Establishment and validation of a prognostic signature for lung adenocarcinoma based on metabolism-related genes.

BACKGROUND: Given that dysregulated metabolism has been recently identified as a hallmark of cancer biology, this study aims to establish and validate a prognostic signature of lung adenocarcinoma (LUAD) based on metabolism-related genes (MRGs). METHODS: The gene sequencing data of LUAD samples with clinical information and the metabolism-related gene set were obtained from The Cancer Genome Atlas (TCGA) and Molecular Signatures Database (MSigDB), respectively. The differentially expressed MRGs were identified by Wilcoxon rank sum test. Then, univariate cox regression analysis was performed to identify MRGs that related to overall survival (OS). A prognostic signature was developed by multivariate Cox regression analysis. Furthermore, the signature was validated in the GSE31210 dataset. In addition, a nomogram that combined the prognostic signature was created for predicting the 1-, 3- and 5-year OS of LUAD. The accuracy of the nomogram prediction was evaluated using a calibration plot. Finally, cox regression analysis was applied to identify the prognostic value and clinical relationship of the signature in LUAD. RESULTS: A total of 116 differentially expressed MRGs were detected in the TCGA dataset. We found that 12 MRGs were most significantly associated with OS by using the univariate regression analysis in LUAD. Then, multivariate Cox regression analyses were applied to construct the prognostic signature, which consisted of six MRGs-aldolase A (ALDOA), catalase (CAT), ectonucleoside triphosphate diphosphohydrolase-2 (ENTPD2), glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1), lactate dehydrogenase A (LDHA), and thymidylate synthetase (TYMS). The prognostic value of this signature was further successfully validated in the GSE31210 dataset. Furthermore, the calibration curve of the prognostic nomogram demonstrated good agreement between the predicted and observed survival rates for each of OS. Further analysis indicated that this signature could be an independent prognostic indicator after adjusting to other clinical factors. The high-risk group patients have higher levels of immune checkpoint molecules and are therefore more sensitive to immunotherapy. Finally, we confirmed six MRGs protein and mRNA expression in six lung cancer cell lines and firstly found that ENTPD2 might played an important role on LUAD cells colon formation and migration. CONCLUSIONS: We established a prognostic signature based on MRGs for LUAD and validated the performance of the model, which may provide a promising tool for the diagnosis, individualized immuno-/chemotherapeutic strategies and prognosis in patients with LUAD.

Clinico-pathologic determinants of non-e-curative outcome following en-bloc endoscopic submucosal dissection in patients with early gastric neoplasia.

BACKGROUND: Endoscopic submucosal dissection (ESD) is gaining enormous popularity in the treatment of early gastric cancers (EGCs) in many institutions across the world. However, appropriate selection of candidates for endoscopic resection is crucial to sufficiently mitigate non-e-curative (NEC) resection. This study aims at identifying the various clinico-pathologic factors that independently predict the NEC outcome and depth of submucosal invasion following ESD procedure in patients with EGC. METHODS: Multiple logistic regression analysis was applied to investigate factors that independently predict both non-curability phenomenon and the level of submucosal invasion in patients with early gastric neoplasia. Statistical Packages for the Social Sciences version 23 was used for analysis. RESULTS: A total of 153 patients (162 EGC lesions) underwent en-bloc ESD after which the rate of complete resection and non-e-curative outcome were 95% and 22.2%, correspondingly. Multivariate analysis depicted that tumor location in the upper two third of stomach (odds ratio [OR], 5.46; 95% confidence interval [95% CI], 1.65-18.12; p = 0.006), tumor size > 2 cm (OR, 7.63; 95% CI, 2.29-25.42; p = 0.001), histologically undifferentiated tumor (OR, 15.54; 95% CI, 1.65-146.22; p = 0.001), and tumors with 0-IIa/0-IIc or their mixed variants with predominant 0-IIa/0-IIc (OR, 9.77; 95% CI, 1.23-77.65; p = 0.031) were all independent predictors of NEC resection for early gastric tumors. Additionally, location in the upper two third of the stomach (OR, 8.88; 95% CI, 2.90-27.17; p < 0.001), ulcerated lesions (OR, 3.70; 95% CI, 1.15-11.90; p = 0.028), lesions with > 2 cm (OR, 2.94; 95% CI, 1.08-8.02; p = 0.036) and those with poor differentiation (OR, 6.51; 95% CI, 2.23-18.98; p = 0.001) were found to have significant association with submucosal invasion. CONCLUSIONS: Tumors located in the upper two third of the stomach having a larger size (> 2 cm), poor histo-differentiation and a gross type of 0-IIa/0-IIc or their mixed variants with predominant 0-IIa/0-IIc were significantly associated with a risk of NEC after ESD procedure. Thus, early gastric tumors displaying these features need to be handled carefully during endoscopic resection. Our findings may shed light on the pre-procedural detection of clinicopathologic factors that determine non-e-curability in patients with EGC.

Predictors of HIV/AIDS comprehensive knowledge and acceptance attitude towards people living with HIV/AIDS among unmarried young females in Uganda: a cross-sectional study.

BACKGROUND: Youth in general and young females, in particular, remain at the center of HIV/AIDS epidemic. To avoid and prevent HIV infection, comprehensive knowledge as well as correct understanding of transmission and prevention strategies are crucial. Thus, the aim of this study is to explore the predictors of comprehensive knowledge on HIV/AIDS and accepting attitude towards PLWHIV. METHODS: A cross-sectional study was conducted using data from the 2016 Uganda Demographic Health Survey. A two-stage probability sampling method was applied and data were collected using a standard questionnaire. Of the total 8674 women aged 15-49 years, 1971 eligible women aged 15-24 years were included in this analysis. Data analysis was done using SPSS version 23. A Chi-square test followed by logistic regression analysis was used to explore the relationship between specific explanatory variables and outcome variables. The results were reported using odds ratios with 95% confidence interval. P value less than 0.05 was considered as statistically significant. RESULTS: Overall, 99.3% of the unmarried women aged 15-24 years were aware of HIV/AIDS, but only 51.9% had comprehensive knowledge on HIV/AIDS. Around 70% of the respondents were aware that "using condoms every time when having sex" and "having only one faithful uninfected partner" can prevent HIV transmission. About 68% of the unmarried women rejected at least two common local misconceptions about HIV/AIDS. An alarmingly small (20.6%) proportion of the respondents had a positive acceptance attitude towards PLWHIV. All variables were significantly associated with having comprehensive knowledge on HIV/AIDS in the unadjusted logistic regression analysis. After adjustment, older age (20-24 years), being educated, wealthier, and ever been tested for HIV/AIDS became predictors of adequate comprehensive HIV/AIDS knowledge. Moreover, respondents with adequate comprehensive knowledge of HIV/AIDS were more likely (OR 1.64, 95% CI 1.30-2.08) to have a positive acceptance attitude towards PLWHIV than their counterparts. CONCLUSION: Our study demonstrated a remarkably high level of awareness about HIV/AIDS among study participants, but the knowledge and positive acceptance attitude towards PLWHIV were not encouraging. Thus, endeavors to expand and strengthen educational campaigns on HIV/AIDS in communities, health facilities, and schools are highly recommended. Attention should particularly focus on young-aged and disadvantaged women with low educational level, poor socioeconomic status and those who have never been tested for HIV/AIDS.

Distribution of breast lesions diagnosed by cytology examination in symptomatic patients at Eritrean National Health Laboratory, Asmara, Eritrea: a retrospective study.

BACKGROUND: Fine needle aspiration cytology is a simple, relatively accurate, non-invasive, and cost-effective method of diagnosing most breast pathologies. To date, there is no sufficient data depicting the distribution of breast lesions detected by fine needle aspiration cytology in our healthcare setting. The aim of this study was to elucidate the general distribution of breast lesions diagnosed by cytology test at Eritrean National Health Laboratory. METHODS: This retrospective study was carried out on 905 symptomatic patients between the years 2013 and 2017 at Eritrean National Health Laboratory. Diagnosis was made by fine needle aspiration cytology in patients with palpable breast lump and in some patients direct smear was prepared from a nipple discharge. Statistical analysis was carried out using Statistical Package for the Social Sciences version 23. RESULTS: A total of 905 patients were included in the study, of whom 871 (96.24%) were females. The age range of patients was from 13 to 93 years with mean and standard deviation of 33 ± 14.9 years. Breast lump, occurring in 892 (98.56%), was the most frequent presenting symptom. Fibroadenoma and fibrocystic breast lesions were the most prevalent lesions accounting for approximately 40% and 15%, respectively. Malignant breast lesions were seen predominantly in females above the age of 40 years with the highest frequency observed in the age range between 51 and 60 years. Pearson Chi-squared test showed significant association between patients' age above 40 years and the risk of having a malignant breast lesion (p < 0.001). The highest number of benign and malignant breast lesions was documented in 2014 with little fluctuation elsewhere in the study period. CONCLUSION: Fine needle aspiration cytology is a procedure of choice for preoperative diagnosis in breast lesions mainly in a resource-limited settings. Our study identified the occurrence of malignant breast lesions in young women, which is of a paramount public health concern. Of note, significant proportion of patients were late to seek medical attention. Therefore, enhancement of community awareness regarding breast disease and implementation of screening programs are necessary to ameliorate the morbidity and mortality associated with the disease.

Biomarkers used in Alzheimer's disease diagnosis, treatment, and prevention.

Alzheimer's disease (AD), being the number one in terms of dementia burden, is an insidious age-related neurodegenerative disease and is presently considered a global public health threat. Its main histological hallmarks are the Aß senile plaques and the P-tau neurofibrillary tangles, while clinically it is marked by a progressive cognitive decline that reflects the underlying synaptic loss and neurodegeneration. Many of the drug therapies targeting the two pathological hallmarks namely Aß and P-tau have been proven futile. This is probably attributed to the initiation of therapy at a stage where cognitive alterations are already obvious. In other words, the underlying neuropathological changes are at a stage where these drugs lack any therapeutic value in reversing the damage. Therefore, there is an urgent need to start treatment in the very early stage where these changes can be reversed, and hence, early diagnosis is of primordial importance. To this aim, the use of robust and informative biomarkers that could provide accurate diagnosis preferably at an earlier phase of the disease is of the essence. To date, several biomarkers have been established that, to a different extent, allow researchers and clinicians to evaluate, diagnose, and more specially exclude other related pathologies. In this study, we extensively reviewed data on the currently explored biomarkers in terms of AD pathology-specific and non-specific biomarkers and highlighted the recent developments in the diagnostic and theragnostic domains. In the end, we have presented a separate elaboration on aspects of future perspectives and concluding remarks.

The Implication of STEP in Synaptic Plasticity and Cognitive Impairments in Alzheimer's Disease and Other Neurological Disorders.

STriatal-Enriched protein tyrosine Phosphatase (STEP) is a tyrosine phosphatase that has been implicated in Alzheimer's disease (AD), the most common form of dementia, and many other neurological diseases. The protein level and activity of STEP have been found to be elevated in most of these disorders, and specifically in AD as a result of dysregulation of different pathways including PP2B/DARPP32/PP1, PKA as well as impairments of both proteasomal and lysosomal systems. The upregulation in STEP leads to increased binding to, and dephosphorylation of, its substrates which are mainly found to be synaptic plasticity and thus learning and memory related proteins. These proteins include kinases like Fyn, Pyk2, ERK1/2 and both NMDA and AMPA receptor subunits GluN2B and GluA2. The dephosphorylation of these molecules results in inactivation of these kinases and internalization of NMDA and AMPA receptor complexes leading to synapse loss and cognitive impairments. In this study, we aim to review STEP regulation and its implications in AD as well as other neurological disorders and then summarize data on targeting STEP as therapeutic strategy in these diseases.

Development and validation of a novel epigenetic-related prognostic signature and candidate drugs for patients with lung adenocarcinoma.

BACKGROUND: Epigenetic dysregulation has been increasingly proposed as a hallmark of cancer. Here, the aim of this study is to establish an epigenetic-related signature for predicting the prognosis of lung adenocarcinoma (LUAD) patients. RESULTS: Five epigenetic-related genes (ERGs) (ARRB1, PARP1, PKM, TFDP1, and YWHAZ) were identified as prognostic hub genes and used to establish a prognostic signature. According our risk score system, LUAD patients were stratified into high and low risk groups, and patients in the high risk group had a worse prognosis. ROC analysis indicated that the signature was precise in predicting the prognosis. A new nomogram was constructed based on the five hub genes, which can predict the OS of every LUAD patients. The calibration curves showed that the nomogram had better accuracy in prediction. Finally, candidate drugs that aimed at hub ERGs were identified, which included 47 compounds. CONCLUSIONS: Our epigenetic-related signature nomogram can effectively and reliably predict OS of LUAD patients, also we provide precise targeted chemotherapeutic drugs. METHODS: The genomic data and clinical data of LUAD cohort were downloaded from the TCGA database and ERGs were obtained from the EpiFactors database. GSE31210 and GSE50081 microarray datasets were included as independent external datasets. Univariate Cox, LASSO regression, and multivariate Cox analyses were applied to construct the epigenetic-related signature.

A Novel Metabolism-Related Signature as a Candidate Prognostic Biomarker for Hepatocellular Carcinoma.

PURPOSE: Given that metabolic reprogramming has been recognized as an essential hallmark of cancer cells, this study sought to investigate the potential prognostic values of metabolism-related genes (MRGs) for the diagnosis and treatment of hepatocellular carcinoma (HCC). METHODS: In total, 2752 metabolism-related gene sequencing data of HCC samples with clinical information were obtained from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). One hundred and seventy-eight the differentially expressed MRGs were identified from the ICGC cohort and TCGA cohort. Then, univariate Cox regression analysis was performed to identify these genes that were related to overall survival (OS). A novel metabolism-related prognostic signature was developed using the least absolute shrinkage and selection operator (Lasso) and multivariate Cox regression analyses in the ICGC dataset. The Broad Institute's Connectivity Map (CMap) was used in predicting which compounds on the basis of the prognostic MRGs. Furthermore, the signature was validated in the TCGA dataset. Finally, the expression levels of hub genes were validated in HCC cell lines by Western blotting (WB) and quantitative real-time PCR (qRT-PCR). RESULTS: We found that 17 MRGs were most significantly associated with OS in HCC. Then, the Lasso and multivariate Cox regression analyses were applied to construct the novel metabolism-relevant prognostic signature, which consisted of six MRGs. The prognostic value of this prognostic model was further successfully validated in the TCGA dataset. Further analysis indicated that this particular signature could be an independent prognostic indicator after adjusting to other clinical factors. Six MRGs (FLVCR1, MOGAT2, SLC5A11, RRM2, COX7B2, and SCN4A) showed high prognostic performance in predicting HCC outcomes. Candidate drugs that aimed at hub ERGs were identified. Finally, hub genes were chosen for validation and the protein, mRNA expression of FLVCR1, SLC5A11, and RRM2 were significantly increased in human HCC cell lines compared to normal human hepatic cell lines, which were in agreement with the results of differential expression analysis. CONCLUSION: Our data provided evidence that the metabolism-related signature could serve as a reliable prognostic and predictive tool for OS in patients with HCC.