Protein disulfide isomerase blocks the interaction of LC3II-PHB2 and promotes mTOR signaling to regulate autophagy and radio/chemo-sensitivity.

Protein disulfide isomerase (PDI) is an endoplasmic reticulum (ER) enzyme that mediates the formation of disulfide bonds, and is also a therapeutic target for cancer treatment. Our previous studies found that PDI mediates apoptotic signaling by inducing mitochondrial dysfunction. Considering that mitochondrial dysfunction is a major contributor to autophagy, how PDI regulates autophagy remains unclear. Here, we provide evidence that high expression of PDI in colorectal cancer tumors significantly increases the risk of metastasis and poor prognosis of cancer patients. PDI inhibits radio/chemo-induced cell death by regulating autophagy signaling. Mechanistically, the combination of PDI and GRP78 was enhanced after ER stress, which inhibits the degradation of AKT by GRP78, and eventually activates the mTOR pathway to inhibit autophagy initiation. In parallel, PDI can directly interact with the mitophagy receptor PHB2 in mitochondrial, then competitively blocks the binding of LC3II and PHB2 and inhibits the mitophagy signaling. Collectively, our results identify that PDI can reduce radio/chemo-sensitivity by regulating autophagy, which could be served as a potential target for radio/chemo-therapy.

Application of PET/CT in Preoperative Evaluation and Diagnosis of Gastric Cancer.

The aim study to study the significance of pet clinical examination image technology for early gastric mucosal adenocarcinoma, improve the accuracy and accuracy of image examination results of gastric cancer, and provide important reference significance and value for early treatment. Study methods, we used the experimental method of clinical medicine to obtain some reference data through the intervention of different image examinations on experimental patients of different groups and stages, These data show that the use of PET-CT imaging can improve the one-year survival rate of patients and reduce the one-year recurrence rate. Lymphatic metastasis rate and hematogenous metastasis rate, so as to highlight the advantages of PET-CT imaging.

Research on Diagnosis Architecture of Cardiovascular Diseases Based on Multimedical Images.

OBJECTIVE: To study the effect of a multi-image source 3D modeling imaging examination system on the diagnosis of cardiovascular diseases in cardiac surgery. METHODS: The data of 680 confirmed patients and 1590 suspected patients in the cardiac surgery department of all hospitals of a large chain hospital management group were selected. All patients gave the examination results of multiple image sources and independent examination results of multiple image sources, respectively, their examination sensitivity, specificity, and reliability were compared, and the treatment efficiency and nursing satisfaction of the virtual reference group were deduced in MATLAB. Perform the bivariate t-test and comparative statistics in SPSS. RESULTS: The multi-image source 3D modeling examination system had higher examination sensitivity, specificity, and reliability and higher examination sensitivity in the early stage of the disease. It was deduced that the clinical efficiency and nursing satisfaction based on the examination results were significantly improved (t < 10.000, p < 0.01). CONCLUSION: The multi-image source 3D modeling imaging examination system is suitable for the diagnosis of cardiovascular diseases in cardiac surgery.

CBX1 is a direct target of miR-205-5p and contributes to the progression of pituitary tumor.

MicroRNAs (miRs) are crucial regulators for tumorigenesis through negatively regulating their target genes expression in the manner of 3'-untranslated region (3'-UTR) binding. MiR-205-5p has been reported to function as a tumor suppressor in several cancer types. The aim of this study was to investigate the role of miR-205-5p/chromobox homolog 1 (CBX1) axis in human pituitary tumors. The expression of miR-205-5p was firstly examined by quantitative real-time PCR and the results revealed that miR-205-5p expression was declined in pituitary cell lines compared with normal cell line. Overexpression of miR-205-5p effectively decreased cell proliferation and cell migration. Based on the results of bioinformatic analysis, luciferase reporter assay, and western blot, we identified CBX1 as a direct target of miR-205-5p. Notably, overexpression of CBX1 promoted cell proliferation and migration. The effects of miR-205-5p overexpression on cell proliferation and migration can be reversed by CBX1 overexpression. Based on these findings, we deducted that miR-205-5p inhibits the cell proliferation and migration through directly targeting CBX1.

Cerebral Edema in Chronic Mountain Sickness: a New Finding.

We observed patients with chronic mountain sickness (CMS) in our clinic who developed progressive neurological deterioration (encephalopathy) and we wished to investigate this. We studied nine such CMS patients, and compared them to 21 CMS patients without encephalopathy, and to 15 healthy control subjects without CMS. All 45 subjects lived permanently at 3200-4000 m. Measurements at 2260 m included CMS symptom score, multi-slice CT, perfusion CT, pulse oximetry (SpO2%), and hemoglobin concentration (Hb). One patient had MRI imaging but not CT; 5 had CSF pressure measurements. CMS subjects had lower SpO2, higher Hb, higher brain blood density, lower mean cerebral blood flow (CBF), and significant cerebral circulatory delay compared to controls. The nine CMS subjects with neurological deterioration showed diffuse cerebral edema on imaging and more deranged cerebral hemodynamics. CSF pressure was elevated in those with edema. We conclude that cerebral edema, a previously unrecognized complication, may develop in CMS patients and cause encephalopathy. Contributing factors appear to be exaggerated polycythemia and hypoxemia, and lower and sluggish CBF compared to CMS patients without cerebral edema; but what triggers this complication is unknown. Recognition and treatment of this serious complication will help reduce morbidity and mortality from CMS.

Valproic acid causes radiosensitivity of breast cancer cells via disrupting the DNA repair pathway.

Valproic acid (VPA) is one of the representative compounds of histone deacetylase inhibitors (HDACis) and is used widely for the clinical treatment of epilepsy and other convulsive diseases. Current reports indicate that HDACis may also be an attractive radiosensitizer for some tumor cells; however, it is unknown whether the safe blood concentration of VPA (0.3-0.8 mM) used for the treatment of epilepsy can also induce radiosensitivity in breast cancer cells. In addition, the mechanism by which VPA may induce radiosensitivity in breast cancer cells is yet to be determined. Our results clearly indicated that VPA at a safe dose (0.5 mM) could significantly increase the radiosensitivity of MCF7 breast cancer cells and result in more accumulation of DNA double strand breaks in response to DNA damage. After VPA treatment, the frequencies of homologous recombination (HR) and non-homologous end joining (NHEJ) tested by recombination substrates, pDR-GFP and EJ5-GFP, were dramatically decreased in the cells without the change of the cell cycle profile. It was further found that VPA could inhibit the recruitment of key repair proteins to DNA break areas, such as Rad51, BRCA1, and Ku80. Thus, our results demonstrated that a safe dose of VPA causes radiosensitivity in breast cancer cells through disrupting the molecular mechanisms of both BRCA1-Rad51-mediated HR and Ku80-mediated NHEJ pathways.

p53 suppresses hyper-recombination by modulating BRCA1 function.

Both p53 and BRCA1 are tumor suppressors and are involved in a number of cellular processes including cell cycle arrest, apoptosis, transcriptional regulation, and DNA damage repair. Some studies have suggested that the association of BRCA1 and p53 is required for transcriptional regulation of genes involved in cell replication and DNA repair pathways. However, the relationship between the two proteins in molecular mechanisms of DNA repair is still not clear. Therefore, we sought to determine whether there is a functional link between p53 and BRCA1 in DNA repair. Firstly, using a plasmid recombination substrate, pDR-GFP, integrated into the genome of breast cancer cell line MCF7, we have demonstrated that p53 suppressed Rad51-mediated hyper-recombinational repair by two independent cell models of HPV-E6 induced p53 inactivation and p53 knockdown assay. Our study further indicated that p53 mediated homologous recombination (HR) through inhibiting BRCA1 over-function via mechanism of transcription regulation in response to DNA repair. Since it was found p53 and BRCA1 existed in a protein complex, indicating both proteins may be associated at post-transcriptional level. Moreover, defective p53-induced hyper-recombination was associated with cell radioresistance and chromosomal stability, strongly supporting the involvement of p53 in the inhibition of hyper-recombination, which led to genetic stability and cellular function in response to DNA damage. In addition, it was found that p53 loss rescued BRCA1 deficiency via recovering HR and chromosomal stability, suggesting that p53 is also involved in the HR-inhibition independently of BRCA1. Thus, our data indicated that p53 was involved in inhibiting recombination by both BRCA1-dependent and -independent mechanisms, and there is a functional link between p53-suppression and BRCA1-promotion in regulation of HR activity at transcription level and possible post-transcription level.

[Comparative study on functional characters of MCF7 and HCC1937 cell lines in response to DNA damage].

OBJECTIVE: The functional characters of MCF7 and HCC1937 cell lines were compared through the activity of BRCA1 and p53 following DNA damage in order to provide more research evidence for the related studies in both breast cancer cell lines. METHODS: The protein level of BRCA1 and p53 in two breast cancer cell lines and the protein level of BRCA1 in MCF7, HCC1937 and HCC1937 wtBRCA1 breast cancer cell lines treated with 10Gy after 1 h, 4 h or 8 h were detected by western blotting analysis. The distribution and foci formation of BRCA1 in the cells were observed through immunostaining assay and the percentage of BRCA1 or Rad51 foci formation after ionizing radiation was calculated. Cell cycle profiling was analyzed using flow cytometry. RESULTS: Most of BRCA1 and p53 localized in nucleus, and both proteins responded to DNA damage in MCF7 cells. In MCF7 cells,BRCA1 and Rad51 foci formation respectively increased to (59.40 ± 3.66)% from (11.80 ± 3.51)% (t = 16.26, P < 0.05) and (73.90 ± 8.66) % from (16.70 ± 3.76) % (t = 10.49, P < 0.05) after 10 Gy 8 h ; p53 and p21 protein level was further separately induced and enhanced to (82.54 ± 1.04) from (23.75 ± 0.51) (t = 87.90, P < 0.05) and (90.95 ± 1.13) from (50.19 ± 0.89) ( t = 49.11, P < 0.05) after 10 Gy 8 h; and the cells were accumulated in G1 phase. In contrast to MCF7, in HCC1937 cell line, both of BRCA1 and p53 were defective in nucleus since both proteins were mutated; in response to DNA damage, BRCA1 foci formation was not found, p53 and p21 was not induced; there was no cell accumulation in both of G1-S and G2-M phases. However, after complementation of wild-type BRCA1 in HCC1937 cells, DNA damage-induced Rad51 foci formation increased to (61.70 ± 4.03) % from (6.22 ± 2.27) % (t = 20.78, P < 0.05) and accumulation of cells in G2-M phase was also restored after 10 Gy 8h , which was similar to that of in MCF7 cells. CONCLUSIONS: We have identified that BRCA1 and p53 have dramatically different functions in MCF7 and HCC1937 cell lines in response to DNA damage.

Changes of cardiac structure and function in pediatric patients with high altitude pulmonary hypertension in Tibet.

This study was performed to evaluate the structural and functional cardiac changes in pediatric high altitude pulmonary hypertension (HAPH) using magnetic resonance imaging (MRI) and Doppler echocardiography (Echo). Ten patients with infantile HAPH (aged 12 to 24 months) and eight healthy age-matched children (control group) underwent MRI and Echo studies. All participants were born and living in the Qinghai-Tibetan Plateau (3600 to 4600 m). The studies were performed at the Children's Hospital located in Xining, Qinghai (2260 m). The right and left ventricular end-systolic (RVEST and LVEST, respectively) and end-diastolic (RVEDT and LVEDT, respectively) wall thicknesses were calculated directly from the MRI scans. The mean pulmonary arterial pressure (mPAP) was measured using Echo. RVEST was significantly higher in the HAPH group than in the control group (6.8 +/- 0.6 and 3.7 +/- 0.5 mm, respectively; p < 0.001). RVEDT was significantly higher in the HAPH patients when compared with the control group (4.9 +/- 1.1 and 2.1 +/- 0.3 mm, respectively; p < 0.05). Mean PAP in the HAPH group was significantly higher than in the control group (66.8 +/- 6.7 and 33.8 +/- 3.6 mmHg, respectively; p < 0.001) and was positively correlated with RVEDT (r(2) = 0.562, p < 0.001). Right ventricular ejection fraction was significantly lower in the HAPH group when compared with the control group (29.8 +/- 11.8 and 55.5 +/- 9.9%, respectively; p < 0.001); however, left ventricular ejection fraction was similar in both groups. These results indicate that hypoxia-induced infantile HAPH leads to right ventricular hypertrophy in these patients. These structural cardiac changes may lead to right ventricular dysfunction and right heart failure; however, left ventricular function is preserved.