Genetic variants play a critical role in the development of breast cancer. This investigation aimed to explore the association between CASC16 polymorphisms and breast cancer susceptibility.
We ...conducted a case-control study of 681 patients and 680 healthy individuals to investigate the correlation of five SNPs with breast cancer in a Northwest Chinese female population. Odds ratios (OR) and 95% confidence intervals (CIs) were used to assess the association.
Our study found that rs4784227 and rs12922061 were significantly related to an increased susceptibility to breast cancer (OR 1.22, p = 0.022; OR 1.21, p = 0.026). While rs3803662 was a protective role in breast cancer risk (OR 0.69, p = 0.042). Stratified analyses indicated that rs4784227 and rs12922061 would increase breast cancer susceptibility at age > 50 years. Rs3803662 was a reduced factor of breast cancer risk by age ≤ 50 years. Rs4784227 was significantly increased risk of breast cancer in stage III/IV. The rs45544231 and rs3112612 had a protective effect on breast cancer with tumor size > 2 cm. Rs4784227 and rs12922061 could enhance breast cancer risk in lymph node metastasis positive individuals. CASC16 rs12922061 and rs4784227 polymorphisms correlated with an increased risk of breast cancer in BMI > 24 kg/m
. Haplotype analyses revealed that G
T
A
and G
C
A
haplotypes decreased breast cancer risk.
Our study revealed that CASC16 genetic variants were significantly related to breast cancer susceptibility, which might give scientific evidence for exploring the molecular mechanism of breast cancer.
Compelling evidence has indicated the vital role of lysine-specific demethylase 4 A (KDM4A), hypoxia-inducible factor-1α (HIF1α) and the mechanistic target of rapamycin (mTOR) signaling pathway in ...nasopharyngeal carcinoma (NPC). Therefore, we aimed to investigate whether KDM4A affects NPC progression by regulating the HIF1α/DDIT4/mTOR signaling pathway. First, NPC and adjacent tissue samples were collected, and KDM4A protein expression was examined by immunohistochemistry. Then, the interactions among KDM4A, HIF1α and DDIT4 were assessed. Gain- and loss-of-function approaches were used to alter KDM4A, HIF1α and DDIT4 expression in NPC cells. The mechanism of KDM4A in NPC was evaluated both in vivo and in vitro via RT-qPCR, Western blot analysis, MTT assay, Transwell assay, flow cytometry and tumor formation experiments. KDM4A, HIF1α, and DDIT4 were highly expressed in NPC tissues and cells. Mechanistically, KDM4A inhibited the enrichment of histone H3 lysine 9 trimethylation (H3K9me3) in the HIF1α promoter region and thus inhibited the methylation of HIF1α to promote HIF1α expression, thus upregulating DDIT4 and activating the mTOR signaling pathway. Overexpression of KDM4A, HIF1α, or DDIT4 or activation of the mTOR signaling pathway promoted SUNE1 cell proliferation, migration, and invasion but inhibited apoptosis. KDM4A silencing blocked the mTOR signaling pathway by inhibiting the HIF1α/DDIT4 axis to inhibit the growth of SUNE1 cells in vivo. Collectively, KDM4A silencing could inhibit NPC progression by blocking the activation of the HIF1α/DDIT4/mTOR signaling pathway by increasing H3K9me3, highlighting a promising therapeutic target for NPC.
Peroxisome proliferator-activated receptors (PPARs) are members of nuclear transcription factors. The functions of the PPAR family (PPARA, PPARD, and PPARG) and their coactivators (PPARGC1A and ...PPARGC1B) in maintenance of lipid and glucose homeostasis have been unveiled. However, the roles of PPARs in cancer development remain elusive. In this work, we made use of 11,057 samples across 33 TCGA tumor types to analyze the relationship between PPAR transcriptional expression and tumorigenesis as well as drug sensitivity. We performed multidimensional analyses on PPARA, PPARG, PPARD, PPARGC1A, and PPARGC1B, including differential expression analysis in pan-cancer, immune subtype analysis, clinical analysis, tumor purity analysis, stemness correlation analysis, and drug responses. PPARs and their coactivators expressed differently in different types of cancers, in different immune subtypes. This analysis reveals various expression patterns of the PPAR family at a level of pan-cancer and provides new clues for the therapeutic strategies of cancer.
Breast cancer (BRCA) ranks among the top most common female malignancies and was regarded as incurable when combined with bone and distant metastasis. Alternative splicing events (ASEs) together with ...splicing factors (SFs) were considered responsible for the development and progression of tumors.
Datasets including RNA sequencing and ASEs of BRCA samples were achieved from TCGA and TCGASpliceSeq databases. Then, a survival model was built including 15 overall-survival-associated splicing events (OS-SEs) by Cox regression and Lasso regression. The co-expressed SFs of each bone-and-distant-metastasis-related OS-SE were discovered by Pearson correlation analysis. Additionally, Gene Set Variation Analysis (GSVA) was performed to identify the downstream mechanisms of the key OS-SEs. Finally, the results were validated in different online platforms.
A reliable survival model was established (the area under ROC = 0.856), and CIRBP was found co-expressed with FAM110B (
= 0.320,
< 0.001) associated with the fatty acid metabolism pathway.
Aberrant SF, CIRBP, regulated a specific ASE, exon skip (ES) of FAM110B, during which the fatty acid metabolism pathway played an essential part in tumorigenesis and prognosis of BRCA.
BACKGROUND Malignant giant cell tumor of bone (MGCTB) is a rare histological type of malignant tumor that has a high tendency for local relapse and distant metastasis and ultimately leads to a poor ...prognosis. The purpose of this study was to describe the epidemiological features, identify the prognostic factors, and construct nomograms for patients with MGCTB. MATERIAL AND METHODS Patients with MGCTB that was histologically diagnosed between 1973 and 2014 were selected from the Surveillance, Epidemiology, and End Results (SEER) database as a training set. Survival analysis, Lasso regression, and random forests were used to identify the prognostic variables and establish the nomograms for patients with MGCTB, while an external cohort of 37 patients from our own institution and an external cohort of 163 patients from the SEER database in 2016 were used to validate the generalization performance of the nomograms. RESULTS In total, univariate and multivariable analysis indicated that age, International Classification of Diseases for Oncology, historical stage, primary site, surgery information, radiotherapy, and chemotherapy were independent prognostic variables for overall survival or cause-specific survival. Nomograms based on the multivariable models were built to predict survival, and we achieved a higher C-index in subsequent multidimensional validation. CONCLUSIONS Age, historical stage, and chemotherapy were independent prognostic variables for overall survival and cause-specific survival of MGCTB patients, and radiotherapy and primary site were independent prognostic variables for overall survival. Nomograms based on significant clinicopathological features and clinical experience can be effective in predicting the probability of survival for MGCTB patients.
Adamantinomatous craniopharyngioma (ACP) is a neuroendocrine tumor whose pathogenesis remains unclear. This study investigated the role of glioma-associated oncogene family zinc finger 1 (GLI1), a ...transcription factor in the sonic hedgehog (SHH) signaling pathway, in ACP. We discovered that GLI1 regulates the expression of IL-6, thereby triggering inflammatory responses in ACP and influencing the tumor’s progression. Analyzing the Gene Expression Omnibus (GEO) database chip GSE68015, we found that GLI1 is overexpressed in ACP, correlating positively with the spite of ACP and inflammation markers. Knockdown of GLI1 significantly inhibited the levels of tumor necrosis factor α, interleukin-6 (IL-6), and IL-1β in ACP cells, as well as cell proliferation and migration. We further identified a binding site between GLI1 and the promoter region of IL-6, demonstrating that GLI1 can enhance the expression of IL-6. These findings were verified in vivo, where activation of the SHH pathway significantly promoted GLI1 and IL-6 expressions in nude mice, inducing inflammation and tumor growth. Conversely, GLI1 knockdown markedly suppressed these processes. Our study uncovers a potential molecular mechanism for the occurrence of inflammatory responses and tumor progression in ACP.
•Synthesized ZIF nanocrystals own extremely small size and narrow size distribution.•Reverse microemulsion is superior to the conventional water synthesis of ZIFs.•DLS characterization revealed the ...controlling mechanism of particle size distribution.
With the particles size down to nanoscale, porous materials with well-controllable dimension will have more promising applications in biologically relevant fields and even in the areas of traditional selective separation and catalysis. By using reverse microemulsions the nanoscale zeolitic imidazolate frameworks (ZIFs) such as ZIF-8 and ZIF-67 were synthesized at room temperature with uniform grain size distribution and extremely small crystal dimension (mean particle size less than 5nm). The ZIF-8 and ZIF-67 synthesized by reverse microemulsion have much larger surface areas and micropores volume than samples obtained from water, but are comparative to those obtained from methanol. The thermal stability of the synthesized ZIF-8 and ZIF-67 by microemulsion is also excellent. The DLS characterization revealed that it is the size of micelles in microemulsion that controls the dimension of ZIF crystals. This is different comparing to the controlling mechanisms of other common synthesis methods of MOFs. We believe that the microemulsion method developed in this work can enrich the synthesis strategies of other nanoscale ZIF or MOF particles.
Immune checkpoint inhibitors are approved for the treatment of various tumors, but the response rate is not satisfactory in certain malignancies. Inhibitor of apoptosis proteins (IAP) ubiquitin-E3 ...ligase activity is involved in the regulation of immune responses. APG-1387 is a novel second mitochondria-derived activator of caspase (Smac) mimetic IAP inhibitor. The aim of this study was to explore the synergistic effect of APG-1387 when combined with anti-PD-1 antibody in a preclinical setting.
We utilized syngeneic mouse models of ovarian cancer (ID8), colon cancer (MC38), malignant melanoma (B16), and liver cancer (Hepa1-6) to assess the combination effect of APG-1387 and anti-PD-1 antibody, including immune-related factors, tumor growth, and survival. MSD V-PLEX validated assays were used to measure in vitro and in vivo cytokine release.
In ID8 ovarian cancer and MC38 colon cancer models, APG-1387 and anti-PD1 antibody had synergistic antitumor effects. In the MC38 model, the combination of APG-1387 and anti-PD-1 antibody significantly inhibited tumor growth (P < 0.0001) and increased the survival rate of tumor-bearing animals (P < 0.001). Moreover, we found that APG-1387 upregulated tumor-infiltrating CD3 + NK1.1 + cells by nearly 2-fold, by promoting tumor cell secretion of IL-12. Blocking IL-12 secretion abrogated the synergistic effects of APG-1387 and anti-PD-1 antibody in both MC38 and ID8 models.
APG-1387 has the potential to turn "cold tumors" into hot ones by recruiting more CD3 + NK1.1 + cells into certain tumors. Based on these and other data, the safety and therapeutic effect of this combination will be investigated in a phase 1/2 trial in patients with advanced solid tumors or hematologic malignancies (NCT03386526).
We have identified a GRAP variant (c.311A>T; p.Gln104Leu) cosegregating with autosomal recessive nonsyndromic deafness in two unrelated families. GRAP encodes a member of the highly conserved growth ...factor receptor-bound protein 2 (GRB2)/Sem-5/drk family of proteins, which are involved in Ras signaling; however, the function of the growth factor receptor-bound protein 2 (GRB2)-related adaptor protein (GRAP) in the auditory system is not known. Here, we show that, in mouse, Grap is expressed in the inner ear and the protein localizes to the neuronal fibers innervating cochlear and utricular auditory hair cells. Downstream of receptor kinase (drk), the Drosophila homolog of human GRAP, is expressed in Johnston’s organ (JO), the fly hearing organ, and the loss of drk in JO causes scolopidium abnormalities. drk mutant flies present deficits in negative geotaxis behavior, which can be suppressed by human wild-type but not mutant GRAP. Furthermore, drk specifically colocalizes with synapsin at synapses, suggesting a potential role of such adaptor proteins in regulating actin cytoskeleton dynamics in the nervous system. Our findings establish a causative link between GRAP mutation and nonsyndromic deafness and suggest a function of GRAP/drk in hearing.
•TCFR had higher removal of total PBDEs than TCFR+P in 70days.•TCFR and TCFR+P could decrease soil organic matter (SOM) contents.•TCFR could improve polarity and aromaticity of soil humic acid and ...humin.•TCFR could increase soil fungal ergosterol contents.•Oxidation degradation products of BDE-47 and -153 were analyzed by LC–MS/MS.
We carried out the 70-day remediation process for soil contaminated polybrominated diphenyl ethers (PBDEs) using a novel technology, a tourmaline catalyzed Fenton-like reaction (TCFR) combined with Phanerochaete chrysosporium (TCFR+P) in field soil microcosms. The results showed that the TCFR is more efficient in removing PBDE compounds with lower numbers of bromine (Br) atoms such as BDE-28, BDE-47, BDE-99, BDE-100, while the TCFR+P is a good method to remove the PBDEs with greater number of Br atoms. For the total PBDE removal from soil, the TCFR was more efficient than that in the soil added TCFR+P. SEM analysis showed that lower PBDE removal using TCFR+P may be due to the mycelium produced by P. chrysosporium covering the humin (HM) surface, thereby decreasing the effective contact between hydroxyl radicals (OH) and PBDEs. Moreover, a systemic series of experiments on the effects of the TCFR and TCFR+P on soil pH, soil organic matter (SOM) content, humic acid (HA) and HM compositions and structure, soil fungi, and degradation pathways were designed to discuss the removal mechanisms of the TCFR and the TCFR+P. Both of the TCFR and the TCFR+P caused a decrease in the SOM contents, a decline in aromaticity, an increase in surface hydrophilicity, an improvement in the polarity index of HA and HM, and an unexpected increased ergosterol content, compared to that of the soil added H2O2, tourmaline or P. chrysosporium alone, which in turn, enhanced the removal of PBDEs. Additionally, the five and nine oxidation degradation products of BDE-47, -153, respectively, were analyzed by LC–MS/MS. To the best of our knowledge, this study is the first report demonstrating that PBDEs in soil can be removed through TCFR oxidization.
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