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Apoptosis plays a dual role in cancer development and malignancy. The role of apoptosis-related caspases in cancer remains controversial, particularly in oral tongue squamous cell carcinoma (OTSCC). In this study, we examined the protein levels of cleaved caspase-3, caspase-3, caspase-8, and caspase-9 on tissue microarrays consisting of samples from 246 OTSCC patients by immunohistochemistry. Wilcoxon signed-rank test indicated that the protein levels of cleaved caspase-3, caspase-3, caspase-8, and caspase-9 in tumor tissues were significantly higher compared to those in adjacent normal tissues (all p<0.001). The expression level of caspase-8 in tumors was elevated in patients with lymph node invasion. Moreover, positive expression of cleaved caspase-3 was associated with shorter disease-free survival (DFS) in OTSCC patients with moderate differentiation and lymph node invasion. Combination of either positive cleaved caspase-3 or higher caspase-3 expression or both was associated with poor DFS. Interestingly, stratification analysis showed that co-expression levels of positive cleaved caspase-3 or/and higher caspase-3 were associated with better disease-specific survival in patients with advanced stages of the disease, such as large tumor size and lymph node invasion, whereas it was associated with poor DFS in OTSCC patients with moderate cell differentiation and small tumor size. Taken together, cleaved caspase-3 and caspase-3/8/9 could be biomarkers for tumorigenesis in OTSCC patients. The co-expression level of cleaved caspase-3 and caspase-3 might be a prognostic biomarker for OTSCC patients, particular in those patients with certain tumor stages and cell differentiation status.

We aimed to investigate the association of the expression levels of five epithelial-mesenchymal transition (EMT)-related proteins (Snail, Twist, E-cadherin, N-cadherin, and Vimentin) with tumorigenesis, pathologic parameters and prognosis in tongue squamous cell carcinoma (TSCC) patients by immunohistochemistry of tissue microarray. The expression levels of Snail, E-cadherin, N-cadherin and Vimentin were significantly different between the tumor adjacent normal and tumor tissues. In tumor tissues, lower E-cadherin and higher N-cadherin levels were associated with a higher grade of cell differentiation, advanced stage of disease, and lymph node metastasis. However, higher Vimentin expression was associated with poor cell differentiation and lymph node metastasis. Patients with low E-cadherin expression had poor disease-specific survival (DSS). Conversely, positive N-cadherin and higher Vimentin expression levels were associated with poor DSS and disease-free survival. Notably, our multivariate Cox regression model indicated that high Vimentin expression was an adverse prognostic factor for DSS in TSCC patients, even after the adjustment for cell differentiation, pathological stage, and expression levels of Snail, Twist, E-cadherin, and N-cadherin. Snail, E-cadherin, N-cadherin, and Vimentin were associated with tumorigenesis and pathological outcomes. Among the five EMT-related proteins, Vimentin was a potential prognostic factor for TSCC patients.

Buccal mucosa squamous cell carcinoma (BMSCC) is one of major subsites of oral cancer and is associated with a high rate of metastasis and poor prognosis. Heat shock proteins (HSPs) act as potential prognostic biomarkers in many cancer types. However, the role of HSPD1 in oral cancer, especially in BMSCC, is still unknown. Through data analysis with The Cancer Genome Atlas (TCGA), we found the association of HSPD1 gene expression with tumorigenesis and poor prognosis in oral cancer patients. Our cohort study showed that higher HSPD1 protein level was associated with tumorigenesis and poor prognosis in BMSCC patients with lymph node invasion, suggesting that HSPD1 may be involved in tumor metastasis. Moreover, knockdown of HSPD1 induced E-cadherin expression and decreased the migration and invasion of BMSCC cells. In contrast, ectopic expression of HSPD1 diminished E-cadherin expression and promoted the migration/invasion of BMSCC cells. Further, HSPD1 regulated RelA activation to repress E-cadherin expression, enhancing the migration and invasion of BMSCC cells. Furthermore, HSPD1 protein level was inversely correlated with E-cadherin protein level in tumor tissues and co-expression of high HSPD1/low E-cadherin showed a significant association with poor prognosis in BMSCC patients. Taken together, HSPD1 might repress E-cadherin expression and promote metastatic characters of BMSCC cells for poor prognosis of BMSCC patients.

Background The isocitrate dehydrogenase (IDH) gene family expresses key functional metabolic enzymes in the Krebs cycle and mediates the epigenetic reprogramming, which serves as an important biomarker of breast cancer. However, the expression levels of the IDH protein and their biological function in human breast cancer remain largely unknown. Methods In this study, the clinical impact of IDH1 expression on the progression and prognosis of breast cancer was evaluated using immunohistochemistry assay (IHC) of the corresponding tumor-adjacent normal, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) tissues from 309 patients with breast ductal carcinoma. The relationship between microRNA (miRNA) and IDH1 were examined by a bioinformatics approach, western blot and reporter assay. The biological functions of IDH1 were examined in breast cancer cells with IDH1 knockdown, including proliferation, migration and invasion. Results The present findings revealed that the mRNA and protein expression levels of IDH1 were both significantly lower in breast cancer tissues than in adjacent normal tissues. A low expression level of IDH1 in breast cancer significantly correlated with advanced stage ( p = 0.012), lymph node metastasis ( p = 0.018), and poor disease-specific survival (DSS) (adjusted hazard ratio (AHR), 1.57, 95% confidence interval (CI), 1.08–2.30; p = 0.02). Furthermore, oncogenic miR-32 and miR-92b were identified to suppress IDH1 expression, leading to the inhibition of cell migration and invasion. We further explored whether reduced expression of IDH1 significantly increases snail expression by activating HIFα (hypoxia-inducible factor-1 alpha) and NFκB (nuclear factor kappa B) signaling. Multivariate Cox regression analysis revealed that the combination of low IDH1 and high snail expression could be an independent risk factor for shorter DSS (AHR, 2.34; 95% CI, 1.32–4.16; p = 0.004) and shorter disease-free survival (AHR, 2.50; 95% CI, 1.39–4.50; p = 0.002) in patients with breast cancer. Conclusion Our findings revealed that a IDH1 low /Snail high molecular signature could serve as an independent biomarker for poor prognosis in breast cancer

Breast cancer is a common type of cancer in women, and metastasis frequently leads to therapy failure. Using next-generation sequencing (NGS), we aspired to identify the optimal differentially expressed genes (DEGs) for use as prognostic biomarkers for breast cancer. NGS was used to determine transcriptome profiles in breast cancer tissues and their corresponding adjacent normal tissues from three patients with breast cancer. Herein, 15 DEGs (fold change >4 and <0.25) involved in extracellular matrix (ECM)-receptor interaction signaling were identified through NGS. Among them, our data indicated that high HMMR expression levels were correlated with a poor pathological stage (p<0.001) and large tumor size (p<0.001), whereas high COL6A6 and Reelin (RELN) expression levels were significantly correlated with an early pathological stage (COL6A6: p=0.003 and RELN: p<0.001). Multivariate analysis revealed that high HMMR and SDC1 expression levels were significantly correlated with poor overall survival (OS; HMMR: adjusted hazard ratio [aHR] 1.93, 95% confidence interval [CI]=1.10-3.41, p=0.023; SDC1: [aHR] 2.47, 95%CI=1.28-4.77, p=0.007) for breast cancer. Combined, the effects of HMMR and SDC1 showed a significant correlation with poor OS for patients with breast cancer (high expression for both HMMR and SDC1: [aHR] 3.29, 95%CI=1.52-7.12, p=0.003). These findings suggest that HMMR and SDC1 involved in the ECM-receptor interaction signaling pathway could act as effective independent prognostic biomarkers for breast ductal carcinoma.

DNA methylation at the 5 position of cytosine (5mC) is an epigenetic hallmark in cancer. The 5mC can be converted to 5-hydroxymethylcytosine (5hmC) through a ten-eleven-translocation (TET). We investigated the impact of 5mC, 5hmC, TET1, and TET2 on tumorigenesis and prognosis of breast cancer. Immunohistochemistry was used to assess the levels of 5mC, 5hmC, TET1, and TET2 in the corresponding tumor adjacent normal ( n  = 309), ductal carcinoma in situ (DCIS, n  = 120), and invasive ductal carcinoma (IDC, n  = 309) tissues for 309 breast ductal carcinoma patients. 5mC, 5hmC, TET1-n, and TET2-n were significantly decreased during DCIS and IDC progression. In IDC, the decrease of 5hmC was correlated with the cytoplasmic mislocalization of TET1 ( p  < 0.001) as well as poor disease-specific survival (DSS) (adjusted hazard ratio [AHR] 1.95, p  = 0.003) and disease-free survival (DFS) (AHR 1.91, p  = 0.006). The combined decrease of 5mC and 5hmC was correlated with worse DSS (AHR 2.19, p  = 0.008) and DFS (AHR 1.99, p  = 0.036). Stratification analysis revealed that the low level of 5mC was associated with poor DSS (AHR 1.89, p  = 0.044) and DFS (AHR 2.02, p  = 0.035) for the ER/PR-positive subtype. Conversely, the low level of 5hmC was associated with worse DSS (AHR 2.77, p  = 0.002) and DFS (AHR 2.69, p  = 0.006) for the ER/PR-negative subtype. The decreases of 5mC, 5hmC, TET1-n, and TET2-n were biomarkers of tumor development. The global reduction of 5hmC was a poor prognostic factor for IDC, especially for ER/PR-negative subtype.

Hippocampal malrotation (HIMAL) is an increasingly recognized neuroimaging feature but the clinical correlation and significance in epilepsies remain under debate. It is characterized by rounded hippocampal shape, deep collateral, or occipitotemporal sulcus, and medial localization of the hippocampus. In this review, we describe the embryonic development of the hippocampus and HIMAL, the qualitative and quantitative diagnosis issues, and the pathological findings of HIMAL. HIMAL can be bilateral or unilateral and more on the left side. Furthermore, the relevance of HIMAL diagnosis in clinical practice, including its role in epileptogenesis and the impact on the pre-surgical decision are reviewed. Finally, the relationship between HIMAL and hippocampal sclerosis (HS) and the possible role of genetics in the etiology of HIMAL are discussed. The evidence so far suggested that HIMAL does not have a significant role in epileptogenesis or surgical decision. HIMAL could be a genetic developmental imaging feature that represents a more diffuse but subtle structural error during brain development. Many questions remain to be explored, such as possible cognitive alteration associated with HIMAL and whether HIMAL predisposes to the development of HS. Further studies using high-quality MRI, unified consensus qualitative and quantitative diagnostic criteria, and comprehensive cognitive assessment are recommended.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

BackgroundTo describe the clinical characteristics of EATL with intracranial metastasis from cases published in literatureSubjectsEATL is a rare disease of the gastrointestinal tract. Intracranial metastasis associated with EATL is even rare. Six cases including one of ours were recruited in the study. Five reported cases were found between 1997 and 2012 in the English literature (table 1).Abstract IDDF2018-ABS-0169 Table 1Cases Age Sex Celiac Disease Primary lesion Symptoms and Sign Tx Location of intracranial metastasis Neurological symptoms Tx Overall survival after initial diagnosis (1)Tutt et al* 45 M (+) Small bowel Abd pain, diarrhoea; Supportive Supratentorial(Rt ventricle) Headache, confusion, memory impairment, C/T, radiotherapy 11 M (2)Shams et al* 54 M (-) Jejunum Perforation OP(+), C/T lnfratentorial(Lt cerebellum) Ataxia, slurred speech Nil 3 M (3)Gobbi et al* 56 F (+) StomachDuodenum Perforation OP(+), C/T Supratentorial(SubcorticaI and periventricular) Headache,Depression,Cognitive decline C/T, radiotherapy 9 M (4)Berman et al. 70 M (-) Jejunum Abd pain, weight loss OP(+), C/T Supratentorial(Bil occipital and temporal) Seizure Steroid (+), radiotherapy 16M (5)Defillo et al. 65 F (-) Jejunum Abd pain,Obstruction OP(+), C/T Supratentorial(Rt frontal- parietal) Change in MS;Left facial brachial weakness; OP (+) Nil (6)Chuah et al. 35 M (-) Jejunum Diarrhoea OP(+), C/T Supratentorial(Frontal and corpus callosum) Change in MS;Left sided weakness; Steroid (+) 9M MethodsOurs was a 35-year-old man who presented initially with diarrhoea, and he was later confirmed to have EATL from biopsy at jejunum that showing positive in CD3, CD8 and CD56 with negative in CD4. Since diagnosis, he had received 11 cycles of adjuvant chemotherapy. He underwent laparotomy with resection and anastomosis of jejunum due to the acute abdomen. An episode of left-sided weakness after having received his 11th cycle of chemotherapy led to brain computed tomography scan, which it showed brain metastasis. He expired 9 months later after initial diagnosis. Altogether, six cases of EATL with intracranial metastasis were reviewed for their clinical characteristics.ResultsThe mean age was 54 years old (range from 35 to 65 years old). Two-thirds were males. Many (two-thirds) were without a history of celiac disease. One-half of the patients had abdominal pain as the initial gastrointestinal presentation. The primary lesion site was in the small intestine with jejunum predominance (66.6%). Eighty-three percent of patients had abdominal surgery and adjuvant chemotherapy for the primary lesion. The majority site of intracranial metastasis was supratentorial V.S. infratentorial; 83% V.S 17%. Half of intracranial metastasis (50%) presented with a change of mental status. Headache (33.3%) and weakness of extremities (33.3%) were the next most common presentations of metastasis. Radiotherapy, chemotherapy and steroid therapy were used to treat intracranial metastasis. The survival was an average of 9.6 months (3 months to 16 months) after the initial diagnosis of EATL.ConclusionsThe prognosis of EATL with intracranial metastasis is generally poor with a mean survival time of fewer than 10 months.