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Journal of Intensive Medicine 2022年第4期2卷 233-240页

作者： Yonatan Perez Jian Luo Miguel Ibarra-Estrada Jie Li Stephan Ehrmann Médecine Intensive Réanimation Hôpital de HautepierreHôpitaux universitaires de StrasbourgStrasbourg 67000France Respiratory Medicine Unit and Oxford NIHR Biomedical research Centre NDM Experimental MedicineUniversity of OxfordOxford OX39DUUK Unidad de Terapia Intensiva Hospital Civil Fray Antonio Alcalde.Universidad de Guadalajara.GuadalajaraJalisco 44280Mexico Department of Cardiopulmonary Sciences Division of Respiratory CareRush UniversityChicagoIL 60612USA Médecine Intensive Réanimation CIC 1415 INSERMCRICS-TriggerSep F-CRIN research networkCHRU de ToursTours France and Centre d’étude des pathologies respiratoires(CEPR)INSERM U1100Universitéde ToursTours 37000France

Whereas prone positioning of intubated patients suffering from acute respiratory distress syndrome represents the standard of care,proning non-intubated patients,so-called“awake prone positioning(APP),”has only recently gained popularity and undergone scientific evaluation.In this review,we summarize current evidence on physiological and clinical effects of APP on patients’centered outcomes,such as intubation and mortality,the safety of the technique,factors and predictors of success,practical issues for optimal implementation,and future areas of research.Current evidence supports using APP among patients suffering from acute hypoxemic respiratory failure due to COVID-19 and undergoing advanced respiratory support,such as high-flow nasal cannula,in an intensive care unit setting.Healthcare teams should aim to prone patients at least 8 h daily.Future research should focus on optimizing the tolerance of the technique and comprehensively evaluating benefits in other patient populations.

关键词： Respiratory distress syndrome Intensive care units Prone position Intubation

Identification of anticancer drugs to radiosensitise BRAF-wild-type and mutant colorectal cancer

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Cancer Biology & Medicine 2019年第2期16卷 234-246页

作者： Rebecca Carter Azadeh Cheraghchi-Bashi Adam Westhorpe Sheng Yu Yasmin Shanneik Elena Seraia Djamila Ouaret Yasuhiro Inoue Catherine Koch Jenny Wilding Daniel Ebner Anderson J. Ryan Francesca M. Buffa Ricky A. Sharma NIHR University College London Hospitals Biomedical research Centre/ UCL Cancer Institute University College London London WC1E 6DD UK NIHR Oxford Biomedical research Centre Department of Oncology University of Oxford Oxford 0X1 2JD UK Computational Biology and Integrative Genomics University of Oxford Oxford 0X1 2JD UK ndm research building Nuffield Department of Medicine University of Oxford Oxford 0X1 2JD UK Weatherall Institute of Molecular Medicine John Radcliffe Hospital University of Oxford Oxford 0X1 2JD UK Mie University Graduate School of Medicine Department of Gastrointestinal and Pediatric Surgery Division of Reparative Medicine Institute of Life Sciences Edobashi 2-174 Tsu Japan Departme nt of Biology Massachusetts In stitute of Tech no logy Cambridge Massachusetts 02142 USA Target Discovery Institute National Phenotypic Screening Centre Nuffield Department of Medicine University of OxfordOxford 0X1 2JD UK CRUK & MRC Oxford Institute for Radiation Oncology University of Oxford Oxford 0X1 2JD UK

Objective: Patients with BRAF-mutant colorectal cancer(CRC) have a poor prognosis. Molecular status is not currently used to select which drug to use in combination with radiotherapy. Our aim was to identify drugs that radiosensitise CRC cells with known BRAF status.Methods: We screened 298 oncological drugs with and without ionising radiation in colorectal cancer cells isogenic for BRAF. Hits from rank product analysis were validated in a 16-cell line panel of human CRC cell lines, using clonogenic survival assays and xenograft models in vivo.Results: Most consistently identified hits were drugs targeting cell growth/proliferation or DNA damage repair. The most effective class of drugs that radiosensitised wild-type and mutant cell lines was PARP inhibitors. In clonogenic survival assays, talazoparib produced a radiation enhancement ratio of 1.9 in DLD1(BRAF-wildtype) cells and 1.8 in RKO(BRAF V600 E) cells. In DLD1 xenografts, talazoparib significantly increased the inhibitory effect of radiation on tumour growth(P ≤ 0.01).Conclusions: Our method for screening large drug libraries for radiosensitisation has identified PARP inhibitors as promising radiosensitisers of colorectal cancer cells with wild-type and mutant BRAF backgrounds.

关键词： Radiosensitizer colorectal cancer PARP inhibitor radiotherapy

A Five-year Surveillance of Carbapenemase-producing Klebsiella pneumoniae in a Pediatric Hospital in China Reveals Increased Predominance of ndm-1

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Biomedical and Environmental Sciences 2017年第8期30卷 562-569页

作者： DONG Fang LU Jie WANG Yan SHI Jin ZHEN Jing Hui CHU Ping ZHEN Yang HAN Shu Jing GUO Yong Li SONG Wen Qi Department of Laboratory Medicine Beo'ing Children's Hospital Capital Medical University Beijing 100045 China Key Laboratory of Major Diseases in Children Ministry of Education Beijing Pediatric Research Institute Beijing Children's' Hospital Capital Medical University Beijing 100045 China Beijing Key Laboratory for Pediatric Diseases of Otolaryngology Head and Neck Surgery Biobank for Clinical Data and Samples' in Pediatric Beijing Pediatric Research Institute Beijing Children's Hospital Capital Medical University Beijing 100045 China

Objective To characterize carbapenem （CPM）-non-susceptible Klebsiella pneumoniae （K. pneumoniae） and carbape-nemase produced by these strains isolated from Beijing Children＇s Hospital based on a five-year surveillance. Methods The Minimal Inhibition Concentration values for 15 antibiotics were assessed using the Phonixl00 compact system. PCR amplification and DNA sequencing were used to detect genes encoding carbapenemases. WHONET 5.6 was finally used for resistance analysis. Results In total, 179 strains of CPM-non-susceptible K. pneumoniae were isolated from January, 2010 to December, 2014. The rates of non-susceptible to imipenem and meropenem were 95.0% and 95.6%, respectively. In the 179 strains, 95 （53.1%） strains carried the blalMP gene, and IMP-4 and IMP-8 were detected in 92 （96.8%） and 3 （3.2%） IMP-producing isolates, respectively. 65 （36.3%） strains carried the blandm_1 gene. 6 （3.4%） strains carried the blaKpc gene, and KPC-2 were detected in 6 KPC-producing isolates. In addition, New Delhi-Metallo-1 （ndm-1） producing isolates increased from 7.1% to 63.0% in five years and IMP-4 producing isolates decreased from 75.0% to 28.3%. Conclusion High frequencies of multiple resistances to antibiotics were observed in the CPM-non-susceptible K. pneumoniae strains isolated from Beijing Children＇s Hospital. The production of IMP-4 and ndm-1 metallo-13-1actamases appears to be an important mechanism for CPM-non- susceptible in K. pneumoniae.

关键词： Klebsiella pneumoniae Carbapenemases Microbial drug resistance

ndm-1 in the Indian environment:hitherto the problem is not disquieting

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Asian Pacific Journal of Tropical Medicine 2012年第4期5卷 335-336页

作者： Mohd Shahid Fatima Khan M Salman Shah Indu Shukla Fatima Shujatullah Haris M Khan Abida Malik lqbal M Khan Section of Antimicrobial Agents & Drug Resistance research and Molecular Biology Department of Medical MicrobiologyJawaharlal Nehru Medical College & HospitalAligarh Muslim UniversityAligarh-202002Ultar PradeshIndia Department of Community Medicine Jawaharlal Nehru Medical College & HospitalAligarh Muslim UniversityAligarh-202002Uttar PradeshIndia Section of Antimicrobial Agents & Drug Resistance research and Molecular Biology Department of Medical MicrobiologyJawaharlal Nehru Medical College & HospitalAligarh Muslim UniversityAligarh-202002Uttar PradeshIndia

blandm-1 is a recently described novel plasmid-mediated resis tance determinant that confes resistance to carbapenems. Bacteria harbouring ndm-1 have been reported from the clinical specimens.These are also reported and warned as impending gut colonist,and recently described from the environment of the capital city of India,indicating the potential as a reservoir for future infections.

关键词： reservoir Indian Bacteria plasmid determinant latter isolates award preventive

First identification of isatin-β-thiosemicarbazones as novel inhibitors of New Delhi metallo-β-lactamase-1： Chemical synthesis, biological evaluation and molecular simulation

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Chinese Chemical Letters 2018年第6期29卷 899-902页

作者： Guo-Qing Song Wei-Min Wang Zai-Shun Li Ying Wang Jian-Guo Wang State-Key Laboratory and research Institute of Elemento-Organic Chemistry National Pesticide Engineering Research Center College of Chemistry Nankai University Tianjin 300071 China Tianjin International Joint Academy of Biotechnology and Medicine Tianjin 300457 China Patent Examination Cooperation Jiangsu Center of the Patent Office SIPO Suzhou 215163 China

New Delhi metallo-b-lactmase-1（ndm-1） catalyzes the hydrolysis of b-lactam antibiotics and cleaves the b-lactam ring of the molecule, conferring bacterial resistance against these medicines. In an effort to discover novel agents to treat this superbug, an old drug methisazone was found to be a weak ndm-1 inhibitor, with an IC50 of 297.6 mmol/L. Based on this result, a series of isatin-β-thiosemicarbazones（IBTs）were synthesized and biologically evaluated as novel ndm-1 inhibitors. Nine of the IBT compounds showed IC50 values of 〈10 mmol/L, the best of which was 2.72 mmol/L. Comparative field analysis（Co MFA） contour maps were generated to depict the structural features and molecular docking was performed to understand the possible binding mode of these inhibitors. The present research hereby has provided valuable information for further discovery of ndm-1 inhibitors.

关键词： New Delhi metallo-β-lactmase-1 Isatin-β-thiosemicarbazones In vitro enzyme inhibition Molecular docking

pH effect of· OH radical induced oxidation of phosphoryl- methionine in aqueous solution

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Chinese Science Bulletin 1997年第4期42卷 296-301页

作者： CHUGaosheng, YAO Side, ZHANG Zhicheng, ZHANG Manwei and WANG Wenfeng1.Department of Applied Chemistry, University of Science and Technology of China, Hefei 230026, China 2 Shanghai Institute of Nuclear research, Chinese Academy of Sciences, Shanghai 201800, China Department of Applied Chemistry University of Science and Technology of China Hefei China Shanghai Institute of Nudear research Chinese Academy of Sciences Shanghai China

STUDIES of radiation chemistry on methionine (Met) were very active in previous years because of its actions of radioprotection to biological systems by quenching·OH radicals. On the other hand, people have paid more and more attention to the researches on the phosphorylation of the biological polymolecules. It is wall known that phosphate ester is regarded as the deposi-

关键词： pulse radiolysis ndm a-amino radical pH effect.

Interactions of oxidative radicals with N-phosphoryl dipeptide derivatives

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Chinese Journal of Chemistry 1999年第6期17卷 592-598,4页

作者：储高升陈家富张志成姚思德 Department of Applied Chemistry University of Science and Technology of China Hefei Anhui 230026 China Laboratory of Radiation Chemistry Chinese Academy of Sciences Shanghai Institute of Nuclear Research Shanghai 201800 China

The interactions of oxidative radicals (Br2?-, HO?etc.) with N-phosphoryl dipeptide derivatives (ndm-TrpOMe and NDT-MetOMe) have been investigated by using pulse radiolysis at different pH values. It has been found that Br2?- and HO? radicals oxidize the Met-site and Trp-site in the dipeptide derivatives via formation of the three-electron-bonded intermediate and indolyl radical simultaneously. Then the intramolecular electron transfer along the peptide backbone occurs. The rate constants of electron transfer, k, have been determined and the reaction mechanism has been deduced.

关键词： N-Phosphoryl dipeptide oxidation electron transfer pulse radiolysis

Discovery of thiosemicarbazone derivatives as effective New Delhi metallo-β-lactamase-1(ndm-1) inhibitors against ndm-1 producing clinical isolates

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Acta Pharmaceutica Sinica B 2021年第1期11卷 203-221页

作者： Bing Zhao Xinhui Zhang Tingting Yu Ying Liu Xiaoling Zhang Yongfang Yao Xuejian Feng Hongmin Liu Dequan Yu Liying Ma Shangshang Qin State Key Laboratory of Esophageal Cancer Prevention and Treament Key Laboratory of Technology of Drug Preparation(Zhengzhou University)Ministry of Education of ChinaKey Laboratory of Henan Province for Drug Quality and EvaluationInstitute of Pharmaceutical Research and School of Pharmaceutical SciencesZhengzhou UniversityZhengzhou 450001China State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

New Delhi metallo-b-lactamase-1(ndm-1)is capable of hydrolyzing nearly allβ-lactam antibiotics,posing an emerging threat to public health.There are currently less effective treatment options for treating ndm-1 positive"superbug",and no promising ndm-1 inhibitors were used in clinical practice.In this study,structure eactivity relationship based on thiosemicarbazone derivatives wassystematically characterized and their potential activities combined with meropenem(MEM)were evaluated.Compounds 19 bg and 19 bh exhibited excellent activity against 10 ndm-positive isolate clinical isolates in reversing MEM resistance.Further studies demonstrated compounds 19 bg and 19 bh were uncompetitive ndm-1 inhibitors with Ki Z 0.63 and 0.44 mmol/L,respectively.Molecular docking speculated that compounds 19 bg and 19 bh were most likely to bind in the allosteric pocket which would affect the catalytic effect of ndm-1 on the substrate meropenem.Toxicity evaluation experiment showed that no hemolysis activities even at concentrations of 1000 mg/m L against red blood cells.In vivo experimental results showed combination of MEM and compound 19 bh was markedly effective in treating infections caused by ndm-1 positive strain and prolonging the survival time of sepsis mice.Our finding showed that compound 19 bh might be a promising lead in developing new inhibitor to treat ndm-1 producing superbug.

关键词： Thiosemicarbazone derivatives New Delhi metallo-β-lactamase-1 Inhibitor Antibiotic resistance

Antimicrobial Susceptibility and Genetic Basis of Resistance of <i>Klebsiella spp</i>Isolated from Diarrheic and Non-Diarrheic Children at Health Facilities in Mukuru Informal Settlement, Nairobi, Kenya

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Advances in Microbiology 2021年第10期11卷 554-578页

作者： Celestine Wanjiku Wairimu Eddy Okoth Odari Celestine Khalechi Makobe Samuel Kariuki Department of Medical Microbiology College of health Science Jomo Kenyatta University of Agriculture and Technology Nairobi Kenya Centre for Microbiology research Kenya Medical Research Institute Nairobi Kenya

Antimicrobial resistance (AMR) is a global threat to public health and particularly to children. This study aimed to determine the prevalence of multidrug resistance of fecal Klebsiella spp on selected beta lactam (3rd generation cephalosporins and carbapenems) and fluoroquinolone classes of drugs in four health facilities serving the slum communities of Nairobi city in Kenya. Additionally, determine the genetic basis for the multidrug resistance observed. A cross sectional laboratory based study was undertaken where a total of 1171 children below 16 years were selected, from whom stool samples were collected, tested and analyzed. 395 (33.73%) Klebsiella spp were isolated, consisting of 365 (92.4%) Klebsiella pneumoniae and 30 (7.6%) Klebsiella oxytoca were isolated. The proportion of multi-drug resistance (MDR) K. pneumoniae and MDR K. oxytoca was 64.1% (234/365) and 96.67% (29/30) respectively. Third generation cephalosporins, cefotaxime ceftriaxone and ceftazidime showed the highest resistance of 30.7%, 29.9% and 27.4% respectively, whereas carbapenems including imipenem and meropenem had the least resistance of 1.6%, each, to K. pneumoniae. A significant association was observed in diarrheic children (OR = 1.88;p = 0.01) and those below 50 months (OR = 0.43;p = 0.002) and carrying K. pneumoniae resistance to one or more third generation cephalosporins. Genes associated with resistance included bla TEM 100%, bla CTX-M 95.2%, bla SHV 57.1%, bla OXA-1 66.7%, qnrS 54.1%, qnrB 47.6% and bla ndm 7.1%. In conclusion, there’s need for more effective infection control measures, antimicrobial stewardship to reduce emergence of antimicrobial resistance, improved drinking water, sanitation and hygiene (WASH) practices.

关键词： Klebsiella Antimicrobial Resistance Carriage Community Children Slums Kenya