Altered RECQ Helicase Expression in Sporadic Primary Colorectal Cancers

AbstractDeregulation of DNA repair enzymes occurs in cancers and may create a susceptibility to chemotherapy. Expression levels of DNA repair enzymes have been shown to predict the responsiveness of cancers to certain chemotherapeutic agents. The RECQ helicases repair damaged DNA including damage caused by topoisomerase I inhibitors, such as irinotecan. Altered expression levels of these enzymes in colorectal cancer (CRC) may influence the response of the cancers to irinotecan. Thus, we assessed RECQ helicase (WRN, BLM, RECQL, RECQL4, and RECQL5) expression in primary CRCs, matched normal colon, and CRC cell lines. We found that BLM and RECQL4 mRNA levels are significantly increased in CRC (P = .0011 and P < .0001, respectively), whereas RECQL and RECQL5 are significantly decreased (P = .0103 and P = .0029, respectively). RECQ helicase expression patterns varied between specific molecular subtypes of CRCs. The mRNA and protein expression of the majority of the RECQ helicases was closely correlated, suggesting that altered mRNA expression is the predominant mechanism for deregulated RECQ helicase expression. Immunohistochemistry localized the RECQ helicases to the nucleus. RECQ helicase expression is altered in CRC, suggesting that RECQ helicase expression has potential to identify CRCs that are susceptible to specific chemotherapeutic agents

RESEARCH Open Access

Involving consumers and the community in the development of a diagnostic instrument for fetal alcohol spectrum disorders in Australi

Thyroid-Hormone–Disrupting Chemicals: Evidence for Dose-Dependent Additivity or Synergism

Endocrine disruption from environmental contaminants has been linked to a broad spectrum of adverse outcomes. One concern about endocrine-disrupting xenobiotics is the potential for additive or synergistic (i.e., greater-than-additive) effects of mixtures. A short-term dosing model to examine the effects of environmental mixtures on thyroid homeostasis has been developed. Prototypic thyroid-disrupting chemicals (TDCs) such as dioxins, polychlorinated biphenyls (PCBs), and poly-brominated diphenyl ethers have been shown to alter thyroid hormone homeostasis in this model primarily by up-regulating hepatic catabolism of thyroid hormones via at least two mechanisms. Our present effort tested the hypothesis that a mixture of TDCs will affect serum total thyroxine (T(4)) concentrations in a dose-additive manner. Young female Long-Evans rats were dosed via gavage with 18 different polyyhalogenated aromatic hydrocarbons [2 dioxins, 4 dibenzofurans, and 12 PCBs, including dioxin-like and non-dioxin-like PCBs] for 4 consecutive days. Serum total T(4) was measured via radioimmunoassay in samples collected 24 hr after the last dose. Extensive dose–response functions (based on seven to nine doses per chemical) were determined for individual chemicals. A mixture was custom synthesized with the ratio of chemicals based on environmental concentrations. Serial dilutions of this mixture ranged from approximately background levels to 100-fold greater than background human daily intakes. Six serial dilutions of the mixture were tested in the same 4-day assay. Doses of individual chemicals that were associated with a 30% TH decrease from control (ED(30)), as well as predicted mixture outcomes were calculated using a flexible single-chemical-required method applicable to chemicals with differing dose thresholds and maximum-effect asymptotes. The single-chemical data were modeled without and with the mixture data to determine, respectively, the expected mixture response (the additivity model) and the experimentally observed mixture response (the empirical model). A likelihood-ratio test revealed statistically significant departure from dose additivity. There was no deviation from additivity at the lowest doses of the mixture, but there was a greater-than-additive effect at the three highest mixtures doses. At high doses the additivity model underpredicted the empirical effects by 2- to 3-fold. These are the first results to suggest dose-dependent additivity and synergism in TDCs that may act via different mechanisms in a complex mixture. The results imply that cumulative risk approaches be considered when assessing the risk of exposure to chemical mixtures that contain TDCs

Biological Case Against Downlisting the Whooping Crane and for Improving Implementation under the Endangered Species Act

The Whooping Crane (Grus americana; WHCR) is a large, long-lived bird endemic to North America. The remnant population migrates between Aransas National Wildlife Refuge, USA, and Wood Buffalo National Park, Canada (AWBP), and has recovered from a nadir of 15-16 birds in 1941 to ~540 birds in 2022. Two ongoing reintroduction efforts in Louisiana and the Eastern Flyway together total ~150 birds. Evidence indicates the U.S. Fish and Wildlife Service (USFWS) is strongly considering downlisting the species from an endangered to a threatened status under the Endangered Species Act (ESA). We examined the current status of the WHCR through the lens of ESA threat factors, the USFWS’s Species Status Assessment (SSA) framework, and other avian downlisting actions to determine if the action is biologically warranted. Our research indicates that WHCRs are facing an intensification of most threat drivers across populations and important ranges. The AWBP is still relatively small compared to other crane species and most birds of conservation concern. To date, only one avian species has been downlisted from an endangered status with an estimated population of \u3c3,000 individuals. Representation in terms of WHCRs historic genetic, geographic, and life history variation remains limited. Also, the lack of spatial connectivity among populations, reliance of the reintroduced populations on supplementation, and continued habitat loss suggest that WHCR populations may not be resilient to large stochastic disturbances. Given that reintroduced populations are not self-sustaining, neither supplies true redundancy for the AWBP. Proposed downlisting before recovery plan population criteria have been met is objectively unwarranted 3 and reflects USFWS inconsistency across ESA actions. Only by incorporating basic quantitative criteria and added oversight into ESA listing decisions can we avoid an action as misguided as downlisting the Whooping Crane without consideration of its recovery plan criteria or ostensibly its population ecology

A Partial Response to Reintroduced Chemotherapy in a Resistant Small Cell Lung Cancer Patient after Priming with RRx-001

As an exceedingly recalcitrant and highly aggressive tumor type without Food and Drug Administration-approved treatment or a known cure, the prognosis of recurrent extensive stage platinum-resistant/refractory small cell lung cancer (SCLC) is worse than other types of lung cancer, and many other tumor types, given a response rate of less than 10% and an overall survival of less than six months. It was broadly classified into three groups based on the initial response to cisplatin/etoposide therapy, platinum-refractory, platinum-resistant, and platinum-sensitive, extensive stage SCLC inevitably relapses, at which point the only standard options are to rechallenge with the first-line chemotherapeutic regimen in the case of sensitive disease or to start the topoisomerase I inhibitor, topotecan. Sensitive disease is defined by a response to the first-line therapy and a treatment-free interval of at least 90 days, while the definitions of refractory and resistant disease, respectively, are nonresponse to the first-line treatment or relapse within 90 days. As an important predictor of response to the second-line treatment, the clinical cutoff of three months (or two months in some cases) for resistant and sensitive disease, which along with performance status prognostically separates patients into high- and low-risk categories, dictates subsequent management. This case report presents a resistant SCLC patient enrolled on a Phase II clinical trial called QUADRUPLE THREAT (formerly TRIPLE THREAT, NCT02489903) who responded to reintroduced platinum doublets after sequential priming with the resistance-reversing epi-immunotherapeutic agent, RRx-001. In the QUADRUPLE THREAT clinical trial, both during priming with RRx-001 and during sequential treatment with platinum doublets, the patient maintained a good quality of life and performance status.Peer reviewe

The role of emergency department HIV care in resource-poor settings: lessons learned in western Kenya

The human immunodeficiency virus (HIV) pandemic in sub-Saharan Africa and other high prevalence regions continues to overwhelm health care systems. While there has been a global response to improve the delivery of antiretroviral therapy in these high prevalence regions, there are few models that have developed an adequate plan to deal with HIV specifically in resource-poor emergency department settings. In this manuscript, we report on the experience scaling up HIV care at one emergency department in a large referral hospital located in western Kenya. Specifically, we describe how rapid bedside HIV testing helps to narrow the differential diagnosis of disease processes in acute care patients and how HIV screening of patients discharged from the emergency department can detect HIV-infected individuals