Detection of double-stranded RNA in Mucor ramannianus

Double-stranded RNA (dsRNA) molecules have been found in numerous fungal species and are considered to be indicators of the presence of virus-like particles (VLPs) in the cells (Hollings 1978 Adv. Virus Res. 22:1-53; Buck ed., 1986 Fungal Virology, CRC Press, Boca Raton, FL). Such mycoviruses have been found mainly from studies of the nucleic acids of different strains. In this respect, fungal species belonging to the Zygomycetes are rarely screened. We have investigated the nucleic acids of 30 Mucor strains representing ten different species. The presence of dsRNA molecules was detected in only one of the two Mucor ramannianus strains examined

The role of ligand efficiency metrics in drug discovery

The judicious application of ligand or binding efficiencies, which quantify the molecular properties required to gain binding affinity for a drug target, is gaining traction in the selection and optimisation of fragments, hits, and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimised ligand efficiency values for their target. Optimising ligand efficiencies based on both molecular size and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the molecular inflation that pervades current practice in medicinal chemistry, and to increase the developability of drug candidates

HPV testing in primary screening of older women

Certain types of the human papilloma virus (HPV) are well established as the primary cause of cervical cancer. Several studies have shown that HPV testing can improve the detection rate of high-grade cervical intraepithelial neoplasia (CIN), but these have been carried out primarily in younger women. In this study we evaluated the role of HPV testing as an adjunct to cytology in women aged 35 or over. An additional aim was to evaluate commercially available kits for HPV testing. A total of 2988 eligible women aged 34 or more attending for a routine smear in 40 general practitioner practices received HPV testing in addition to routine cytology, after having given written informed consent. Samples were assayed by polymerase chain reaction (PCR) and two versions of the Hybrid Capture test for HPV, and women were invited for colposcopy if there was any cytological abnormality (including borderline smears) or the PCR test was positive. Any apparent abnormality was biopsied and loop-excision was performed as necessary. CIN was judged by histology; 42 women had high-grade CIN, of which six were cytology negative (86% sensitivity for borderline or worse) and three had a borderline smear (79% sensitivity for mild dyskaryosis or worse). The positive predictive value of a borderline smear was only 3.1%. Eleven high-grade lesions were negative by the PCR HPV test (sensitivity 74%). The first generation Hybrid Capture II test had a similar sensitivity but an unacceptably high false positive rate (18.3%), while the newer Hybrid Capture II microtitre kit had a 95% sensitivity and a 2.3% positivity rate in normal women when used at a 2 pg ml−1 cut-off (positive predictive value 27%). Cytology performed very well in this older cohort of women. The newer Hybrid Capture II microtitre test may be a useful adjunct, especially if the results reported here are reproducible in other studies. A combined screening test offers the possibility of greater protection and/or longer screening intervals, which could reduce the overall cost of the screening programme. © 1999 Cancer Research Campaig

Primary screening for cervical cancer precursors by the combined use of liquid-based cytology, computer-assisted cytology and HPV DNA testing

Primary screening for cervical cancer precursors has considerably evolved with the introduction of new technology to improve the early detection of disease. The objective of this study was to elaborate a diagnostic pathway integrating liquid-based and computer-assisted cytology and human papillomavirus DNA testing to focus screening on women at risk which may be more cost-effective for the healthcare system. A single laboratory analysis was conducted during a 5-month period using liquid-based cytology followed by human papillomavirus DNA testing for women with an abnormal result or with previous abnormal cytology. Human papillomavirus prevalence was estimated by testing 909 consecutive unselected samples. All slides were then rescreened using automated cytologic testing and triaged into a high- or low-score group according to computer results. Of the 8676 slides scanned, 352 had a test result of atypical squamous cells of undetermined significance or worse. Two hundred and ninety-seven (84.3%) samples with an atypical squamous cells of undetermined significance or worse result and 100% of those with detection of high-grade squamous intraepithelial lesions and carcinomas (HSIL+) were triaged into the high-score group. The combination of instrument scores and human papillomavirus results indicated that 51.0% of high score/human papillomavirus-positive cases should be considered as ASCUS+, while 99.6% of low-score/human papillomavirus negative cases remained negative in the final cytologic diagnosis, representing 49.0% of all cases. Of the screened women 89.5% should test negative for human papillomavirus and be reported as such in the final cytologic diagnosis. In conclusion, preliminary results suggest that this diagnostic pathway has the potential to improve primary cervical cancer screening and cost-effectiveness. By using a combination of testing methods to focus screening and clinical attention to cases at risk, it would be possible to lengthen screening intervals for 90% of women and to archive without further review all low-score/human papillomavirus-negative slides, representing 50% of the screening workload

Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia

Fragment-based drug discovery (FBDD) is well suited for discovering both drug leads and chemical probes of protein function; it can cover broad swaths of chemical space and allows the use of creative chemistry. FBDD is widely implemented for lead discovery in industry but is sometimes. used less systematically in academia. Design principles and implementation approaches for fragment libraries are continually evolving, and the lack of up-to-date guidance may prevent more effective application of FBDD in academia. This Perspective explores many of the theoretical, practical, and strategic considerations that occur within FBDD programs, including the optimal size, complexity, physicochemical profile, and shape profile of fragments in FBDD libraries, as well as compound storage, evaluation; and screening technologies. This:compilation of industry experience in FBDD will hopefully be useful for those pursuing FBDD in academia

The Combined Influence of Oral Contraceptives and Human Papillomavirus Virus on Cutaneous Squamous Cell Carcinoma

The vast majority of cutaneous squamous cell carcinoma (CSCC) will occur in those with fair complexion, tendency to burn, and high ultraviolet radiation (UVR) exposure. Organ transplant recipients also are an important population at great risk for CSCC. An association has been reported between oral contraceptive (OC) use, human papillomavirus virus (HPV) and cervical cancer, and there could be a similar association for CSCC. The cutaneous HPV β-E6 protein, a close cousin of the transformative E6 protein underlying anogenital cancers, has been shown to inhibit apoptosis in response to UVR damage and stimulate morphologic transformation in rodent fibroblast cell lines. Furthermore, OC use has been shown to enhance HPV transcription and may contribute to CSCC risk through this pathway