Diagnosis of Cardiac Amyloidosis Using a Radiomics Approach Applied to Late Gadolinium-Enhanced Cardiac Magnetic Resonance Images: A Retrospective, Multicohort, Diagnostic Study.

Objectives: To assess the potential of a radiomics approach of late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) in the diagnosis of cardiac amyloidosis (CA). Materials and Methods: This retrospective study included 200 patients with biopsy-proven light-chain (AL) amyloidosis. CA was diagnosed on the basis of systemic amyloidosis confirmed with evidence of cardiac involvement by imaging and clinical biomarkers. A total of 139 patients [54 ± 8 years, 75 (54%) men] in our institution were divided into training cohort [n = 97, mean age of 53 ± 8 years, 54 (56%) men] and internal validation cohort [n = 42, mean age: 56 ± 8 years, 21 (50%) men] with a ratio of 7:3, while 61 patients [mean age: 60 ± 9 years, 42 (69%) men] from the other two institutions were enrolled for external validation. Radiomics features were extracted from global (all short-axis images from base-to-apex) left ventricular (LV) myocardium and three different segments (basal, midventricular, and apex) on short-axis LGE images using the phase-sensitive reconstruction (PSIR) sequence. The Boruta algorithm was used to select the radiomics features. This model was built using the XGBoost algorithm. The two readers performed qualitative and semiquantitative assessment of the LGE images based on the visual LGE patterns, while the quantitative assessment was measured using a dedicated semi-automatic CMR software. The diagnostic performance of the radiomics and other qualitative and quantitative parameters were compared by a receiver operating characteristic (ROC) curve analysis. A correlation between radiomics and the degree of myocardial involvement by amyloidosis was tested. Results: A total of 1,906 radiomics features were extracted for each LV section. No statistical significance was indicated between any two slices for diagnosing CA, and the highest area under the curve (AUC) was found in basal section {0.92 [95% confidence interval (CI), 0.86-0.97] in the LGE images in the training set, 0.89 (95% CI, 0.79-1.00) in the internal validation set, and 0.92 (95% CI, 0.85-0.99) in the external validation set}, which was superior to the visual assessment and quantitative LGE parameters. Moderate correlations between global or basal radiomics scores (Rad-scores) and Mayo stage in all patients were reported (Spearman's Rho = 0.61, 0.62; all p < 0.01). Conclusion: A radiomics analysis of the LGE images provides incremental information compared with the visual assessment and quantitative parameters on CMR to diagnose CA. Radiomics was moderately correlated with the severity of CA. Further studies are needed to assess the prognostic significance of radiomics in patients with CA.

Development and Validation of a Nomogram for Predicting Prognosis to Immune Checkpoint Inhibitors Plus Chemotherapy in Patients With Non-Small Cell Lung Cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) plus chemotherapy improved the prognosis of patients with non-small cell lung cancer (NSCLC); however, reliable prognostic biomarkers are lacking. We explored factors associated with prognosis and developed a predictive model. METHODS: We retrospectively analyzed 130 consecutive stage IIIA-IVB NSCLC patients treated with ICIs combined with chemotherapy. Cox univariate and multivariate proportional hazards regression analyses were used to identify prognostic factors associated with progression-free survival (PFS). A nomogram was developed based on key factors in the training cohort (n = 86) and evaluated in the validation cohort (n = 44). According to the nomogram-based total point scores, we divided patients into low- and high-risk groups. RESULTS: In the training cohort, bone metastases (p = 0.017) and an increased derived neutrophil-to-lymphocyte ratio (p = 0.018) were significantly associated with poor PFS, while smoking (p = 0.007) and programmed death-ligand 1 (PD-L1) ≥50% (p = 0.001) were associated with improved PFS. A nomogram based on these factors was developed to predict PFS at 3, 6, and 12 months. The C-index of the nomogram to predict PFS was 0.725 (95% CI: 0.711-0.739) in the training cohort and 0.688 (95% CI: 0.665-0.711) in the validation cohort. The area under the curve (AUC) exhibited an acceptable discriminative ability, and calibration curves demonstrated a consistency between the actual results and predictions. In the training cohort, the median PFS (mPFS) was 12.3 and 5.7 months in the low- and high-risk groups, respectively (p < 0.001). In the validation cohort, the mPFS was 12.6 and 6.2 months in the low- and high-risk groups, respectively (p = 0.021). CONCLUSIONS: A predictive nomogram was developed to help clinicians assess prognosis early for advanced NSCLC patients who received ICI plus chemotherapy.

Protective effect of hsa-miR-570-3p targeting CD274 on triple negative breast cancer by blocking PI3K/AKT/mTOR signaling pathway.

To find out the role of hsa-miR-570-3p targeting CD274 in triple negative breast cancer (TNBC) via PI3K/AKT/mTOR signaling pathway. Hsa-miR-570-3p and CD274 expressions in 175 TNBC patients were detected by qRT-PCR and immunohistochemistry respectively. The human TNBC cell lines (MDA-MB-468 and MDA-MB-231) were used to verify the targeting relationship between hsa-miR-570-3p and CD274 via dual-luciferase reporter gene assay. Then, MDA-MB-468 and MDA-MB-231 cells were divided into Blank, miR-NC, miR-570-3p mimics, NC siRNA, CD274 siRNA, and miR-570-3p inhibitors + CD274 siRNA groups. Next, the biological activities of cells were detected by MTT, Cell-Light EdU, Annexin-V-FITC/PI, wound healing and Transwell invasion assays. Western blotting was conducted to detect protein expressions.MiR-570-3p expression was lower in tumor tissues than that in adjacent normal tissues, which was more obvious in CD274-positive TNBC patients, which targeted CD274 in TNBC cell lines. MiR-570-3p inhibited cell proliferation, invasion and migration, but induced cell apoptosis accompanying the upregulation of apoptotic proteins and downregulation of anti-apoptotic protein. CD274 siRNA had the similar results of miR-570-3p mimics, which could be reversed by miR-570-3p inhibitors. Besides, both miR-570-3p mimics and CD274 siRNA blocked PI3K/AKT/mTOR signaling pathway in TNBC cell lines. Hsa-miR-570-3p was downregulated and CD274 was upregulated in TNBC patients. Besides, hsa-miR-570-3p targeted CD274 to inhibit cell proliferation, invasion, migration, and induce cell apoptosis, which may be related to the suppression of PI3K/AKT/mTOR pathway.

Polyamine analogue QMA attenuated ischemic injury in MCAO rats via ERK and Akt activated Nrf2/HO-1 signaling pathway.

Previous research showed N1-(quinolin-2-ylmethy) butane-1, 4-diamine (QMA), a polyamine analogue, was efficacious in the prevention of oxidative injury in models of cerebral ischemia. The present study manifested that pretreatment with QMA attenuated ischemic damage accompanying up regulation of Nuclear factor erythroid 2­related factor (Nrf2), Heme oxygenase­1 (HO­1), p-ERK and p-Akt in cerebral cortex tissues of middle cerebral artery occlusion (MCAO) rats and oxygen-glucose deprivation (OGD)-treated PC12 cells. Further more, treatment with LY294002 (specific PI3K inhibitor), PD98059 (specific ERK inhibitor), brusatol (specific Nrf2 inhibitor) and SnPP (specific HO-1 inhibitor) deprived almost all the effects of QMA in MCAO rats and OGD-treated PC12 cells. These data suggested that the protective actions of QMA on the cerebral ischemia may be related to activation of endogenous cytoprotective mechanism via ERK and Akt activated Nrf2/HO-1 signaling pathway.

Association between tobacco smoking and drug-resistant tuberculosis.

BACKGROUND: Tobacco smoking is a risk factor for tuberculosis but little is known about the relationship between tobacco smoking and drug-resistant tuberculosis (DR-TB). We undertook a systematic review and meta-analysis to quantitatively assess the association between DR-TB and tobacco smoking. METHODS: We searched for relevant studies in the Ovid MEDLINE, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, WANFANG, and WEIPU data-bases from inception to September 1, 2017. Results were expressed as odds ratios (ORs) with accompanying 95% CIs, and subgroup analyses were performed by study design, smoking type, DR-TB type, and multivariate analysis. RESULTS: Thirty-three studies related to tobacco smoking and DR-TB were included. We found substantial evidence that tobacco smoking is associated with an increased risk of DR-TB (OR 1.57, 95% CI 1.33-1.86). Associations were also found in subgroup analyses: for multidrug-resistant tuberculosis (OR 1.49, 95% CI 1.19-1.86) and for any DR-TB (OR 1.70, 95% CI 1.3-2.23); the pooled OR was 1.45 (95% CI 1.11-1.90) for current smoking, 2.25 (95% CI 1.46-3.47) for past smoking, and 1.56 (95% CI 1.22-1.98) for smoking history; and similar ORs were also observed in study design and multivariate analysis subgroup analysis. CONCLUSION: This study demonstrated that tobacco smoking is an independent risk factor for DR-TB.

Noninvasive detection of fetal subchromosomal abnormalities by semiconductor sequencing of maternal plasma DNA.

Noninvasive prenatal testing (NIPT) using sequencing of fetal cell-free DNA from maternal plasma has enabled accurate prenatal diagnosis of aneuploidy and become increasingly accepted in clinical practice. We investigated whether NIPT using semiconductor sequencing platform (SSP) could reliably detect subchromosomal deletions/duplications in women carrying high-risk fetuses. We first showed that increasing concentration of abnormal DNA and sequencing depth improved detection. Subsequently, we analyzed plasma from 1,456 pregnant women to develop a method for estimating fetal DNA concentration based on the size distribution of DNA fragments. Finally, we collected plasma from 1,476 pregnant women with fetal structural abnormalities detected on ultrasound who also underwent an invasive diagnostic procedure. We used SSP of maternal plasma DNA to detect subchromosomal abnormalities and validated our results with array comparative genomic hybridization (aCGH). With 3.5 million reads, SSP detected 56 of 78 (71.8%) subchromosomal abnormalities detected by aCGH. With increased sequencing depth up to 10 million reads and restriction of the size of abnormalities to more than 1 Mb, sensitivity improved to 69 of 73 (94.5%). Of 55 false-positive samples, 35 were caused by deletions/duplications present in maternal DNA, indicating the necessity of a validation test to exclude maternal karyotype abnormalities. This study shows that detection of fetal subchromosomal abnormalities is a viable extension of NIPT based on SSP. Although we focused on the application of cell-free DNA sequencing for NIPT, we believe that this method has broader applications for genetic diagnosis, such as analysis of circulating tumor DNA for detection of cancer.

Triptolide inhibits histone methyltransferase EZH2 and modulates the expression of its target genes in prostate cancer cells.

The histone methyltransferase EZH2 (enhancer of zeste homolog 2) plays critical roles in prostate cancer (PCa) development and is a potential target for PCa treatment. Triptolide possesses anti-tumor activity, but it is unknown whether its therapeutic effect relates with EZH2 in PCa. Here we described EZH2 as a target for Triptolide in PCa cells. Our data showed that Triptolide suppressed PCa cell growth and reduced the expression of EZH2. Overexpression of EZH2 attenuated the Triptolide induced cell growth inhibition. Moreover, Triptolide treatment of PC-3 cells resulted in elevated mRNA levels of target genes (ADRB2, CDH1, CDKN2A and DAB2IP) negatively regulated by EZH2 as well as reduced mRNA levelsan of EZH2 positively regulated gene (cyclin D1). Our findings suggest the PCa cell growth inhibition mediated by Triptolide might be associated with downregulation of EZH2 expression and the subsequent modulation of target genes.

A vacuolar processing enzyme RsVPE1 gene of radish is involved in floral bud abortion under heat stress.

Radish floral bud abortion (FBA) is an adverse biological phenomenon that occurs during reproduction. Although FBA is a frequent occurrence, its molecular mechanism remains unknown. A transcript-derived fragment (TDF72), which was obtained by cDNA amplified fragment length polymorphism (cDNA-AFLP), was up-regulated in the aborted buds and exhibited 89% sequence homology with the AtγVPE gene. In this study, TDF72 was used to clarify the role of VPE in FBA by isolation of the VPE gene RsVPE1 from radish flower buds. The full-length genomic DNA was 2346 bp including nine exons and eight introns. The full-length cDNA was 1825 bp, containing a complete open reading frame (ORF) of 1470 bp, which encoded a predicted protein containing 489 amino acid residues, with a calculated molecular mass of 53.735 kDa. Expression analysis demonstrated that RsVPE1 was expressed in all tested organs of radish at different levels. Highest expression was detected in aborted flower buds, suggesting that RsVPE1 has a role in FBA. In order to analyze the role of RsVPE1 in FBA, RsVPE1 was overexpressed in transgenic Arabidopsis thaliana plants. Aborted flower buds appeared in transgenic plants subjected to heat stress. In addition, RsVPE1 expression in the transgenic plants reached a maximum when subjected to heat stress for 24 h and increased by 2.1-fold to 2.8-fold in three homozygous transgenic lines. These results indicated that RsVPE1 led to FBA when its expression levels exceeded a particular threshold, and provided evidence for the involvement of RsVPE1 in promoting FBA under heat stress.

Chemical composition and antioxidant activities of three polysaccharide fractions from pine cones.

The traditional method of gas chromatography-mass spectrometry for monosaccharide component analysis with pretreatment of acetylation is described with slight modifications and verified in detail in this paper. It was then successfully applied to the quantitative analysis of component monosaccharides in polysaccharides extracted from the pine cones. The results demonstrated that the three pine cone polysaccharides all consisted of ribose, rhamnose, arabinose, xylose, mannose, glucose and galactose in different molar ratios. According to the recovery experiment, the described method was proved accurate and practical for the analysis of pine cone polysaccharides, meeting the need in the field of chemical analysis of Pinus plants. Furthermore; the chemical characteristics, such as neutral sugar, uronic acids, amino acids, molecular weights, and antioxidant activities of the polysaccharides were investigated by chemical and instrumental methods. The results showed that the chemical compositions of the polysaccharides differed from each other, especially in the content of neutral sugar and uronic acid. In the antioxidant assays, the polysaccharide fractions exhibited effective scavenging activities on ABTS radical and hydroxyl radical, with their antioxidant capabilities decreasing in the order of PKP > PAP > PSP. Therefore, although the polysaccharide fractions had little effect on superoxide radical scavenging, they still have potential to be developed as natural antioxidant agents in functional foods or medicine.

Zoledronic acid as an adjuvant therapy in patients with breast cancer: a systematic review and meta-analysis.

BACKGROUND: Zoledronic acid is widely used as adjuvant chemotherapy for the treatment of breast cancer. However, previous trials reported inconsistent findings regarding their clinical efficacy and safety. We carried out a comprehensive systematic review and meta-analysis to evaluate the effects of zoledronic acid on disease-free survival (DFS), overall survival (OS), and drug-related toxicities. METHODOLOGY AND PRINCIPAL FINDINGS: We systematically searched Medline, EmBase, the Cochrane Central Register of Controlled Trials, reference lists of articles and proceedings of major meetings for relevant literatures with a time limit of Dec. 1, 2011. Randomized controlled trials evaluated the effects of zoledronic acid on OS, DFS, and RFS compared with control were eligible for inclusion in our research. Of 175 identified studies, we collected data from 7 randomized controlled trials of zoledronic acid that had OS, DFS, and RFS reported as one of the endpoint. Overall, we noted that patients receiving zoledronic acid therapy had significant longer OS than the group with non-zoledronic acid therapy (HR, 0.85, 95%CI, 0.73 to 1.00, P = 0.047). Furthermore, zoledronic acid therapy also had a clear effect on frature events (RR, 0.66, 95%CI, 0.52 to 0.84, P<0.001). Subgroup analysis indicated that zoledronic acid therapy showed a great beneficial effect on disease recurrence in patients with early-stage breast cancer, however, it also significantly increased the harm of disease recurrence in patients with advanced breast cancer. Bone pain, neutropenic fever, pyrexia, rash were more frequent in the zoledronic acid therapy group. CONCLUSION/SIGNIFICANCE: Treatment with zoledronic acid had a clear effect on fracture events, and it might contribute an important role for overall survival.

[Recent advances in the study of accelerated blood clearance phenomenon of PEGylated liposomes].

It is generally believed that liposomes modified with polyethylene glycol (PEG) have no or lower immunogenicity. However, based on many recent literatures, when the PEGylated liposomes were repeatedly applied to the same animal, the immune responses occurred. The first injection of PEGylated liposomes resulted in a reduction in the circulation time and an increase in hepatic and splenic accumulation of the second dose of PEGylated liposomes in a time-interval, which was called "accelerated blood clearance (ABC)" phenomenon. Such immunogenicity of PEGylated liposomes presents a barrier in the research of liposomal formulations and their use in the clinics. This review focused on the definition, the method of verification, the development of the reason for ABC phenomenon, influencing factors of ABC phenomenon, and discussed if other PEGylated nanocarriers also induce ABC phenomenon.

[mRNA expression of CK19 and CEA in peripheral blood of patients with breast cancer detected by real-time quantitative PCR].

OBJECTIVE: To explore the clinical significance of detection of cytokeratin 19 (CK19) mRNA and carcinoembryonic antigen (CEA) mRNA expression in the diagnosis of micrometastasis in the peripheral blood of patients with breast cancer, and the relationship with other clinicopathological characteristics. METHODS: Peripheral blood samples were collected from 28 normal female healthy volunteers, 20 patients with benign breast disease, and 108 patients with breast cancer (88 had undergone operation and 20 with metastasis). Real-time quantitative PCR was used to detect the mRNA expression of CK19 and CEA in the peripheral blood. RESULTS: mRNA expression was negative in the blood samples from the 28 normal volunteers for both CK19 and CEA. None of the 20 patients with benign breast disease was positive for CEA mRNA, but one was positive for CK19 mRNA (5%). Of the 108 patients with breast cancer, 26 (24.1%) were positive for CK19 mRNA, 23 (21.3%) were positive for CEA mRNA, and 15 (13.9%) were positive for both CK19 mRNA and CEA mRNA. The positive rates of CK19 mRNA and/or CEA mRNA of the metastatic breast cancer patients were higher than those of the operable breast cancer patients. Statistically significant differences in tumor size, clinical stage, and expression levels of k(i)67, variant exon 6 containing isoforms of CD44 (CD44v6), and vascular endothelial growth factor (VEGF) were found between the operable breast cancer patients with micrometastasis in peripheral blood and the patients without micrometastasis (all P < 0.05). And there was no statistically significant difference between the two groups in age, tumor location, pathological histological type, nodal metastasis, and expression levels of estrogen receptor (ER), pregnant receptor (PR), CerbB2, and matrix metalloproteinase-9 (MMP9) (all P > 0.05). Multivariate analysis showed that tumor size, clinical stage, expressions of ki67, CD44v6, and VEGF were associated with micrometastasis in peripheral blood. CONCLUSION: The combined detection of CK19 and CEA mRNA raises the detection rate of micrometastasis in the peripheral blood of breast cancer patients. Tumor size, clinical stage, expressions of ki67, CD44v6, and VEGF are effective predictors of micrometastasis in the peripheral blood of breast cancer patients.

[The roles of soluble MICA in immune escape of breast tumor].

AIM: To determine the expression of soluble MICA (sMICA) in serum of patients with breast tumor, and explore the roles of sMICA in immune escape. METHODS: ELISA was used to examine the sMICA in peripheral blood. The expression of NKG2D were identified by Flow cytometry. The cytotoxicity of NK cells to breast cancer cells was observed with MTT assay. RESULTS: sMICA was not detected in the serum of healthy person, but(76.8+/-22.3) ng/L in breast benign tumor patients and (205.4+/-71.3) ng/L in breast malignant tumor patients. There was positive correlation between sMICA levels and breast cancer stage. After incubation with sMICA, NK cells got decrease in cytotoxicity from (76.2+/-6.7) % to (48.4+/-4.1) % .The expression of NKG2D and secretion of IFN-gamma decreased at the same time. IL-15 up-regulated the expression of NKG2D on NK cells and increased NK cells cytotoxicity to breast cancer cells. CONCLUSION: sMICA level is positive correlated with breast cancer TNM stage. sMICA reduced the expression of NKG2D, impaired NK-mediated immune surveillance and led to immune escape of breast tumor. IL-15 could up-regulate the expression of NKG2D and increase NK cells cytotoxicity.

Estrogen suppresses uterine epithelial apoptosis by inducing birc1 expression.

The decision whether or not a cell undergoes apoptosis is determined by the opposing forces of pro- and antiapoptotic effectors. Here we demonstrate genetically that estrogen can tip this balance toward cell survival in uterine epithelial cells by inducing the expression of baculoviral inhibitors of apoptosis repeat-containing 1 (Birc1), a family of antiapoptotic proteins. In neonatal mice, both 17beta-estradiol and the potent synthetic estrogen diethylstilbestrol strongly suppress uterine epithelial apoptosis while markedly elevating Birc1 transcript level in an estrogen receptor-alpha-dependent manner. The induction of Birc1 before any effect on apoptosis suppression and failure of diethylstilbestrol to completely inhibit apoptosis in Birc1a-deficient uterine epithelium indicate a functional role for Birc1a in estrogen-mediated apoptosis suppression. In ovariectomized adult mice, expression of Birc1 is also induced by ovarian hormones, suggesting a role for these proteins in normal uterine physiology. We propose that by binding to active caspases, Birc1 proteins can eliminate them through proteasome degradation. These results for the first time establish Birc1 proteins as functional targets of estrogen in suppressing apoptosis in the uterus.

Developmental diethylstilbestrol exposure alters genetic pathways of uterine cytodifferentiation.

The formation of a simple columnar epithelium in the uterus is essential for implantation. Perturbation of this developmental process by exogenous estrogen, such as diethylstilbestrol (DES), results in uterine metaplasia that contributes to infertility. The cellular and molecular mechanism underlying this transformation event is not well understood. Here we use a combination of global gene expression analysis and a knockout mouse model to delineate genetic pathways affected by DES. Global gene expression profiling experiment revealed that neonatal DES treatment alters uterine cell fate, particularly in the luminal epithelium by inducing abnormal differentiation, characterized by the induction of stratified epithelial markers including members of the small proline-rich protein family and epidermal keratins. We show that Msx2, a homeodomain transcription factor, functions downstream of DES and is required for the proper expression of several genes in the uterine epithelium including Wnt7a, PLAP, and K2.16. Finally, Msx2-/- uteri were found to exhibit abnormal water trafficking upon DES exposure, demonstrating the importance of Msx2 in tissue responsiveness to estrogen exposure. Together, these results indicate that developmental exposure to DES can perturb normal uterine development by affecting genetic pathways governing uterine differentiation.