Comparative chemical genomics in Babesia species identifies the alkaline phosphatase PhoD as a determinant of antiparasitic resistance.

Babesiosis is an emerging zoonosis and widely distributed veterinary infection caused by 100+ species of Babesia parasites. The diversity of Babesia parasites and the lack of specific drugs necessitate the discovery of broadly effective antibabesials. Here, we describe a comparative chemogenomics (CCG) pipeline for the identification of conserved targets. CCG relies on parallel in vitro evolution of resistance in independent populations of Babesia spp. (B. bovis and B. divergens). We identified a potent antibabesial, MMV019266, from the Malaria Box, and selected for resistance in two species of Babesia. After sequencing of multiple independently derived lines in the two species, we identified mutations in a membrane-bound metallodependent phosphatase (phoD). In both species, the mutations were found in the phoD-like phosphatase domain. Using reverse genetics, we validated that mutations in bdphoD confer resistance to MMV019266 in B. divergens. We have also demonstrated that BdPhoD localizes to the endomembrane system and partially with the apicoplast. Finally, conditional knockdown and constitutive overexpression of BdPhoD alter the sensitivity to MMV019266 in the parasite. Overexpression of BdPhoD results in increased sensitivity to the compound, while knockdown increases resistance, suggesting BdPhoD is a pro-susceptibility factor. Together, we have generated a robust pipeline for identification of resistance loci and identified BdPhoD as a resistance mechanism in Babesia species.

Analysis of Spin in the Reporting of Studies on Electroanalgesia for Musculoskeletal Pain.

OBJECTIVE: The purpose of this study was to analyze the quality of reporting and presence of spin in abstracts of randomized clinical trials (RCTs) on the use of electroanalgesia for musculoskeletal pain. METHODS: The Physiotherapy Evidence Database (PEDro) was searched from 2010 to June 2021. Inclusion criteria were RCTs using electroanalgesia in individuals with musculoskeletal pain, written in any language, comparing 2 or more groups, and with pain as 1 of the outcomes. Two blinded, independent, and calibrated evaluators (Gwet's AC1 agreement analysis) performed eligibility and data extraction. General characteristics, report of outcomes, quality of reporting (Consolidated Standards of Reporting Trials for Abstracts [CONSORT-A]), and spin analysis (7-item spin checklist and spin analysis per section) were extracted from abstracts. RESULTS: Of 989 studies selected, 173 abstracts were analyzed after screening and eligibility criteria. Mean risk of bias on the PEDro scale was 6.02 ± 1.6 points. Most abstracts did not report significant differences for primary (51.4%) and secondary (63%) outcomes. Mean quality of reporting was 5.10 ± 2.4 points in the CONSORT-A, and spin was 2.97 ± 1.7. Abstracts had at least 1 type of spin (93%), and the conclusion presented the greatest number of spin types. More than 50% of abstracts recommended an intervention without significant differences between groups. CONCLUSION: This study found that the majority of RCT abstracts on electroanalgesia for musculoskeletal conditions in our sample had a moderate to high risk of bias, incomplete or missing information, and some type of spin. We recommend that health care providers who use electroanalgesia and the scientific community be aware of spin in published studies.

Genomic analysis of an outbreak of bovine tuberculosis in a man-made multi-host species system: A call for action on wildlife in Brazil.

We report on a 15-year-long outbreak of bovine tuberculosis (bTB) in wildlife from a Brazilian safari park. A timeline of diagnostic events and whole-genome sequencing (WGS) of 21 Mycobacterium bovis isolates from deer and llamas were analyzed. Accordingly, from 2003 to 2018, at least 16 animals, from eight species, died due to TB, which is likely an underestimated number. In three occasions since 2013, the deer presented positive tuberculin tests, leading to the park closure and culling of all deer. WGS indicated that multiple M. bovis strains were circulating, with at least three founding introductions since the park inauguration in 1977. Using a previously sequenced dataset of 71 M. bovis genomes from cattle, we found no recent transmission events between nearby farms and the park based on WGS. Lastly, by discussing socio-economic and environmental factors escaping current regulatory gaps that were determinant of this outbreak, we pledge for the development of a plan to report and control bTB in wildlife in Brazil.

NMR and EPR reveal a compaction of the RNA-binding protein FUS upon droplet formation.

Many RNA-binding proteins undergo liquid-liquid phase separation, which underlies the formation of membraneless organelles, such as stress granules and P-bodies. Studies of the molecular mechanism of phase separation in vitro are hampered by the coalescence and sedimentation of organelle-sized droplets interacting with glass surfaces. Here, we demonstrate that liquid droplets of fused in sarcoma (FUS)-a protein found in cytoplasmic aggregates of amyotrophic lateral sclerosis and frontotemporal dementia patients-can be stabilized in vitro using an agarose hydrogel that acts as a cytoskeleton mimic. This allows their spectroscopic characterization by liquid-phase NMR and electron paramagnetic resonance spectroscopy. Protein signals from both dispersed and condensed phases can be observed simultaneously, and their respective proportions can be quantified precisely. Furthermore, the agarose hydrogel acts as a cryoprotectant during shock-freezing, which facilitates pulsed electron paramagnetic resonance measurements at cryogenic temperatures. Surprisingly, double electron-electron resonance measurements revealed a compaction of FUS in the condensed phase.

Structure of SRSF1 RRM1 bound to RNA reveals an unexpected bimodal mode of interaction and explains its involvement in SMN1 exon7 splicing.

The human prototypical SR protein SRSF1 is an oncoprotein that contains two RRMs and plays a pivotal role in RNA metabolism. We determined the structure of the RRM1 bound to RNA and found that the domain binds preferentially to a CN motif (N is for any nucleotide). Based on this solution structure, we engineered a protein containing a single glutamate to asparagine mutation (E87N), which gains the ability to bind to uridines and thereby activates SMN exon7 inclusion, a strategy that is used to cure spinal muscular atrophy. Finally, we revealed that the flexible inter-RRM linker of SRSF1 allows RRM1 to bind RNA on both sides of RRM2 binding site. Besides revealing an unexpected bimodal mode of interaction of SRSF1 with RNA, which will be of interest to design new therapeutic strategies, this study brings a new perspective on the mode of action of SRSF1 in cells.

Targeted Detection of Cyclooxygenase-1 in Ovarian Cancer.

Overexpression of cyclooxygenase-1 (COX-1) is associated with the initiation and progression of ovarian cancer, and targeted imaging of COX-1 is a promising strategy for early detection of this disease. We report the discovery of N-[(5-carboxy-X-rhodaminyl)but-4-yl]-3-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)propenamide (CMP) as the first COX-1-targeted optical agent for imaging of ovarian cancer. CMP exhibits light emission at 604 nm (λmax), thereby minimizing tissue autofluorescence interference. In both purified enzyme and COX-1-expressing human ovarian adenocarcinoma (OVCAR-3) cells, CMP inhibits COX-1 at low nanomolar potencies (IC50 = 94 and 44 nM, respectively). CMP's selective binding to COX-1 in OVCAR-3 cells was visualized microscopically as intense intracellular fluorescence. In vivo optical imaging of xenografts in athymic nude mice revealed COX-1-dependent accumulation of CMP in COX-1-expressing mouse ovarian surface epithelial carcinoma (ID8-NGL) and OVCAR-3 cells. These results establish proof-of-principle for the feasibility of targeting COX-1 in the development of new imaging and therapeutic strategies for ovarian cancer.

Mycobacterium bovis: From Genotyping to Genome Sequencing.

Mycobacterium bovis is the main pathogen of bovine, zoonotic, and wildlife tuberculosis. Despite the existence of programs for bovine tuberculosis (bTB) control in many regions, the disease remains a challenge for the veterinary and public health sectors, especially in developing countries and in high-income nations with wildlife reservoirs. Current bTB control programs are mostly based on test-and-slaughter, movement restrictions, and post-mortem inspection measures. In certain settings, contact tracing and surveillance has benefited from M. bovis genotyping techniques. More recently, whole-genome sequencing (WGS) has become the preferential technique to inform outbreak response through contact tracing and source identification for many infectious diseases. As the cost per genome decreases, the application of WGS to bTB control programs is inevitable moving forward. However, there are technical challenges in data analyses and interpretation that hinder the implementation of M. bovis WGS as a molecular epidemiology tool. Therefore, the aim of this review is to describe M. bovis genotyping techniques and discuss current standards and challenges of the use of M. bovis WGS for transmission investigation, surveillance, and global lineages distribution. We compiled a series of associated research gaps to be explored with the ultimate goal of implementing M. bovis WGS in a standardized manner in bTB control programs.

Discovery of Furanone-Based Radiopharmaceuticals for Diagnostic Targeting of COX-1 in Ovarian Cancer.

In vivo targeting and visualization of cyclooxygenase-1 (COX-1) using multimodal positron emission tomography/computed tomography imaging represents a unique opportunity for early detection and/or therapeutic evaluation of ovarian cancer because overexpression of COX-1 has been characterized as a pathologic hallmark of the initiation and progression of this disease. The furanone core is a common building block of many synthetic and natural products that exhibit a wide range of biological activities. We hypothesize that furanone-based COX-1 inhibitors can be designed as imaging agents for the early detection, delineation of tumor margin, and evaluation of treatment response of ovarian cancer. We report the discovery of 3-(4-fluorophenyl)-5,5-dimethyl-4-(p-tolyl)furan-2(5H)-one (FDF), a furanone-based novel COX-1-selective inhibitor that exhibits adequate in vivo stability, plasma half-life, and pharmacokinetic properties for use as an imaging agent. We describe a novel synthetic scheme in which a Lewis acid-catalyzed nucleophilic aromatic deiodo[18F]fluorination reaction is utilized for the radiosynthesis of [18F]FDF. [18F]FDF binds efficiently to COX-1 in vivo and enables sensitive detection of ovarian cancer in subcutaneous and peritoneal xenograft models in mice. These results provide the proof of principle for COX-1-targeted imaging of ovarian cancer and identify [18F]FDF as a promising lead compound for further preclinical and clinical development.

A Step-by-Step Guide to Study Protein-RNA Interactions.

Protein-RNA complex formation is at the center of RNA metabolism and leads to the modulation of protein and RNA functions. We propose here a step-by-step guide to investigate these interactions including the identification of the protein and RNA parts involved in complex formation, the determination of the affinity of the complex and the characterization of the protein-RNA interface at amino acid and nucleotide level. Moreover, we briefly review the methods that are the most often used to obtain this information using primarily examples from our lab and finally mention what we perceive as the next challenges in the field.

Genome sequencing of Mycobacterium pinnipedii strains: genetic characterization and evidence of superinfection in a South American sea lion (Otaria flavescens).

BACKGROUND: Mycobacterium pinnipedii, a member of the Mycobacterium tuberculosis Complex (MTBC), is capable of infecting several host species, including humans. Recently, ancient DNA from this organism was recovered from pre-Columbian mummies of Peru, sparking debate over the origin and frequency of tuberculosis in the Americas prior to European colonization. RESULTS: We present the first comparative genomic study of this bacterial species, starting from the genome sequencing of two M. pinnipedii isolates (MP1 and MP2) obtained from different organs of a stranded South American sea lion. Our results indicate that MP1 and MP2 differ by 113 SNPs (single nucleotide polymorphisms) and 46 indels, constituting the first report of a mixed-strain infection in a sea lion. SNP annotation analyses indicate that genes of the VapBC family, a toxin-antitoxin system, and genes related to cell wall remodeling are under evolutionary pressure for protein sequence change in these strains. OrthoMCL analysis with seven modern isolates of M. pinnipedii shows that these strains have highly similar proteomes. Gene variations were only marginally associated with hypothetical proteins and PE/PPE (proline-glutamate and proline-proline-glutamate, respectively) gene families. We also detected large deletions in ancient and modern M. pinnipedii strains, including a few occurring only in modern strains, indicating a process of genome reduction occurring over the past one thousand years. Our phylogenomic analyses suggest the existence of two modern clusters of M. pinnipedii associated with geographic location, and possibly host species, and one basal node associated with the ancient M. pinnipedii strains. Previously described MiD3 and MiD4 deletions may have occurred independently, twice, over the evolutionary course of the MTBC. CONCLUSION: The presence of superinfection (i.e. mixed-strain infection) in this sea lion suggests that M. pinnipedii is highly endemic in this population. Mycobacterium pinnipedii proteomes of the studied isolates showed a high degree of conservation, despite being under genomic decay when compared to M. tuberculosis. This finding indicates that further genomes need to be sequenced and analyzed to increase the chances of finding variably present genes among strains or that M. pinnipedii genome remodeling occurred prior to bacterial speciation.

Informações de Enfermagem registradas nos prontuários frente às exigências do Conselho Federal de Enfermagem / Nursing information recorded in medical records in response to the requirements of the Federal Nursing Council / Información de Enfermería registrada en los prontuarios frente a las exigencias del Consejo Federal de Enfermería

Estudo exploratório retrospectivo de investigação de informações nos prontuários de pacientes internados\r\nem um hospital público, durante um trimestre. O objetivo foi avaliar o padrão de registro de enfermagem,\r\na identificação do profissional após o registro e a checagem da prescrição do enfermeiro e do médico,\r\nem relação aos requisitos já estabelecidos pela instituição e pela legislação. A partir da análise de 287\r\nprontuários, verificou-se os itens: avaliação da assistência de enfermagem, exame do prontuário do paciente, anotação de enfermagem e checagem da prescrição do enfermeiro e do médico. Nos resultados\r\nconstatou-se que dos prontuários auditados, cerca de 88% destes estavam em conformidade. Quanto\r\nà identificação, 82% estavam conforme; e ao verificar a checagem da prescrição do enfermeiro e do\r\nmédico, estavam conformes 86,5% e 90% respectivamente.

A descriptive, exploratory study of research information in the records of patients admitted to a public\r\nhospital, during a quarter. The objective of this study was to evaluate the standard of nursing record, the\r\nidentification of the work after the registration and checking of the prescription the nurse and physician,\r\nin relation to requirements established by the institution and legislation. Being analyzed 287 medical\r\nrecords, checking the items: evaluation of nursing care, examining the patient's medical record, nursing\r\nrecords and checking the prescription and the nurse médico.Nos results showed that of 287 medical\r\nrecords audited on average 88% of these were accordingly. How to identify 82% were compliant. And to\r\nverify the check prescription nurse, 86.5% and 90% of the physician was in compliance.

Un estudio descriptivo y exploratorio de información de la investigación en los registros de los pacientes\r\ningresados en un hospital público, durante un trimestre. El objetivo de este estudio fue evaluar el nivel de\r\nregistro de enfermería, la identificación de la obra después de la inscripción y el control de la prescripción\r\nde la enfermera y el médico, en relación con los requisitos establecidos por la institución y la legislación.\r\nQue se está analizando 287 expedientes médicos, control de los elementos: la evaluación de los cuidados\r\nde enfermería, examinar el historial médico del paciente, registros de enfermería y control de la prescripción enfermera y médico.Nos los resultados mostraron que de 287 expedientes médicos comprobados\r\nen promedio el 88% de éstos eran en consecuencia. ¿Cómo identificar el 82% fueron conformes. Y para\r\nverificar la enfermera de la prescripción de verificación, el 86,5% y el 90% de los médicos estaban de acuerdo

Serological survey of anti-Leptospira spp. antibodies in Barbary sheep (Ammotragus lervia) at the Curitiba Zoo, southern Brazil / Estudo sorológico de anticorpos anti-Leptospira spp. em aoudads (Ammotragus lervia) no zoológico de Curitiba, sul do Brasil

Leptospirosis is a worldwide zoonosis, affecting humans, domestic and wild animals. The present study aimed to evaluate prevalence of anti-Leptospira spp. antibodies in Barbary sheep at the Curitiba zoo. Microscopic agglutination test (MAT) was performed using 17 serogroups. Antibodies against Leptospira spp. were observed in 23.5% samples and Icterohaemorrhagiae was the only prevalent serogroup. The presence of anti-Leptospira antibodies in Barbary sheep indicates exposure to leptospires; thus monitoring and preventive measures are necessary in zoo's captive animals, since they can act as sentinels of environmental exposure in an area with high movement of people.(AU)

A leptospirose é uma zoonose mundial que afeta seres humanos, animais domésticos e selvagens. O presente estudo objetivou avaliar a prevalência de anticorpos anti-Leptospira spp. em aoudads do zoológico de Curitiba. Foi realizado o teste de Soroaglutinação microscópica (SAM) utilizando 17 sorogrupos. Anticorpos contra Leptospira spp. foram observados em 23.5% das amostras de aoudads e Icterohaemorrhagiae foi o único sorogrupo prevalente. A presença de anticorpos em aoudads indica exposição a leptospiras portanto monitoramento e medidas preventivas são necessários em animais confinados em zoológicos, uma vez eles podem atuar como sentinelas de exposição ambiental em uma área com alta circulação de pessoas.(AU)

Consequences of work group manpower and expertise understaffing: A multilevel approach.

Complaints of chronic understaffing in organizations have become common among workers as employers face increasing pressures to do more with less. Unfortunately, despite its prevalence, there is currently limited research in the literature regarding the nature of workplace understaffing and its consequences. Taking a multilevel approach, this study introduces a new multidimensional conceptualization of subjective work group understaffing, comprising of manpower and expertise understaffing, and examines both its performance and well-being consequences for individual workers (Study 1) and work groups (Study 2). Results show that the relationship between work group understaffing and individual and work group emotional exhaustion is mediated through quantitative workload and role ambiguity for both levels of analysis. Work group understaffing was also related to individual job performance, but not group performance, and this relationship was mediated by role ambiguity. Results were generally similar for the 2 dimensions of understaffing. Implications for theory and research and future research directions are discussed. (PsycINFO Database Record

Stereotactic radiosurgery in the treatment of brain metastases from gynecologic primary cancer.

BACKGROUND: Brain metastases from gynecologic primary cancers are rare events, but they can be a cause of morbidity and mortality when they occur. METHODS: This is a single institution retrospective study on patients with brain metastases from gynecologic primary cancer who received Gamma Knife stereotactic radiosurgery (SRS). Between 2000 and 2013, a total of 33 patients with brain metastases from gynecologic primary including cervical (n=2), endometrial (n=6) and ovarian cancers (n=25) were treated with SRS at our institution. Electronic medical records were reviewed to determine survival, patterns of failure and cause of death. RESULTS: Overall survival at 1, 2 and 5 years for the entire population was 47.1%, 21.7%, and 14.5%, respectively. There was no difference in survival between the primary cancers (log-rank p = 0.33). 36.4% patients died of neurologic death. Local failure at 1 and 2 years for the entire population was 10.4% and 14.3%, respectively. There was no difference in local failure between the primary cancers. Distant brain failure at 1, 2 and 5 years for the entire population was 20.6%, 27.7%, and 31.3%, respectively. On multivariate Cox Proportional Hazards analysis, age was the only predictor of overall survival (HR = 1.03, p = 0.01). Ovarian cancer patients had decreased risk of distant brain failure (HR = 0.17, p=0.005), whereas cervical cancer patients had an increased risk of distant brain failure (HR = 35.7, p = 0.001). CONCLUSIONS: SRS represents a feasible treatment option for patients with brain metastases from gynecologic cancer. Younger age is a positive prognostic factor. Ovarian cancer patients have lower risk of distant brain failure.

Fluorocoxib A enables targeted detection of cyclooxygenase-2 in laser-induced choroidal neovascularization.

Ocular angiogenesis is a blinding complication of age-related macular degeneration and other retinal vascular diseases. Clinical imaging approaches to detect inflammation prior to the onset of neovascularization in these diseases may enable early detection and timely therapeutic intervention. We demonstrate the feasibility of a previously developed cyclooxygenase-2 (COX-2) targeted molecular imaging probe, fluorocoxib A, for imaging retinal inflammation in a mouse model of laser-induced choroidal neovascularization. This imaging probe exhibited focal accumulation within laser-induced neovascular lesions, with minimal detection in proximal healthy tissue. The selectivity of the probe for COX-2 was validated

Antitumor Activity of Cytotoxic Cyclooxygenase-2 Inhibitors.

Targeted delivery of chemotherapeutic agents to tumors has been explored as a means to increase the selectivity and potency of cytotoxicity. Most efforts in this area have exploited the molecular recognition of proteins highly expressed on the surface of cancer cells followed by internalization. A related approach that has received less attention is the targeting of intracellular proteins by ligands conjugated to anticancer drugs. An attractive target for this approach is the enzyme cyclooxygenase-2 (COX-2), which is highly expressed in a range of malignant tumors. Herein, we describe the synthesis and evaluation of a series of chemotherapeutic agents targeted to COX-2 by conjugation to indomethacin. Detailed characterization of compound 12, a conjugate of indomethacin with podophyllotoxin, revealed highly potent and selective COX-2 inhibition in vitro and in intact cells. Kinetics and X-ray crystallographic studies demonstrated that compound 12 is a slow, tight-binding inhibitor that likely binds to COX-2's allosteric site with its indomethacin moiety in a conformation similar to that of indomethacin. Compound 12 exhibited cytotoxicity in cell culture similar to that of podophyllotoxin with no evidence of COX-2-dependent selectivity. However, in vivo, compound 12 accumulated selectively in and more effectively inhibited the growth of a COX-2-expressing xenograft compared to a xenograft that did not express COX-2. Compound 12, which we have named chemocoxib A, provides proof-of-concept for the in vivo targeting of chemotherapeutic agents to COX-2 but suggests that COX-2-dependent selectivity may not be evident in cell culture-based assays.

Extensive Shared Chemosensitivity between Malaria and Babesiosis Blood-Stage Parasites.

The apicomplexan parasites that cause malaria and babesiosis invade and proliferate within erythrocytes. To assess the potential for common antiparasitic treatments, we measured the sensitivities of multiple species of Plasmodium and Babesia parasites to the chemically diverse collection of antimalarial compounds in the Malaria Box library. We observed that these parasites share sensitivities to a large fraction of the same inhibitors and we identified compounds with strong babesiacidal activity.

The Plasmodium PHIST and RESA-Like Protein Families of Human and Rodent Malaria Parasites.

The phist gene family has members identified across the Plasmodium genus, defined by the presence of a domain of roughly 150 amino acids having conserved aromatic residues and an all alpha-helical structure. The family is highly amplified in P. falciparum, with 65 predicted genes in the genome of the 3D7 isolate. In contrast, in the rodent malaria parasite P. berghei 3 genes are identified, one of which is an apparent pseudogene. Transcripts of the P. berghei phist genes are predominant in schizonts, whereas in P. falciparum transcript profiles span different asexual blood stages and gametocytes. We pursued targeted disruption of P. berghei phist genes in order to characterize a simplistic model for the expanded phist gene repertoire in P. falciparum. Unsuccessful attempts to disrupt P. berghei PBANKA_114540 suggest that this phist gene is essential, while knockout of phist PBANKA_122900 shows an apparent normal progression and non-essential function throughout the life cycle. Epitope-tagging of P. falciparum and P. berghei phist genes confirmed protein export to the erythrocyte cytoplasm and localization with a punctate pattern. Three P. berghei PEXEL/HT-positive exported proteins exhibit at least partial co-localization, in support of a common vesicular compartment in the cytoplasm of erythrocytes infected with rodent malaria parasites.

Targeted imaging of cancer by fluorocoxib C, a near-infrared cyclooxygenase-2 probe.

Cyclooxygenase-2 (COX-2) is a promising target for the imaging of cancer in a range of diagnostic and therapeutic settings. We report a near-infrared COX-2-targeted probe, fluorocoxib C (FC), for visualization of solid tumors by optical imaging. FC exhibits selective and potent COX-2 inhibition in both purified protein and human cancercell lines. In vivo optical imaging shows selective accumulation of FC in COX-2-overexpressing human tumor xenografts [1483 head and neck squamous cell carcinoma (HNSCC)] implanted in nude mice, while minimal uptake is detectable in COX-2-negative tumor xenografts (HCT116)or 1483 HNSCC xenografts preblocked with the COX-2-selective inhibitor celecoxib. Time course imaging studies conducted from 3 h to 7-day post-FC injection revealed a marked reduction in nonspecific fluorescent signals with retention of fluorescence in 1483 HNSCC tumors. Thus, use of FC in a delayed imaging protocol offers an approach to improve imaging signal-to-noise that should improve cancer detection in multiple preclinical and clinical settings.

Design of Fluorine-Containing 3,4-Diarylfuran-2(5H)-ones as Selective COX-1 Inhibitors.

We report the design and synthesis of fluorine-containing cyclooxygenase-1 (COX-1)-selective inhibitors to serve as prototypes for the development of a COX-1-targeted imaging agent. Deletion of the SO2CH3 group of rofecoxib switches the compound from a COX-2- to a COX-1-selective inhibitor, providing a 3,4-diarylfuran-2(5H)-one scaffold for structure-activity relationship studies of COX-1 inhibition. A wide range of fluorine-containing 3,4-diarylfuran-2(5H)-ones were designed, synthesized, and tested for their ability to selectively inhibit COX-1 in purified protein and human cancer cell assays. Compounds containing a fluoro-substituent on the C-3 phenyl ring and a methoxy-substituent on the C-4 phenyl ring of the 3,4-diarylfuran-2(5H)-one scaffold were the best COX-1-selective agents of those evaluated, exhibiting IC50s in the submicromolar range. These compounds provide the foundation for development of an agent to facilitate radiologic imaging of ovarian cancer expressing elevated levels of COX-1.