patients receiving CCRT. Conduct of additional studies will be required in order to confirm these findings.
Uterine cervical neoplasms; Radiotherapy; Survival rate; Lymph nodes; Neoplasm metastasis
Pulmonary tuberculosis (TB) can produce unusual radiographic findings. Further, negative sputum and bronchoscopic results are common. Early diagnosis is equally as significant as treatment in the reduction of morbidity and mortality associated with pulmonary TB.
The aim of this study was to assess computed tomography (CT) findings of pulmonary TB, confirmed via percutaneous transthoracic needle biopsy (PTNB), and to correlate these findings with coexisting, underlying, lung diseases if present.
Cross sectional study.
We selected eighty-four patients who were diagnosed with pulmonary TB by way of PTNB. Initially, acid-fast bacilli smear test results from these patients were negative. CT findings were reviewed to detect the presence of parenchymal abnormalities as follows: nodule(s) (<3 cm in diameter), mass (any masses ≥3 cm), daughter nodules, air-space consolidation, cavitation, calcification, lymphadenopathy, mediastinal lymphadenopathy, and associated lung parenchymal disease.
The CT findings of pulmonary TB confirmed by PTNB included nodules in 44 of 84 (52.4%) cases; 15 of these 44 cases (34.1%) had daughter nodules. The second most common finding was masses in 24 cases (28.6%), nine of which also had daughter nodules. 16 cases (19.0%) displayed nonsegmental consolidation. Of these 16 cases, four had coexisting usual interstitial pneumonia; four others had emphysema. Two patients with a mass had underlying pneumoconiosis.
Nodules or a mass mimicking lung cancer were the most common findings on CT scans in patients with pulmonary TB, confirmed via PTNB. The second most common finding was airspace consolidation. Therefore, PNTB is useful for the accurate diagnosis of pulmonary TB in the following cases: airspace consolidation or mass associated with underlying usual interstitial pneumonia, emphysema mimicking lung malignancy or cases of bacterial pneumonia.
Percutaneous transthoracic needle biopsy; pulmonary; tuberculosis
Myocardial cell death due to occlusion of the coronary arteries leads to myocardial infarction, a subset of coronary heart disease (CHD). Dietary fiber is known to be associated with a reduced risk of CHD, the underlying mechanisms of which were suggested to delay the onset of occlusion by ameliorating risk factors. In this study, we tested a hypothesis that a beneficial role of dietary fiber could arise from protection of myocardial cells against ischemic injury, manifested after occlusion of the arteries.
Three days after rats were fed apple pectin (AP) (with 10, 40, 100, and 400 mg/kg/day), myocardial ischemic injury was induced by 30 min-ligation of the left anterior descending coronary artery, followed by 3 hr-reperfusion. The area at risk and infarct area were evaluated using Evans blue dye and 2,3,5-triphenyltetrazolium chloride (TTC) staining, respectively. DNA nicks reflecting the extent of myocardial apoptosis were assessed by TUNEL assay. Levels of cleaved caspase-3, Bcl-2, and Bax were assessed by immunohistochemistry.
Supplementation of AP (with 100 and 400 mg/kg/day) resulted in significantly attenuated infarct size (IS) (ratio of infarct area to area at risk) by 21.9 and 22.4%, respectively, in the AP-treated group, compared with that in the control group. This attenuation in IS showed correlation with improvement in biomarkers involved in the apoptotic cascades: reduction of apoptotic cells, inhibition of conversion of procaspase-3 to caspase-3, and increase of Bcl-2/Bax ratio, a determinant of cell fate.
The findings indicate that supplementation of AP results in amelioration of myocardial infarction by inhibition of apoptosis. Thus, the current study suggests that intake of dietary fiber reduces the risk of CHD, not only by blocking steps leading to occlusion, but also by protecting against ischemic injury caused by occlusion of the arteries.
Apple pectin; coronary heart disease; ischemia; apoptosis; dietary fiber
Impedance analysis using high-resolution impedance manometry (HRIM) enables the recognition of pharyngeal residue in patients with oropharyngeal dysphagia. The aims of this study were to evaluate appropriate criteria for impedance analysis in a large patient cohort, as well as the diagnostic accuracy and agreement of analysis performed by HRIM trainees.
We reviewed 33 controls (13 males; median age, 61.2 years) and 104 oropharyngeal dysphagia patients (61 males; median age, 70.4 years) who underwent a flexible endoscopic evaluation of swallowing study (FEES) and HRIM. Two experts compared the pharyngeal residue on FEES and impedance color pattern at 1,000, 1,500 and 2,000 Ω of the impedance bar. Three trainees were given a 60 minutes tutorial to determine the diagnostic accuracy and agreement of this analysis.
The diagnostic sensitivity of experts for predicting liquid residue was 73.1% for 1,000 Ω, 96.2% for 1,500 Ω and 100% for 2,000 Ω. Significantly higher sensitivity was observed at 1,500 Ω compared to 1,000 Ω (P < 0.001). The diagnostic specificity of experts for liquid residue was 98.3% for 1,000 Ω, 96.6% for 1,500 Ω and 83.1% for 2,000 Ω. There was a higher specificity at 1,500 Ω compared to 2,000 Ω (P = 0.008). The κ value among the 3 trainees was 0.89 and the diagnostic accuracy of the trainees for liquid residue was comparable to that of the experts.
The impedance analysis at 1,500 Ω provides more accurate information for the detection of liquid residue, irrespective of the level of expertise.
Deglutition disorders; Diagnosis; Pharynx
The major inducible 70-kDa heat shock protein (hsp70) protects against measles virus (MeV) neurovirulence in the mouse that is caused by a cell-associated noncytolytic neuronal infection. Protection is type I interferon (IFN) dependent, and we have established a novel axis of antiviral immunity in which hsp70 is released from virus-infected neurons to induce IFN-β in macrophages. The present work used vesicular stomatitis virus (VSV) to establish the relevance of hsp70-dependent antiviral immunity to fulminant cytopathic neuronal infections. In vitro, hsp70 that was constitutively expressed in mouse neuronal cells caused a modest increase in VSV replication. Infection induced an early extracellular release of hsp70 from viable cells, and the release was progressive, increasing with virus-induced apoptosis and cell lysis. The impact of this VSV-hsp70 interaction on neurovirulence was established in weanling male hsp70 transgenic and nontransgenic mice. Constitutive expression of hsp70 in neurons of transgenic mice enhanced viral clearance from brain and reduced mortality, and it was correlated with enhanced expression of type I IFN mRNA. Nontransgenic mice were also protected against neurovirulence and expressed increased type I IFN mRNA in brain when hsp70 was expressed by a recombinant VSV (rVSV-hsp70), indicating that hsp70 in the virus-infected cell is sufficient for host protection. In vitro data confirmed extracellular release of hsp70 from cells infected with rVSV-hsp70 and also showed that viral replication is not enhanced when hsp70 is expressed in this manner, suggesting that hsp70-mediated protection in vivo is not dependent on stimulatory effects of hsp70 on virus gene expression.
Identification of tolerable alternative analgesics is crucial for management in nonsteroidal anti-inflammatory drug (NSAID)-sensitive patients. We investigated cross-reactivity of acetaminophen and celecoxib according to the type of aspirin/NSAID hypersensitivity and aimed to determine the risk factors for cross-intolerance.
We retrospectively reviewed the medical records of patients intolerant to aspirin and NSAIDs who had undergone an acetaminophen and/or celecoxib oral provocation test. Aspirin/NSAID hypersensitivity was classified into 4 types according to a recently proposed classification: aspirin-exacerbated respiratory disease (AERD), aspirin-exacerbated chronic urticaria (AECU), aspirin-induced acute urticaria/angioedema (AIAU), and NSAID-induced blended reaction (NIRD).
A total of 180 patients with hypersensitivity to aspirin and NSAIDs were enrolled; 149 acetaminophen provocation test results and 145 celecoxib provocation test results were analyzed. The overall cross-reaction rates to acetaminophen and celecoxib were 24.8% and 10.3%, respectively. There was a significant difference in the cross-reactivity to acetaminophen according to the type of NSAID hypersensitivity. Cross-reactivity to acetaminophen was highest in the AECU group (43.9%), followed by the AERD (33.3%), NIBR (16.7%), and AIAU (12.5%) groups. Underlying chronic urticaria was more prevalent in patients with cross-intolerance to both acetaminophen (P=0.001) and celecoxib (P=0.033). Intolerance to acetaminophen was associated with intolerance to celecoxib (P<0.001).
Acetaminophen and celecoxib may induce adverse reactions in a non-negligible portion of aspirin/NSAID-sensitive patients. Physicians should be aware of the possible cross-reactions of these alternative drugs and consider an oral challenge test to confirm their tolerability.
Acetaminophen; celecoxib; cross reactions; hypersensitivity; intolerance; anti-inflammatory agents; non-steroidal
We report the first case of hypercalcemia-induced acute pancreatitis caused by a functioning parathyroid cyst in a 67-year-old man. Laboratory investigation revealed increased serum amylase and lipase, increased serum ionized calcium and parathyroid hormone (PTH) levels, and decreased serum phosphate, indicating pancreatitis and primary hyperparathyroidism (PHPT). Abdominal computed tomography (CT) revealed mild swelling of the pancreatic head with peri-pancreatic fat infiltration and fluid collection around the pancreatic tail. Ultrasonography and CT of the neck showed a cystic lesion at the inferior portion of the left thyroid gland, suggesting a parathyroid cyst. There was no evidence of parathyroid adenoma by 99mTc sestamibi scintigraphy. PHPT caused by a functioning parathyroid cyst was suspected. The patient underwent surgical resection of the functioning parathyroid cyst owing to his prolonged hypercalcemia. At 3 weeks after the operation, his serum levels of PTH, total calcium, ionized calcium, inorganic phosphate, amylase, and lipase were normalized. At the follow-up examinations, he has remained asymptomatic.
Pancreatitis; Hyperparathyroidism, Primary; Cysts
Locally advanced esophageal cancers are generally treated with neoadjuvant chemoradiotherapy, followed by surgery in operable candidates. However, even if the patients were diagnosed as operable disease, surgery could not be performed on patients with poor condition or other comorbidity. In this case, definitive chemoradiotherapy (dCRT) is the other option for localized esophageal cancer. Therefore, the purpose of this study was to evaluate the efficacy and clinical prognostic factors for dCRT in locally advanced esophageal cancer.
Materials and Methods
We conducted a review of patients who received dCRT for locally advanced squamous esophageal cancer from 2004 to 2010, focusing on stages III and IVa. All patients received at least two cycles of platinum-based chemotherapy during radiation, and all tumor burdens were included in the radiation field. The treatment results were analyzed for patterns of failure and prognostic factors associated with survival.
In total, 63 patients were enrolled in this study. The overall response rate was 84.1%. Relief from dysphagia after dCRT was achieved in 48 patients. The most frequent failure was local recurrence. The median overall survival (OS) was 23.0 months, and the 2-year survival rate was 45.4%. Similar results were observed for elderly study patients. Significant prognostic factors for OS were duration of smoking, high grade of dysphagia (score of 3 or 4), and shorter duration of progression-free and dysphagia-free survival. Maintenance chemotherapy after dCRT did not influence OS. However, "good risk" patients receiving maintenance chemotherapy showed better OS than those who did not receive maintenance chemotherapy (30.4 months vs. 12.0 months, p=0.002).
dCRT has a major role in improving survival and palliation of dysphagia in inoperable advanced esophageal cancer, even in elderly patients. Maintenance chemotherapy after dCRT may be effective in prolonging survival in "good risk" patients.
Esophageal squamous cell carcinoma; Chemoradiotherapy; Prognosis
Cri-du-Chat syndrome, also called the 5p-syndrome, is a rare genetic abnormality, and only few cases have been reported on its brain MRI findings. We describe the magnetic resonance imaging findings of a 1-year-old girl with Cri-du-Chat syndrome who showed brain stem hypoplasia, particularly in the pons, with normal cerebellum and diffuse hypoplasia of the cerebral hemispheres. We suggest that Cri-du-Chat syndrome chould be suspected in children with brain stem hypoplasia, particularly for those with high-pitched cries.
Cri-du-Chat syndrome; Genetic disorder; Brain stem hypoplasia; Brain MRI
In the present study, we investigated the effect of intracellular glutathione (GSH) depletion in heart-derived H9c2 cells and its mechanism. L-buthionine-S,R-sulfoximine (BSO) induced the depletion of cellular GSH, and BSO-induced reactive oxygen species (ROS) production was inhibited by glutathione monoethyl ester (GME). Additionally, GME inhibited BSO-induced caspase-3 activation, annexin V-positive cells, and annexin V-negative/propidium iodide (PI)-positive cells. Treatment with rottlerin completely blocked BSO-induced cell death and ROS generation. BSO-induced GSH depletion caused a translocation of PKC-δ from the cytosol to the membrane fraction, which was inhibited by treatment with GME. From these results, it is suggested that BSO-induced depletion of cellular GSH causes an activation of PKC-δ and, subsequently, generation of ROS, thereby inducing H9c2 cell death.
Glutathione; Reactive oxygen species; H9c2; Cell death; PKC-δ
The major inducible 70-kDa heat shock protein (hsp70) is host protective in a mouse model of measles virus (MeV) brain infection. Transgenic constitutive expression of hsp70 in neurons, the primary target of MeV infection, abrogates neurovirulence in neonatal H-2d congenic C57BL/6 mice. A significant level of protection is retained after depletion of T lymphocytes, implicating innate immune mechanisms. The focus of the present work was to elucidate the basis for hsp70-dependent innate immunity using this model. Transcriptome analysis of brains from transgenic (TG) and nontransgenic (NT) mice 5 days after infection identified type I interferon (IFN) signaling, macrophage activation, and antigen presentation as the main differences linked to survival. The pivotal role of type I IFN in hsp70-mediated protection was demonstrated in mice with a genetically disrupted type I IFN receptor (IFNAR−/−), where IFNAR−/− eliminated the difference in survival between TG and NT mice. Brain macrophages, not neurons, are the predominant source of type I IFN in the virus-infected brain, and in vitro studies provided a mechanistic basis by which MeV-infected neurons can induce IFN-β in uninfected microglia in an hsp70-dependent manner. MeV infection induced extracellular release of hsp70 from mouse neuronal cells that constitutively express hsp70, and extracellular hsp70 induced IFN-β transcription in mouse microglial cells through Toll-like receptors 2 and 4. Collectively, our results support a novel axis of type I IFN-dependent antiviral immunity in the virus-infected brain that is driven by hsp70.
To evaluate the additional effect of sonoelastography on the radiologist's ability for distinguishing benign from malignant complex breast masses and to decide whether to perform biopsy by B-mode US.
Materials and Methods
One hundred eighteen complex breast masses (15 malignant lesions, 103 benign lesions) were included. Five blinded readers independently assessed the likelihood of the malignancy score from 1 to 5 for two data sets (B-mode ultrasound alone and B-mode ultrasound with sonoelastography). Elasticity scores were categorized as 0, 1, or 2 based on the degree and distribution of strain of the echogenic component within complex masses. The readers were asked to downgrade the likelihood of the malignancy score when an elasticity score of 0 was assigned and to upgrade the likelihood of the malignancy score when an elasticity score of 2 was assigned. The likelihood of the malignancy score was maintained as it was for the lesions with an elasticity score of 1. The Az values, sensitivities, and specificities were compared.
The Az value of B-mode ultrasound with sonoelastography (mean, 0.863) was greater than that of B-mode ultrasound alone (mean, 0.731; p = 0.001-0.007) for all authors. The specificity of B-mode ultrasound with sonoelastography (mean, 37.1%) was greater than that of B-mode ultrasound alone (mean, 3.8%; p < 0.001) for all readers. The addition of sonoelastography led to changes in decisions. A mean of 33.6% of benign masses were recommended for follow-up instead of biopsy.
For complex breast masses, sonoelastography allows increase in both the accuracy in distinguishing benign from malignant lesions and the specificity in deciding whether to perform biopsy.
Breast; Neoplasm; Sonoelastography
Peroxisome proliferator-activated receptor gamma (PPARγ) belongs to a nuclear receptor superfamily; members of which play key roles in the control of body metabolism principally by acting on adipose tissue. Ligands of PPARγ, such as thiazolidinediones, are widely used in the treatment of metabolic syndromes and type 2 diabetes mellitus (T2DM). Although these drugs have potential benefits in the treatment of T2DM, they also cause unwanted side effects. Thus, understanding the molecular mechanisms governing the transcriptional activity of PPARγ is of prime importance in the development of new selective drugs or drugs with fewer side effects. Recent advancements in molecular biology have made it possible to obtain a deeper understanding of the role of PPARγ in body homeostasis. The transcriptional activity of PPARγ is subject to regulation either by interacting proteins or by modification of the protein itself. New interacting partners of PPARγ with new functions are being unveiled. In addition, post-translational modification by various cellular signals contributes to fine-tuning of the transcriptional activities of PPARγ. In this review, we will summarize recent advancements in our understanding of the post-translational modifications of, and proteins interacting with, PPARγ, both of which affect its transcriptional activities in relation to adipogenesis.
PPARγ; coregulator; post-translational modifications; transcriptional activity; adipogenesis; metabolic syndrome
Several chemotherapeutic agents are known to develop pulmonary toxicities in cancer patients, although the frequency of incidence varies. Cyclophosphamide is a commonly encountered agent that is toxic to the lung. Additionally, granulocyte colony-stimulating factor (G-CSF) being used for the recovery from neutropenia can exacerbate lung injury. However, most of the patients reported previously that the drug-induced interstitial pneumonitis were developed after three to four cycles of chemotherapy. Hereby, we report a case of peripheral T cell lymphoma which rapidly developed a fatal interstitial pneumonitis after the first cycle of combined chemotherapy with cyclophosphamide, adriamycin, vincristine, prednisolone, and etoposide and the patient had also treated with G-CSF during neutropenic period.
Lymphoma; Lung Diseases, Interstitial; Granulocyte Colony-Stimulating Factor; Drug Therapy
Bortezomib administration leads to a transient decrease in CD4+ T cells, increasing the susceptibility to opportunistic infections. The activation and proliferation of CD4+ T cells are particularly important in the host's defense against tuberculosis infection. The aim of this study was to determine the incidence and clinical significance of tuberculosis infection in patients with multiple myeloma (MM) treated with a bortezomib-containing regimen.
We retrospectively investigated the incidence of Mycobacterium tuberculosis in 115 patients with MM who were given a bortezomib-containing regimen and studied the disease prognosis.
All patients received chemotherapy prior to bortezomib administration, and the median duration from diagnosis to bortezomib administration was 12.4 months (range, 0.2-230). We diagnosed tuberculosis in 8 patients (8/115, 7%): 7 patients had a pulmonary granulomatous lesion prior to chemotherapy and 1 developed reactivation of tuberculosis, but none of them died of uncontrolled tuberculosis infection. In 50% of patients with tuberculosis, bortezomib-containing therapy was interrupted. This resulted in significantly lower response rates to the bortezomib-containing therapy (P<0.05) and significantly shorter overall survival times amongst tuberculosis vs. non-tuberculosis patients (P=0.017).
Tuberculosis infection was not uncommon among the patients with MM who were treated with bortezomib-containing therapy, and tuberculosis infection in these patients resulted in an interruption of bortezomib administration, which significantly affected patient outcomes. Therefore, early diagnosis and treatment of tuberculosis infection are critical to avoid worsening outcomes in such patients.
Bortezomib; Mycobacterium tuberculosis; Multiple myeloma