重型颅脑损伤持续颅内压,脑灌注压监护的临床研究

对５０例重型颅脑损伤患者及５０例伤情与诊断和手术方式基本相似的另一组患者进行颅人压与脑灌注压连续监测对比研究。结果表明，监护组除８例ＩＣＰ压力＜２．００ｋＰａ，ＣＰＰ＞９．３３ｋＰａ外，余４２例均有不同程度ＩＣＰ增高与ＣＰＰ降低。     

High throughput image cytometry micronucleus assay to investigate the presence or absence of mutagenic effects of cold physical plasma

Promising cold physical plasma sources have been developed in the field of plasma medicine. An important prerequisite to their clinical use is lack of genotoxic effects in cells. During optimization of one or even different plasma sources for a specific application, large numbers of samples need to be analyzed. There are soft and easy‐to‐assess markers for genotoxic stress such as phosphorylation of histone H2AX (γH2AX) but only few tests are accredited by the OECD with regard to mutagenicity detection. The micronucleus (MN) assay is among them but often requires manual counting of many thousands of cells per sample under the microscope. A high‐throughput MN assay is presented using image flow cytometry and image analysis software. A human lymphocyte cell line was treated with plasma generated with ten different feed gas conditions corresponding to distinct reactive species patterns that were investigated for their genotoxic potential. Several millions of cells were automatically analyzed by a MN quantification strategy outlined in detail in this work. Our data demonstrates the absence of newly formed MN in any feed gas condition using the atmospheric pressure plasma jet kINPen. As positive control, ionizing radiation gave a significant 5‐fold increase in micronucleus frequency. Thus, this assay is suitable to assess the genotoxic potential in large sample sets of cells exposed chemical or physical agents including plasmas in an efficient, reliable, and semiautomated manner. Environ. Mol. Mutagen. 59:268–277, 2018. © 2018 Wiley Periodicals, Inc.     

The zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic beta cells and intestinal endocrine cells

The pancreatic and intestinal primordia contain epithelial progenitor cells that generate many cell types. During development, specific programs of gene expression restrict the developmental potential of such progenitors and promote their differentiation. The Insm1 (insulinoma-associated 1, IA-1) gene encodes a Zinc-finger factor that was discovered in an insulinoma cDNA library. We show that pancreatic and intestinal endocrine cells express Insm1 and require Insm1 for their development. In the pancreas of Insm1 mutant mice, endocrine precursors are formed, but only few insulin-positive beta cells are generated. Instead, endocrine precursor cells accumulate that express none of the pancreatic hormones. A similar change is observed in the development of intestine, where endocrine precursor cells are formed but do not differentiate correctly. A hallmark of endocrine cell differentiation is the accumulation of proteins that participate in secretion and vesicle transport, and we find many of the corresponding genes to be down-regulated in Insm1 mutant mice. Insm1 thus controls a gene expression program that comprises hormones and proteins of the secretory machinery. Our genetic analysis has revealed a key role of Insm1 in differentiation of pancreatic and intestinal endocrine cells.     

Molecular mechanisms of breast cancer metastases to bone

Bone metastases lead to hypercalcemia, bone pain, fractures, and nerve compression. They cause increased morbidity and mortality in patients with advanced breast cancer. Animal models reproduce many of the features seen in patients with breast cancer and permit identification of tumor- and bone-derived factors important in skeletal metastasis. These factors provide novel targets for therapeutic interventions. Specific tumor-bone molecular interactions mediated by these factors drive a vicious cycle that perpetuates skeletal metastases. In breast cancer, osteolytic metastases are most common, but mixed and osteoblastic metastases occur in a significant number of patients. Parathyroid hormone-related protein is a common osteolytic factor, and vascular endothelial growth factor and interleukins 8 and 11 also contribute. Osteoblastic metastases can be caused by tumor-secreted endothelin-1 (ET-1), but there are a variety of other potential osteoblastic factors. Stimulation of osteoblasts can paradoxically increase osteoclast function, as bone-synthesizing osteoblasts are the main regulators of bone-destroying osteoclasts. Coexpression of osteolytic and osteoblastic factors can thus produce mixed metastases or increased osteolysis. Cancer treatments, especially sex steroid deprivation therapies, stimulate bone loss. Bone resorption results in the release of bone growth factors, which may unintentionally increase the formation of bone metastases by activating the vicious cycle. Clinically approved bisphosphonates prevent bone resorption and reduce the release of bone growth factors. Parathyroid hormone-related protein-neutralizing antibody, inhibitors of the receptor activator of nuclear factor-kB ligand pathway, and ET-1 receptor antagonists are in clinical trials. These agents act on bone cells rather than tumor cells. Recent experiments identify new potential targets for prevention of bone metastases.     

Blocking the formation of radiation–induced breast cancer stem cells

The goal of adjuvant (post-surgery) radiation therapy (RT) for breast cancer (BC) is to eliminate residual cancer cells, leading to better local tumor control and thus improving patient survival. However, radioresistance increases the risk of tumor recurrence and negatively affects survival. Recent evidence shows that breast cancer stem cells (BCSCs) are radiation-resistant and that relatively differentiated BC cells can be reprogrammed into induced BCSCs (iBCSCs) via radiation-induced re-expression of the stemness genes. Here we show that in irradiation (IR)-treated mice bearing syngeneic mammary tumors, IR-induced stemness correlated with increased spontaneous lung metastasis (51.7%). However, IR-induced stemness was blocked by targeting the NF-κB- stemness gene pathway with disulfiram (DSF)and Copper (Cu²⁺). DSF is an inhibitor of aldehyde dehydrogenase (ALDH) and an FDA-approved drug for treating alcoholism. DSF binds to Cu²⁺ to form DSF-Cu complexes (DSF/Cu), which act as a potent apoptosis inducer and an effective proteasome inhibitor, which, in turn, inhibits NF-κB activation. Treatment of mice with RT and DSF significantly inhibited mammary primary tumor growth (79.4%) and spontaneous lung metastasis (89.6%) compared to vehicle treated mice. This anti-tumor efficacy was associated with decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical investigation of RT and DSF as a novel combinatorial treatment for breast cancer.     

Stimulating effects of <Emphasis Type="Italic">Grifola frondosa</Emphasis> (Maitake) on human osteoblastic cell cultures

The effect of Grifola frondosa (GF) total water extract on two osteoblastic cell cultures (HOS58 and SaOS-2) was investigated to determine if this edible medicinal mushroom has osteoinductive properties. The activity of alkaline phosphate and mineralization were used as indicators for the vitality and maturation of bone cells. The cultivation of human osteosarcoma cells HOS58 for 5 days in the presence of an aqueous extract of G. frondosa (0.8–120 μg/ml) resulted in a significant elevation of alkaline phosphatase activity of the cells in comparison to untreated cells. SaOS-2 cells, incubated with GF (20 μg/ml) for 21 days, showed a nearly two times higher mineralization than cells cultured with the positive control β-glycerophosphate. The obtained results clearly indicate the activity of GF extract as a bone-inducing agent. Therefore, GF could be applied supportively in case of diseases accompanied with bone disorder, like osteoporosis, osteopenia and late complication of diabetes.     

用高效液相色谱法测定莫雷西嗪及其代谢产物在血及尿中的浓度

应用高效液相色谱法测定人体血浆、尿液中莫雷西嗪及其亚砜、砜代谢产物的生物浓度，本法选用国产硅胶ＹＷＧ－Ｃ１８为固定要，甲醇、乙腈、水、三乙胺为流动相，检测波长２５４ｎｍ．采用离子对一步提取法提取样品，莫雷西嗪，莫雷西嗪亚砜和莫雷西嗪亚砜和莫西嗪的最低血浆检测浓度为３０、８、１０ｎｍ／ｇｍｌ，绝对回收率大于８５％。     

Expression of monocyte chemoattractant protein-1 cDNA in vascular smooth muscle cells: induction of the synthetic phenotype: a possible clue to SMC differentiation in the process of atherogenesis.

In the arterial wall, smooth muscle cells (SMC) normally exist in a quiescent, differentiated state, representing the contractile phenotype. During the development of atherosclerosis SMC change towards the synthetic phenotype going along with proliferation, chemotactic response and increased monocyte binding. Expression of monocyte chemoattractant protein-1 (MCP-1), a potent chemoattractant for monocytes, has been shown to be among the earliest events in atherogenesis. We investigated the effect of MCP-1 on differentiated and dedifferentiated SMC. Differentiation of SMC was induced using Matrigel as a matrix for cultivation. MCP-1 was expressed in SMC by means of a recombinant adenovirus. Expression of MCP-1 led to dedifferentiation of SMC as demonstrated by induction of cytokeratin 18, a marker for the synthetic phenotype. Concurrently, migration was only detectable in MCP-1 expressing cells, whereas SMC infected with a control virus, coding for the nuclear-targeted lacZ gene showed no migration. The expression of intercellular adhesion molecule-1 (ICAM-1) could be demonstrated in synthetic SMC and was induced after infection of differentiated cells with recombinant adenovirus, coding for MCP-1 (AdMCP-1). Expression of ICAM-1 was associated with a tenfold higher monocyte binding compared to lacZ infected cells. Our data suggest that MCP-1 plays an important role for SMC in the functional switch from the contractile to the synthetic phenotype in the course of atherogenesis.     

Breast Cancer Metastasis to Bone: Mechanisms of Osteolysis and Implications for Therapy

The most common skeletal complication of breast cancer is osteolytic bone metastasis. Bone metastases are present in 80% of patients with advanced disease and cause significant morbidity. They are most often osteolytic, but can be osteoblastic or mixed. Tumor cells, osteoblasts, osteoclasts and bone matrix are the four components of a vicious cycle necessary for the initiation and development of bone metastases. Tumor cell gene expression is modified by interaction with bone-derived factors. For example, parathyroid hormone related protein (PTHrP), a tumor cell factor, is upregulated by bone-derived transforming growth factor β (TGFβ). Tumor cell factors, in turn, act upon bone cells to cause dysregulated bone destruction and formation. PTHrP increases osteoblast expression of RANK (receptor activator of NFκB) ligand which, in turn, activates osteoclasts. PTHrP-independent osteolytic factors, such as interleukin [IL]-11 and IL-8, also contribute to the vicious cycle. Other tumor-bone interactions, such as stimulation of tumor-homing through the CXCR4 chemokine receptor by its bone-derived ligand stromal-derived factor-1 (SDF-1), may be responsible for the site-specific predilection of breast cancer for bone. These factors and their roles in fueling the vicious cycle may identify novel targets for therapies to prevent metastasis.