• 【在来自非洲的未暴露的恶性疟原虫分离株中,与atovaquone-proguanil抗性相关的突变的出现证实。】 复制标题 收藏 收藏
    DOI:10.1186/1475-2875-5-82 复制DOI
    作者列表:Happi CT,Gbotosho GO,Folarin OA,Milner D,Sarr O,Sowunmi A,Kyle DE,Milhous WK,Wirth DF,Oduola AM
    BACKGROUND & AIMS: BACKGROUND:In vitro and in vivo resistance of Plasmodium falciparum to atovaquone or atovaquone-proguanil hydrochloride combination has been associated to two point mutations in the parasite cytochrome b (cytb) gene (Tyr268Ser and Tyr268Asn). However, little is known about the prevalence of codon-268 mutations in natural populations of P. falciparum without previous exposure to the drug in Africa. METHODS:The prevalence of codon-268 mutations in the cytb gene of African P. falciparum isolates from Nigeria, Malawi and Senegal, where atovaquone-proguanil has not been introduced for treatment of malaria was assessed. Genotyping of the cytb gene in isolates of P. falciparum was performed by PCR-restriction fragment length polymorphism and confirmed by sequencing. RESULTS:295 samples from Nigeria (111), Malawi (91) and Senegal (93) were successfully analyzed for detection of either mutant Tyr268Ser or Tyr268Asn. No case of Ser268 or Asn268 was detected in cytb gene of parasites from Malawi or Senegal. However, Asn268 was detected in five out of 111 (4.5%) unexposed P. falciparum isolates from Nigeria. In addition, one out of these five mutant Asn268 isolates showed an additional cytb mutation leading to a Pro266Thr substitution inside the ubiquinone reduction site. CONCLUSION:No Tyr268Ser mutation is found in cytb of P. falciparum isolates from Nigeria, Malawi or Senegal. This study reports for the first time cytb Tyr268Asn mutation in unexposed P. falciparum isolates from Nigeria. The emergence in Africa of P. falciparum isolates with cytb Tyr268Asn mutation is a matter of serious concern. Continuous monitoring of atovaquone-proguanil resistant P. falciparum in Africa is warranted for the rational use of this new antimalarial drug, especially in non-immune travelers.
    背景与目标:
  • 2 Drill biopsy confirmation of breast cancer. 复制标题 收藏 收藏

    【乳腺癌的钻孔活检确认。】 复制标题 收藏 收藏
    DOI:10.1001/archsurg.1976.01360250102022 复制DOI
    作者列表:Meyerowitz BR
    BACKGROUND & AIMS: The technique of drill biopsy of suspicious masses in the breast has been used in 135 patients, with 98.5% accuracy. It has permitted discrimination in the application of expensive scanning studies. Prior confirmation of the diagnosis of carcinoma reduces operating room and anesthesia time, and eliminates the need for two sets of instruments.

    背景与目标: 乳腺可疑肿块的钻孔活检技术已用于135患者,准确性98.5%。它允许在昂贵的扫描研究应用中进行歧视。事先确认癌症的诊断可减少手术室和麻醉时间,并且无需使用两套仪器。
  • 【部分尿道切除术在外阴癌的手术治疗中对尿失禁没有明显影响。对基于权威的意见的确认。】 复制标题 收藏 收藏
    DOI:10.1111/j.1525-1438.2007.00788.x 复制DOI
    作者列表:de Mooij Y,Burger MP,Schilthuis MS,Buist M,van der Velden J
    BACKGROUND & AIMS: :Partial resection of the urethra is sometimes necessary in the surgical treatment of locally advanced vulvar cancer. In this study, the frequency of urinary incontinence after partial urethral resection was compared with that of patients who were treated without partial resection of the urethra. Eighteen patients with vulvar cancer encroaching or infiltrating the urethra, treated by a radical vulvectomy and partial urethrectomy, were compared with 17 patients treated by vulvectomy without partial removal of the urethra. Data on urinary incontinence pre- and postoperatively from both groups were retrospectively collected from the patient files. A questionnaire on urinary incontinence was sent to a subset of patients from both groups in order to get information on the current micturation pattern. In four out of 18 patients (22%) with a partial urethrectomy, incontinence was reported, versus two out of 17 patients (12%) in the control group (P= 0.860). Eight patients in the study group and 12 in the control group are currently alive, and all responded to the questionnaire. Two (25%) in the study group and three (25%) in the control group reported to have current symptoms of urinary incontinence. This retrospective study shows that partial resection of 1-1.5 cm of the distal urethra in addition to a radical local excision for vulvar cancer does not result in a significant increase in the frequency of urinary incontinence, compared with vulvar cancer patients without partial urethrectomy.
    背景与目标: : 在局部晚期外阴癌的手术治疗中,有时需要部分切除尿道。在这项研究中,将部分尿道切除术后的尿失禁频率与未部分尿道切除术的患者进行了比较。将通过根治性外阴切除术和部分尿道切除术治疗的18例外阴癌侵犯或浸润尿道的患者与17例未部分切除尿道的外阴切除术治疗的患者进行了比较。从患者档案中回顾性收集两组术前和术后尿失禁的数据。向两组患者的一部分发送了有关尿失禁的问卷,以获取有关当前排尿方式的信息。在接受部分输尿管切除术的18例患者中,有4例 (22% 例) 报告了尿失禁,而对照组的17例患者中有2例 (12% 例) 报告了尿失禁 (P = 0.860)。研究组的8名患者和对照组的12名患者目前还活着,并且都对问卷进行了答复。研究组中有两个 (25%) 和对照组中有三个 (25%) 报告有尿失禁的当前症状。这项回顾性研究表明,与没有部分尿道切除术的外阴癌患者相比,除了根治性局部切除外阴癌外,部分切除1-1.5厘米远端尿道不会导致尿失禁的频率显着增加。
  • 【具有广泛结蛋白表达的巨细胞不良关节外弥漫型腱膜巨细胞瘤: 细胞遗传学确认的潜在诊断陷阱。】 复制标题 收藏 收藏
    DOI:10.1177/1066896918788678 复制DOI
    作者列表:Lopez L,Schoedel K,John I
    BACKGROUND & AIMS: :Diffuse-type tenosynovial giant cell tumor can rarely present as an entirely extra-articular mass, which can be misdiagnosed as a sarcoma especially when giant cells are absent, dominated by large dendritic mononuclear cells, and desmin expression is extensive.
    背景与目标: : 弥漫性腱膜巨细胞瘤很少以完全关节外肿块的形式存在,尤其是当没有巨细胞,以大的树突状单核细胞为主,并且结蛋白表达广泛时,可被误诊为肉瘤。
  • 【东非的侵入性牛tick虫: 乌干达东南部Rhipicephalus microplus的形态和分子确认。】 复制标题 收藏 收藏
    DOI:10.1186/s13071-020-04043-z 复制DOI
    作者列表:Muhanguzi D,Byaruhanga J,Amanyire W,Ndekezi C,Ochwo S,Nkamwesiga J,Mwiine FN,Tweyongyere R,Fourie J,Madder M,Schetters T,Horak I,Juleff N,Jongejan F
    BACKGROUND & AIMS: BACKGROUND:Rhipicephalus microplus, an invasive tick species of Asian origin and the main vector of Babesia species, is considered one of the most widespread ectoparasites of livestock. The tick has spread from its native habitats on translocated livestock to large parts of the tropical world, where it has replaced some of the local populations of Rhipicephalus decoloratus ticks. Although the tick was reported in Uganda 70 years ago, it has not been found in any subsequent surveys. This study was carried out to update the national tick species distribution on livestock in Uganda as a basis for tick and tick-borne disease control, with particular reference to R. microplus. METHODS:The study was carried out in Kadungulu, Serere district, south-eastern Uganda, which is dominated by small scale livestock producers. All the ticks collected from 240 cattle from six villages were identified microscopically. Five R. microplus specimens were further processed for phylogenetic analysis and species confirmation. RESULTS:The predominant tick species found on cattle was Rhipicephalus appendiculatus (86.9 %; n = 16,509). Other species found were Amblyomma variegatum (7.2 %; n = 1377), Rhipicephalus evertsi (2.3 %; n = 434) and R. microplus (3.6 %; n = 687). Phylogenetic analysis of the 12S rRNA, 16S rRNA and ITS2 gene sequences of R. microplus confirmed the morphological identification. CONCLUSIONS:It is concluded that R. microplus has replaced R. decoloratus in the sampled villages in Kadungulu sub-county, since the latter was not any longer found in this area. There is currently no livestock movement policy in force in Uganda, which could possibly limit the further spread of R. microplus ticks. Future surveys, but also retrospective surveys of museum specimens, will reveal the extent of distribution of R. microplus in Uganda and also for how long this tick has been present on livestock without being noticed.
    背景与目标:
  • 【极低剂量计算机断层扫描用于确认尿路结石的存在。】 复制标题 收藏 收藏
    DOI:10.1007/s00345-020-03142-x 复制DOI
    作者列表:Raskin D,Winkler H,Kleinmann N,Schor-Bardach R,Guranda L,Muzikansky G,Portnoy O
    BACKGROUND & AIMS: PURPOSE:To determine whether a modified non-contrast very low-dose computed tomography (VLD-CT) protocol is applicable for confirmation of known urolithiasis. METHODS AND MATERIALS:Consecutive adult patients with a CT scan showing urinary tract stone(s) between 6/2017-12/2018 were included. They were referred to a modified VLD-CT protocol if stone presence was equivocal or if stone location needed reassessment before an endourological interventional procedure. The scanned area was limited to the level of initial stone location caudally. Data on patients' demographics andbody mass index, were collected. The scanned length and radiation dose were calculated. Images were reviewed by two radiologists who assessed stone size and location. Follow-up reference standard included stone passage, surgical removal, and other imaging and clinical information. RESULTS:Sixty-three patients [63 stones, mean BMI 28.7 (range 19-41.9)] were included. VLD-CTs revealed 31 stones in 31 patients, with a mean stone length of 5.5 mm. Fifteen stones remained at the same location, and 16 had migrated, of which two appeared in the bladder. Thirty-two stones were not observed on VLD-CT. The mean span scanned on the VLD-CT was 274 mm (± 80). The average radiation exposure was 1.47 mGy (range 1.09-3.3), and the absorbed dose was 0.77 mSv (range 0.39-1.43), compared to 10.24 mGy (range 1.75-28.9) and 7.87 mSv (range 1.44-18.5) in the previous scan. The mean radiation dose reduction between scans was 89%. On follow-up, all VLD-CT findings were confirmed. CONCLUSION:A modified imaging protocol is applicable for confirmation of stone presence and location by utilizing very low-dose radiation exposure.
    背景与目标:
  • 【使用DNA熔化模拟软件进行计算机诊断试验设计: 靶向具有复杂熔化曲线的区域,并使用嵌入染料通过实时PCR进行确认。】 复制标题 收藏 收藏
    DOI:10.1186/1471-2105-8-107 复制DOI
    作者列表:Rasmussen JP,Saint CP,Monis PT
    BACKGROUND & AIMS: BACKGROUND:DNA melting curve analysis using double-stranded DNA-specific dyes such as SYTO9 produce complex and reproducible melting profiles, resulting in the detection of multiple melting peaks from a single amplicon and allowing the discrimination of different species. We compare the melting curves of several Naegleria and Cryptosporidium amplicons generated in vitro with in silico DNA melting simulations using the programs POLAND and MELTSIM., then test the utility of these programs for assay design using a genetic marker for toxin production in cyanobacteria. RESULTS:The SYTO9 melting curve profiles of three species of Naegleria and two species of Cryptosporidium were similar to POLAND and MELTSIM melting simulations, excepting some differences in the relative peak heights and the absolute melting temperatures of these peaks. MELTSIM and POLAND were used to screen sequences from a putative toxin gene in two different species of cyanobacteria and identify regions exhibiting diagnostic melting profiles. For one of these diagnostic regions the POLAND and MELTSIM melting simulations were observed to be different, with POLAND more accurately predicting the melting curve generated in vitro. Upon further investigation of this region with MELTSIM, inconsistencies between the melting simulation for forward and reverse complement sequences were observed. The assay was used to accurately type twenty seven cyanobacterial DNA extracts in vitro. CONCLUSION:Whilst neither POLAND nor MELTSIM simulation programs were capable of exactly predicting DNA dissociation in the presence of an intercalating dye, the programs were successfully used as tools to identify regions where melting curve differences could be exploited for diagnostic melting curve assay design. Refinements in the simulation parameters would be required to account for the effect of the intercalating dye and salt concentrations used in real-time PCR. The agreement between the melting curve simulations for different species of Naegleria and Cryptosporidium and the complex melting profiles generated in vitro using SYTO9 verified that the complex melting profile of PCR amplicons was solely the result of DNA dissociation. Other data outputs from these simulations were also used to identify the melting domains that contributed to the observed melting peaks for each of the different PCR amplicons.
    背景与目标:
  • 【立体选择性首次全合成,确定了botryoolide-E的绝对构型和生物评估。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmcl.2010.12.024 复制DOI
    作者列表:Reddy DK,Shekhar V,Prabhakar P,Babu DC,Ramesh D,Siddhardha B,Murthy US,Venkateswarlu Y
    BACKGROUND & AIMS: :A simple, first stereoselective total synthesis of botryolide-E has been described. The synthesis started from propylene oxide employing Jacobsen's hydrolytic kinetic resolution (HKR), selective epoxide opening, sharpless asymmetric dihydroxylation, one pot acetonide deprotection and lactonization as key steps. Further, the synthesis confirms the absolute configuration of the natural product botryolide-E and we evaluated the biological behavior of natural product botryolide-E against a panel of bacteria and fungi. Botryolide-E exhibits significant potent activity against Staphylococcus aureus (MTCC 96) (6.25 μg/ml), good against Escherichia coli (MTCC 443) (12.5 μg/ml), Bacillus subtilis (MTCC 441) (25 μg/ml) and compound 1 exhibited good to moderate antifungal activity.
    背景与目标: : 已经描述了一种简单的,首次立体选择性的botryoolide-E全合成。该合成从环氧丙烷开始,采用Jacobsen水解动力学拆分 (HKR),选择性环氧开放,sharpless不对称二羟基化,一锅丙酮脱保护和内酯化作为关键步骤。此外,该合成证实了天然产物botryoolide-E的绝对构型,并且我们评估了天然产物botryoolide-E对一组细菌和真菌的生物学行为。葡萄糖醇内酯-E对金黄色葡萄球菌 (mtcc96) (6.25 μ g/ml) 表现出显著的有效活性,对大肠杆菌 (MTCC 443) (12.5 μ g/ml),枯草芽孢杆菌 (MTCC 441) (25 μ g/ml) 表现出良好的抗真菌活性,化合物1表现出良好至中等的抗真菌活性。
  • 【显微镜凝集试验: 影响人类钩端螺旋体病病例血清学确认时间的变量。】 复制标题 收藏 收藏
    DOI:10.1016/j.ram.2019.11.005 复制DOI
    作者列表:Scialfa E,Rivero M,Moreno S,Ortiz M,Bongiorno F
    BACKGROUND & AIMS: :Leptospirosis is considered an endemic disease in Buenos Aires province, Argentina, with human cases reported annually from rural and urban areas. The aim of the study was to describe the variables that influence the delay in the serological confirmation of leptospirosis in human cases (period 2006-2014) from Buenos Aires province. Sixty-four percent (64%) of cases could be confirmed by microscopic agglutination test (MAT) with the first sample. The time of confirmation of the human leptospirosis cases was on average 21 days from the onset of the first clinical signs, and varied depending on the distance of the different sanitary regions. The geographical distribution of the confirmed leptospirosis human cases, in addition to the high number of suspected cases and probable cases (which could not be confirmed by MAT), demonstrate that leptospirosis is endemic and underreported in Buenos Aires province, and that distance and lack of resources could be determinant factors of this situation.
    背景与目标: : 钩端螺旋体病被认为是阿根廷布宜诺斯艾利斯省的一种地方病,每年从农村和城市地区报告人类病例。该研究的目的是描述影响布宜诺斯艾利斯省人类病例 (2006-2014年) 中钩端螺旋体病血清学确认延迟的变量。通过第一个样品的显微凝集试验 (MAT) 可以确认60 4% (64%) 的病例。人类钩端螺旋体病病例的确认时间平均为从首次临床体征开始的21天,并且根据不同卫生区域的距离而变化。确诊的钩端螺旋体病人类病例的地理分布,以及大量疑似病例和可能的病例 (MAT无法证实),表明钩端螺旋体病在布宜诺斯艾利斯省是地方性的,报道不足,距离和缺乏资源可能是这种情况的决定因素。
  • 【活检还是不活检?: 立体定向放射治疗的早期肺癌的匹配队列分析,有无组织学证实。】 复制标题 收藏 收藏
    DOI:10.1016/j.ijrobp.2020.01.018 复制DOI
    作者列表:Dautruche A,Filion E,Mathieu D,Bahig H,Roberge D,Lambert L,Vu T,Campeau MP
    BACKGROUND & AIMS: PURPOSE:For nonoperable stage I non-small cell lung cancer, stereotactic body radiation therapy (SBRT) has emerged as a standard treatment option. We aimed to compare the clinical outcomes of lung SBRT between patients with versus without pathologic cancer diagnosis. METHODS AND MATERIALS:We included patients treated by SBRT for a single pulmonary lesion between July 2009 and July 2017. Patients in the clinical diagnosis group had a positron emission tomography/computed tomography scan showing hypermetabolism, growth of the mass on sequential computed tomography, and were not eligible for biopsy, refused biopsy, or had an inconclusive biopsy. For each of those patients, a matched pair in the pathologic diagnosis group was identified by matching for patient, treatment, and tumoral characteristics. We performed a power calculation to estimate the sample size required to detect a difference arising from a 5% or 15% rate of benign processes in the group without pathology. RESULTS:A total of 924 lung SBRT treatments were performed among 878 patients from 2009 to 2017. Within this population, 131 patients were treated based on clinical findings. They were matched with 131 patients with a pathologic diagnosis who received treatment. At 3 years, no significant differences were observed in overall survival (hazard ratio [HR], 1.2; 95% confidence interval [CI], 0.7-2.1), local control (HR, 0.9; 95% CI, 0.4-2), or regional (HR, 0.5; 95% CI, 0.2-1.4) or distant recurrence (HR, 0.6; 95% CI, 0.3-1.1). CONCLUSIONS:In our population, we found no clinically significant difference in patterns of recurrence or survival after lung SBRT for patients who had received clinical versus pathological diagnoses. There was, however, a trend toward more distant recurrences in the pathologic diagnosis group. Our power calculation suggests that data from multiple institutions would be required to rule out a difference in outcomes due to 5% to 15% of clinically diagnosed cases being treated for benign processes.
    背景与目标:
  • 【人类雄激素受体的表位预测和确认: 根据合成肽策略产生用于多测定性能的单克隆抗体。】 复制标题 收藏 收藏
    DOI:10.1016/0304-4165(91)90178-j 复制DOI
    作者列表:Zegers ND,Claassen E,Neelen C,Mulder E,van Laar JH,Voorhorst MM,Berrevoets CA,Brinkmann AO,van der Kwast TH,Ruizeveld de Winter JA
    BACKGROUND & AIMS: :The human androgen receptor (hAR) is an important regulatory protein particularly in male sexual differentiation. The investigation of hAR functionality has been hampered by the lack of AR specific monoclonal antibodies recognizing the functional domains of the receptor. Therefore production of high affinity mono-specific polyclonal (PAbs) and monoclonal antibodies (MAbs) directed to the hAR was initiated following the synthetic peptide (SP) strategy. Five hAR specific peptides were selected on the basis of their predicted antigenic properties avoiding homology with other steroid hormone receptors. Peptide specific polyclonal antisera were obtained following selected immunization protocols. Mono-specific polyclonal antibody responses were elicited to all peptides in mice and rabbits. Crossreactivity of the peptide specific antisera with the native hAR in various biochemical assays was observed with two out of five peptides. Peptide SP61 (hAR residues 301-320) was used for the generation site-directed MAbs specific for the hAR. Specificity for the hAR was established by immunoprecipitation, immune-complex density gradient centrifugation and immunohistochemistry on human prostate tissue sections. The multi-assay performance of the selected high affinity antibodies proved the usefulness of the straight forward peptide approach and opens a wide field of possible biochemical and physiological investigations into questions related to androgen action.
    背景与目标: : 人类雄激素受体 (hAR) 是一种重要的调节蛋白,尤其是在男性性别分化中。缺乏识别受体功能域的AR特异性单克隆抗体,阻碍了对hAR功能的研究。因此,按照合成肽 (SP) 策略开始生产针对hAR的高亲和力单特异性多克隆 (PAbs) 和单克隆抗体 (mab)。根据其预测的抗原特性选择了五种hAR特异性肽,以避免与其他类固醇激素受体的同源性。按照选定预防接种方案获得了肽特异性多克隆抗血清。对小鼠和兔子的所有肽均产生单特异性多克隆抗体反应。在各种生化测定中,用五分之二的肽观察到肽特异性抗血清与天然hAR的交叉反应性。肽SP61 (hAR残基301-320) 用于hAR特异性的生成定点mab。通过免疫沉淀,免疫复合物密度梯度离心和免疫组织化学对人前列腺组织切片确定hAR的特异性。所选的高亲和力抗体的多测定性能证明了直接肽方法的有用性,并为与雄激素作用有关的问题开辟了可能的生化和生理研究的广阔领域。
  • 【在抗伤害感受试验中比较 (-)-eseroline与 ()-eseroline和二氢seco类似物: 通过x射线分析确认rubreserine结构。】 复制标题 收藏 收藏
    DOI:10.1021/jm00161a023 复制DOI
    作者列表:Schönenberger B,Jacobson AE,Brossi A,Streaty R,Klee WA,Flippen-Anderson JL,Gilardi R
    BACKGROUND & AIMS: :The enantiomers of eseroline bind to opiate receptors of rat brain membranes with equal affinities and show opiate agonist properties as inhibitors of adenylate cyclase in vitro. However, only (-)-eseroline shows potent narcotic agonist activity in vivo, similar to that of morphine. Neither (-)-noreseroline, (+)-eseroline, nor the open dihydroseco analogue (-)-8 shows analgetic effects in vivo. The structure of rubreserine being a resonance hybrid of an o-quinone with its zwitterionic mesomer is confirmed by solid-state X-ray diffraction analysis.
    背景与目标: : eseroline的对映体以相同的亲和力与大鼠脑膜的阿片受体结合,并在体外显示阿片激动剂作为腺苷酸环化酶抑制剂的特性。然而,只有 (-)-eseroline在体内显示出有效的麻醉激动剂活性,类似于吗啡。(-)-noreseroline,()-eseroline和开放的二氢seco类似物 (-)-8在体内均未显示出镇痛作用。通过固态x射线衍射分析证实了rubreserine的结构是邻醌与其两性离子介体的共振杂种。
  • 【Tc-99m HMPAO SPECT鉴别诊断疾病痴呆并进行组织病理学确认。】 复制标题 收藏 收藏
    DOI:10.1097/01.rlu.0000222736.81365.63 复制DOI
    作者列表:Bonte FJ,Harris TS,Hynan LS,Bigio EH,White CL 3rd
    BACKGROUND & AIMS: PURPOSE:The purpose of this study is to determine the value of Tc-99m HMPAO SPECT in the diagnosis of the dementias, with particular reference to Alzheimer disease. MATERIALS AND METHODS:Tc-99m HMPAO was used with a 3-camera scanner to produce 5 sets of sectional images of the brain. Diagnosis was made by a physician blinded to the clinical diagnosis. Results in 49 subjects were ultimately compared with neuropathologic study of the brain at autopsy. RESULTS:Sensitivity = 86.7% (68.4-95.6%, 95% confidence interval [CI]), specificity = 89.5% (65.5-98.2% CI), positive predictive value = 92.9% (75.0-98.8% CI), negative predictive value = 81% (57.4-93.7% CI), accuracy = 87.8% (74.5-94.9% CI), likelihood ratio = 8.23% (7.09-9.57% CI). CONCLUSIONS:Comparison is made with several other SPECT and PET series with histopathologic correlation. Brain blood flow SPECT is useful in the diagnosis and differential diagnosis of the dementias.
    背景与目标:
  • 【千方百计: 一个难以置信的骨结核病例的分子确认。】 复制标题 收藏 收藏
    DOI:10.1086/503571 复制DOI
    作者列表:Loïez C,Willery E,Legrand JL,Vincent V,Gutierrez MC,Courcol RJ,Supply P
    BACKGROUND & AIMS: :We report the use of typing based on a variable number of tandem repeats of genetic elements called "mycobacterial interspersed repetitive units" to clarify a puzzling situation involving a patient with an exceptional case of spondylodiskitis that initially led to the suspicion of a possible event of laboratory cross-contamination with Mycobacterium tuberculosis.
    背景与目标: : 我们报告了基于称为 “分枝杆菌穿插重复单位” 的遗传元素的可变数量的串联重复序列进行分型的使用,以阐明一种令人费解的情况,涉及患有特殊脊椎炎的患者,该患者最初导致怀疑可能的事件结核分枝杆菌的实验室交叉污染。
  • 【复杂疾病相关药物遗传学: 药物疗效、药物安全性和致病假说的确认 (阿尔茨海默氏病)。】 复制标题 收藏 收藏
    DOI:10.1038/sj.tpj.6500397 复制DOI
    作者列表:Roses AD,Saunders AM,Huang Y,Strum J,Weisgraber KH,Mahley RW
    BACKGROUND & AIMS: :Safety and efficacy pharmacogenetics can be applied successfully to the drug discovery and development pipeline at multiple phases. We review drug-target screening using high throughput SNP associations with complex diseases testing more than 1,800 candidate targets with approximately 7,000 SNPs. Alzheimer's disease data are provided as an example. The supplementation of target-selected screening with genome-wide SNP association, to also define susceptibility genes and relevant disease pathways for human diseases, is discussed. Applications for determining predictive genetic or genomic profiles, or derived biomarkers, for drug efficacy and safety during clinical development are exemplified by several successful experiments at different phases of development. A Phase I-IIA study of side effects using an oral drug for the treatment of breast cancer is used as an example of early pipeline pharmacogenetics to predict side effects and allow optimization of dosing. References are provided for several other recently published genetic association studies of adverse events during drug development. We illustrate the early identification of gene variant candidates related to efficacy in a Phase IIA obesity drug trial to generate hypotheses for testing in subsequent development. How these genetic data generated in Phase IIA are subsequently incorporated as hypotheses into later Phase clinical protocols is discussed. A Phase IIB clinical trial for Alzheimer's disease is described that exemplifies the major pipeline decision between program attrition and further clinical development. In this case, there was no significant improvement in 511 intention-to-treat patients but, applying a confirmed prognostic biomarker (APOE4) to segment the clinical trial population, all three doses of rosiglitazone demonstrated improvement in patients who did not carry the APOE4 allele. The data for the APOE4 carriers demonstrated no significant improvement but suggested that there may be a need for higher doses. Thus, a development program that would have been terminated progressed to Phase III registration trials based on the results of prospective efficacy pharmacogenetic analyses. The implications of using APOE genotype as a biomarker to predict efficacy and possibly dose, as well as supporting the basic neurobiology and pharmacology that provided the original target validation, is discussed. Citations are provided that support a slow neurotoxic effect over many years of a specific fragment of apoE protein (over-produced by apoE4 substrate compared to apoE3) on mitochondria and the use of rosiglitazone to increase mitochondrial biogenesis and improve glucose utilization. Pharmacogenetics is currently being used across the pipeline to prevent attrition and to create safer and more effective medicines.
    背景与目标: : 安全性和有效性药物遗传学可以在多个阶段成功应用于药物发现和开发管道。我们回顾了使用高通量SNP与复杂疾病关联的药物靶标筛选,测试了1,800多个具有约7,000个SNP的候选靶标。以阿尔茨海默氏病数据为例。讨论了通过全基因组SNP关联补充靶标筛选,以定义人类疾病的易感基因和相关疾病途径。在临床开发过程中,用于确定预测性遗传或基因组图谱或衍生的生物标志物以用于药物功效和安全性的应用在不同开发阶段的几个成功实验中得到了例证。使用口服药物治疗乳腺癌的副作用i-iia期研究被用作早期管道药物遗传学的示例,以预测副作用并允许优化剂量。提供了其他一些最近发表的药物开发过程中不良事件的遗传关联研究的参考。我们说明了IIA期肥胖药物试验中与功效相关的基因变异候选者的早期鉴定,以产生假设以供后续开发测试。讨论了如何将IIA期产生的这些遗传数据作为假设合并到后期临床方案中。描述了针对阿尔茨海默氏病的IIB期临床试验,该试验举例说明了程序损耗和进一步临床开发之间的主要管道决策。在这种情况下,511意向治疗患者没有显着改善,但是,应用已确认的预后生物标志物 (APOE4) 对临床试验人群进行细分,所有三个剂量的罗格列酮在不携带APOE4等位基因的患者中均表现出改善。APOE4携带者的数据没有明显改善,但表明可能需要更高的剂量。因此,根据前瞻性功效药物遗传学分析的结果,本可以终止的开发计划进入III期注册试验。讨论了使用APOE基因型作为生物标志物来预测功效和可能的剂量,以及支持提供原始靶标验证的基本神经生物学和药理学的意义。提供的引文支持apoE蛋白的特定片段 (与apoE3相比,apoE4底物过度产生) 对线粒体的缓慢神经毒性作用,并支持使用罗格列酮增加线粒体生物发生并改善葡萄糖利用。药物遗传学目前正在整个管道中使用,以防止磨损并创建更安全,更有效的药物。

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