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1.  14-3-3ζ Orchestrates Mammary Tumor Onset and Progression via miR221-Mediated Cell Proliferation 
Cancer research  2013;74(1):363-373.
14-3-3ζ is overexpressed in over 40% of breast cancers but its pathophysiological relevance to tumorigenesis has not been established. Here we show that 14-3-3ζ overexpression is sufficient to induce tumorigenesis in a transgenic mouse model of breast cancer. MMTV-LTR promoter driven HA-14-3-3ζ transgenic mice (MMTV-HA-14-3-3ζ) developed mammary tumors whereas control mice did not. Whey acidic protein promoter driven HA-14-3-3ζ transgenic mice (WAP-HA-14-3-3ζ) developed hyperplastic lesions and showed increased susceptibility to carcinogen-induced tumorigenesis. When crossed with MMTV-neu transgenic mice, 14-3-3ζ.neu transgenic mice exhibited accelerated mammary tumorigenesis and metastasis compared to MMTV-neu mice. Mechanistically, 14-3-3ζ overexpression enhanced MAPK/c-Jun signaling leading to increased miR-221 transcription, which inhibited p27 CDKI translation, and consequently, promoted cell proliferation. Importantly, this 14-3-3ζ/miR-221/p27/proliferation axis is also functioning in patients' breast tumors and associates with high grade cancers. Taken together, our findings show that 14-3-3ζ overexpression has a causal role in mammary tumorigenesis and progression, acting through miR-221 in cooperation with known oncogenic events to drive neoplastic cell proliferation.
doi:10.1158/0008-5472.CAN-13-2016
PMCID: PMC3947305  PMID: 24197133
Breast cancer; 14-3-3ζ; microRNA; transgenic mice
2.  Longitudinal Brain White Matter Alterations in Minimal Hepatic Encephalopathy before and after Liver Transplantation 
PLoS ONE  2014;9(8):e105887.
Cerebral edema is the common pathogenic mechanism for cognitive impairment in minimal hepatic encephalopathy. Whether complete reversibility of brain edema, cognitive deficits, and their associated imaging can be achieved after liver transplantation remains an open question. To characterize white matter integrity before and after liver transplantation in patients with minimal hepatic encephalopathy, multiple diffusivity indices acquired via diffusion tensor imaging was applied. Twenty-eight patients and thirty age- and sex-matched healthy volunteers were included. Multiple diffusivity indices were obtained from diffusion tensor images, including mean diffusivity, fractional anisotropy, axial diffusivity and radial diffusivity. The assessment was repeated 6–12 month after transplantation. Differences in white matter integrity between groups, as well as longitudinal changes, were evaluated using tract-based spatial statistical analysis. Correlation analyses were performed to identify first scan before transplantation and interval changes among the neuropsychiatric tests, clinical laboratory tests, and diffusion tensor imaging indices. After transplantation, decreased water diffusivity without fractional anisotropy change indicating reversible cerebral edema was found in the left anterior cingulate, claustrum, postcentral gyrus, and right corpus callosum. However, a progressive decrease in fractional anisotropy and an increase in radial diffusivity suggesting demyelination were noted in temporal lobe. Improved pre-transplantation albumin levels and interval changes were associated with better recoveries of diffusion tensor imaging indices. Improvements in interval diffusion tensor imaging indices in the right postcentral gyrus were correlated with visuospatial function score correction. In conclusion, longitudinal voxel-wise analysis of multiple diffusion tensor imaging indices demonstrated different white matter changes in minimal hepatic encephalopathy patients. Transplantation improved extracellular cerebral edema and the results of associated cognition tests. However, white matter demyelination may advance in temporal lobe.
doi:10.1371/journal.pone.0105887
PMCID: PMC4148329  PMID: 25166619
3.  Diffusion Tensor Imaging Study of White Matter Damage in Chronic Meningitis 
PLoS ONE  2014;9(6):e98210.
Tuberculous meningitis (TBM) and cryptococcal meningitis (CM) are two of the most common types of chronic meningitis. This study aimed to assess whether chronic neuro-psychological sequelae are associated with micro-structure white matter (WM) damage in HIV-negative chronic meningitis. Nineteen HIV-negative TBM patients, 13 HIV-negative CM patients, and 32 sex- and age-matched healthy volunteers were evaluated and compared. The clinical relevance of WM integrity was studied using voxel-based diffusion tensor imaging (DTI) magnetic resonance imaging. All of the participants underwent complete medical and neurologic examinations, and neuro-psychological testing. Differences in DTI indices correlated with the presence of neuro-psychological rating scores and cerebrospinal fluid (CSF) analysis during the initial hospitalization. Patients with CM had more severe cognitive deficits than healthy subjects, especially in TBM. There were changes in WM integrity in several limbic regions, including the para-hippocampal gyrus and cingulate gyrus, and in the WM close to the globus pallidus. A decline in WM integrity close to the globus pallidus and anterior cingulate gyrus was associated with worse CSF analysis profiles. Poorer DTI parameters directly correlated with worse cognitive performance on follow-up. These correlations suggest that WM alterations may be involved in the psychopathology and pathophysiology of co-morbidities. Abnormalities in the limbic system and globus pallidus, with their close relationship to the CSF space, may be specific biomarkers for disease evaluation.
doi:10.1371/journal.pone.0098210
PMCID: PMC4043527  PMID: 24892826
4.  Intra-Arterial Chemotherapy with Doxorubicin and Cisplatin Is Effective for Advanced Hepatocellular Cell Carcinoma 
The Scientific World Journal  2014;2014:160138.
Advanced hepatocellular carcinoma (HCC) remains a fatal disease even in the era of targeted therapies. Intra-arterial chemotherapy (IACT) can provide therapeutic benefits for patients with locally advanced HCC who are not eligible for local therapies or are refractory to targeted therapies. The aim of this retrospective study was to analyze the effect of IACT with cisplatin and doxorubicin on advanced HCC. Methods. Patients with advanced HCC who were not eligible for local therapies or were refractory to sorafenib received doxorubicin (50 mg/m2) and cisplatin (50 mg/m2) infusions into the liver via the transhepatic artery. Between January 2005 and December 2011, a total of 50 patients with advanced HCC received this treatment regimen. The overall response rate (ORR) was 22% in all treated patients. In patients who received at least 2 cycles of IACT, the ORR was 36.7%, and the disease control rate was 70%. Survival rate differed significantly between patients who received only one cycle of IACT (group I) and those who received several cycles (group II). The median progression-free survival was 1.3 months and 5.8 months in groups I and II, respectively (P < 0.0001). The median overall survival was 8.3 months for all patients and was 3.1 months and 12.0 months in groups I and II, respectively (P < 0.0001). The most common toxicity was alopecia. Four patients developed grade 3 or 4 leukopenia. Worsening of liver function, nausea, and vomiting were uncommon side effects. This study demonstrated clinical efficacy and tolerable side effects of repeated IACT with doxorubicin and cisplatin in advanced HCC. Our regimen can be an alternative choice for patients with adequate liver function who do not want to receive continuous infusion of IACT.
doi:10.1155/2014/160138
PMCID: PMC4055608  PMID: 24967421
5.  Association between Peripheral Oxidative Stress and White Matter Damage in Acute Traumatic Brain Injury 
BioMed Research International  2014;2014:340936.
The oxidative stress is believed to be one of the mechanisms involved in the neuronal damage after acute traumatic brain injury (TBI). However, the disease severity correlation between oxidative stress biomarker level and deep brain microstructural changes in acute TBI remains unknown. In present study, twenty-four patients with acute TBI and 24 healthy volunteers underwent DTI. The peripheral blood oxidative biomarkers, like serum thiol and thiobarbituric acid-reactive substances (TBARS) concentrations, were also obtained. The DTI metrics of the deep brain regions, as well as the fractional anisotropy (FA) and apparent diffusion coefficient, were measured and correlated with disease severity, serum thiol, and TBARS levels. We found that patients with TBI displayed lower FAs in deep brain regions with abundant WMs and further correlated with increased serum TBARS level. Our study has shown a level of anatomic detail to the relationship between white matter (WM) damage and increased systemic oxidative stress in TBI which suggests common inflammatory processes that covary in both the peripheral and central reactions after TBI.
doi:10.1155/2014/340936
PMCID: PMC3996315  PMID: 24804213
6.  Peripheral Leukocyte Apoptosis in Patients with Parkinsonism: Correlation with Clinical Characteristics and Neuroimaging Findings 
BioMed Research International  2014;2014:635923.
Apoptosis of both brain neurons and peripheral blood leukocyte is believed to be an important biomarker for evaluating the functional status of Parkinson's disease (PD). However, their correlation remains unknown. A better understanding of the pathophysiology of neurodegeneration is essential for the treatment and prevention of PD. The present study demonstrated that leukocyte apoptosis is significantly higher in PD patients and is associated with central dopamine neuron loss by using 99mTc-TRODAT-1 SPECT. The leukocyte apoptosis and striatal dopamine transporter uptake ratios were further associated with increased severity and longer duration of disease. The interaction between brain and systemic inflammation may be responsible for the neurodegenerative disease progression.
doi:10.1155/2014/635923
PMCID: PMC3984850  PMID: 24795890
7.  Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways 
Nature medicine  2011;17(4):10.1038/nm.2309.
Trastuzumab is a successful rationally designed ERBB2-targeted therapy. However, about half of individuals with ERBB2-overexpressing breast cancer do not respond to trastuzumab-based therapies, owing to various resistance mechanisms. Clinically applicable regimens for overcoming trastuzumab resistance of different mechanisms are not yet available. We show that the nonreceptor tyrosine kinase c-SRC (SRC) is a key modulator of trastuzumab response and a common node downstream of multiple trastuzumab resistance pathways. We find that SRC is activated in both acquired and de novo trastuzumab-resistant cells and uncover a novel mechanism of SRC regulation involving dephosphorylation by PTEN. Increased SRC activation conferred considerable trastuzumab resistance in breast cancer cells and correlated with trastuzumab resistance in patients. Targeting SRC in combination with trastuzumab sensitized multiple lines of trastuzumab-resistant cells to trastuzumab and eliminated trastuzumab-resistant tumors in vivo, suggesting the potential clinical application of this strategy to overcome trastuzumab resistance.
doi:10.1038/nm.2309
PMCID: PMC3877934  PMID: 21399647
8.  Structural and cognitive deficits in chronic carbon monoxide intoxication: a voxel-based morphometry study 
BMC Neurology  2013;13:129.
Background
Patients with carbon monoxide (CO) intoxication may develop ongoing neurological and psychiatric symptoms that ebb and flow, a condition often called delayed encephalopathy (DE). The association between morphologic changes in the brain and neuropsychological deficits in DE is poorly understood.
Methods
Magnetic resonance imaging and neuropsychological tests were conducted on 11 CO patients with DE, 11 patients without DE, and 15 age-, sex-, and education-matched healthy subjects. Differences in gray matter volume (GMV) between the subgroups were assessed and further correlated with diminished cognitive functioning.
Results
As a group, the patients had lower regional GMV compared to controls in the following regions: basal ganglia, left claustrum, right amygdala, left hippocampus, parietal lobes, and left frontal lobe. The reduced GMV in the bilateral basal ganglia, left post-central gyrus, and left hippocampus correlated with decreased perceptual organization and processing speed function. Those CO patients characterized by DE patients had a lower GMV in the left anterior cingulate and right amygdala, as well as lower levels of cognitive function, than the non-DE patients.
Conclusions
Patients with CO intoxication in the chronic stage showed a worse cognitive and morphologic outcome, especially those with DE. This study provides additional evidence of gray matter structural abnormalities in the pathophysiology of DE in chronic CO intoxicated patients.
doi:10.1186/1471-2377-13-129
PMCID: PMC3850907  PMID: 24083408
Carbon monoxide intoxication; Cognitive deficits; Delayed encephalopathy; Magnetic resonance imaging; Voxel-based morphometry
9.  Concomitant Targeting of Tumor Cells and Induction of T-cell Response Synergizes to Effectively Inhibit Trastuzumab-Resistant Breast Cancer 
Cancer research  2012;72(17):4417-4428.
Trastuzumab is an iconic rationally designed targeted therapy for HER2-positive breast cancers. However, the low response rate and development of resistance call for novel approaches for the treatment of patients. Here, we report that concurrent targeting of tumor cells and activation of T cells in the tumor microenvironment results in a synergistic inhibitory effect on tumor growth and overcomes resistance in two distinct PTEN loss–mediated trastuzumab-resistant mammary tumor mouse models. In vivo combination treatment with HER2/Neu antibody and Akt inhibitor triciribine effectively inhibited tumor growth in both models via inhibiting PI3K/AKT and mitogen-activated protein kinase signaling accompanied by increased T-cell infiltration in the tumor microenvironment. We showed that both CD8+ and CD4+ T cells were essential to the optimal antitumor effect of this combination treatment in an IFN- γ–dependent manner. Importantly, the antitumor activities of HER2/Neu antibody and triciribine combination treatment were further improved when coinhibitory receptor cytotoxic T-lymphocyte–associated antigen 4 was blocked to enhance the T-cell response. Our data indicate that multitargeted combinatorial therapies targeting tumor cells and concomitantly enhancing T-cell response in the tumor microenvironment could cooperate to exert maximal therapeutic activity, suggesting a promising clinical strategy for treating trastuzumab-resistant breast cancers and other advanced malignancies.
doi:10.1158/0008-5472.CAN-12-1339-T
PMCID: PMC3556997  PMID: 22773664
10.  Discrepancy between effects of carbapenems and flomoxef in treating nosocomial hemodialysis access-related bacteremia secondary to extended spectrum beta-lactamase producing klebsiella pneumoniae in patients on maintenance hemodialysis 
BMC Infectious Diseases  2012;12:206.
Background
Hemodialysis (HD) patients are susceptible to extended spectrum beta-lactamase (ESBL)-producing bacterial infections. Because the optimal treatment and clinical significance of ESBL-producing Klebsiella pneumoniae (ESBL-Kp) HD access-related bacteremia remain unclear, we conducted this retrospective study to determine the clinical outcomes of patients treated with either flomoxef or a carbapenem.
Methods
The eligibility criterion was fistula or graft- or catheter- related ESBL-Kp bacteremia in patients on maintenance HD. The clinical characteristics and antibiotic management were analyzed. Outcome was determined by mortality resulting from bacteremia during the 14‐day period after the first positive blood culture for flomoxef-susceptible ESBL-Kp.
Results
The 57 patients studied were predominantly elderly, malnourished, with a history of severe illnesses and broad-spectrum antibiotic use before the onset of bacteremia, and with severe septicemia as determined by the Pitt bacteremia score (PBS). The study population comprised 7 fistula, 8 graft, and 42 HD catheter-related bacteremia (CRB) cases, and the mortality rate was high (36/57, 63.2%) in these 57 patients. Of 42 patients with CRB, those in the deceased group (27/42, 64.3%) had significantly lower levels of serum albumin, longer prior hospital stay and duration of catheter-dependent HD, and higher PBS than patients in the survived group. Failure to receive effective antibiotics (flomoxef or a carbapenem) within 5 days after onset of bacteremia and treatment with flomoxef both significantly contributed to higher mortality. Multivariate analyses revealed that flomoxef use, PBS, and catheter-dependent HD >30 days were independently associated with increased mortality (OR, 3.52; 95% CI, 1.19–58.17, OR, 2.92; 95% CI, 1.36–6.26 and OR, 5.73; 95% CI, 1.21–63.2, respectively).
Conclusions
Considering the high mortality rate, ESBL-Kp should be recognized as a possible pathogen in patients on maintenance HD at high risk of acquiring HD access infections associated with ESBL-producing bacteria. Carbapenems rather than flomoxef should be the therapy of choice in these critically vulnerable patients.
doi:10.1186/1471-2334-12-206
PMCID: PMC3507710  PMID: 22947300
Bacteremia; Carbapenems; Extended spectrum beta-lactamase; Flomoxef; Hemodialysis access; Klebsiella pneumoniae
11.  Comparative Study of Esophageal Stent and Feeding Gastrostomy/Jejunostomy for Tracheoesophageal Fistula Caused by Esophageal Squamous Cell Carcinoma 
PLoS ONE  2012;7(8):e42766.
Background
A malignant tracheoesophageal/bronchoesophageal fistula (TEF) is a life-threatening complication of esophageal squamous cell carcinoma. A feeding gastrostomy/jejunostomy had been the most common treatment method for patients with TEF before the era of stenting. The aim of this retrospective study is to compare the prognosis of esophageal squamous cell carcinoma patients with TEF treated with an esophageal metallic stent to those treated with a feeding gastrostomy/jejunostomy.
Methods
We retrospectively reviewed a total of 1011 patients with esophageal squamous cell carcinoma between 1996 and 2011 at Kaohsiung Chang Gung Memorial Hospital, and 86 patients with TEF (8.5%) were identified. The overall survival and other clinical data were compared between 30 patients treated with an esophageal metallic stent and 35 patients treated with a feeding gastrostomy/jejunostomy.
Results
Among the 65 patients receiving either an esophageal metallic stent or a feeding gastrostomy/jejunostomy, univariate analysis showed that treatment modality with an esophageal metallic stent (P = 0.007) and radiotherapy treatment after fistula diagnosis (P = 0.04) were predictive of superior overall survival. In the multivariate comparison, treatment modality with an esophageal metallic stent (P = 0.026, odds ratio: 1.859) represented the independent predictive factor of superior overall survival. There were no significant differences between groups in mean decrease in serum albumin or mean body weight loss. Compared to the feeding gastrostomy/jejunostomy group, a significantly higher proportion of patients in the stenting group (53% versus 14%, P = 0.001) were able to receive chemotherapy within 30 days after fistula diagnosis, indicating better infection control in the stenting group.
Conclusions
Compared with a feeding gastrostomy/jejunostomy, an esophageal metallic stent significantly improves overall survival in patients with malignant TEF in our retrospective analysis. Esophageal metallic stent placement may be considered the first-line of treatment for patients with malignant TEF.
doi:10.1371/journal.pone.0042766
PMCID: PMC3418295  PMID: 22912737
12.  Is there a role of whole-body bone scan in patients with esophageal squamous cell carcinoma 
BMC Cancer  2012;12:328.
Background
Correct detection of bone metastases in patients with esophageal squamous cell carcinoma is pivotal for prognosis and selection of an appropriate treatment regimen. Whole-body bone scan for staging is not routinely recommended in patients with esophageal squamous cell carcinoma. The aim of this study was to investigate the role of bone scan in detecting bone metastases in patients with esophageal squamous cell carcinoma.
Methods
We retrospectively evaluated the radiographic and scintigraphic images of 360 esophageal squamous cell carcinoma patients between 1999 and 2008. Of these 360 patients, 288 patients received bone scan during pretreatment staging, and sensitivity, specificity, positive predictive value, and negative predictive value of bone scan were determined. Of these 360 patients, surgery was performed in 161 patients including 119 patients with preoperative bone scan and 42 patients without preoperative bone scan. Among these 161 patients receiving surgery, 133 patients had stages II + III disease, including 99 patients with preoperative bone scan and 34 patients without preoperative bone scan. Bone recurrence-free survival and overall survival were compared in all 161 patients and 133 stages II + III patients, respectively.
Results
The diagnostic performance for bone metastasis was as follows: sensitivity, 80%; specificity, 90.1%; positive predictive value, 43.5%; and negative predictive value, 97.9%. In all 161 patients receiving surgery, absence of preoperative bone scan was significantly associated with inferior bone recurrence-free survival (P = 0.009, univariately). In multivariate comparison, absence of preoperative bone scan (P = 0.012, odds ratio: 5.053) represented the independent adverse prognosticator for bone recurrence-free survival. In 133 stages II + III patients receiving surgery, absence of preoperative bone scan was significantly associated with inferior bone recurrence-free survival (P = 0.003, univariately) and overall survival (P = 0.037, univariately). In multivariate comparison, absence of preoperative bone scan was independently associated with inferior bone recurrence-free survival (P = 0.009, odds ratio: 5.832) and overall survival (P = 0.029, odds ratio: 1.603).
Conclusions
Absence of preoperative bone scan was significantly associated with inferior bone recurrence-free survival, suggesting that whole-body bone scan should be performed before esophagectomy in patients with esophageal squamous cell carcinoma, especially in patients with advanced stages.
doi:10.1186/1471-2407-12-328
PMCID: PMC3443043  PMID: 22853826
Radionuclide imaging; Esophageal cancer; Squamous cell carcinoma; Metastasis; Esophagectomy
13.  Connectivity of Default-Mode Network Is Associated with Cerebral Edema in Hepatic Encephalopathy 
PLoS ONE  2012;7(5):e36986.
Cerebral edema, a well-known feature of acute liver disease, can occur in cirrhotic patients regardless of hepatic encephalopathy (HE) and adversely affect prognosis. This study characterized and correlated functional HE abnormalities in the brain to cerebral edema using resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI). Forty-one cirrhotic patients (16 without HE, 14 minimal HE, 11 overt HE) and 32 healthy controls were assessed. The HE grade in cirrhotic patients was evaluated by the West Haven criteria and neuro-psychological examinations. Functional connectivity correlation coefficient (fc-CC) of the default mode network (DMN) was determined by rs-fMRI, while the corresponding mean diffusivity (MD) was obtained from DTI. Correlations among inter-cortical fc-CC, DTI indices, Cognitive Ability Screening Instrument scores, and laboratory tests were also analyzed. Results showed that gradual reductions of HE-related consciousness levels, from “without HE” or “minimal HE” to “overt HE”, correlated with decreased anterior-posterior fc-CC in DMN [F(4.415), p = 0.000)]. The MD values from regions with anterior-posterior fc-CC differences in DMN revealed significant differences between the overt HE group and other groups. Increased MD in this network was inversely associated with decreased fc-CC in DMN and linearly correlated with poor cognitive performance. In conclusion, cerebral edema can be linked to altered cerebral temporal architecture that modifies both within- and between-network connectivity in HE. Reduced fc-CC in DMN is associated with behavior and consciousness deterioration. Through appropriate targets, rs-fMRI technology may provide relevant supplemental information for monitoring HE and serve as a new biomarker for clinical diagnosis.
doi:10.1371/journal.pone.0036986
PMCID: PMC3356373  PMID: 22623966
14.  White Matter Abnormalities Correlating with Memory and Depression in Heroin Users under Methadone Maintenance Treatment 
PLoS ONE  2012;7(4):e33809.
Methadone maintenance treatment (MMT) has elevated rates of co-morbid memory deficit and depression that are associated with higher relapse rates for substance abuse. White matter (WM) disruption in MMT patients have been reported but their impact on these co-morbidities is unknown. This study aimed to investigate changes in WM integrity of MMT subjects using diffusion tensor image (DTI), and their relationship with history of heroin and methadone use in treated opiate-dependent individuals. The association between WM integrity changes from direct group comparisons and the severity of memory deficit and depression was also investigated. Differences in WM integrity between 35 MMT patients and 23 healthy controls were evaluated using DTI with tract-based spatial statistical analysis. Differences in DTI indices correlated with diminished memory function, Beck Depression Inventory, duration of heroin use and MMT, and dose of heroin and methadone administration. Changes in WM integrity were found in several WM regions, including the temporal and frontal lobes, pons, cerebellum, and cingulum bundles. The duration of MMT was associated with declining DTI indices in the superior longitudinal fasciculus and para-hippocampus. MMT patients had more memory and emotional deficits than healthy subjects. Worse scores in both depression and memory functions were associated with altered WM integrity in the superior longitudinal fasciculus, para-hippocampus, and middle cerebellar peduncle in MMT. Patients on MMT also had significant WM differences in the reward circuit and in depression- and memory-associated regions. Correlations among decreased DTI indices, disease severity, and accumulation effects of methadone suggest that WM alterations may be involved in the psychopathology and pathophysiology of co-morbidities in MMT.
doi:10.1371/journal.pone.0033809
PMCID: PMC3322116  PMID: 22496768
15.  The Relationship between Brown Adipose Tissue Activity and Neoplastic Status: an 18F-FDG PET/CT Study in the Tropics 
Background
Brown adipose tissue (BAT) has thermogenic potential. For its activation, cold exposure is considered a critical factor though other determinants have also been reported. The purpose of this study was to assess the relationship between neoplastic status and BAT activity by 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in people living in the tropics, where the influence of outdoor temperature was low.
Methods
18F-FDG PET/CT scans were reviewed and the total metabolic activity (TMA) of identified activated BAT quantified. The distribution and TMA of activated BAT were compared between patients with and without a cancer history. The neoplastic status of patients was scored according to their cancer history and 18F-FDG PET/CT findings. We evaluated the relationships between the TMA of BAT and neoplastic status along with other factors: age, body mass index, fasting blood sugar, gender, and outdoor temperature.
Results
Thirty of 1740 patients had activated BAT. Those with a cancer history had wider BAT distribution (p = 0.043) and a higher TMA (p = 0.028) than those without. A higher neoplastic status score was associated with a higher average TMA. Multivariate analyses showed that neoplastic status was the only factor significantly associated with the TMA of activated BAT (p = 0.016).
Conclusions
Neoplastic status is a critical determinant of BAT activity in patients living in the tropics. More active neoplastic status was associated with more vigorous TMA of BAT.
doi:10.1186/1476-511X-10-238
PMCID: PMC3267802  PMID: 22182284
Neoplastic status; BAT; 18F-FDG PET
16.  High ERCC1 expression predicts cisplatin-based chemotherapy resistance and poor outcome in unresectable squamous cell carcinoma of head and neck in a betel-chewing area 
Background
This study was to evaluate the effect of excision repair cross-complementation group 1(ERCC1) expression on response to cisplatin-based induction chemotherapy (IC) followed by concurrent chemoradiation (CCRT) in locally advanced unresectable head and neck squamous cell carcinoma (HNSCC) patients.
Methods
Fifty-seven patients with locally advanced unresectable HNSCC who received cisplatin-based IC followed by CCRT from January 1, 2006 through January 1, 2008. Eligibility criteria included presence of biopsy-proven HNSCC without a prior history of chemotherapy or radiotherapy. Immunohistochemistry was used to assess ERCC1 expression in pretreatment biopsy specimens from paraffin blocks. Clinical parameters, including smoking, alcohol consumption and betel nuts chewing, were obtained from the medical records.
Results
The 12-month progression-free survival (PFS) and 2-year overall survival (OS) rates of fifty-seven patients were 61.1% and 61.0%, respectively. Among these patients, thirty-one patients had low ERCC1 expression and forty-one patients responded to IC followed by CCRT. Univariate analyses showed that patients with low expression of ERCC1 had a significantly higher 12-month PFS rates (73.3% vs. 42.3%, p < 0.001) and 2-year OS (74.2 vs. 44.4%, p = 0.023) rates. Multivariate analysis showed that for patients who did not chew betel nuts and had low expression of ERCC1 were independent predictors for prolonged survival.
Conclusions
Our study suggest that a high expression of ERCC1 predict a poor response and survival to cisplatin-based IC followed by CCRT in patients with locally advanced unresectable HNSCC in betel nut chewing area.
doi:10.1186/1479-5876-9-31
PMCID: PMC3072326  PMID: 21426588
ERCC1, squamous cell carcinoma of head and neck, betel nuts, induction chemotherapy, chemoradiation
17.  Upregulation of Neutrophil Gelatinase-Associated Lipocalin by ErbB2 Through NF-κB Activation 
Cancer research  2009;69(24):9163-9168.
ErbB2 (HER2, neu) is a receptor tyrosine kinase overexpressed in about 25% of invasive breast carcinomas. Neutrophil gelatinase-associated lipocalin (NGAL) is a secreted glycoprotein expressed in a variety of cancers including breast carcinomas. NGAL can inhibit erythroid cell production leading to anemia. Anemia usually occurs in cancer patients and negatively impacts quality of life. However, current treatment for cancer-related anemia has potential complications. ErbB2, NGAL, and anemia have all been associated with increased metastasis and poor prognosis in breast cancer patients, although the relationship between ErbB2 and NGAL expression is not clear. Here, using breast cancer cell lines in vitro and transgenic mice carrying the activated c-neu oncogene driven by a mouse mammary tumor virus (MMTV-neu) in vivo, we demonstrate that ErbB2 overexpression leads to NGAL upregulation, which is dependent on nuclear factor kappa B (NF-κB) activity. MMTV-neu transgenic mice developed anemia after tumor onset, and anemia progression could be partially arrested by an NF-κB inhibitor and an ErbB2-targeted therapy. Taken together, upregulation of NGAL by ErbB2 through NF-κB activation is involved in cancer-related anemia, and ErbB2, NF-κB, NGAL pathway may serve as potential therapeutic targets for cancer-related anemia.
doi:10.1158/0008-5472.CAN-09-2483
PMCID: PMC2794902  PMID: 19951994
ErbB2; neutrophil gelatinase-associated lipocalin (NGAL); nuclear factor kappa B (NF-κB); anemia; breast cancer

Results 1-17 (17)