Solid basal adenoid cystic carcinoma of the breast: A case report and literature review.

RATIONALE: Adenoid cystic carcinoma (AdCC) is a rare malignancy of the breast with a low Ki-67 index and good prognosis. Owing to the rarity of breast AdCC, the misdiagnosis rate is as high as 50%, and there is no consensus or recognized guidelines for the treatment of this disease. Therefore, it is necessary to conduct a detailed clinical and pathological analysis in combination with a literature review to improve our understanding, diagnosis, and treatment of the disease. METHODS: A 68-year-old woman sought medical attention due to a recently increasing mass in the breast. The left breast mass was 1.3 cm × 1 cm in size. We analyzed the morphology, immunohistochemistry, and molecular characteristics of the tumor removed by surgery, and reviewed relevant literature. DIAGNOSES: Solid basal AdCC of the breast. INTERVENTIONS: We performed biopsy, immunohistochemistry and molecular testing on surgical resection specimens. OUTCOMES: Combining morphological and immunohistochemical features, it is consistent with solid basal AdCC of the breast, and Fish detected MYB gene break. LESSONS: Due to the high misdiagnosis rate of AdCC, accurate histopathological diagnosis is particularly important. At present, breast conserving surgery and local tumor resection are mainly used for the treatment of breast AdCC, and postoperative adjuvant radiotherapy is feasible.

Stromal cell-derived factor-1 exerts opposing roles through CXCR4 and CXCR7 in angiotensin II-induced adventitial remodeling.

Recent studies have emphasized the role of vascular adventitia inflammation and immune response in hypertension. It has been reported that stromal cell-derived factor-1 (SDF-1) plays various biological functions through its receptors C-X-C motif chemokine receptor 4 (CXCR4) and CXCR7 in tumor growth and tissue repair. However, it is unclear that whether SDF-1/CXCR4/CXCR7 axis is involved in hypertensive vascular remodeling. In the present study, the involvement of SDF-1/CXCR4/CXCR7 axis was evaluated with lentivirus-mediated shRNA of SDF-1 and CXCR7, CXCR4 antagonist AMD3100 and CXCR7 agonist VUF11207 in angiotensin II (AngII)-induced hypertensive mice and in cultured adventitial fibroblasts (AFs). Results showed that AngII infusion markedly increased SDF-1 expressed in vascular adventitia, but not in media and endothelium. Importantly, blockade of SDF-1/CXCR4 axis strikingly potentiated AngII-induced adventitial thickening and fibrosis, as indicated by enhanced collagen I deposition. In contrast, CXCR7 shRNA largely attenuated AngII-induced adventitial thickness and fibrosis, whereas CXCR7 activation with VUF11207 significantly potentiated AngII-induced adventitial thickening and fibrosis. In consistent with these in vivo study, CXCR4 inhibition with AMD3100 and CXCR7 activation with VUF11207 aggravated AngII-induced inflammation, proliferation and migration in cultured AFs. In summary, these results suggested that SDF-1 exerted opposing effects through CXCR4 and CXCR7 in AngII-induced vascular adventitial remodeling.

The potential mechanism of Astragali Radix in the treatment of children with nephrotic syndrome.

BACKGROUND: The molecular mechanism of Astragali Radix in the treatment of children with nephrotic syndrome (NS) is unclear. This study aimed to use network pharmacology to explore this potential mechanism. METHODS: The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to identify the main active ingredients of Astragali Radix. The PharmMapper, Online Mendelian Inheritance in Man (OMIM), and GeneCards databases were then used to identify the active ingredients of Astragali Radix. The String database and Cytoscape software were used to construct the protein-protein network. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using DAVID Database. RESULTS: In the TCMSP Database, a total of 20 chemical constituents of Astragali Radix were screened. After removing the duplicates and false positive genes, 394 targets of these active ingredients were obtained from PharmMapper. By comparing the NS-related genes in the GeneCards and OMIM Databases, a total of 39 potential NS-related targets were ultimately identified. The protein-protein-interaction network included 39 nodes and 366 edges. The top 5 proteins were albumin (ALB), serine/threonine kinase (AKT1), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), and matrix metallopeptidase 9 (MMP9). The GO analysis showed that the target genes were mainly involved in biological processes (e.g., signal transduction, the positive regulation of cell proliferation, and the positive regulation of migration). The cellular components included a plasma membrane, extracellular exosome, and extracellular space. The molecular functions included protein binding, zinc-ion binding, protein tyrosine kinase activity, and enzyme binding. The KEGG analysis showed that the treatment of NS by Astragali Radix mainly involved pathways in cancer, proteoglycans in cancer, the phosphatidylinositol 3-kinase and protein kinase B (PI3K-Akt) signaling pathway, the rennin-angiotensin-system (Ras) signaling pathways, and Forkhead box protein O1 (FoxO) signaling pathways. CONCLUSIONS: In the present study, the network pharmacology method was used to explore the potential targets and pathways of Astragali Radix in the treatment of NS. We also provided future research directions for the treatment of NS with a complex pathogenesis.

Optimal timing of coronary angiograms for patients with chronic kidney disease: association between the duration of kidney dysfunction and SYNTAX scores.

BACKGROUND: Chronic kidney disease (CKD) is associated with an increased risk of the progression of coronary artery disease (CAD). However, there are few data on the relationship between CAD severity and the duration of CKD. This study assessed the predictive value of the duration of kidney dysfunction in CKD patients with CAD severity. METHODS: In 145 patients (63.4% male, n = 92; mean age, 68.8 ± 12.8 years) with CKD, severity of CAD was assessed by coronary angiography and quantified by SYNTAX scores, and duration of kidney dysfunction was either assessed by checking historical biochemical parameters of individuals or was based on enquiries. RESULTS: Patients with high SYNTAX scores (≥ 22) had a greater prevalence of cardiovascular risk factors including age, gender, history of heart failure and smoking. In CKD patients, SYNTAX scores were positively correlated to duration of CKD and serum uric acid (UA), and negatively correlated to high-density lipoprotein-cholesterol (HDL-C) and ApoA1 levels. Univariate binary logistic regression and multivariate logistic analyses showed that SYNTAX scores correlated significantly with CKD duration, UA, and HDL-C. Receiver-operating characteristic analysis was used to explore a time point when coronary angiography application was economical and effective and yielded a Youden index of 6.5 years. CONCLUSIONS: Together, our results demonstrated that the duration of kidney dysfunction was an independent correlate of the severity of CAD in patients with CKD. Our findings suggest that coronary angiography should be considered for CKD patients with renal insufficiency having lasted for more than 6.5 years.

AdipoRon Attenuates Hypertension-Induced Epithelial-Mesenchymal Transition and Renal Fibrosis via Promoting Epithelial Autophagy.

Hypertension-induced epithelial-mesenchymal transition (EMT) is a major mechanism of renal fibrosis. Adiponectin protects against hypertension-induced target organ damage. AdipoRon is an orally active synthetic adiponectin receptor agonist. However, it is unclear whether AdipoRon could attenuate EMT and renal fibrosis in hypertensive mice. C57BJ/6J mice were utilized to induce DOCA-salt-sensitive hypertensive model. Hypertension results in an altered adiponectin expression and promotes EMT in the kidney. In vitro, AdipoRon inhibits aldosterone (Aldo)-induced EMT and promotes autophagic flux in HK-2 epithelial cells. Mechanically, AdipoRon activates AMPK/ULK1 pathway in epithelial cells. Blockade of AMPK activation, as well as inhibition of autophagy, blocks the effects of AdipoRon on Aldo-induced EMT. Moreover, AdipoRon treatment promotes autophagy and improves renal fibrosis in DOCA-salt-hypertensive mice. Our data suggest that AdipoRon could be a potential therapeutic option to prevent renal fibrosis in hypertensive patients. Graphical abstract.

Three new steroidal saponins from the roots and rhizomes of Rohdea chinensis (Baker) N.Tanaka (synonym Tupistra chinensis Baker).

Three new steroidal saponins (1-3), together with four known compounds (4-7), were isolated from the roots and rhizomes of Rohdea chinensis Baker, and their structures were determined as (24S, 25 R)-1ß-hydroxy-3ß-[(ß-D-glucopyranoside)oxy]-spirost-5-en-24-yl-ß-D-glucopyranoside (1) and (24S)-spirost-25(27)-en-1ß, 3ß, 4ß, 5ß, 6ß, 24ß-hexahydroxy-24-O-ß-D-glucopyranoside (2), (22S, 25S)-1ß, 3ß, 4ß, 5ß, 26, 27-hexanol-furospirost-5, 26-O-ß-D-glucopyranoside (3), together with four known compounds 3-epi-diosgenin-3-ß-D-glucopyranosid (4), 3-epiruscogenin (5), 25(R)-1ß-hydroxy-spirost-5-en-3α-yl-O-ß-D-glucopyranoside (6) and tupichinin A (7), on the basis of physico-chemical properties and spectral analysis. In this study, compounds 1-3 and 5-7 were evaluated for their cytotoxic activity against SW620, A549 and HepG2 tumor cell lines. Among them, compound 7 showed moderate cytotoxicity against two human cancer cell lines A549 and HepG 2 with IC50 values of 25.3 ± 2.6 and 26.1 ± 2.5 µM, respectively.

HIF-1α-BNIP3-mediated mitophagy in tubular cells protects against renal ischemia/reperfusion injury.

In the present study, we hypothesized that hypoxia-inducible factor 1α (HIF-1α)-mediated mitophagy plays a protective role in ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). Mitophagy was evaluated by measuring the changes of mitophagy flux, mitochondria DNA copy number, and the changes of mitophagy-related proteins including translocase of outer mitochondrial membrane 20 (TOMM20), cytochrome c oxidase IV (COX IV), microtubule-associated protein 1 light chain 3B (LC3B), and mitochondria adaptor nucleoporin p62 in HK2 cells, a human tubular cell line. Results show that HIF-1α knockout significantly attenuated hypoxia/reoxygenation (H/R)-induced mitophagy, aggravated H/R-induced apoptosis, and increased the production of reactive oxygen species (ROS). Similarly, H/R induced significantly increase in Bcl-2 19-kDa interacting protein 3 (BNIP3), a downstream regulator of HIF-1α. Notably, BNIP3 overexpression reversed the inhibitory effect of HIF-1α knockout on H/R-induced mitophagy, and prevented the enhancing effect of HIF-1α knockout on H/R-induced apoptosis and ROS production. For in vivo study, we established HIF-1αflox/flox; cadherin-16-cre mice in which tubular HIF-1α was specifically knockout. It was found that tubular HIF-1α knockout significantly inhibited I/R-induced mitophagy, and aggravated I/R-induced tubular apoptosis and kidney damage. In contrast, adenovirus-mediated BNIP3 overexpression significantly reversed the decreased mitophagy, and prevented enhanced kidney damage in tubular HIF-1α knockout mice with I/R injury. In summary, our study demonstrated that HIF-1α-BNIP3-mediated mitophagy in tubular cells plays a protective role through inhibition of apoptosis and ROS production in acute kidney damage.

New cytotoxic bufadienolides from the roots and rhizomes of Helleborus thibetanus Franch.

Three new bufadienolides 14ß, 16ß-dihydroxy-3ß-[ß-D-glucopyranosyl-(1→6)-(ß-D-glucopyranosyl)oxy]-5α-bufa-20, 22-dienolide (1), 14ß-hydroxy-3ß-[ß-D-glucopyranosyl-(1→4)-(ß-D-glucopyranosyl)oxy]-5α-bufa-20, 22-dienolide (2) and hellebrigenin-3-O-ß-D-glucosyl-(1→4)-ß-D-glucoside (3), together with eight known bufadienolides (4-11) were isolated from the roots and rhizomes of Helleborus thibetanus. Their structures were elucidated by extensive spectroscopic methods and acid hydrolysis. Compounds 1-7 were evaluated for their cytotoxic activity against HCT116, A549 and HepG2 tumor cell lines. Compound 1 exhibited moderate cytotoxicity against HepG2 cells with IC50 value of 15.1 ± 1.72 µM. Compounds 5 and 6 exhibited moderate cytotoxicity against HCT116 cells with IC50 values of 15.12 ± 0.58 µM and 13.17 ± 2.34 µM, respectively.

The Effects of Matrine in Combination with Docetaxel on Castration-Resistant (Androgen-Independent) Prostate Cancer.

BACKGROUND: Matrine (MAT) exhibits higher efficacy of chemotherapy when it is combined with other chemotherapeutic drugs; however, the therapeutic efficacy of matrine in combination with docetaxel (DOC) for prostate cancer, or even androgen-independent prostate cancer, remains poorly understood and the underlying molecular mechanisms have not yet been clearly defined. In the present study, we investigated whether matrine combined with docetaxel can strengthen anti-cancer effect. METHODS: In this study, 7 groups were established, including (1) blank control group (cells). (2) 0.1 g/L MAT group, (3) 0.5 g/L MAT group, (4) 0.1 g/L MAT+ 50 µg/L DOC group, (5) 0.5 g/L MAT+ 50 µg/L DOC group, (6) 0.1 g/L MAT+ 100 µg/L DOC group, and (7) 0.5 g/L MAT+ 100 µg/L DOC group. MTS assay was performed to detect the anti-proliferative effects of each group on DU145 and PC-3 cells. At the same time, Transwell assay was performed to detect anti-migrative and anti-invasive effects of each group on DU145 and PC-3 cells. Biochemical colorimetric method and enzyme-linked immunosorbent assay were performed to detect the levels of LDH, IL-1ß and IL-18 of each group on DU145 and PC-3 cells. Flow cytometry (FCM) assay was used to do the apoptosis analysis on DU145 and PC-3 cells of each group. At last, Western blot analysis was performed to investigate the expression levels of caspase1 in cells of each group. Statistical analyses were performed with SPSS 17.0 (SPSS Inc, USA) software, and one-way ANOVA and Fisher's exact test was taken. RESULTS: MTS assay showed that matrine combined with docetaxel could inhibit both DU145 and PC-3 cells' proliferation in a dose- and time-dependent manner. Transwell assay showed that matrine combined with docetaxel could inhibit both DU145 and PC-3 cells' migration and invasion in a dose- and time-dependent manner. The levels of LDH, IL-1ß and IL-18 of matrine combined with docetaxel-treated DU145 and PC-3 cells were significantly increased, compared with the untreated control cells. Flow cytometry, as well as Annexin-V/PI staining, showed a significant and dose-dependent increase in the number of early, as well as late-stage apoptotic cells in both DU145 and PC-3 cells compared with the untreated control cells. Western blot analysis showed that matrine combined with docetaxel treatment led to the expression of caspase1 in both DU145 and PC-3 cells. CONCLUSION: It may be more effective to use matrine in combination with docetaxel to treat androgen-resistant prostate cancer because matrine can help to affect proliferation, migration, invasion, apoptosis, metabolism, and have anti-inflammation effect on the tumor cells.

Steroidal constituents from Helleborus thibetanus and their cytotoxicities.

Thibetanosides E-H (1-4), four new steroidal constituents including three rare sulfonates (2-4), were isolated from the roots and rhizomes of Helleborus thibetanus, together with nine known steroidal compounds (5-13). Their structures were elucidated by detailed spectroscopic analysis, including 1D and 2D NMR techniques and chemical evidence. In this study, compounds 2-13 were evaluated for their cytotoxic activities against HCT116, A549 and HepG2 tumor cell lines in vitro. Among them, compound 8 (thibetanoside C) showed cytotoxicities against A549 cells(IC50 39.6 ± 1.9 µmol·L-1) and HepG2 cells(IC50 41.5 ± 1.1 µmol·L-1), respectively. Compound 9 (23S, 24S)-24-[(O-ß-D-fucopyranosyl)oxy]-3ß, 23-dihydroxy-spirosta-5, 25(27)-diene-1ß-ylO-(4-O-acetyl- α-L-rhamnopyranosyl)-(1→2)-O-[ß-D-xylopyranosyl-(1→3)]-α-L-arabinopyranoside) showed cytotoxicity against HCT116 cells(IC50 33.6 ± 2.1 µmol·L-1).

Five new polyhydroxylated furostanol saponins from the rhizomes of Tupistra chinensis.

Five new polyhydroxylated furostanol saponins were isolated from the roots and rhizomes of Tupistra chinensis, and their structures were determined as tupistrosides J-N (1-5), together with four known furostanol saponins (6-9), on the basis of physico-chemical properties and spectral analysis. Among them, compounds 3 and 5 showed cytotoxicity against human cancer cell lines SW620 with IC50 values of 72.5 ± 2.4 and 77.3 ± 2.5 µmol·L-1, respectively. Compound 4 showed cytotoxicity against human cancer cell line HepG2 with IC50 value of 88.6 ± 2.1 µmol·L-1.

Diagnosis of central nervous system lymphoma via cerebrospinal fluid cytology: a case report.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is the most prevalent brain, spinal cord, eyes, and leptomeningeal lymphoma. It is often misdiagnosed due to an unspecific presentation or unavailable biopsy and results in a poor prognosis. Although the craniocerebral imaging examination of PCNSL has some characteristics, it is limited, and atypical cases are especially difficult to identify with intracranial tumours and other diseases. The biopsy, as the gold standard for PCNSL diagnosis, is not eligible for all patients suspected of having PCNSL. CASE PRESENTATION: This report documents a woman who presented with a three-month history of numbness and weakness in the right leg. She was treated with drugs at a local hospital for one month. She developed demyelination lesions and her symptoms were aggravated. The patient was admitted to the Department of Nerve Infection and Immunology at Tiantan Hospital. Head magnetic resonance imaging (MRI) enhanced scanning indicated significant inflammatory demyelinating disease, and lymphoma was not excluded. CSF revealed a high protein level and CSF cytology detected abnormal cells, PCNSL was eventually presumed according to positive CSF cytology and cytological detection of the cerebrospinal fluid flow. CONCLUSIONS: PCNSL is a highly invasive tumour. With the development of technologies such as cerebrospinal fluid cytology and flow cytology, CSF analysis has become one of the definite diagnosis methods, and the tumour cell finding in CSF is the only reliable basis for diagnosis. Flow cytometric analysis and gene rearrangement testing also provide objective evidence.

Steroidal Constituents from Roots and Rhizomes of Smilacina japonica.

Four new steroidal constituents (1-4) along with two known steroidal glycosides (5 and 6) were isolated from the roots and rhizomes of Smilacina japonica. Analysis of their physicochemical properties and spectroscopic profiles identified the compounds as (25S)-5α-spirostan-9(11)-en-3ß, 17α-diol (1); (25S)-5α-spirostan-9(11)-en-3ß, 12ß-diol (2); (25S)-5α-spirostan-9(11)-en-3ß, 17α-diol-3-O-ß-d-glucopyranoside (3); (25S)-5α-spirostan-9(11)-en-3ß, 17α-diol-3-O-ß-d-glucopyranosyl-(1→2)-[ß-d-glucopyranosyl-(1→3)]-ß-d-galactopyranoside (4); japonicoside B (5); and japonicoside C (6). All six compounds showed cytotoxic activity against SMMC-7712, Bel-7402, A549, H460, and K562 human cancer cells.

The sirtuin 6 prevents angiotensin II-mediated myocardial fibrosis and injury by targeting AMPK-ACE2 signaling.

Sirtuin 6 (SIRT6) is an important modulator of cardiovascular functions in health and diseases. However, the exact role of SIRT6 in heart disease is poorly defined. We hypothesized that SIRT6 is a negative regulator of angiotensin II (Ang II)-mediated myocardial remodeling, fibrosis and injury. The male Sprague-Dawley rats were randomized to Ang II (200 ng/kg/min) infusion with an osmotic minipump and pretreated with recombinant plasmids adeno-associated viral vector (AAV)-SIRT6 (pAAV-SIRT6) or pAAV-GFP for 4 weeks. Ang II triggered downregulated levels of SIRT6 and angiotensin-converting enzyme 2 (ACE2) and upregulated expression of connective tissue growth factor (CTGF) and proinflammatory chemokine fractalkine (FKN), contributing to enhanced cardiac fibrosis and ultrastructural injury. Reduced levels of phosphorylated pAMPK-α, increased myocardial hypertrophy and impaired heart dysfunction were observed in both Ang II-induced hypertensive rats and ACE2 knockout rats, characterized with increases in heart weight and left ventricular (LV) posterior wall thickness and decreases in LV ejection fraction and LV fractional shortening. More importantly, pAAV-SIRT6 treatment strikingly potentiated cardiac levels of pAMPKα and ACE2 as well as decreased levels of CTGF, FKN, TGFß1, collagen I and collagen III, resulting in alleviation of Ang II-induced pathological hypertrophy, myocardial fibrosis, cardiac dysfunction and ultrastructural injury in hypertensive rats. In conclusion, our findings confirmed cardioprotective effects of SIRT6 on pathological remodeling, fibrosis and myocardial injury through activation of AMPK-ACE2 signaling and suppression of CTGF-FKN pathway, indicating that SIRT6 functions as a partial agonist of ACE2 and targeting SIRT6 has potential therapeutic importance for cardiac fibrosis and heart disease.

Deletion of angiotensin-converting enzyme 2 exacerbates renal inflammation and injury in apolipoprotein E-deficient mice through modulation of the nephrin and TNF-alpha-TNFRSF1A signaling.

BACKGROUND: The renin-angiotensin system (RAS) has been implicated in atherosclerotic lesions and progression to chronic kidney diseases. We examined regulatory roles of angiotensin-converting enzyme 2 (ACE2) in the apolipoprotein E (ApoE) knockout (KO) kidneys. METHODS: The 3-month-old wild-type, ApoEKO, ACE2KO and ApoE/ACE2 double-KO (DKO) mice in a C57BL/6 background were used. The ApoEKO mice were randomized to daily deliver either Ang II (1.5 mg/kg) and/or human recombinant ACE2 (rhACE2; 2 mg/kg) for 2 weeks. We examined changes in pro-inflammatory cytokines, renal ultrastructure, and pathological signaling in mouse kidneys. RESULTS: Downregulation of ACE2 and nephrin levels was observed in ApoEKO kidneys. Genetic ACE2 deletion resulted in modest elevations in systolic blood pressure levels and Ang II type 1 receptor expression and reduced nephrin expression in kidneys of the ApoE/ACE2 DKO mice with a decrease in renal Ang-(1-7) levels. These changes were linked with marked increases in renal superoxide generation, NADPH oxidase (NOX) 4 and proinflammatory factors levels, including interleukin (IL)-1beta, IL-6, IL-17A, RANTES, ICAM-1, Tumor necrosis factor-alpha (TNF-alpha) and TNFRSF1A. Renal dysfunction and ultrastructure injury were aggravated in the ApoE/ACE2 DKO mice and Ang II-infused ApoEKO mice with increased plasma levels of creatinine, blood urea nitrogen and enhanced levels of Ang II in plasma and kidneys. The Ang II-mediated reductions of renal ACE2 and nephrin levels in ApoEKO mice were remarkably rescued by rhACE2 supplementation, along with augmentation of renal Ang-(1-7) levels. More importantly, rhACE2 treatment significantly reversed Ang II-induced renal inflammation, superoxide generation, kidney dysfunction and adverse renal injury in ApoEKO mice with suppression of the NOX4 and TNF-alpha-TNFRSF1A signaling. However, rhACE2 had no effect on renal NOX2 and TNFRSF1B expression and circulating lipid levels. CONCLUSIONS: ACE2 deficiency exacerbates kidney inflammation, oxidative stress and adverse renal injury in the ApoE-mutant mice through modulation of the nephrin, NOX4 and TNF-alpha-TNFRSF1A signaling. While rhACE2 supplementation alleviates inflammation, renal dysfunction and glomerulus injury in the ApoE-mutant mice associated with upregulations of Ang-(1-7) levels and nephrin expression and suppression of the TNF-alpha-TNFRSF1A signaling. Strategies aimed at enhancing the ACE2/Ang-(1-7) actions may have important therapeutic potential for atherosclerotic renal injury and kidney diseases.

The relationship between XRCC1 and XRCC3 gene polymorphisms and lung cancer risk in northeastern Chinese.

BACKGROUND: The prevalence of lung cancer in China will be the world's highest if allowed to proceed uncurbed. To unravel its genetic underpinnings, we sought to investigate the association of three well-characterized nonsynonymous polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) and XRCC3 (Thr241Met) genes with lung cancer risk in northeastern Chinese. METHODOLOGY/PRINCIPAL FINDINGS: This study was hospital-based in design, encompassing 684 patients with lung cancer and 604 cancer-free controls. Genotyping was performed using the PCR-LDR (ligase detection reactions) method. Data were analyzed by R language and multifactor dimensionality reduction (MDR) software. Single-locus analysis identified significance in genotype distributions of polymorphism Arg194Trp (P = 0.002) and Arg399Gln (P = 0.017), and in allele distributions of Thr241Met (P = 0.005). Carriers of 399Gln/Gln genotype conferred a 147% increased risk relative to the non-carriers (odds ratio (OR): 2.47; 95% confidence interval (95% CI): 1.48-4.13; P<0.001). For Thr241Met, significance persisted under allelic (OR = 1.63; 95% CI: 1.14-2.33; P = 0.005), additive (OR = 1.64; 95% CI: 1.16-2.32; P = 0.005) and dominant (OR = 1.67; 95% CI: 1.17-2.38; P = 0.004) models. However, common allele combinations were comparable in frequency between patients and controls. In interaction analysis, the overall best MDR model included Arg399Gln and Thr241Met polymorphisms, with a maximal testing accuracy of 63.18% and a maximal cross-validation consistency of 10 out of 10 (P = 0.0175). CONCLUSIONS: Our study significantly demonstrated an independent and synergistic contribution of XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms to lung cancer susceptibility in northeastern Chinese.

ACE2 deficiency enhances angiotensin II-mediated aortic profilin-1 expression, inflammation and peroxynitrite production.

Inflammation and oxidative stress play a crucial role in angiotensin (Ang) II-mediated vascular injury. Angiotensin-converting enzyme 2 (ACE2) has recently been identified as a specific Ang II-degrading enzyme but its role in vascular biology remains elusive. We hypothesized that loss of ACE2 would facilitate Ang II-mediated vascular inflammation and peroxynitrite production. 10-week wildtype (WT, Ace2(+/y)) and ACE2 knockout (ACE2KO, Ace2(-/y)) mice received with mini-osmotic pumps with Ang II (1.5 mg.kg⁻¹.d⁻¹) or saline for 2 weeks. Aortic ACE2 protein was obviously reduced in WT mice in response to Ang II related to increases in profilin-1 protein and plasma levels of Ang II and Ang-(1-7). Loss of ACE2 resulted in greater increases in Ang II-induced mRNA expressions of inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1ß, and IL-6 without affecting tumor necrosis factor-α in aortas of ACE2KO mice. Furthermore, ACE2 deficiency led to greater increases in Ang II-mediated profilin-1 expression, NADPH oxidase activity, and superoxide and peroxynitrite production in the aortas of ACE2KO mice associated with enhanced phosphorylated levels of Akt, p70S6 kinase, extracellular signal-regulated kinases (ERK1/2) and endothelial nitric oxide synthase (eNOS). Interestingly, daily treatment with AT1 receptor blocker irbesartan (50 mg/kg) significantly prevented Ang II-mediated aortic profilin-1 expression, inflammation, and peroxynitrite production in WT mice with enhanced ACE2 levels and the suppression of the Akt-ERK-eNOS signaling pathways. Our findings reveal that ACE2 deficiency worsens Ang II-mediated aortic inflammation and peroxynitrite production associated with the augmentation of profilin-1 expression and the activation of the Akt-ERK-eNOS signaling, suggesting potential therapeutic approaches by enhancing ACE2 action for patients with vascular diseases.

[Evaluation of the bleb morphology and the function of post filtration surgery using slit-lamp adapted optical coherence tomography and ultrasound biomicroscopy in glaucoma patients].

OBJECTIVE: To analyze the morphology and the function of subconjunctival filtering bleb in patients with glaucoma by slit-lamp adapted optical coherence tomography (SL-OCT) and ultrasound biomicroscopy (UBM). METHODS: This retrospective study comprised 53 patients with glaucoma filtering surgery from 2002 to 2006. The post-operation blebs in 69 eyes of 53 patients were scanned by a SL-OCT or UBM and categorized by the reference of intrableb morphology. The function of post operation bleb was clarified using Singh's or Yamamoto's criterion. The results of SL-OCT scanning were compared with those of UBM. RESULTS: This is a comparative study. The blebs were classified into four categories according to the images of filtering blebs' by SL-OCT or UBM. SL-OCT had 92.7% (38/41 eyes) sensitivity in predicting a functioning bleb by Singh's standard and 83.3% (20/24 eyes) specificity in predicting a nonfunctioning bleb, whereas, UBM had 66.7% (30/45 eyes) and 75.0% (18/24 eyes) by Yamamoto's criterion, respectively. The sensitivity in predicting a functioning bleb in the SL-OCT group was significantly (P = 0.003, Fisher exact test) different from the UBM group. CONCLUSIONS: Our results suggest that SL-OCT scanning has more sensitivity and specificity than UBM in evaluating the function of filtering bleb. The close relationship between the function and the morphological classification provides an important objective basis in evaluating the outcome of antiglaucomatous surgery.

Evaluating subconjunctival bleb function after trabeculectomy using slit-lamp optical coherence tomography and ultrasound biomicroscopy.

BACKGROUND: The existing classifications for evaluating glaucoma filtering blebs rely mostly on external bleb characteristics and the postoperative control of intraocular pressure (IOP). Internal bleb structures are not carefully observed. This study aimed to analyze and compare glaucoma filtering bleb morphology using slit-lamp-adapted optical coherence tomography (SL-OCT) and ultrasound biomicroscopy (UBM), and to classify blebs according to results and intraocular pressure. METHODS: We followed 29 eyes of 21 male patients and 40 eyes of 32 female patients who underwent glaucoma filtering surgery in Sixth People's Hospital of Shanghai, between 2002 and 2006. The blebs were imaged using SL-OCT and UBM and classified according to the intrableb morphology and control of IOP after surgery. A Fisher's exact test was used to compare the sensitivity for predicting a functioning bleb differed significantly between SL-OCT and UBM. A Fisher's exact test was also used for morphological analysis of the trabeculectomy blebs based on SL-OCT. RESULTS: In the 69 eyes, there were 45 (65.2%) functioning blebs and 24 (34.8%) non-functioning blebs. We classified the blebs into four categories on the basis of SL-OCT images: diffuse, cystic, encapsulated and flat. Diffuse and cystic blebs were typically functional, whereas the other two types were always non-functional. The sensitivity of SL-OCT for predicting a functioning bleb was 92.7% (38/41 eyes) and specificity of predicting a non-functioning bleb was 83.3% (20/24 eyes). By contrast, sensitivity of UBM was 66.7% (30/45 eyes) and specificity was 75.0% (18/24 eyes). The sensitivity for predicting a functioning bleb differed significantly between the two techniques (P = 0.003). CONCLUSIONS: SL-OCT provides high-axial-resolution images of anterior segment structures. The non-contact approach of SL-OCT enables visualization of intrableb structures at any time after surgery. SL-OCT has greater sensitivity and specificity than UBM in evaluating filtering bleb function. The morphological classification supported the assessment of bleb function and could provide objective data for evaluating the outcome of antiglaucoma surgery or the need for a second procedure.

Expression of ciliary neurotrophic factor after induction of ocular hypertension in the retina of rats.

BACKGROUND: Glaucoma is mainly characterized by the loss of retinal ganglion cells. Ciliary neurotrophic factor (CNTF) is believed to stimulate the regeneration of axons of retinal ganglion cells. The objective of our study was to detect the expression of CNTF in the retina of a rat glaucoma model with increased intraocular pressure (IOP). METHODS: The rat glaucoma model was set up by electrocoagulating at least three episcleral and limbal veins. The location and the expression level of CNTF were detected at 1, 3, 7, 14, and 28 days post-surgery by immunohistochemistry, semiquantitative reverse-transcription polymerase chain reaction (RT-PCR), and Western blot analysis. RESULTS: The rat glaucoma model with chronic, moderately elevated IOP was successfully produced. A minimum expression of CNTF was found in the ganglion cell layer of the retinas of the control group, and temporally increased expression and intensity of CNTF were found in the experimental retinas. CONCLUSION: The expression of endogenous CNTF in the rat retina was found altered after the induction of ocular hypertension.