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Synthetic lethal short hairpin RNA screening reveals that ring finger protein 183 confers resistance to trametinib in colorectal cancer cells

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Chinese Journal of Cancer 2017年第12期36卷 726-736页

作者： Rong Geng Xin Tan Zhixiang Zuo Jiangxue Wu Zhizhong Pan Wei Shi Ranyi Liu Chen Yao Gaoyuan Wang Jiaxin Lin Lin Qiu Wenlin Huang Shuai Chen State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer MedicineSun Yat-sen University Cancer Center651 Dongfeng Road EastGuangzhou 510507GuangdongP.R.China Department of Experimental Research Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China Department of Colorectal Surgery Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China Guangdong Esophageal Cancer Institute Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China Guangdong Provincial Key Laboratory of Tumor.Targeted Drugs and Guangzhou Enterprise Key Laboratory of Gene Medicine Guangzhou Doublle Bioproducts Co.Ltd.Guangzhou 510507GuangdongP.R.China

Background: The mitogen-activated extracellular signal-regulated kinase 1/2(MEK1/2) inhibitor trametinib has shown promising therapeutic effects on melanoma, but its efficacy on colorectal cancer(CRC) is limited. Synthetic lethality arises with a combination of two or more separate gene mutations that causes cell death, whereas individual mutations keep cells alive. This study aimed to identify the genes responsible for resistance to trametinib in CRC cells,using a synthetic lethal short hairpin RNA(shRNA) screening approach.Methods: We infected HT29 cells with a pooled lentiviral shRNA library and applied next-generation sequencing to identify shRNAs with reduced abundance after 8-day treatment of 20 nmol/L trametinib. HCT116 and HT29 cells were used in validation studies. Stable ring finger protein 183(RNF183)-overexpressing cell lines were generated by pcDNA4-myc/his-RNF183 transfection. Stable RNF 183-knockdown cell lines were generated by infection of lentiviruses that express RNF183 shRNA, and small interference RNA(siRNA) was used to knock down RNF183 transiently.Quantitative real-time PCR was used to determine the mRNA expression. Western blotting, immunohistochemical analysis, and enzyme-linked immunosorbent assay(ELISA) were used to evaluate the protein abundance. MTT assay,colony formation assay, and subcutaneous xenograft tumor growth model were used to evaluate cell proliferation.Results: In the primary screening, we found that the abundance of RNF183 shRNA was markedly reduced after treatment with trametinib. Trametinib induced the expression of RNF183, which conferred resistance to drug-induced cell growth repression and apoptotic and non-apoptotic cell deaths. Moreover, interleukin-8(IL-8) was a downstream gene of RNF183 and was required for the function of RNF183 in facilitating cell growth. Additionally, elevated RNF183 expression partly reduced the inhibitory effect of trametinib on IL-8 expression. Finally, xenograft tumor model showed the synergism of RNF183 knockdown and trametinib in repres

关键词： Synthetic lethal Colorectal cancer Ring finger protein 183 Mitogen-activated extracellular signalregulated kinase 1/2 Trametinib

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lethal Factors of Diseases and Protective Countermeasures of Wild and Penned Giant Pandas

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Journal of Forestry Research 1998年第2期9卷 77-80页

作者：邹兴淮王爱民曾鲁军何光昕吴孔菊陈玉村翁妮娜

Statistical analysis of certain major diseases Jethal to the animal was carried out through on-spot investigations and consultations to related documentary materials. The resufts show that the first serious lethal factor is digestive system diseases. Next comes malnutrition and organic exhaustion. In order of decremental percentages, other diseases are roundworm disease, epilepsy, toxicosis, pneumonia, tumor, pericarditis, etc. In relation to 54 wild giant pandas taken for statistics, the death of malnutrition, organic exhaustion caused accounts for 42.78%. In order of reducing percentages, other diseases are roundworm disease, toxicosis. epilepsy, etc..Based on the statistics of 22 penned giant pandas, the death out of the digestive system diseases comes first,accounting for 63.64%. Other diseases nil order of decremental proportion are epilepsy, organic exhaustion, etc.,Gastroenteric hemorrhage is one of the highest mortality in digestive system diseases. the next comes orderly roundworm disease, hemorrhage, gatroenteritis and intestinal obstruction. The mortality of the sub-adults is the highest, accounting for 64.29%, or 2.6 times as that of the adults, or 7 times as that of the aged giant pandas.Some prevention measures of diseases for Giant pandas were also discussed in this paper.

关键词： Giant pandas Disease lethal factors

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Africa Development Indicators 2010: Silent And lethal: How Quiet Corruption Undermines Africa's Development Efforts (African Development Indicators) Pap/Cdr

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2010年

作者： World Bank

ISBN: (纸本)9780821382028

Reliable quantitative data are essential for understanding economic, social and governance development because it provides evidence, and evidence are crucial to set policies, monitor progress and evaluate results. Africa Development Indicators 2010 (ADI) provides the most detailed collection of data on Africa available. It puts together data from different sources, and is an essential tool for policy makers, researchers, and other people interested in Africa. The opening articles of the ADI 2010 print edition focus on behaviors that are difficult to observe and quantify, but whose impact on service delivery and regulation has adverse long-term effects on households. The term "quiet corruption" is introduced to indicate various types of malpractice of frontline providers (teachers, doctors, and other government officials at the front lines of service provision) that do not involve monetary exchange. The prevalence of quiet corruption and its long-term consequences might be even more harmful for developing countries, and for the poor in particular who are more exposed to adverse shocks to their income and are more reliant on government services to satisfy their most basic needs

关键词： quiet corruption unde lethal silent development indicators africa

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The expression of human mutant DHFR gene in murine bone marrow and long-term protection of murine hemacytogenesic function from lethal doses of MTX

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中国实验血液学杂志 1997年第3期5卷 329-330页

作者： Wen-Qing Zhang, Guang-Wei Xu, Zuo-Liang Xu Beijing Instiiute for Cancer Research, School of Oncology, Beijing Medical University, Beijing100034

Chemotherapy is one of the curative treatmentmodality for several types of tumors. However, thedosage of antitumor drugs was limited by cytotoxicityof drugs to normal tissues, especially for bone marrow(myelosuppression). Drug resistantce gene (hMDRI,hDHFR etc.) is expressed in many normal tissues. Itsover-expression in tumor cells give rise to the tumorresistant to many drugs. But, if we transfer the drugresistance gene into the normal hematopoietic stemcell (HSC), the expression of the foreign gene

关键词： lethal curative antitumor doses hematopoietic mutant murine mucosa cytotoxicity markedly

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lethal Developmental Defects: An Overview

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Open Journal of Obstetrics and Gynecology 2014年第16期4卷 1006-1036页

作者： Ashutosh Halder Department of Reproductive Biology All India Institute of Medical Sciences New Delhi India

About 3% of all conceptions are associated with major congenital malformations, many of them are lethal developmental defect and genetic in origin or teratogenic (adverse effects of the environment during gametogenesis or early embryogenesis). Genetics with or without adverse environment has role in virtually every developmental defect/malformation disorders in causation, predisposition, susceptibility & modulation of disease. Advances in genetics, introduction of triple marker screening, routine obstetric ultrasound examination into obstetric practice & accesses to prenatal diagnosis helped in secondary prevention (early detection & termination) of lethal developmental defects. Ultrasound detection of fetal developmental defects/malformation is common now and often decision on pregnancy solely based on ultrasonic morphological description. This practice leads to difficulty in providing accurate counseling as well as preventing disorder in subsequent pregnancy, in particular early. Hence an understanding of reproductive genetics of major developmental disorders is important for today’s perinatal care specialists. This overview will outline the various lethal developmental defects observed in an advanced reproductive genetics set up and various approaches adopted to derive diagnosis. Detailed assessment of fetus after termination of pregnancy (spontaneous/induced) for fetal anomalies was carried out in most cases. As most cases was referred after termination in formalin routine chromosomal analysis was not possible however, in selected cases targeted FISH analysis with specific chromosomal probe was carried out to confirm clinical diagnosis. Detailed evaluation of fetus is important as this practice often helped in modification of genetic counseling, as well as course of management in the next pregnancy. No molecular diagnostic or screening work was carried out due to non availability of information and facility in past. However, this is important today as many of the lethal developmental defects are yet to be cat

关键词： lethal Developmental Defect lethal Malformation Neural Tube Defect Chromosomal Abnormality Amniotic Band Syndrome Skeletal Dysplasia Nonimmune Hydrops Fetalis

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COVID-19 Coronavirus: Is Infection along with <i>Mycoplasma</i>or Other Bacteria Linked to Progression to a lethal Outcome?

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International Journal of Clinical Medicine 2020年第5期11卷 282-302页

作者： Garth L. Nicolson Gonzalo Ferreira de Mattos

Most patients with COVID-19 disease caused by the SARS-CoV-2 virus recover from this infection, but a significant fraction progress to a fatal outcome. As with some other RNA viruses, co-infection or activation of latent bacterial infections along with pre-existing health conditions in COVID-19 disease may be important in determining a fatal disease course. Mycoplasma spp. (M. pneumonaie, M. fermentans, etc.) have been routinely found as co-infections in a wide number of clinical conditions, and in some cases this has progressed to a fatal disease. Although preliminary, Mycoplasma pneumoniae has been identified in COVID-19 disease, and the severity of some signs and symptoms in progressive COVID-19 patients could be due, in part, to Mycoplasma or other bacterial infections. Moreover, the presence of pathogenic Mycoplasma species or other pathogenic bacteria in COVID-19 disease may confer a perfect storm of cytokine and hemodynamic dysfunction, autoimmune activation, mitochondrial dysfunction and other complications that together cannot be easily corrected in patients with pre-existing health conditions. The positive responses of only some COVID-19 patients to antibiotic and anti-malaria therapy could have been the result of suppression of Mycoplasma species and other bacterial co-infections in subsets of patients. Thus it may be useful to use molecular tests to determine the presence of pathogenic Mycoplasma species and other pathogenic bacteria that are commonly found in atypical pneumonia in all hospitalized COVID-19 patients, and when positive results are obtained, these patients should treated accordingly in order to improve clinical responses and patient outcomes.

关键词： Pathogenic Mycoplasma SARS-CoV-2 Virus COVID-19 Disease Acute Respiratory Distress Syndrome Co-Infection Pneumonia lethal Infection Mitochondria Cytokines Anti-Microbial Therapy Antibiotics Anti-Malarial Therapy Virus Bacteria

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Acute Toxicity (lethal Dose 50 Calculation) of Herbal Drug Somina in Rats and Mice

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Pharmacology & Pharmacy 2015年第3期6卷 185-189页

作者： Muhammad Ahmed Department of Pharmacology and Toxicology Faculty of Pharmacy Umm Al-Qura University Makkah Kingdom of Saudi Arabia

Somina (herbal preparation) prepared by Hamdard Laboratories (Waqf) Pakistan is a mixture of five different medicinal plants, widely prescribed for the treatment of mental illness. For acute toxicity, the Karber arithmetic method for the calculation of LD50 and Hodge and Sterner toxicity scale was used. In this study, different doses (10, 100, 285, 500, 1000, 5000 and 10,000 mg/kg) of the extract was administered orally to the different groups of rats and mice. Signs of toxicity and possible death of animals were monitored for 24 hrs to calculate the median lethal dose (LD50) of somina. At the end of the study, all the animals in all the dose groups were sacrificed and the internal organ-body was compared with values from the control group. The LD50 was found to be >10,000 mg/kg body weight upon oral administration in mice and rats as no mortality was observed after single dose administration. According to Hodge and Sterner toxicity scale, the obtained value of LD 50 > 10,000 mg/kg classified the Somina as Practically non-toxic herbal medicine.

关键词： Acute Toxicity Somina Median lethal Dose (LD50) Karber Arithmetic Method for the Calculation of LD50 Hodge and Sterner Toxicity Scale

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Ethyl Methane Sulphonate (EMS) Induced Mutagenesis in Malaysian Rice (cv. MR219) for lethal Dose Determination

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American Journal of Plant Sciences 2012年第12期3卷 1661-1665页

作者： Ali Benjavad Talebi Amin Benjavad Talebi Behzad Shahrokhifar 2De- partment of Computer Sciences Faculty of Science and Information Technology National University of Malaysia (UKM) Bangi Malaysia Department of Plant Biotechnology National Institute of Genetic Engineering and Biotechnology (NIGEB) Tehran Iran Department of Weed Science Shoushtar Branch Islamic Azad University Shoushtar Iran

Chemical and physical mutagenesis has been used to increase genetic variability in crop plants. More than 430 new varieties have been derived as mutants of rice (Oryza sativa L.) via the application of different mutagenic agents. Chemical mutagens such as ethyl methane sulphonate (EMS), diepoxybutane-derived (DEB), sodium azide and irradiation (Gamma rays, X-rays and fast neutrons) have been widely used to induce a large number of functional variations in rice and others crops. Among chemical mutagens, the alkylating agent, ethyl methane sulfonate (EMS) is the most commonly used in plants as it causes a high frequency of nucleotide substitutions, as detected in different genomes. In this study, seeds of potential genotype of the popular variety, (Oryza sativa L. spp. Indica cv. MR219) were treated with EMS at concentrations of 0.25%, 0.50%, 0.75%, 1%, 1.25%, 1.5% and 2%. Sensitivity to EMS was determined by various measurements on the M1 generation. As concentration of applied EMS increased, will decrease in germination, seedling height, root length and emergence under field conditions was observed in M1 generation as compared to the non-treatment control. Plant height and root length also decreased with increases in EMS mutagenesis in an approximately linear fashion. The LD25 and LD50 values were observed based on growth reduction of seedlings after EMS treatment with 0.25% and 0.50% on the rice variety (Oryza sativa L. spp. Indica cv. MR219).

关键词： EMS lethal Dose Chemical Mutagenesis Ethyl-Methane Sulfonate Oryza Sativa Indica cv. MR219

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EXPLORATION OF THE lethal CAUSE OF GUINEA-PIG IN THE HIGH-INTENSITY SOUND FIELD

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Chinese Science Bulletin 1982年第7期27卷 771-775页

作者：沈(山豪) 陈定楚莫中廉茅宏迪钱维权黄端生郑素贤杜永义 Institute of Acoustics Academia Sinica Beijing Beijing Institute of Space Medico-Engineering Beijing Institute of Space Medico-Engineeringesearches have not yet been made on the biological effects of broad-band highintensity noise both in China and in other countries. Up to now the effects of highintensity noise on the viscera the central nervous system and the physiological functions of experimental animals and the mechanism of causing stupor and death to them

Researches have not yet been made on the biological effects of broad-band highintensity noise both in China and in other countries. Up to now, the effects of highintensity noise on the viscera, the central nervous sys... 详细信息

关键词： physiological guinea causing injured lethal organs injuries filled brown abnormal

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Obtaining the Minimum lethal Dose against <i>Fasciola hepatica in Vitro</i>Using Plant Extract Hexanes with Fasciolicide Activity and Toxicity Evaluation on CD1 Male Mice

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American Journal of Plant Sciences 2012年第7期3卷 899-903页

作者： Stephanie Ibarra-Moreno Froylan Ibarra-Velarde Jose Guillermo Avila-Acevedo Depto. De Parasitología. Facultad de Medicina Veterinaria. Y Zootecnia. UNAM. Ciudad Universitaria 04510 México D.F. México Lab. De Fitoquímica. UBIPRO. Facultad de Estudios Superiores Iztacala. UNAM. Avenida de los Barrios S/N Tlalnepantla de Baz Edo. De México.

Fascioliasis is a parasitic disease of worldwide distribution affecting mainly cattle and sheep. Its importance lies in the economic losses it produces in the livestock industry. Its control is carried out by using a chemical fasciolicide showing resistance problems and environmental contamination. Looking for an alternative control for this disease the present study was aimed at determining the hexane anti-Fasciola hepatica in the in vitro effect of some plant extracts and the minimum lethal dose of the mentioned extracts. All selected plants were tested in vitro at concentrations of 500, 250, 125 and 50 mg/L):Achilleamillefolium (plumajillo), Artemisiaabsinthium (wormwood), Artemisia mexicana (estafiate), Castelatortuousa (chaparroamargo), Chenopodiumgraveolens (epazote de zorrillo), Gymnospermaglutinosum (popote) Justicia spicigera (muicle), Limpia critridora (cedron), Lippiagraveolens (oregano), Menthapiperita (Mint), Populus alba (alamo) and Thymusvulgaris (thyme). Subsequently proceeded to perform a toxicity study with these fractions in CD1 male mice 10-13 weeks of age, forming groups of 3-5 animals they were administered a single oral dose being (5 mg/kg, 50 mg/kg, 500 mg/kg, 2500 mg/kg and 5000 mg/kg) and were kept under observation 20 days, later were sacrificed and a kidney and liver histology was performed, finding the safety of the extracts. To perform the toxicity study with these fractions, groups of five CD1 male-mice were formed, they were treated with oral doses of 5, 50, 500, 2500 and 5000 mg/kg, administered with a cannule. All mice were kept under observation for 20 days. Finally they were sacrificed to perform histology of the kidney and liver in search of possible side effects. Results show that none of the extracts exhibited that fasciolocide activity for mice CD1 even at the highest dose thereforefinding the safety of the extracts.

关键词： Fasciola hepatica Plant Extracts In Vitro Minimum lethal Dose Toxicity

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