Transcriptional factor MdESE3 controls fruit acidity by activating genes regulating malic acid content in apple.

Acidity is a key factor controlling fruit flavor and quality. In a previous study, combined transcriptome and methylation analyses identified a P3A-type ATPase from apple (Malus domestica), MdMa11, which regulates vacuolar pH when expressed in Nicotiana benthamiana leaves. In this study, the role of MdMa11 in controlling fruit acidity was verified in apple calli, fruits, and plantlets. In addition, we isolated an AP2 domain-containing transcription factor, designated MdESE3, based on yeast one-hybrid (Y1H) screening using the MdMa11 promoter as bait. A subcellular localization assay indicated that MdESE3 localized to the nucleus. Analyses of transgenic apple calli, fruits, and plantlets, as well as tomatoes, demonstrated that MdESE3 enhances fruit acidity and organic acid accumulation. Meanwhile, chromatin immunoprecipitation quantitative PCR (ChIP-qPCR), luciferase (LUC) transactivation assays, and GUS reporter assays indicated that MdESE3 could bind to the ethylene-responsive element (ERE; 5'-TTTAAAAT-3') upstream of the MdMa11 transcription start site, thereby activating its expression. Furthermore, MdtDT, MdDTC2, and MdMDH12 expression increased in apple fruits and plantlets overexpressing MdESE3 and decreased in apple fruits and plantlets where MdESE3 was silenced. The ERE was found in MdtDT and MdMDH12 promoters, but not in the MdDTC2 promoter. The Y1H, LUC transactivation assays, and GUS reporter assays indicated that MdESE3 could bind to the MdtDT and MdMDH12 promoters and activate their expression. Our findings provide valuable functional validation of MdESE3 and its role in the transcriptional regulation of MdMa11, MdtDT, and MdMDH12 and malic acid accumulation in apple.

Long noncoding RNA ALOX12-AS1 inhibits cervical cancer cells proliferation via targeting miR-3171.

Cervical cancer is a common female malignancy worldwide, and the molecular mechanism of cervical tumorigenesis remains poorly understood. A large piece of evidence have demonstrated the important roles of long noncoding RNAs (lncRNAs) in tumorigenesis, cancer progression and drug resistance. In this study, we comprehensively analyzed the lncRNAs expression pattern in cervical cancer using RNA sequencing and microarray data from the cancer genome atlas, gene expression omnibus and Genotype Tissue Expression. Moreover, we assessed the correlation between lncRNA expression levels and cervical cancer patient's survival. We uncovered hundreds of lncRNAs that are upregulated or downregulated in cervical cancer tissues. Among these aberrantly lncRNAs, some are significantly associated with cervical patients' poorer prognosis, such as ALOX12-AS1 and LINC00173. ALOX12-AS1 expression is downregulated in cervical cancer, and over-expression of ALOX12-AS1 could inhibit cervical cancer cells proliferation in vitro. Further, mechanistically investigation revealed that ALOX12-AS1 could interact with AGO2 and sponge miR-3171, thereby antagonizing its' repression of tumor suppressor phosphatase and tensin homolog expression in cervical cancer cell. Taken together, this study provides lncRNA candidates in cervical cancer and highlights the critical role of ALOX12-AS1 in cervical cancer.

The interaction between mitochondria and oncoviruses.

Mitochondria play important roles in multiple aspects of viral tumorigenesis. Mitochondrial genomes contribute to the host's genetic background. After viruses enter the cell, they modulate mitochondrial function and thus alter bioenergetics and retrograde signaling pathways. At the same time, mitochondria also regulate and mediate viral oncogenesis. In this context, oncogenesis by oncoviruses like Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human papilloma virus (HPV), Human Immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) will be discussed.

Endoscopic band ligation versus endoscopic submucosal dissection and laparoscopic resection for small gastric stromal tumors.

BACKGROUND AND AIM: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Previous studies have addressed the safety and feasibility of endoscopic band ligation (EBL) for the treatment of small gastric GISTs. However, published reports comparing EBL with other interventions are limited. This current study evaluates the efficacy of EBL and compares EBL to both endoscopic submucosal dissection (ESD) and laparoscopic resection (LAP) for small gastric GISTs less than 15 mm. METHODS: A total of 339 patients who underwent endoscopic therapy or laparoscopic resection for gastric GISTs between 1998 and 2012 were retrospectively identified and collected from medical records in our hospital. The parameters measured for each procedure type includes clinicopathological characteristics, length of stay, hospitalization expense and surgical outcomes. RESULTS: Among the 147 patients included in our study, 72 (48.98 %) received EBL, 27 (18.37 %) received ESD, and 48 (32.65 %) received LAP. The demographic and clinical characteristics of the patients such as gender, age, tumor site and size were well balanced between the study groups. There was also no significant difference in follow-up time between the study groups. The mean operating time was significantly shorter in the patients receiving EBL than patients receiving ESD and LAP (p < 0.001). The estimated blood loss was significantly different between the three groups (p < 0.001). Complications occurred in 1.39 % of the patients receiving EBL, 18.52 % of the patients receiving ESD and 4.17 % of the patients receiving LAP (p = 0.004), and recurrence rate in 15.00, 9.10 and 11.76 %, respectively (p = 0.705). There was also significant difference about mean hospital stay and hospital cost between three groups (p < 0.001). CONCLUSION: Our results show a significant advantage in the short-term outcome for EBL compared to ESD and LAP. However, long-term randomized controlled trials are needed to compare the three methods for the treatment of small GISTs.

Epb41l3 suppresses esophageal squamous cell carcinoma invasion and inhibits MMP2 and MMP9 expression.

EPB41L3 may play a role as a metastasis suppressor by supporting regular arrangements of actin stress fibres and alleviating the increase in cell motility associated with enhanced metastatic potential. Downregulation of epb41l3 has been observed in many cancers, but the role of this gene in esophageal squamous cell carcinoma (ESCC) remains unclear. Our study aimed to determine the effect of epb41l3 on ESCC cell migration and invasion. We investigated epb41l3 protein expression in tumour and non-tumour tissues by immunohistochemical staining. Expression in the non-neoplastic human esophageal cell line Het-1a and four ESCC cell lines - Kyse150, Kyse510, Kyse450 and Caes17 - was assessed by quantitative Polymerase Chain Reaction (qPCR) and Western blotting. Furthermore, an EPB41L3 overexpression plasmid and EPB41L3-specific small interfering RNA were used to upregulate EPB41L3 expression in Kyse150 cells and to downregulate EPB41L3 expression in Kyse450 cells, respectively. Cell migration and invasion were evaluated by wound healing and transwell assays, respectively. The expression levels of p-AKT, matrix metalloproteinase (MMP)2 and MMP9 were evaluated. Expression of epb41l3 was significantly lower in tumour tissues than in non-tumour tissues and in ESCC cell lines compared with the Het-1a cell line. Kyse450 and Caes17 cells exhibited higher expression of epb41l3 than Kyse150 and Kyse510 cells. Overexpressing epb41l3 decreased Kyse150 cell migration and invasion, whereas EPB41L3-specific small interfering RNA silencing increased these functions in Kyse450 cells. Furthermore, overexpressing epb41l3 led to downregulation of MMP2 and MMP9 in Kyse150 and Kyse510 cells. Our findings reveal that EPB41L3 suppresses tumour cell invasion and inhibits MMP2 and MMP9 expression in ESCC cells.

Improving heterologous polyketide production in Escherichia coli by transporter engineering.

Expelling heterologous compounds out of hosts by transporters is a potential strategy to enhance product titers in microbial cell factories. In this work, to increase heterologous polyketide 6-deoxyerythronolide B (6dEB, erythromycin precursor) production, tripartite multidrug efflux pumps MacAB-TolC, AcrAB-TolC, MdtEF-TolC, and MexAB-OprM were modulated in a 6dEB production strain. Compared with the control, overexpression of a single component of efflux pumps (except oprM) repressed 6dEB production, but modulation of two components MacA and MacB or the complete pumps MacAB-TolC and MdtEF-TolC significantly improved 6dEB titer by 100 ± 11, 118 ± 54, and 98 ± 12 %, respectively. In addition, to avoid the challenging fine-tuning components of pumps, the transcriptional regulators of efflux pumps were modulated to improve the 6dEB production. Overexpression of RpoH (activator of MdtEF-TolC) and EvgA (activator of EmrKY-TolC and AcrAD-TolC) strongly increased 6dEB titer by 152 ± 54 and 142 ± 85 %, respectively. This is the first report of transporter engineering for improving heterologous polyketide production in Escherichia coli. Our results provide an effective strategy for improving the yield of the heterologous products in chassis cell.

Morphological Characteristics of Various Cells in Esophageal Squamous Dysplasia: Extremely Wide Morphological Spectrum.

The WHO classification of esophageal tumors divides esophageal squamous intraepithelial dysplasia into high and low grades, but does not specify its morphological spectrum. Here, the morphological characteristics of various cells were investigated in esophageal squamous (high-grade) dysplasia, and a morphological spectrum and terminology for this lesion were proposed to avoid misdiagnosis. The clinicopathological data of 540 patients with esophageal squamous dysplasia were analyzed retrospectively. According to the unique cytomorphological characteristics of the lesions and the predominant cell type, the esophageal squamous dysplasia was divided into the following morphological groups: classic type (34.6%, 187/540), basaloid subtype (10.7%, 58/540), spindle-cell subtype (4.6%, 25/540), differentiated subtype (48.9%, 264/540), and verrucous subtype (1.1%, 6/540). Gender, age, and lesions location did not differ among the subtypes (P > 0.05), while Paris classification and lesions diameter significantly differed among the subtypes (P < 0.01). Classic-type cells showed severe atypia. In the basaloid subtype, the cells were small, and resembled basal cells; most of these lesions were of the 0-IIb type with small lesion diameter. In the spindle-cell subtype, the cells and nuclei were spindle-shaped or long and spindle-shaped and arranged in parallel. Differentiated-subtype showed well-to-moderately differentiated cells, and epithelial basal cells were mature. Verrucous-subtype showed well-differentiated cells, and were characterized by verrucous or papillary structures. Esophageal squamous dysplasia has extremely wide morphological spectrum. Awareness of the spectrum of morphological presentations of this lesion, specifically the basaloid subtype, spindle-cell subtype, differentiated subtype, and verrucous subtype, is important for accurate diagnosis.

A Hierarchical Graph V-Net With Semi-Supervised Pre-Training for Histological Image Based Breast Cancer Classification.

Numerous patch-based methods have recently been proposed for histological image based breast cancer classification. However, their performance could be highly affected by ignoring spatial contextual information in the whole slide image (WSI). To address this issue, we propose a novel hierarchical Graph V-Net by integrating 1) patch-level pre-training and 2) context-based fine-tuning, with a hierarchical graph network. Specifically, a semi-supervised framework based on knowledge distillation is first developed to pre-train a patch encoder for extracting disease-relevant features. Then, a hierarchical Graph V-Net is designed to construct a hierarchical graph representation from neighboring/similar individual patches for coarse-to-fine classification, where each graph node (corresponding to one patch) is attached with extracted disease-relevant features and its target label during training is the average label of all pixels in the corresponding patch. To evaluate the performance of our proposed hierarchical Graph V-Net, we collect a large WSI dataset of 560 WSIs, with 30 labeled WSIs from the BACH dataset (through our further refinement), 30 labeled WSIs and 500 unlabeled WSIs from Yunnan Cancer Hospital. Those 500 unlabeled WSIs are employed for patch-level pre-training to improve feature representation, while 60 labeled WSIs are used to train and test our proposed hierarchical Graph V-Net. Both comparative assessment and ablation studies demonstrate the superiority of our proposed hierarchical Graph V-Net over state-of-the-art methods in classifying breast cancer from WSIs. The source code and our annotations for the BACH dataset have been released at https://github.com/lyhkevin/Graph-V-Net.

Advances in Imaging in Evaluating the Efficacy of Neoadjuvant Chemotherapy for Breast Cancer.

Neoadjuvant chemotherapy (NAC) is increasingly widely used in breast cancer treatment, and accurate evaluation of its response provides essential information for treatment and prognosis. Thus, the imaging tools used to quantify the disease response are critical in evaluating and managing patients treated with NAC. We discussed the recent progress, advantages, and disadvantages of common imaging methods in assessing the efficacy of NAC for breast cancer.

Gastritis cystica profunda: clinical and pathologic study of seven cases and review of literature.

Gastritis cystica profunda (GCP) is a rare lesion characterized by hyperplasia and cystic dilatation of the gastric glands in the submucosal layer. Here we report seven cases of GCP. The patients are 5 women and 2 men with a mean age of 62 (range, 42-82) years at the time of diagnosis. The patients presented with abdominal distension, sour regurgitation, and heartburn. One case had the previous gastric surgery and the other six cases had no special history. The lesions were located in the fundus (4/7), corpus (1/7), cardia (1/7), and antrum (1/7). Endoscopic analysis revealed pedunculated polyps, or a dome-shaped polyp. Histologically, all cases showed dilated tubular glands, mainly located in the submucosa, among the muscularis mucosa, and occasionally in the lamina propria. The glands were lined by bland single columnar epithelium with infolding features in some areas. Mitotic activity and marked cellular atypia were not present. The stroma in some cases was mildly edematous with infiltrated lymphocytes and plasma cells. There was no epithelial dysplasia in the overlying mucosa. Immunohistochemically, the Ki-67 index was < 1%. P53 immunostaining was generally characterized as wild type in all cases. Based on the morphology of the glands and the cells and the possible mechanism of hyperplasia and cystic dilatation of the gastric glands, it is easy to differentiate GCP from a well-differentiated adenocarcinoma.

Effects of cold plasma treatment on cherry quality during storage.

Cherry samples were treated with cold plasma under different voltages (40, 60, 80 kV) and different treatment durations (60, 80, 100, 140 s), then stored in a refrigerator at 0 ℃. Data on the decay rate, respiration rate, and physiological properties of the cherries and their correlational relationships after different treatments of cold plasma were collected under the conditions of ambient temperature and dry air. The decay rate, respiration rate, total soluble solids, total phenol, flavonoids, anthocyanin, VC, titratable acidity, firmness, and a* value were investigated at regular intervals to analyze the quality of the cherries under different treatment conditions. Additionally, the total colony number was estimated at the end of storage. The results indicated that cold plasma treatment under moderate conditions was effective for prolonging cherry storage, inactivating microorganisms, decreasing the decay rate, and inhibiting respiration with either no compromise on the cherry quality or only a slightly noticeable influence. A significant positive correlation was found between the decay rate and respiration rate, as well as between the VC content and titratable acidity. Antioxidant contents and firmness were found to be negatively correlated with the a* value. In conclusion, this study demonstrated that cold plasma has potential applications in the storage and preservation of cherries.

Diagnostic value of circulating cell-free mtDNA in patients with suspected thyroid cancer: ND4/ND1 ratio as a new potential plasma marker.

Thyroid cancer is the most common endocrine malignancy, and its incidence continues to rise. For clinicians with cancer patients, choosing and interpreting diagnostic laboratory studies has become increasingly important. Previously, changes in plasma free mitochondrial DNA levels have been found in colorectal, breast, lung, and urinary cancers, and have demonstrated diagnostic value. In this study, we investigated whether the occurrence and development of thyroid cancer might be predicted using mtDNA copy number (ND1), mtDNA integrity (ND4/ND1) and levels of cell-free nDNA (GAPDH). We analyzed ND1, ND4, and GAPDH levels in plasma and blood cells from 75 patients with thyroid cancer, 40 patients with nodular goiter, and 107 normal controls using real-time PCR. Although both the thyroid nodule and thyroid cancer patients had significantly increased ND1 levels, the ND4/ND1 ratio in the thyroid cancer group was higher than the thyroid nodule group (P < 0.05), and significantly higher than the normal control group (P < 0.01). Plasma levels of nuclear DNA (GAPDH) in the thyroid cancer group were also higher compared to normal (P < 0.05). These results indicate that increased intactness of plasma free mtDNA is associated with increased levels of plasma cell-free nDNA, and that the ND4/ND1 ratio has the potential to be a new detection indicator in thyroid cancer. Furthermore, we classified thyroid cancer patients according to clinical data including age, tumor size, and metastasis. We found significantly higher levels of GAPDH in malignant tissues. Because ND4/ND1 correlated with plasma GAPDH in the plasma studies, this also suggests a potential relationship between ND4 intactness and thyroid tumor tissue size. Taken together, our findings suggest a tumor-specific process involving increased release of intact mtDNA, detectable in the plasma, which differentiates normal patients from patients with thyroid cancer.

BHRF1 Enhances EBV Mediated Nasopharyngeal Carcinoma Tumorigenesis through Modulating Mitophagy Associated with Mitochondrial Membrane Permeabilization Transition.

Epstein-Barr virus (EBV) is a major contributor to nasopharyngeal carcinoma (NPC) tumorigenesis. Mitochondria have been shown to be a target for tumor viral invasion, and to mediate viral tumorigenesis. In this study, we detected that mitochondrial morphological changes in tumor tissues of NPC patients infected with EBV were accompanied by an elevated expression of BHRF1, an EBV encoded protein homologue to Bcl-2. High expression of BHRF1 in human NPC cell lines enhanced tumorigenesis and metastasis features. With BHRF1 localized to mitochondria, its expression induced cyclophlin D dependent mitochondrial membrane permeabilization transition (MMPT). The MMPT further modulated mitochondrial function, increased ROS production and activated mitophagy, leading to enhanced tumorigenesis. Altogether, our results indicated that EBV-encoded BHRF1 plays an important role in NPC tumorigenesis through regulating cyclophlin D dependent MMPT.

Loss of SWI/SNF Chromatin Remodeling Alters NRF2 Signaling in Non-Small Cell Lung Carcinoma.

The NF-E2-related factor 2 (referred to as NRF2) transcription factor binds antioxidant responsive elements within the promoters of cytoprotective genes to induce their expression. Next-generation sequencing studies in lung cancer have shown a significant number of activating mutations within the NRF2 signaling pathway. Mutations in components of the SWI/SNF chromatin-remodeling complex, a general regulator of transcription using either BRG1 or BRM as the catalytic subunit, also frequently occur in lung cancers. Importantly, low BRG1 expression levels in primary human NSCLC correlated with increased NRF2-target gene expression. Here, we show that loss of SWI/SNF complex function activated a subset of NRF2-mediated transcriptional targets. Using a series of isogenic NSCLC lines with reduced or depleted BRG1 and/or BRM expression, we observed significantly increased expression of the NRF2-target genes HMOX1 and GSTM4. In contrast, expression of the NRF2 target genes NQO1 and GCLM modestly increased following BRM reduction. Chromatin immunoprecipitation showed that BRG1 knockdown led to increased NRF2 binding at its respective ARE sites in the HMOX1 promoter but not in NQO1 and GCLM. Our data demonstrate that loss of BRG1 or BRM in lung cancer results in activation of the NRF2/KEAP1 pathway and HMOX1 expression. Therefore, we provide an additional molecular explanation for why patients harboring BRG1 or BRM mutations show poor prognoses. A better understanding of this mechanism may yield novel insights into the design of targeted treatment modalities. IMPLICATIONS: Our study identifies a novel mechanism for how mutations in the SMARCA4 gene may drive progression of human lung adenocarcinomas.

Anlotinib is effective in the treatment of advanced carcinoma ex pleomorphic adenoma of the submandibular gland.

Background: Carcinoma ex pleomorphic adenoma (CXPA), a very rare malignancy found mostly in the major salivary glands, has no established standardized treatment. Case presentation: This report describes a 67-year-old male with advanced CXPA who was effectively treated by anlotinib. Pleomorphic adenoma of the submandibular gland was first diagnosed in 1976 after a surgical resection of a mass underneath the jaw. The patient underwent re-excision 3 years later due to a recurrent pleomorphic adenoma. CXPA was first diagnosed in 2016 after a surgical removal of the left submandibular mass. A lung nodule was found on a chest CT scan in January 2018. Following a CT-guided lung biopsy that demonstrated findings consistent with pulmonary metastasis, the patient underwent local therapy (microwave ablation and radioactive seed implantation) but suffered a recurrence of disease approximately 6 months later. Anlotinib was administered orally at a dose of 12 mg daily on a 2 weeks on/1 week off schedule. A partial response was observed after two cycles of treatment. The disease remains in continued partial response after completion of his sixth cycle. Conclusion: This is the first report for anlotinib in treating CXPA. Further pre-clinical and clinical studies are needed to validate the efficacy and safety of anlotinib in the treatment of CXPA.

Oncocytic tumors are marked by enhanced mitochondrial content and mtDNA mutations of complex I in Chinese patients.

Oncocytic tumors are composed of oncocytes characterized by acidophilic granular and reticular cytoplasm. Such features have been attributed to the distinctive aggregation of abnormal mitochondria. Sporadic mitochondrial DNA (mtDNA) mutations, particularly those in complex I subunit genes, have been identified as one of the most noticeable alterations. We reviewed 11,051 cases of patients with thyroid tumors who visited the First Affiliated Hospital of Wenzhou Medical University from January 2011 to August 2017, and we were able to identify 123 cases as oncocytic tumors. We found that older people are at higher risk (P < 0.001) for oncocytic tumors. We confirmed an increased mitochondrial mass in representative samples. Furthermore, a comprehensive analysis of the mitochondrial genomes in patients with oncocytomas revealed 1) haplogroups D5 and A exhibit increased risk of oncocytomas; 2) 60% of mtDNA mutations are in genes encoding respiratory complex subunits while 8% occur in rRNA and 4% in tRNA regions; 3) among mutations in coding regions, 50% are in Complex I genes, including most of the disruptive mutations; 4) 64% of mtDNA mutations are heteroplasmic. Our studies imply a tumorigenesis mechanism for oncocytomas involving mitochondrial alterations mediated by genome instability and modified by mitochondrial haplogroups.

Dataset of mitochondrial genome variants in oncocytic tumors.

This dataset presents the mitochondrial genome variants associated with oncocytic tumors. These data were obtained by Sanger sequencing of the whole mitochondrial genomes of oncocytic tumors and the adjacent normal tissues from 32 patients. The mtDNA variants are identified after compared with the revised Cambridge sequence, excluding those defining haplogroups of our patients. The pathogenic prediction for the novel missense variants found in this study was performed with the Mitimpact 2 program.

The association between XPG polymorphisms and cancer susceptibility: Evidence from observational studies.

BACKGROUND: Exposure to environmental carcinogens can cause damages to DNA. If not properly repaired, the DNA damages may increase the risk of carcinogenesis. Xeroderma pigmentosum group G (XPG) gene is an essential gene in the nucleotide excision repair (NER) pathway. The association between XPG polymorphisms and cancer susceptibility has been the focus of attention in the molecular epidemiology of cancer. However, the conclusions have been divergent. Therefore, we conducted a comprehensive meta-analysis to precisely evaluate the association of 3 frequently investigated XPG polymorphisms (rs751402, rs873601, and rs2296147) with cancer risk. METHODS: Pubmed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) were searched for relevant studies in English and Chinese. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the association between XPG polymorphisms (rs751402, rs873601, and rs2296147) and cancer risk. RESULTS: Twenty-three studies were included. Overall, there was no significant association between rs751402 polymorphism and overall cancer risk under the 5 gene models. However, we observed strong correlation between rs751402 polymorphism and gastric cancer (C vs T: OR=1.21, 95% CI = 1.00-1.26, P = .045; TC vs CC: OR = 1.12, 95% CI = 1.00-1.24, P = .041; TC/TT vs CC: OR = 1.13, 95% CI = 1.02-1.26, P = .020). There was a significant correlation between rs873601 polymorphism and cancer risk under the homozygous model (GG vs AA: OR = 1.16, 95% CI = 1.07-1.26, P = .001). Moreover, significant association with breast cancer was detected for rs873601 polymorphism under the allele contrast model (G vs A: OR = 1.10, 95% CI = 1.02-1.20, P = .021). In the subgroup of Asian, rs873601 polymorphism was related to the susceptibility to cancer (G vs A: OR = 1.07, 95% CI = 1.03-1.12, P = .010; GG vs AA: OR = 1.15, 95% CI = 1.06-1.26, P = .001; AG/AA vs GG: OR = 1.08, 95% CI = 1.01-1.15, P = .031; AA vs AG/GG: OR = 1.13, 95% CI = 1.05-1.21, P = .001). Significant association between rs2296147 polymorphism and cancer risk were observed in Asian population (CT vs TT: OR = 0.93, 95% CI = 0.87-0.99, P = .036). CONCLUSIONS: Our meta-analysis suggested that the rs873601 polymorphism was significantly associated with overall cancer risk. The moderate effects of rs751402 and rs2296147 polymorphism on cancer susceptibility might be highly dependent on cancer type and ethnicity, respectively. Large studies are needed to validate our findings, especially in Caucasian and African population.

Construction of polyketide overproducing Escherichia coli strains via synthetic antisense RNAs based on in silico fluxome analysis and comparative transcriptome analysis.

Rapid assessment and optimization of the incompatible metabolic modules remain a challenge. Here, we developed a systematic approach to characterize the module interactions and improve the problematic modules during the 6-deoxyerythronolide B (6dEB) biosynthesis in E. coli. Tremendous differences in the overall trends of flux changes of various metabolic modules were firstly uncovered based on in silico fluxome analysis and comparative transcriptome analysis. Potential targets for improving 6dEB biosynthesis were identified through analyzing these discrepancies. All 25 predicted targets at modules of PP pathway and nucleotide metabolism were firstly tested for improving the 6dEB production in E. coli via synthetic antisense RNAs. Down-regulation of 18 targets genes leads to more than 20% increase in 6dEB yield. Combinatorial repression of targets with greater than 60% increase in 6dEB titer, e.g., anti-guaB/anti-zwf led to a 296.2% increase in 6dEB production (210.4 mg/L in flask) compared to the control (53.1 mg/L). This is the highest yield yet reported for polyketide heterologous biosynthesis in E. coli. This study demonstrates a strategy to enhance the yield of heterologous products in the chassis cell and indicates the effectiveness of antisense RNA for use in metabolic engineering.

MDM4 rs4245739 A > C polymorphism correlates with reduced overall cancer risk in a meta-analysis of 69477 subjects.

Mouse double minute 4 (MDM4) is a p53-interacting oncoprotein that plays an important role in the p53 tumor suppressor pathway. The common rs4245739 A > C polymorphism creates a miR-191 binding site in the MDM4 gene transcript. Numerous studies have investigated the association between this MDM4 polymorphism and cancer risk, but have failed to reach a definitive conclusion. To address this issue, we conducted a meta-analysis by selecting eligible studies from MEDLINE, EMBASE, and Chinese Biomedical databases. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. We also performed genotype-based mRNA expression analysis using data from 270 individuals retrieved from public datasets. A total of 15 studies with 19796 cases and 49681 controls were included in the final meta-analysis. The pooled results revealed that the MDM4 rs4245739C allele is associated with a decreased cancer risk in the heterozygous (AC vs. AA: OR = 0.82, 95% CI = 0.73-0.93), dominant (AC/CC vs. AA: OR = 0.82, 95% CI = 0.72-0.93), and allele contrast models (C vs. A: OR = 0.84, 95% CI = 0.76-0.94). The association was more prominent in Asians and population-based studies. We also found that the rs4245739C allele was associated with decreased MDM4 mRNA expression, especially for Caucasians. Thus the MDM4 rs4245739 A > C polymorphism appears to be associated with decreased cancer risk. These findings would be strengthened by new studies with larger sample sizes and encompassing additional ethnicities.