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Here, we report the fragment-based discovery of BI-9321, a potent, selective and cellular active antagonist of the NSD3-PWWP1 domain. The human NSD3 protein is encoded by the WHSC1L1 gene located in the 8p11-p12 amplicon, frequently amplified in breast and squamous lung cancer. Recently, it was demonstrated that the PWWP1 domain of NSD3 is required for the viability of acute myeloid leukemia cells. To further elucidate the relevance of NSD3 in cancer biology, we developed a chemical probe, BI-9321, targeting the methyl-lysine binding site of the PWWP1 domain with sub-micromolar in vitro activity and cellular target engagement at 1 µM. As a single agent, BI-9321 downregulates Myc messenger RNA expression and reduces proliferation in MOLM-13 cells. This first-in-class chemical probe BI-9321, together with the negative control BI-9466, will greatly facilitate the elucidation of the underexplored biological function of PWWP domains. A chemical probe BI-9321 for the PWWP1 domain of NSD3 and its inactive analog were identified. BI-9321 binds to the methyl-lysine binding site, reduces the association of NSD3 with chromatin and inhibits proliferation of acute myeloid leukemia cells.

Objectives In Australia, surgical treatment options for children with bilateral severe to profound sensorineural hearing loss exist in a continuum ranging from unilateral cochlear implantation (CI), sequential bilateral CI through to simultaneous bilateral CI, depending on the condition. When treatment options are mutually exclusive, the mean costs and benefits of each treatment group are summed together to obtain the total mean costs and benefits. This enables an incremental analysis of treatment options in the context of the treated populations.The objective was to evaluate the cost-utility of current Australian CI treatment practices in children using domestic costs and consequences when compared with bilateral hearing aids (HAs). Research design Economic evaluation including a Markov model based on secondary sources. Setting The base case modeled a government health payer perspective over a child's lifetime. Primary and secondary school education costs were also assessed. Intervention Bilateral HAs compared with CI, including unilateral, sequential bilateral, or simultaneous bilateral CI weighted according to treatment. Main outcome measures Incremental costs per quality adjusted life year. Results Approximately 42% of children in Australia with unilateral CI did not transition to sequential bilateral nor undergo simultaneous bilateral implantation. This differs from previous economic evaluations that assumed 100% of children transitioned to sequential bilateral CI treatment or were treated with simultaneous bilateral CI.The incremental cost utility of unilateral cochlear implantation compared with HAs was AUD 21,947/QALY. The weighted average incremental cost utility of the combined cochlear implantation treatment groups was AUD 31,238/QALY when compared with HAs. Conclusion Previous economic evaluations of cochlear implantation assumed 100% of unilaterally treated patients would transition to sequential bilateral or be treated with simultaneous bilateral implantation. This approach does not take into account the total treated population, where a proportion of patients are treated with unilateral CI.CI was cost effective when compared with HAs, and included children treated with unilateral, sequential bilateral, and simultaneous bilateral CI.The model was sensitive to the number of assessment and habilitation visits. Alternative health service models with cost efficiencies are needed to reduce after care costs.

Here we present a virtual docking screen of 1648 commercially available covalent fragments, and identified covalent inhibitors of cysteine protease cathepsin L. These inhibitors did not inhibit closely related protease cathepsin B. Thus, we have established virtual docking of covalent fragments as an approach to discover covalent enzyme inhibitors.

PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is essential for maturation of ribosomes, may have a role in lipogenesis, and is implicated in several diseases. A potent, selective, and cell- active PRMT3 inhibitor would be a valuable tool for further investigating PRMT3 biology. Here we report the discovery of the first PRMT3 chemical probe, SGC707, by structure-based optimization of the allosteric PRMT3 inhibitors we reported previously, and thorough characterization of this probe in biochemical, biophysical, and cellular assays. SGC707 is a potent PRMT3 inhibitor (IC50 = 31 ± 2 nm, KD = 53 ± 2 nm) with outstanding selectivity (selective against 31 other methyltransferases and more than 250 non-epigenetic targets). The mechanism of action studies and crystal structure of the PRMT3-SGC707 complex confirm the allosteric inhibition mode. Importantly, SGC707 engages PRMT3 and potently inhibits its methyltransferase activity in cells. It is also bioavailable and suitable for animal studies. This well- characterized chemical probe is an excellent tool to further study the role of PRMT3 in health and disease.

In recent years, the concept of circular economy (CE) has increasingly gained traction, especially among practice and policy communities. In academia, research on CE mainly deals with practical and...

Sequential and simultaneous bilateral cochlear implants are emerging as appropriate treatment options for Australian adults with sensory deficits in both cochleae. Current funding of Australian public hospitals does not provide for simultaneous bilateral cochlear implantation (CI) as a separate surgical procedure. Previous cost-effectiveness studies of sequential and simultaneous bilateral CI assumed 100% of unilaterally treated patients' transition to a sequential bilateral CI. This assumption does not place cochlear implantation in the context of the generally treated population. When mutually exclusive treatment options exist, such as unilateral CI, sequential bilateral CI, and simultaneous bilateral CI, the mean costs of the treated populations are weighted in the calculation of incremental cost-utility ratios. The objective was to evaluate the cost-utility of bilateral hearing aids (HAs) compared with unilateral, sequential, and simultaneous bilateral CI in Australian adults with bilateral severe to profound sensorineural hearing loss.Cost-utility analysis of secondary sources input to a Markov model.Australian health care perspective, lifetime horizon with costs and outcomes discounted 5% annually.Bilateral HAs as treatment for bilateral severe to profound sensorineural hearing loss compared with unilateral, sequential, and simultaneous bilateral CI.Incremental costs per quality adjusted life year (AUD/QALY).When compared with bilateral hearing aids the incremental cost-utility ratio for the CI treatment population was AUD11,160/QALY. The incremental cost-utility ratio was weighted according to the number of patients treated unilaterally, sequentially, and simultaneously, as these were mutually exclusive treatment options.No peer-reviewed articles have reported the incremental analysis of cochlear implantation in a continuum of care for surgically treated populations with bilateral severe to profound sensorineural hearing loss. Unilateral, sequential, and simultaneous bilateral CI were cost-effective when compared with bilateral hearing aids. Technologies that reduce the total number of visits for a patient could introduce additional cost efficiencies into clinical practice.

The novel naphthoquinone 12,13-dihydro-N-methyl-6,11,13-trioxo-5H-benzo[4,5]cyclohepta[1,2-b]naphthalen-5,12-imine (hereafter called TU100) was created as a potential chemotherapeutic agent. Previous work showed it is an irreversible inhibitor of type I and II topoisomerases that alkylates specific enzyme thiols. While analyzing the effect of TU100 on cancer cells, we discovered it is a potent inhibitor of luciferase derived from both Photinus pyralis (fireflies) and Renilla reniformis (sea pansy). Pre-incubation experiments showed that TU100 does not irreversibly inactivate luciferase, indicating its mechanism is different from that observed with topoisomerases. Firefly luciferase generates light using ATP and luciferin as substrates (bioluminescence). An examination of TU100 inhibition at varying substrate concentrations revealed the drug is uncompetitive with respect to ATP and competitive with respect to luciferin. The TU100 binding constant (K(I)) is 2.5±0.7 μM as determined by Dixon plot analysis. These data suggest TU100 specifically binds the luciferase-ATP complex and prevents its interaction with luciferin. Given the novel structure of TU100, unique mechanism of action, and ability to target luciferase from different species, these results identify TU100 as an important new reagent for investigating and regulating bioluminescent enzymes.

Cervical cancer is one of the most preventable forms of cancer and the Pap smear test is one of the most widely accessible forms of cancer screening. An important public health issue is the extent to which Canadian women are engaging in regular screening for cervical cancer, particularly potentially at-risk groups such as recent immigrants and women from minority ethnic backgrounds. We use recent population health surveys to analyze immigrant and native-born women's use of Pap smear testing, with a focus on how screening rates differ by ethnic background and characteristics of immigration. We find that almost all recent immigrant women have markedly lower use of Pap smear testing than comparable Canadian-born women, but these rates slowly increase with years in Canada. However, we find wide variation in rates of screening by ethnic background. Screening rates for White immigrant women from countries where the official language is neither English nor French approach Canadian-born women's utilization rates after 15-20 years in Canada, as do the screening rates of Black and Hispanic women. Screening rates for those from Asian backgrounds remain significantly below native-born Canadian levels even after many years in Canada. As well, immigrant women of Asian background who arrived as children and second-generation Asian Canadians both exhibit significantly lower rates of Pap smear testing than Canadian-born White women.

A lack of useful small molecule tools has precluded thorough interrogation of the biological function of SMYD2, a lysine methyltransferase with known tumor-suppressor substrates. Systematic exploration of the structure–activity relationships of a previously known benzoxazinone compound led to the synthesis of A-893, a potent and selective SMYD2 inhibitor (IC50: 2.8 nM). A cocrystal structure reveals the origin of enhanced potency, and effective suppression of p53K370 methylation is observed in a lung carcinoma (A549) cell line.

This paper combines multiple cross-sections of data drawn from the National Population Health Survey and Canadian Community Health Survey to confirm the existence of the 'healthy immigrant effect', specifically that immigrants are in relatively better health on arrival in Canada compared to native-born Canadians, and that immigrant health converges with years in Canada to native-born levels. The paper finds robust evidence that the healthy immigrant effect is present for the incidence of chronic conditions for both men and women, and results in relatively slow convergence to native-born levels. There is only weak evidence in terms of self-assessed health status. The inclusion of controls for region of origin and year of arrival does not account for the observed effects, although region of origin is an important determinants of immigrant health. The paper then considers some alternative explanations for the observed differences, and support is found for the idea that the healthy immigrant effect reflects convergence in physical health rather than convergence in screening and detection of existing health problems.

This chapter discusses the role of cell cycle machinery in initiation and progression of pancreatic cancer. Normal pancreatic cells—their types, organization, and functions—are first described to characterize the environment in which cellular transformation and tumor expansion occurs. The epidemiology and histology of pancreatic cancer is then briefly presented to emphasize the urgent need for earlier diagnosis and more effective treatments. Current efforts towards this goal are focused on understanding the disease at the molecular level, so the hallmarks of cancerous cells are discussed with respect to the progression model of pancreatic cancer development. Because the pancreas is composed of various cell types with different genetic backgrounds and regulatory systems, identifying the cell in which cancer originates is of utmost importance. Molecular mechanisms of normal proliferative control are then presented so that mechanisms by which they are disrupted can be appreciated. Particular attention is paid to how signaling transduction pathways and the cell cycle machinery cooperate to make cell fate decisions at the Restriction point. This analysis sets the stage for evaluating the role of cell cycle control mechanisms in transformation of the initiating cell in pancreatic cancer. The chapter concludes by arguing that genetic alterations associated with pancreatic cancer indicate disrupted cell cycle control mechanisms play a central role in disease development and progression.

Sunscreens are widely utilized due to the adverse effects of ultraviolet (UV) radiation on human health. The safety of their active ingredients as well as that of any modified versions generated during use is thus of concern. Chlorine is used as a chemical disinfectant in swimming pools. Its reactivity suggests sunscreen components might be chlorinated, altering their absorptive and/or cytotoxic properties. To test this hypothesis, the UV-filters oxybenzone, dioxybenzone, and sulisobenzone were reacted with chlorinating agents and their UV spectra analyzed. In all cases, a decrease in UV absorbance was observed. Given that chlorinated compounds can be cytotoxic, the effect of modified UV-filters on cell viability was examined. Chlorinated oxybenzone and dioxybenzone caused significantly more cell death than unchlorinated controls. In contrast, chlorination of sulisobenzone actually reduced cytotoxicity of the parent compound. Exposing a commercially available sunscreen product to chlorine also resulted in decreased UV absorbance, loss of UV protection, and enhanced cytotoxicity. These observations show chlorination of sunscreen active ingredients can dramatically decrease UV absorption and generate derivatives with altered biological properties.

The naphthoquinone adduct 12,13-dihydro-N-methyl-6,11,13-trioxo-5H-benzo[4,5]cyclohepta[1,2-b]naphthalen-5,12-imine (hereafter called TU100) contains structural features of both the anthracycline and isoquinone chemotherapeutics. An initial characterization showed TU100 is cytotoxic to mammalian cells and can inhibit topoisomerase I and II. Analysis using topoisomerase I now reveals TU100 is a slow acting inhibitor targeting the enzyme in the absence of DNA. Diluting pre-incubated TU100 and topoisomerase I failed to alleviate inhibition, suggesting the enzyme is being covalently modified. Critical cysteine thiols were identified as the possible target based on the ability of reducing agents to reverse TU100 inhibition. Consistent with this idea, TU100 protected topoisomerase I from inactivation by the sulfhydryl modifying agent N-ethylmaleimide (NEM). Unlike agents nonspecifically reacting with thiols, however, TU100 is specific for topoisomerase because it failed to inhibit a cysteine dependent protease. These results indicate TU100 is a novel naphthoquinone that inactivates free topoisomerase I via alkylation of cysteine residues.

In an attempt to create more effective chemotherapeutic compounds, the naphthoquinone adduct 12,13-dihydro-N-methyl-6,11,13-trioxo-5H-benzo[4,5]cyclohepta[1,2-b]naphthalen-5,12-imine (hereafter called TU100) was synthesized. Cell viability studies revealed TU100 is specific for eukaryotes and induces cell death. Based on its structural similarities to the anthracyclines and isoquinolines, the ability of TU100 to inhibit topoisomerase I and II was examined. TU100 was an effective inhibitor of both enzymes, as indicated by its ability to prevent topoisomerase-mediated relaxation of supercoiled plasmid DNA. The mechanism of action does not involve TU100 intercalation into DNA, unlike anthracyclines. Pre-incubation of topoisomerase with TU100 dramatically decreased the IC 50 , suggesting the drug is a novel slow acting topoisomerase inhibitor that works in the absence of DNA. Taken together these results indicate the novel naphthoquinone adduct TU100 is a dual topoisomerase I/II inhibitor with a unique mechanism of action and chemotherapeutic potential.

Background: Few studies have monitored physician supply in Canada, and no studies have specifically examined the Canadian plastic surgery workforce. Methods: In this study, data were gathered by three methods. A survey was distributed to all members of the Canadian Society of Plastic Surgeons in October of 2004. Opinions on the availability of plastic surgery services were solicited. A second survey that focused on demographics and workload was distributed in December of 2004. Finally, the locations of all Canadian trainees graduating between 1995 and 2005 were reviewed. Results: The response rate to the first survey was 42 percent. Seventy-eight percent of respondents felt that there was a shortage of plastic surgeons in their community. The response rate to the second survey was 40 percent. Twenty-eight percent of respondents were within 5 years of retirement and 3.2 percent stated that they planned to emigrate by 2010. The mean waiting time for an elective consultation was 32 ± 33 weeks. Review of all 179 plastic surgery graduates over the past 10 years revealed that 23 percent now practice outside of Canada. Conclusions: When these results are projected to the total workforce, they indicate that there will be a future shortage of plastic surgeons in Canada. To prevent a further deficit, there is a need to increase the number of plastic surgery trainees in Canada, to offer incentives for graduates to stay in Canada, and to possibly recruit more foreign-trained plastic surgeons to practice within Canada.

This paper aims to address a gap in our understanding of immigrant health issues by examining the determinants of excess weight--an important indicator of current and future health. The paper combines data drawn from recent large health surveys to identify how the weight of recent immigrants compares with that of native-born people, and how the likelihood of becoming overweight or obese changes with additional years in Canada. We find evidence that on average, immigrants are substantially less likely to be obese or overweight upon arrival in Canada. These measures converge slowly to native-born levels, but there is marked variation by the ethnicity of the immigrant. Since changes in weight will reflect choices with respect to diet and activity, the extent to which overweight and obesity rates change with years in Canada may reflect the extent to which immigrants interact with or are influenced by members of their ethnic group who reside in the same area. We find evidence that ethnic group social network effects exert a quantitatively important influence on the incidence of being overweight and obese for members of most ethnic minorities, tempering the process of adjustment to Canadian lifestyle norms that may be driving excess weight gain with additional years in Canada.

The use of self-assessed health status (SAHS) as a measure of health is common in empirical research. We analyse a unique Australian survey in which a random sub-sample of respondents answer a standard self-assessed health question twice-before and after an additional set of health related questions. A total of 28% of respondents change their reported health status. Response reliability is related to age, income and occupation. We also compare the responses of these individuals to other respondents who are queried only once, to isolate effects of question order and mode of administration.