A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress

Cisplatin and its platinum analogs, carboplatin and oxaliplatin, are some of the most widely used cancer chemotherapeutics. Although cisplatin and carboplatin are used primarily in germ cell, breast and lung malignancies, oxaliplatin is instead used almost exclusively to treat colorectal and other gastrointestinal cancers. Here we utilize a unique, multi-platform genetic approach to study the mechanism of action of these clinically established platinum anti-cancer agents, as well as more recently developed cisplatin analogs. We show that oxaliplatin, unlike cisplatin and carboplatin, does not kill cells through the DNA-damage response. Rather, oxaliplatin kills cells by inducing ribosome biogenesis stress. This difference in drug mechanism explains the distinct clinical implementation of oxaliplatin relative to cisplatin, and it might enable mechanistically informed selection of distinct platinum drugs for distinct malignancies. These data highlight the functional diversity of core components of front-line cancer therapy and the potential benefits of applying a mechanism-based rationale to the use of our current arsenal of anti-cancer drugs

Agent-Based Model Forecasts Aging of the Population of People Who Inject Drugs in Metropolitan Chicago and Changing Prevalence of Hepatitis C Infections

<div><p>People who inject drugs (PWID) are at high risk for blood-borne pathogens transmitted during the sharing of contaminated injection equipment, particularly hepatitis C virus (HCV). HCV prevalence is influenced by a complex interplay of drug-use behaviors, social networks, and geography, as well as the availability of interventions, such as needle exchange programs. To adequately address this complexity in HCV epidemic forecasting, we have developed a computational model, the Agent-based Pathogen Kinetics model (APK). APK simulates the PWID population in metropolitan Chicago, including the social interactions that result in HCV infection. We used multiple empirical data sources on Chicago PWID to build a spatial distribution of an <i>in silico</i> PWID population and modeled networks among the PWID by considering the geography of the city and its suburbs. APK was validated against 2012 empirical data (the latest available) and shown to agree with network and epidemiological surveys to within 1%. For the period 2010–2020, APK forecasts a decline in HCV prevalence of 0.8% per year from 44(±2)% to 36(±5)%, although some sub-populations would continue to have relatively high prevalence, including Non-Hispanic Blacks, 48(±5)%. The rate of decline will be lowest in Non-Hispanic Whites and we find, in a reversal of historical trends, that incidence among non-Hispanic Whites would exceed incidence among Non-Hispanic Blacks (0.66 per 100 per years vs 0.17 per 100 person years). APK also forecasts an increase in PWID mean age from 35(±1) to 40(±2) with a corresponding increase from 59(±2)% to 80(±6)% in the proportion of the population >30 years old. Our studies highlight the importance of analyzing subpopulations in disease predictions, the utility of computer simulation for analyzing demographic and health trends among PWID and serve as a tool for guiding intervention and prevention strategies in Chicago, and other major cities.</p></div

Injection-Related Risk Behavior and Engagement in Outreach, Intervention and Prevention Services Across 20 US Cities

BACKGROUND: Monitoring the effects of HIV prevention efforts on risk behaviors among persons who inject drugs is a key to inform prevention programs and policy. METHODS: Using data from the 2012 National HIV Behavioral Surveillance interviews with persons who inject drugs across 20 US cities (n = 10,171), we conducted latent class analysis to identify injection risk classes and assess the relationship between engagement in prevention services and injection-related risk behavior. We conducted stratified analyses to examine the consistency of these associations across different geographical regions. RESULTS: The latent class analysis identified 6 distinct classes of injection-related risk behavior. The class structure was consistent across regions of the United States, but the distribution of risk classes varied significantly across regions. With covariate adjustment, the South had the most high-risk behavior (21%) and the Midwest had the least (6%). Participation in syringe access services and other prevention services was the lowest in the South. Syringe access was associated with a significantly lower likelihood of membership in the highest risk class in all regions except the Midwest. Participation in individual or group intervention with a practical skills component was associated with less risky injection behavior in all regions except the Northeast. Interventions that featured only safer injection information and discussion had no relationship with risk class. CONCLUSIONS: Our findings support evidence of the effectiveness of syringe service programs and safer injection skills training in reducing high-risk injection behavior and underscore the need to improve access to these prevention interventions in the South of the United States