The prognosis for hepatocellular carcinoma (HCC) remains dismal due to the lack of diagnostic markers for early detection. This review will discuss the clinical potential of the dickkopf (DKK) family members as diagnostic and/or prognostic markers for HCC. In comparison to serum α-fetoprotein (AFP) level, which remains the gold standard for HCC diagnosis, high serum DKK1 levels have higher diagnostic value for HCC, especially for AFP-negative HCC, and can distinguish HCC from non-malignant chronic liver diseases. Additionally, the combination of serum DKK1 and AFP levels enhances diagnostic accuracy for HCC compared to serum DKK1 or AFP levels alone. Although DKK1 offers potential for its use in HCC diagnosis this review will discuss the challenges facing DKK1 and also shed some light on recent developments on the remaining DKK family members: DKK2, DKK3 and DKK4.
Esophageal cancer is the eighth most common cancer worldwide and esophageal squamous cell carcinoma (ESCC) is the predominant type in Asia. Surgical resection of the tumor is the mainstay treatment for ESCC. Recent advances in neoadjuvant or adjuvant chemotherapy/chemoradiotherapy for treatment of ESCC have significantly improved prognosis. Despite these advancements, survival of some patients still remains poor in particular for those diagnosed at a late stage. In view of the asymptomatic nature of early ESCC and the limitations of currently used diagnostic methods, there is a pressing need to identify circulatory biomarkers to allow noninvasive and early detection of ESCC. In this chapter, we summarize circulating cancer biomarkers including circulatory proteins, microRNAs, and tumor cells that are found to have elevated level in serum and plasma of ESCC patients when compared to healthy subjects. These biomarkers could help improve the diagnostic efficiency of ESCC.
Esophageal squamous cell carcinoma (ESCC) shows high frequency and mortality in Asian regions, including China. Previous analysis of genomic DNA of ESCC using comparative genomic hybridization indicated that amplification of the chromosome 5p regions is a common event in ESCC cell lines and patient cases of Hong Kong Chinese origin, and the results suggested that the genes located in the chromosome 5p regions may play crucial roles in the molecular pathogenesis of ESCC. Our previous studies on ESCC confirmed the tumorigenic and overexpression properties of a novel gene JS-1 located in chromosome 5p15.2 upstream to delta-catenin. In the present study, another novel gene JK-1 which is located at 5p15.1 downstream to delta-catenin was characterized for its roles in the pathogenesis of ESCC. Thirteen ESCC cell lines and 30 surgical specimens of esophageal tumors were studied for the overexpression of JK-1 using multiplex RT-PCR analysis. The transforming capacity of overexpression of JK-1 was also investigated by transfecting NIH 3T3 and HEK 293 cells with the expression vector cloned with JK-1, followed by the soft agar and foci formation assays. JK-1 was overexpressed in 9/13 (69%) of the ESCC cell lines and 9/30 (30%) of the ESCC patient cases. Both NIH 3T3 and HEK 293 cells acquired the properties of anchorage-dependent and -independent growth when JK-1 was overexpressed. Most significantly, subcutaneous sarcomas were formed in all (3/3) the athymic nude mice after NIH 3T3 cells overexpressing JK-1 were injected subcutaneously. Our results thus indicated that JK-1 is commonly overexpressed in ESCC and has a prominent capacity to transform normal cells. Our overall results thus provide the first evidence that the overexpression of JK-1 and its transforming capacity in normal cells may play a critical role in the molecular pathogenesis of ESCC.
The need to identify disease biomarkers is critical to ensure fast diagnosis and timely treatment. Surface enhanced laser desorption/ionization time-of-fight mass spectrometry (SELDI-TOF-MS) is a widely used technology platform for diagnostic biomarker discovery. This short review provides an overview of how it functions and also describes its advantages and drawbacks. Keywords: Surface enhanced laser desorption/ionization, proteomics, biomarker, liver diseases
Abstract 5-hydroxytryptamine (5-HT), a neurotransmitter and vasoactive factor, has been reported to promote proliferation of serum-deprived human hepatocellular carcinoma cells (HCC) but the detailed intracellular mechanism is still unknown. As Wnt/β-catenin signaling is highly dysregulated in a majority of HCC, this study explored the regulation of Wnt/β-catenin signaling by 5-HT. 5-HT promoted proliferation of serum-deprived HuH-7 and HepG2 cells and also increased total β-catenin levels, and active β-catenin protein levels compared to just control cells under serum free medium without 5-HT. Furthermore, 5-HT increased β-catenin levels in the presence of cycloheximide, a protein synthesis inhibitor, suggesting increased β-catenin levels due to inhibition of β-catenin degradation. Quantitative real-time polymerase chain reaction (qPCR) showed increased β-catenin downstream target genes, Axin1, cyclin D1, dickoppf-1 (DKK1) and glutamine synthetase (GS), in serum-deprived HCC cell lines treated with 5-HT. We next studied the expression of various 5-HT were receptors (5-HT1D, 5-HT2A, 5-HT2B, 5-HT5 and 5-HT7) by qPCR in 33 pairs of HCC tumors and corresponding adjacent non-tumor tissues. Receptors 5-HT1D (21/33, 64%), 5-HT2B (12/33, 36%) and 5-HT7 (15/33, 45%) were overexpressed in HCC tumour tissues whereas receptor 5-HT5 was reduced (30/33, 91%) in HCC tumour tissues. Receptor 5-HT2A did not show any significant statistical difference between HCC tumour and corresponding non-tumour tissues. We further investigated whether antagonists of the 5-HT receptors attenuated the activity of 5-HT both in vitro and in vivo and we narrowed our study to 5-HT7 antagonist as the expression of 5-HT7 was found to be significantly associated to liver histology and venous infiltration. Antagonist of receptor 5-HT7, SB258719, attenuated growth of serum-deprived HCC cell lines and primary tumor tissues in the presence of 5-HT. Furthermore, SB258719 reduced tumor growth in a xenograft mouse model accompanied by reduced β-catenin and increased GSK-3β levels as observed by immunohistochemical analysis. Conclusion: This study provides evidence of Wnt/β-catenin signaling activation in 5-HT induced proliferation of serum-deprived HCC cells. The proliferation is inhibited by 5-HT7 antagonist, SB258719, which may represent a potential therapeutic target for hepatocarcinogenesis. Citation Format: Sarwat Fatima, Shi Xiaoki, Lin Zesie, Chen Guo, John W. Ho, Nikki P. Lee, Xiang Bian Zhao. 5-HT promotes hepatocellular carcinoma by influencing β-catenin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 58. doi:10.1158/1538-7445.AM2015-58
5‐Hydroxytryptamine (5‐HT), a neurotransmitter and vasoactive factor, has been reported to promote proliferation of serum‐deprived hepatocellular carcinoma (HCC) cells but the detailed intracellular mechanism is unknown. As Wnt/β‐catenin signalling is highly dysregulated in a majority of HCC, this study explored the regulation of Wnt/β‐catenin signalling by 5‐HT. The expression of various 5‐HT receptors was studied by quantitative real‐time polymerase chain reaction (qPCR) in HCC cell lines as well as in 33 pairs of HCC tumours and corresponding adjacent non‐tumour tissues. Receptors 5‐HT1D (21/33, 63.6%), 5‐HT2B (12/33, 36.4%) and 5‐HT7 (15/33, 45.4%) were overexpressed whereas receptors 5‐HT2A (17/33, 51.5%) and 5‐HT5 (30/33, 90.1%) were reduced in HCC tumour tissues. In vitro data suggests 5‐HT increased total β‐catenin, active β‐catenin and decreased phosphorylated β‐catenin protein levels in serum deprived HuH‐7 and HepG2 cells compared to control cells under serum free medium without 5‐HT. Activation of Wnt/β‐catenin signalling was evidenced by increased expression of β‐catenin downstream target genes, Axin2, cyclin D1, dickoppf‐1 (DKK1) and glutamine synthetase (GS) by qPCR in serum‐deprived HCC cell lines treated with 5‐HT. Additionally, biochemical analysis revealed 5‐HT disrupted Axin1/β‐catenin interaction, a critical step in β‐catenin phosphorylation. Increased Wnt/β‐catenin activity was attenuated by antagonist of receptor 5‐HT7 (SB‐258719) in HCC cell lines and patient‐derived primary tumour tissues in the presence of 5‐HT. SB‐258719 also reduced tumour growth in vivo. This study provides evidence of Wnt/β‐catenin signalling activation by 5‐HT and may represent a potential therapeutic target for hepatocarcinogenesis.
ContextGlucose-insulin-potassium (GIK) infusion is a widely applicable, low-cost therapy that has been postulated to improve mortality in patients with acute ST-segment elevation myocardial infarction (STEMI). Given the potential global importance of GIK infusion, a large, adequately powered randomized trial is required to determine the effect of GIK on mortality in patients with STEMI.ObjectiveTo determine the effect of high-dose GIK infusion on mortality in patients with STEMI.Design, Setting, and ParticipantsRandomized controlled trial conducted in 470 centers worldwide among 20 201 patients with STEMI who presented within 12 hours of symptom onset. The mean age of patients was 58.6 years, and evidence-based therapies were commonly used.InterventionPatients were randomly assigned to receive GIK intravenous infusion for 24 hours plus usual care (n = 10 091) or to receive usual care alone (controls; n = 10 110).Main Outcome MeasuresMortality, cardiac arrest, cardiogenic shock, and reinfarction at 30 days after randomization.ResultsAt 30 days, 976 control patients (9.7%) and 1004 GIK infusion patients (10.0%) died (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.95-1.13; P = .45). There were no significant differences in the rates of cardiac arrest (1.5% [151/10 107] in control and 1.4% [139/10 088] in GIK infusion; HR, 0.93; 95% CI, 0.74-1.17; P = .51), cardiogenic shock (6.3% [640/10 107] vs 6.6% [667/10 088]; HR, 1.05; 95% CI, 0.94-1.17; P = .38), or reinfarction (2.4% [246/10 107] vs 2.3% [236/10 088]; HR, 0.98; 95% CI, 0.82-1.17; P = .81). The rates of heart failure at 7 days after randomization were also similar between the groups (16.9% [1711/10 107] vs 17.1% [1721/10 088]; HR, 1.01; 95% CI, 0.95-1.08; P = .72). The lack of benefit of GIK infusion on mortality was consistent in prespecified subgroups, including in those with and without diabetes, in those presenting with and without heart failure, in those presenting early and later after symptom onset, and in those receiving and not receiving reperfusion therapy (thrombolysis or primary percutaneous coronary intervention).ConclusionIn this large, international randomized trial, high-dose GIK infusion had a neutral effect on mortality, cardiac arrest, and cardiogenic shock in patients with acute STEMI.
Introduction: Tuberculosis continues to be the leading cause of morbidity and mortality in developing nations. Off late infections due to mycobacterial species other than tubercle bacilli are being reported frequently. Nontuberculous mycobacteria are being increasingly recognized and isolated as pathogens from immunocompetent host too. They are found in both pulmonary and extrapulmonary form of disease. The prevalence of infections due to NTM is known to vary with place, host and climatic factors. Aim: the present study is a retrospective cross-sectional observational study for a period of two years from Jan.2013- Dec.2014, at Princess Era Hospital,a teaching hospital of Deccan college of medical sciences at Hyderabad. Data from microbiology lab records was retrieved and analysed. Materials and Methods: about 232 specimens from 229 patients with clinical symptoms of tuberculosis were analysed for laboratory diagnosis of nontuberculosis mycobacterial infection in mycobacteriology section of microbiology laboratory. Seventy nine samples were obtained from 78 patients with pulmonary form of disease and 153 samples were from 151 patients with extrapulmonary form of disease. Study was approved by ethical committee of the college and patient consent was obtained prior to sample collection. All the specimens received in the laboratory were processed by direct microscopy for acid fast bacilli using Ziehl Neelsen stain. Culture was performed on conventional LJ media and Middle Brook 7H12 media in MGIT 320 automated system. Identification of culture positive isolates was achieved by standard biochemical test and rapid immunochromatography test for detection of mycobacterial tuberculosis protein 64 antigen [MPT64]. Results: Direct microscopy was positive in 20.52%. and 4.25% of which were later identified as NTM. Culture yielded positive result in 22.27% of the subjects. NTM were isolated in 3.49% of the total subjects studied. Mycobacterium tuberculosis was the most common
Introduction: Extra pulmonary form of tuberculosis is an important public health disease which cannot be ignored because of its low transmissibility. Data on the exact burden of the disease in developing countries is scarce. Aim: To assess the burden of the disease in a tertiary care hospital of India. To study the clinical trends in the disease, and the utility of various diagnostic modalities for its diagnosis. To identify the Mycobacterial species and perform drug susceptibility test. Materials and Methods: A cross sectional study was carried out for a period of two years. A total of one hundred and forty seven samples were tested for extrapulmonary tuberculosis using a combination of bacteriological, cytological, histological and biochemical techniques to achieve proper diagnosis of the disease. Results: Young adults and females predominated in the study group and positive cases. Original Research Article Fatima et al.; BJMMR, 8(6): 495-502, 2015; Article no.BJMMR.2015.472 496 Microbiologically, 26% of the specimens were positive. Eighteen percent of them were found to be culture positive for M. tuberculosis. Smear by Ziehl Neelsen stain was positive in 9%. A combination of culture media both solid and liquid maximized the yield of Mycobacteria. Lymph node tuberculosis was found to be the predominant type followed by others. Fifteen percent of the strains were found to be resistant to the first line drugs used in treatment of tuberculosis. Cytology and biochemical findings were found to be less specific in diagnosis of extrapulmonary tuberculosis. Conclusion: Extrapulmonary form of tuberculosis is seen in significant number of the suspects. Hence, attention should be paid towards its proper and early diagnosis followed by rational management, as if neglected may lead to associated complications and sequalae.
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