Clinicopathological and Immunohistochemical Profile of Mantle Cell Lymphoma: An Institutional Experience.
Introduction Mantle cell lymphoma (MCL) is a biologically aggressive B-cell non-Hodgkin lymphoma (NHL) with distinctive morphologic, immunophenotypic, and molecular characteristics. Differentiation from other chronic lymphoproliferative disorders is essential for prognostication. Aim This paper aims to study the clinicopathological features of MCL with emphasis on immunohistochemical features and disease correlation. Method To do so, clinicopathological characteristics from 21 cases of MCL (14 males, seven females, M:F=2:1) diagnosed in the last five years i.e. 2015 to 2020, were retrospectively reviewed and correlated with immunohistochemistry (IHC) data. Particularly those pertaining to cyclin D1, SRY-box transcription factor 11 (SOX11), cluster of differentiation (CD) 5, CD23, MIB E3 ubiquitin protein ligase 1 (MIB1), tumor protein 53 (TP53), c-myelocytomatosis oncogene product (c-MYC), multiple myeloma oncogene 1 (MUM1), mouse double minute 2 homolog (MDM2), and Epstein-Barr virus latent membrane protein 1 (EBV-LMP1) expression with its aberrations. Observations This study shows that MCL constituted 4.2% (21/500) of all NHLs with a mean age of 57.5 years (median 60 years, range 30 to 80 years). The disease was nodal in 19, and extranodal in the remaining two cases. 14 of 21 (67%) had generalized lymphadenopathy and 71% had bone marrow (BM) involvement. The nodal involvement was diffuse in 9/17 (53%), 8/21 (38%) had a blastoid morphology, and an in-situ MCL pattern was not seen in any of the cases selected for the study. Cyclin D1 immunoexpression correlated well with SOX11; CD5-negative in five cases; and CD23-positive in three cases. TP53 and c-MYC expression were noted in 17/19 (89.4%) and 8/17 (47%), respectively. MUM1 registered positive in six cases. None of the cases showed immunopositivity for MDM2 and EBV-LMP1. Conclusion In essence, this study indicates that morphological and immunophenotypic subclassification of mantle cell lymphoma with a wider panel of IHC markers is essential for understanding disease biology and better prognostication.
Publication Date: 2021-08-26
Aberrant PTEN, PIK3CA, pMAPK, and TP53 expression in human scalp and face angiosarcoma.
Angiosarcoma is a rare, highly aggressive malignant tumor originating from endothelial cells that line the lumen of blood or lymphatic vessels. The molecular mechanisms of scalp and face angiosarcoma still need to be elucidated. This study aimed to investigate the expression of phosphatase and tensin homolog (PTEN), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphorylated mitogen-activated kinase-like protein (pMAPK), and tumor protein p53 (TP53) in scalp and face angiosarcoma and to assess tumor tissue apoptosis.The expression and intracellular distribution of PTEN, PIK3CA, pMAPK, and TP53 proteins in 21 specimens of human scalp and face angiosarcoma and 16 specimens of human benign hemangioma were evaluated using immunohistochemistry. Tumor cell apoptosis was assessed by terminal deoxyribonucleotide transferase-mediated dUTP nick end-labeling staining.Significantly lower PTEN but higher PIK3CA, pMAPK, and TP53 immunostaining were detected in the angiosarcoma specimens than in the benign hemangioma specimens(P < .01). The angiosarcoma tissues exhibited significantly higher apoptosis indices than the benign hemangioma tissues (P < .01). The positive expression rates of PIK3CA, pMAPK, and TP53 were correlated with the degree of tumor differentiation in the human scalp and face angiosarcoma.The PI3K, MAPK, and TP53 pathways might be involved in angiosarcoma tumorigenesis in humans and may serve as therapeutic targets for the effective treatment of this malignancy.
Publication Date: 2021-08-17
The regulation of long non-coding RNA 00958 (LINC00958) for oral squamous cell carcinoma (OSCC) cells death through absent in melanoma 2 (AIM2) depending on microRNA-4306 and Sirtuin1 (SIRT1) in vitro.
Long non-coding RNAs (lncRNAs) have been proposed as potential targets in OSCC gene therapy. Thus, the study aims to analyze how they exert functions in OSCC. LINC00958, AIM2, Gasdermin D (GSDMD) and tumor protein p53 (TP53) expression levels are analyzed by Quantitative Real-time PCR (qPCR) or Western blotting (WB) in OSCC cells lines. The roles of LINC00958 in cell proliferation, cell death, and GSDMD expression respectively were analyzed by Cell Counting Kit-8 (CCK8) assay, flow cytometry and Immunofluorescence (IF) assay. In addition, expressions of pyroptosis- and autophagy-related proteins are evaluated by WB detection. The targeted binding of LINC00958 and miR-4306 or AIM2 mRNA is predicted by bioinformatics analysis and detected by biodual luciferase system. RIP and qPCR assays analyze whether LINC00958 interacts with SIRT1. We found that LINC00958 showed upregulation in OSCC cells compared to normal oral epithelial cells. LINC00958 silencing significantly suppressed OSCC cell proliferation, induced cell death and reduced autophagy. LINC00958 regulated the levels of miR-4306 which binds to the 3'UTR of AIM2, and interacts with and modulates SIRT1 protein expression. LINC00958 regulated GSDMD and AIM2 levels, as well as p53 and SIRT1 levels. SIRT1 overexpression markedly reversed aforementioned effects of LINC00958. LINC00958 not only downregulated miR-4306 levels to activate the pyroptosis pathway mediated by AIM2 and promoted cancer cell survival but also induced a decrease in SIRT protein expression to further reduce p53 levels.
Publication Date: 2021-08-13
Exosomes of Mesenchymal Stem Cells as a Proper Vehicle for Transfecting miR-145 into the Breast Cancer Cell Line and Its Effect on Metastasis.
Despite recent advances in scientific knowledge and clinical practice, management, and treatment of breast cancer, as one of the leading causes of female mortality, breast cancer remains a major burden. Recently, methods employing stem cells and their derivatives, i.e., exosomes, in gene-based therapies hold great promise. Since these natural nanovesicles are able to transmit crucial cellular information which can be engineered to have robust delivery and targeting capacity, they are considered one of the modes of intercellular communication. miR-145, one of the downregulated microRNAs (miRNAs) in various cancers, can regulate tumor cell invasion, metastasis, apoptosis, and proliferation and stem cell differentiation.
The aim of this study was to investigate the role of exosomes secreted from adipose tissue-derived mesenchymal stem cells (MSCs) for miR-145 transfection into breast cancer cells in order to weaken their expansion and metastasis.
Here, we exploited the exosomes from adipose tissue-derived mesenchymal stem cells (MSC-Exo) to deliver miR-145 in the T-47D breast cancer cell line. Lentiviral vectors of miR-145-pLenti-III-enhanced green fluorescent protein (eGFP) and empty pLenti-III-eGFP as the backbone were used to transfect MSCs and T-47D cells. In order to find the efficiency of exosomes as a delivery vehicle, the expression level of some miR-145 target genes, including Rho-Associated Coiled-Coil Containing Protein Kinase 1 (ROCK1), Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2), Matrix Metalloproteinase 9 (MMP9), and Tumor Protein p53 (TP53), was compared in all treatment groups (T-47D cells treated by miR-145-transfected MSCs and their derivatives or their backbone) and control group (untransfected T-47D cells) using real-time PCR.
The obtained data represented the inhibitory effect of miR-145 on apoptosis induction and metastasis in both direct miR-treated groups. However, exosome-mediated delivery caused an improved anticancer property of miR-145.
Restoration of miR-145 using MSC-Exo can be considered a potential novel therapeutic strategy in breast cancer in the future.
Publication Date: 2021-07-27
Journal: BioMed research international
Study on HOXBs of Clear Cell Renal Cell Carcinoma and Detection of New Molecular Target.
Our study examined the transcriptional and survival data of HOXBs in patients with clear cell renal cell carcinoma (ccRCC) from the ONCOMINE database, Human Protein Atlas, and STRING website. We discovered that the expression levels of HOXB3/5/6/8/9 were significantly lower in ccRCC than in normal nephritic tissues. In ccRCC, patients with a high expression of HOXB2/5/6/7/8/9 mRNA have a higher overall survival (OS) than patients with low expression. Further analysis by the GSCALite website revealed that the methylation of HOXB3/5/6/8 in ccRCC was significantly negatively correlated to gene expression, while HOXB5/9 was positively correlated to the CCT036477 drug target. As DNA abnormal methylation is one of the mechanisms of tumorigenesis, we hypothesized that HOXB5/6/8/9 are potential therapeutic targets for patients with ccRCC. We analyzed the function of enrichment data of HOXBs in patients with ccRCC from the Kyoto Encyclopedia of Genes and Genomes pathway enrichment and the PANTHER pathway. The results of the analysis show that the function of HOXBs might be associated with the Wnt pathway and that HOXB5/6/8/9 was coexpressed with multiple Wnt pathway classical genes and proteins, such as MYC, CTNNB, Cyclin D1 (CCND1), and tumor protein P53 (TP53), which further confirms that HOXBs inhibit the growth of renal carcinoma cells through the Wnt signaling pathway. In conclusion, our analysis of the family of HOXBs and their molecular mechanism may provide a theoretical basis for further research.
Publication Date: 2021-07-27
Journal: Journal of oncology
Integration of clinicopathological and mutational data offers insight into lung cancer with tumor spread through air spaces.
Tumor spread through air spaces (STAS) was defined as a unique tumor invasion pattern in adenocarcinoma (ADC) by The World Health Organization Classification of Lung Tumors in 2015. Since then, STAS had been shown to be associated with local recurrence and poor survival results, as the typical signature and potential mechanisms of STAS remained unclear. Our objectives were to comprehensively demonstrate the clinicopathological and genetic signatures in STAS-positive lung cancer patients.
The clinicopathological and gene alteration characteristics of 878 STAS-positive lung cancer patients were presented. Associations between parameters were evaluated using the Chi-square test, Fisher's exact test, and logistic regression. The capture-based targeted next generation sequencing (NGS) with a platform of 68 lung cancer-related genes was conducted in 139 cases, and the mutational spectrum was summarized.
STAS was identified in 391 female and 481 male patients, of which ADC accounted for the majority of cases (92.6%). The concomitant solid or micropapillary subtype was observed in 92.12% patients with ADC. Poorly differentiated histological subtypes were more frequent and negatively correlated with tumor size in smaller tumor cases (P=0.036, Pearson's R=-0.075). Furthermore, in the subgroup of nodules within 3 cm, the distribution of the solid and micropapillary subtypes were significantly frequent in lymph node-positive patients (P<0.001). Tumor protein p53 (TP53) alterations were more frequent in smoking patients (27.6%, P=0.007), human epidermal growth factor receptor 2 (HER2) alterations were more common in female (10.8%, P=0.025), while Kirsten rat sarcoma viral oncogene (KRAS) (20.3%, P=0.024) and TP53 (45.9%, P=0.003) were more prevalent in males.
Poorly differentiated histological subtypes likely played a crucial role in promoting the invasiveness of STAS, especially in small tumor-size cases. Epidermal growth factor receptor (EGFR), TP53, KARS, anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1) were the five most frequent alterations in STAS-positive ADC.
Publication Date: 2021-07-20
Journal: Annals of translational medicine
Therapeutic targets and molecular mechanism of calycosin for the treatment of cerebral ischemia/reperfusion injury.
This study was designed to understand the pivotal anti-cerebral ischemia/reperfusion injury (CIRI) targets and pathways of calycosin through network pharmacology and molecular docking analyses. In this study, bioinformatics tools were employed to characterize and identify the pharmacological functions and mechanisms of calycosin for CIRI management. The network pharmacology data identified potential, merged CIRI-associated targets of calycosin including tumor protein p53 (TP53), protein kinase B (AKT1), vascular endothelial growth factor A (VEGFA), interleukin 6, tumor necrosis factor (TNF), and mitogen-activated protein kinase 1 (MAPK1). Molecular docking analysis indicated the binding efficacy of calycosin with three of the targets, namely TP53, AKT1, and VEGFA. The biological processes of calycosin for the treatment of CIRI are mainly involved in the improvement of endothelial cell proliferation and growth, inflammatory development, and cellular metabolism. In addition, the anti-CIRI actions of calycosin were primarily through suppression of the toll-like receptor, PI3K-AKT, TNF, MAPK, and VEGF signaling pathways. Taken together, the current bioinformatic findings revealed pivotal targets, biological functions, and pharmacological mechanisms of calycosin for the treatment of CIRI. In conclusion, calycosin, a functional phytoestrogen, can be potentially used for the treatment of CIRI in future clinical trials.
Publication Date: 2021-06-29
The preventive effects of aspirin on preeclampsia based on network pharmacology and bioinformatics.
This study aimed to reveal the key targets and molecular mechanisms of aspirin in preventing preeclampsia. We used bioinformatics databases to collect the candidate targets for aspirin and preeclampsia. The biological functions and signaling pathways of the intersecting targets were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Then, the hub targets were identified by cytoscape plugin cytoHubba from the protein-protein interaction network. We collected 90 targets for aspirin in preventing preeclampsia. The biological processes of the intersecting targets are mainly involved in xenobiotic metabolic process, inflammatory response, negative regulation of apoptotic process, and protein phosphorylation. The highly enriched pathways were FoxO signaling pathway, circadian rhythm, insulin resistance, arachidonic acid metabolism, and drug metabolism-cytochrome P450. The hub targets for aspirin in preventing preeclampsia were tumor protein p53 (TP53), C-X-C motif chemokine ligand 8 (CXCL8), mitogen-activated protein kinase 3 (MAPK3), mitogen-activated protein kinase 1 (MAPK1), mitogen-activated protein kinase 14 (MAPK14), epidermal growth factor receptor (EGFR), estrogen receptor (ESR1), and prostaglandin-endoperoxide synthase 2 (PTGS2). Molecular docking results showed good bindings between the proteins and aspirin. In conclusion, these findings highlight the key targets and molecular mechanisms of aspirin in preventing preeclampsia.
Publication Date: 2021-06-26
Journal: Journal of human hypertension
Multi-Omics Data Analyses Construct a Six Immune-Related Genes Prognostic Model for Cervical Cancer in Tumor Microenvironment.
The cross-talk between tumor cells and the tumor microenvironment (TME) is an important factor in determining the tumorigenesis and progression of cervical cancer (CC). However, clarifying the potential mechanisms which trigger the above biological processes remains a challenge. The present study focused on immune-relevant differences at the transcriptome and somatic mutation levels through an integrative multi-omics analysis based on The Cancer Genome Atlas database. The objective of the study was to recognize the specific immune-related prognostic factors predicting the survival and response to immunotherapy of patients with CC. Firstly, eight hub immune-related prognostic genes were ultimately identified through construction of a protein-protein interaction network and Cox regression analysis. Secondly, 32 differentially mutated genes were simultaneously identified based on the different levels of immune infiltration. As a result, an immune gene-related prognostic model (IGRPM), including six factors (chemokine receptor 7 [CCR7], CD3d molecule [CD3D], CD3e molecule [CD3E], and integrin subunit beta 2 [ITGB2], family with sequence similarity 133 member A [FAM133A], and tumor protein p53 [TP53]), was finally constructed to forecast clinical outcomes of CC. Its predictive capability was further assessed and validated using the Gene Expression Omnibus validation set. In conclusion, IGRPM may be a promising prognostic signature to predict the prognoses and responses to immunotherapy of patients with CC. Moreover, the multi-omics study showed that IGRPM could be a novel therapeutic target for CC, which is a promising biomarker for indicating the immune-dominant status of the TME and revealing the potential mechanisms responsible for the tumorigenesis and progression of CC.
Publication Date: 2021-06-11
Journal: Frontiers in genetics
Revealing the therapeutic targets and molecular mechanisms of emodin-treated coronavirus disease 2019 via a systematic study of network pharmacology.
Emodin has shown pharmacological effects in the treatment of infection with severe acute respiratory syndrome coronavirus-2, which leads to coronavirus disease 2019 (COVID-19). Thus, we speculated that emodin may possess anti-COVID-19 activity. In this study, using bioinformatics databases, we screened and harvested the candidate genes or targets of emodin and COVID-19 prior to the determination of pharmacological targets and molecular mechanisms of emodin against COVID-19. We discovered core targets for the treatment of COVID-19, including mitogen-activated protein kinase 1 (MAPK1), tumor protein (TP53), tumor necrosis factor (TNF), caspase-3 (CASP3), epidermal growth factor receptor (EGFR), vascular endothelial growth factor A (VEGFA), interleukin 1B (IL1B), mitogen-activated protein kinase 14 (MAPK14), prostaglandin-endoperoxide synthase 2 (PTGS2), B-cell lymphoma-2-like protein 1 (BCL2L1), interleukin-8 (CXCL8), myeloid cell leukemia-1 (MCL1), and colony stimulating factor 2 (CSF2). The GO analysis of emodin against COVID-19 mainly included cytokine-mediated signaling pathway, response to lipopolysaccharide, response to molecule of bacterial origin, developmental process involved in reproduction, and reproductive structure development. The KEGG results exhibited that the molecular pathways mainly included IL-17 signaling pathway, AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, pertussis, proteoglycans in cancer, pathways in cancer, MAPK signaling pathway, NOD-like receptor signaling pathway, NF-kappa B signaling pathway, etc. Also, molecular docking results revealed the docking capability between emodin and COVID-19 and the potential pharmacological activity of emodin against COVID-19. Taken together, these findings uncovered the targets and pharmacological mechanisms of emodin for treating COVID-19 and suggested that the vital targets might be used as biomarkers against COVID-19.
Publication Date: 2021-06-06
Zmat3 splices together p53-dependent tumor suppression.
The tumor protein p53 (TP53, best known as p53) transcription factor is a critical tumor suppressor, but those p53-inducible genes most important for tumor suppression have remained unclear. Using unbiased RNA interference and CRISPR (Clustered Regularly Interspersed Palindromic Repeats)/Cas9 (CRISPR-associated protein 9) screens, genetically engineered mouse models, human cancer genome analysis, and integrative eCLIP-sequencing and RNA-sequencing analyses, we reveal a new branch of p53-mediated tumor suppression involving the RNA splicing regulator Zinc finger Matrin-type 3, Zmat3.
Publication Date: 2021-05-25
Journal: Molecular & cellular oncology
The association between the expression of nuclear Yes-associated protein 1 (YAP1) and p53 protein expression profile in breast cancer patients.
Yes-associated protein 1 (YAP1) is a key effector molecule regulated by the Hippo pathway and described as a poor prognostic factor in breast cancer. Tumor protein 53 (TP53) mutation is well known as a biomarker related to poor survival outcomes. So far clinical characteristics and survival outcome according to YAP1 and TP53 mutation have been poorly identified in breast cancer.
Retrospectively, 533 breast tumor tissues were collected at the Seoul St Mary's hospital and Gangnam Severance Hospital from 1992 to 2017. Immunohistochemistry with YAP1 and p53 specific antibodies were performed, and the clinical data were analyzed.
Mutant p53 pattern was associated with aggressive tumor features and advanced anatomical stage. Inferior overall survival (OS) and recurrence free survival (RFS) were related with mutant p53 pattern cases with low nuclear YAP1 expression (P = 0.0009 and P = 0.0011, respectively). Multivariate analysis showed that mutant p53 pattern was an independent prognostic marker for OS [hazard ratios (HR): 2.938, 95% confidence intervals (CIs): 1.028-8.395, P = 0.044] and RFS (HR: 1.842, 95% CIs: 1.026-3.304). However, in cases with high nuclear YAP1 expression, there were no significantly difference in OS and RFS according to p53 staining pattern.
We found that mutant p53 pattern is a poor prognostic biomarker in breast tumor with low nuclear YAP1 expression. Our findings suggest that interaction between nuclear YAP1 and p53 expression pattern impact survival outcomes.
Publication Date: 2021-05-11
Journal: PloS one
Dedifferentiated Mesonephric-like Adenocarcinoma of the Uterine Corpus.
We present a case of uterine dedifferentiated mesonephric-like adenocarcinoma (MLA).
A 54-year-old woman underwent total hysterectomy for a uterine mass under the impression of a uterine sarcoma. Histologically, MLA exhibited various growth patterns including tubular and glandular architecture. Undifferentiated carcinoma (UC) displayed discohesive tumor cells without any obvious architecture. Immunohistochemically, UC was positive for epithelial markers in very few scattered tumor cells. MLA exhibited the wild-type p53 expression pattern, whereas UC showed a uniform and strong p53 immunoreactivity. Targeted sequencing analysis revealed an identical Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in both components. A pathogenic missense tumor protein 53 (TP53) mutation was detected in UC, but not in MLA.
The mutant p53 expression pattern exclusively detected in UC was concordant with the presence of missense TP53 mutation. Our observations suggested that TP53 mutation is associated with the possible transformation from MLA to UC.
Publication Date: 2021-05-07
Journal: Anticancer research
The Association of Aging-Related Polymorphisms with Susceptibility to Lung Cancer: A Case-Control Study in a Japanese Population.
Telomere length is associated with cancer as well as aging. Telomerase reverse transcriptase (TERT), telomere RNA component (TERC) and oligonucleotide/oligosaccharide-binding fold containing 1 (OBFC1) are known to be involved in telomere length regulation. The tumor suppressor p53 (TP53), which has been shown to interact with tumor protein p53-binding protein 1 (TP53BP1), is implicated in the response to telomere shortening and aging. Polymorphisms in the TP53 and TP53BP1 genes are associated with various types of cancer. The aim of this study is to evaluate the impact of aging-related polymorphisms on lung cancer risk.
This case-control study consists of 462 lung cancer cases and 379 controls from Japan. We examined the effect of TERT rs2736100, TERC rs1881984, OBFC1 rs11191865, TP53 rs1042522 and TP53BP1 rs560191 on the risk of lung cancer using a Taq-Man real-time PCR assay. Unconditional logistic regression was used to assess the adjusted odds ratios (ORs) and 95% confidence intervals (CIs).
None of the main effects of any of the telomere-related polymorphisms were related to the risk of lung cancer. Similarly, none of the interactive effects of any of the telomere-related polymorphisms with smoking were associated with lung cancer risk. The significant multiplicative interaction between TERT rs2736100 and TP53BP1 rs560191 was statistically significant (OR for interaction = 0.34, 95% CI = 0.14-0.84). The multiplicative interaction between OBFC1 rs11191865 and TP53BP1 rs560191 was also statistically significant (OR for interaction = 2.44, 95% CI = 1.02-5.87) but the OR for interaction was in the opposite direction.
Our findings indicate that TP53BP1 rs560191 may predispose to lung cancer risk depending on the genotypes of telomere-related polymorphisms. Additional studies are warranted to confirm the findings suggested in the present study.
Publication Date: 2021-04-29
Journal: Asian Pacific journal of cancer prevention : APJCP
DNA repair pathways and their roles in drug resistance for lung adenocarcinoma.
Lung cancer is the leading cancer type of death rate. The lung adenocarcinoma subtype is responsible for almost half of the total lung cancer deaths. Despite the improvements in cancer treatment in recent years, lung adenocarcinoma patients' overall survival rate remains poor. Immunetherapy and chemotherapy are two of the most widely used options for the treatment of cancer. Although many cancer types initially respond to these treatments, the development of resistance is inevitable. The rapid development of drug resistance mainly characterizes lung adenocarcinoma. Despite being the subject of many studies in recent years, the resistance initiation and progression mechanism is still unclear. In this review, we have examined the role of the primary DNA repair pathways (non-homologous end joining (NHEJ) pathway, homologous-recombinant repair (HR) pathway, base excision repair (BER) pathway, and nucleotide excision repair (NER) pathway and transactivation mechanisms of tumor protein 53 (TP53) in drug resistance development. This review suggests that mentioned pathways have essential roles in developing the resistance against chemotherapy and immunotherapy in lung adenocarcinoma patients.
Publication Date: 2021-04-16
Journal: Molecular biology reports
A metabolism-related gene signature for predicting the prognosis and therapeutic responses in patients with hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) often has an insidious onset and rapid progression. Often, when the disease is first diagnosed, the opportune time for surgical intervention has already lapsed. In addition, the effects of systemic treatment is relatively unsatisfactory. Metabolic reprogramming is one of the hallmarks of cancer. This study aimed to identify a set of genes related to metabolism to construct a predictive model for the prognosis of HCC.
The transcriptomic and clinical data of 352 HCC patients were obtained from The Cancer Genome Atlas (TCGA) Liver Hepatocellular Carcinoma (LIHC) dataset and divided into a training cohort (n=212) and a testing cohort (n=140) at a ratio of 6:4. Univariate Cox regression analysis and the LASSO Cox regression model were used to identify 5 genes to establish a risk score for predicting the prognosis of HCC patients. Subsequently, the molecular characteristics of the model were assessed and the ability of the model to predict the tumor immune microenvironment and patient response to immunotherapy and chemotherapy was also examined.
The risk score model was constructed based on the five genes, methyltransferase-like protein 6 (METTL6), RNA polymerase III subunit G (POLR3G), phosphoribosyl pyrophosphate amidotransferase (PPAT), SET Domain Bifurcated 2 (SETDB2), and suppressor of variegation 3-9 homolog 2 (SUV39H2). The Kaplan-Meier survival analysis and time-dependent receiver operating characteristic (ROC) curves demonstrated that high-risk patients had a poorer overall survival (OS) compared to low-risk patients. he nomogram score had a better predictive ability compared to the common factors. Our results finally showed that high-risk cases were associated with cell proliferation and cell cycle related gene sets, high tumor protein P53 (TP53) mutation rate, suppressive immunity and increased sensitivity to cisplatin, gemcitabine and docetaxel. Meanwhile, low-risk cases were associated with cell cycle and immune response related pathways, low TP53 mutation rate, active immunity and more benefit from immunotherapy.
This study provided novel insights into the role of metabolism-related genes in HCC, and demonstrated that our model could be a promising prognostic biomarker for distinguishing the molecular and immune characteristics and inferring the potential response to chemotherapy and immunotherapy.
Publication Date: 2021-04-15
Journal: Annals of translational medicine
Acinic Cell Carcinoma of the Breast: Report of a Case With Immunohistochemical and Next-Generation Sequencing Studies.
Acinic cell carcinoma of the breast is a rare subtype of triple-negative breast cancer that recapitulates the appearance of tumors seen in salivary glands. We present the case of a 42-year-old woman with an irregular, nontender mass above the left nipple during routine obstetric appointment at 24 weeks gestation. She was subsequently diagnosed with triple-negative invasive ductal carcinoma of the left breast, Nottingham grade 3, via core needle biopsy. She was treated with neoadjuvant therapy (doxorubucin and cyclophosphamide) antenatally and paclitaxel in the postpartum period followed by left mastectomy with sentinel node biopsy. The carcinoma in the mastectomy specimen showed a spectrum of morphologic patterns with immunohistochemistry revealing strong positivity for alpha-1-antichymotrypsin, epithelial membrane antigen (EMA), lysozyme, and S100. The histomorphology paired with the immunoprofile led us to the diagnosis of acinic cell carcinoma. We retrospectively performed immunostains in the core biopsy specimen, which demonstrated GATA-3 and DOG-1 positivity. Next-generation sequencing of the postneoadjuvant specimen using a 70-gene panel revealed 2 single-nucleotide variant (SNV) mutations: tumor protein 53 (TP53) (c.747G>T) SNV mutation and rearranged during transfection (RET) (c.2899G>A) SNV mutation.
Publication Date: 2021-04-09
Journal: International journal of surgical pathology
Transcriptomic signaling pathways involved in a naturalistic model of inflammation-related depression and its remission.
This study aimed at identifying molecular biomarkers of inflammation-related depression in order to improve diagnosis and treatment. For this, we performed whole-genome expression profiling from peripheral blood in a naturalistic model of inflammation-associated major depressive disorder (MDD) represented by comorbid depression in obese patients. We took advantage of the marked reduction of depressive symptoms and inflammation following bariatric surgery to test the robustness of the identified biomarkers. Depression was assessed during a clinical interview using Mini-International Neuropsychiatric Interview and the 10-item, clinician-administered, Montgomery-Asberg Depression Rating Scale. From a cohort of 100 massively obese patients, we selected 33 of them for transcriptomic analysis. Twenty-four of them were again analyzed 4-12 months after bariatric surgery. We conducted differential gene expression analyses before and after surgery in unmedicated MDD and non-depressed obese subjects. We found that TP53 (Tumor Protein 53), GR (Glucocorticoid Receptor), and NFκB (Nuclear Factor kappa B) pathways were the most discriminating pathways associated with inflammation-related MDD. These signaling pathways were processed in composite z-scores of gene expression that were used as biomarkers in regression analyses. Results showed that these transcriptomic biomarkers highly predicted depressive symptom intensity at baseline and their remission after bariatric surgery. While inflammation was present in all patients, GR signaling over-activation was found only in depressed ones where it may further increase inflammatory and apoptosis pathways. In conclusion, using an original model of inflammation-related depression and its remission without antidepressants, we provide molecular predictors of inflammation-related MDD and new insights in the molecular pathways involved.
Publication Date: 2021-04-08
Journal: Translational psychiatry
Exploring the mechanisms underlying the therapeutic effect of Salvia miltiorrhiza in diabetic nephropathy using network pharmacology and molecular docking.
The mechanisms underlying the therapeutic effect of Salvia miltiorrhiza (SM) on diabetic nephropathy (DN) were examined using a systematic network pharmacology approach and molecular docking. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen active ingredients of SM. Targets were obtained using the SwissTargetPrediction and TCMSP databases. Proteins related to DN were retrieved from the GeneCards and DisGeNET databases. A protein-protein interaction (PPI) network was constructed using common SM/DN targets in the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The Metascape platform was used for Gene Ontology (GO) function analysis, and the Cytoscape plug-in ClueGO was used for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Molecular docking was performed using iGEMDOCK and AutoDock Vina software. Pymol and LigPlos were used for network mapping. Sixty-six active ingredients and 189 targets of SM were found. Sixty-four targets overlapped with DN-related proteins. The PPI network revealed that AKT serine/threonine kinase 1 (AKT1), VEGFA, interleukin 6 (IL6), TNF, mitogen-activated protein kinase 1 (MAPK1), tumor protein p53 (TP53), epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase 14 (MAPK14), and JUN were the ten most relevant targets. GO and KEGG analyses revealed that the common targets of DN and SM were mainly involved in advanced glycation end-products, oxidative stress, inflammatory response, and immune regulation. Molecular docking revealed that potential DN-related targets, including tumor necrosis factor (TNF), NOS2, and AKT1, more stably bound with salvianolic acid B than with tanshinone IIA. In conclusion, the present study revealed the active components and potential molecular therapeutic mechanisms of SM in DN and provides a reference for the wide application of SM in clinically managing DN.
Publication Date: 2021-02-27
Journal: Bioscience reports
Valproic acid combined with cisplatin-based chemoradiation in locally advanced head and neck squamous cell carcinoma patients and associated biomarkers.
Cisplatin-based chemoradiation (CCRT) offers locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients high local control rate, however, relapses are frequent. Our goal was to evaluate if association of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, with CCRT improved response rate (RR) and associated biomarkers.
This phase II trial included patients with unresectable locally advanced (LA) oropharynx (OP) squamous cell carcinoma. CCRT began after 2 weeks of VPA (P1). Primary goal was RR at 8 weeks after chemoradiation (CRT)+VPA (P2). Biomarkers included microRNA (miR) polymerase chain reaction (PCR)-array profiling in plasma compared to healthy controls by two-sample t-test. Distribution of p-values was analysed by beta-uniform mixture. Findings were validated by real-time PCR quantitative polymerase chain reaction (qPCR) for selected miRs in plasma and saliva. p16, HDAC2 and RAD23 Homolog B, Nucleotide Excision Repair Protein (HR23B) tumour immunohistochemistry were evaluated.
Given significant toxicities, accrual was interrupted after inclusion of ten LA p16 negative OP patients. All were male, smokers/ex-smokers, aged 41-65 and with previous moderate/high alcohol intake. Nine evaluable patients yielded a RR of 88%. At false discovery rate of 5%, 169 miRs were differentially expressed between patients and controls, including lower expression of tumour suppressors (TSs) such as miR-31, -222, -let-7a/b/e and -145. miR-let-7a/e expression was validated by qPCR using saliva. A HDAC2 H-score above 170 was 90% accurate in predicting 6-month disease-free survival.
VPA and CRT offered high RR; however, with prohibitive toxicities, which led to early trial termination. Patients and controls had a distinct pattern of miR expression, mainly with low levels of TS miRs targeting Tumor protein P53 (TP53). miR-let-7a/e levels were lower in patients compared to controls, which reinforces the aggressive nature of such tumours (NCT01695122).
Publication Date: 2021-02-13