Phenotypic screen for oxygen consumption rate identifies an anti-cancer naphthoquinone that induces mitochondrial oxidative stress.

A hallmark of cancer cells is their ability to reprogram nutrient metabolism. Thus, disruption to this phenotype is a potential avenue for anti-cancer therapy. Herein we used a phenotypic chemical library screening approach to identify molecules that disrupted nutrient metabolism (by increasing cellular oxygen consumption rate) and were toxic to cancer cells. From this screen we discovered a 1,4-Naphthoquinone (referred to as BH10) that is toxic to a broad range of cancer cell types. BH10 has improved cancer-selective toxicity compared to doxorubicin, 17-AAG, vitamin K3, and other known anti-cancer quinones. BH10 increases glucose oxidation via both mitochondrial and pentose phosphate pathways, decreases glycolysis, lowers GSH:GSSG and NAPDH/NAPD+ ratios exclusively in cancer cells, and induces necrosis. BH10 targets mitochondrial redox defence as evidenced by increased mitochondrial peroxiredoxin 3 oxidation and decreased mitochondrial aconitase activity, without changes in markers of cytosolic or nuclear damage. Over-expression of mitochondria-targeted catalase protects cells from BH10-mediated toxicity, while the thioredoxin reductase inhibitor auranofin synergistically enhances BH10-induced peroxiredoxin 3 oxidation and cytotoxicity. Overall, BH10 represents a 1,4-Naphthoquinone with an improved cancer-selective cytotoxicity profile via its mitochondrial specificity

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Colon and rectal cancer treatment patterns and their associations with clinical, sociodemographic and lifestyle characteristics: analysis of the Australian 45 and Up Study cohort

Abstract Background Colorectal cancer is the third most diagnosed cancer globally and the second leading cause of cancer death. We examined colon and rectal cancer treatment patterns in Australia. Methods From cancer registry records, we identified 1,236 and 542 people with incident colon and rectal cancer, respectively, diagnosed during 2006-2013 in the 45 and Up Study cohort (267,357 participants). Cancer treatment and deaths were determined via linkage to routinely collected data, including hospital and medical services records. For colon cancer, we examined treatment categories of “surgery only”, “surgery plus chemotherapy”, “other treatment” (i.e. other combinations of surgery/chemotherapy/radiotherapy), “no record of cancer-related treatment, died”; and, for rectal cancer, “surgery only”, “surgery plus chemotherapy and/or radiotherapy”, “other treatment”, and “no record of cancer-related treatment, died”. We analysed survival, time to first treatment, and characteristics associated with treatment receipt using competing risks regression. Results 86.4% and 86.5% of people with colon and rectal cancer, respectively, had a record of receiving any treatment ≤2 years post-diagnosis. Of those treated, 93.2% and 90.8% started treatment ≤2 months post-diagnosis, respectively. Characteristics significantly associated with treatment receipt were similar for colon and rectal cancer, with strongest associations for spread of disease and age at diagnosis (p<0.003). For colon cancer, the rate of “no record of cancer-related treatment, died” was higher for people with distant spread of disease (versus localised, subdistribution hazard ratio (SHR)=13.6, 95% confidence interval (CI):5.5-33.9), age ≥75 years (versus age 45-74, SHR=3.6, 95%CI:1.8-7.1), and visiting an emergency department ≤1 month pre-diagnosis (SHR=2.9, 95%CI:1.6-5.2). For rectal cancer, the rate of “surgery plus chemotherapy and/or radiotherapy” was higher for people with regional spread of disease (versus localised, SHR=5.2, 95%CI:3.6-7.7) and lower for people with poorer physical functioning (SHR=0.5, 95%CI:0.3-0.8) or no private health insurance (SHR=0.7, 95%CI:0.5-0.9). Conclusion Before the COVID-19 pandemic, most people with colon or rectal cancer received treatment ≤2 months post-diagnosis, however, treatment patterns varied by spread of disease and age. This work can be used to inform future healthcare requirements, to estimate the impact of cancer control interventions to improve prevention and early diagnosis, and serve as a benchmark to assess treatment delays/disruptions during the pandemic. Future work should examine associations with clinical factors (e.g. performance status at diagnosis) and interdependencies between characteristics such as age, comorbidities, and emergency department visits

RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study

<p><strong>Article full text</strong></p> <p><br> The full text of this article can be found <a href="https://link.springer.com/article/10.1007/s12325-017-0525-8"><b>here</b>.</a><br> <br> <strong>Provide enhanced digital features for this article</strong><br> If you are an author of this publication and would like to provide additional enhanced digital features for your article then please contact <u>[email protected]</u>.<br> <br> The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.<br> <br> Other enhanced features include, but are not limited to:<br> • Slide decks<br> • Videos and animations<br> • Audio abstracts<br> • Audio slides<u></u></p

Rethinking Practices and Structures

Social theory remains puzzled by the relation between practices and structures, or the link between ‘micro’ and ‘macro’. Grand theorists including Giddens and Bourdieu have gained distinction for their writings on these questions, trying to marry insights and concerns of a ‘micro’ sociological nature with traditional ‘macro’ structural questions including inequality, power relations, and social reproduction. These theorists arguably fail, however, in their attempts to move social theory beyond traditional dualisms. Relevant but neglected contributions from ethnomethodology are introduced and compared to the work of Giddens and Bourdieu in an attempt to identify and outline an approach to practices and structures that more reliably avoids problems of dualism and reification, and at the same time offers an understanding of structures and their relations to practices that can be much more closely grounded in empirical studies