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Tumour hypoxia renders cancer cells resistant to cancer therapy, resulting in markedly worse clinical outcomes. To find clinical candidate compounds that reduce hypoxia in tumours, we conduct a high-throughput screen for oxygen consumption rate (OCR) reduction and identify a number of drugs with this property. For this study we focus on the anti-malarial, atovaquone. Atovaquone rapidly decreases the OCR by more than 80% in a wide range of cancer cell lines at pharmacological concentrations. In addition, atovaquone eradicates hypoxia in FaDu, HCT116 and H1299 spheroids. Similarly, it reduces hypoxia in FaDu and HCT116 xenografts in nude mice, and causes a significant tumour growth delay when combined with radiation. Atovaquone is a ubiquinone analogue, and decreases the OCR by inhibiting mitochondrial complex III. We are now undertaking clinical studies to assess whether atovaquone reduces tumour hypoxia in patients, thereby increasing the efficacy of radiotherapy. Tumour hypoxia reduces the efficacy of radiotherapy. Starting from a drug screen, here the authors demonstrate that the anti-malarial, atovaquone, reduces the oxygen consumption rate of cancer cells by inhibition of mitochondrial complex III and sensitises to radiotherapy by reducing tumour hypoxia.

Theranostic biomarkers for putative cancer stem-like cells (CSC) in colorectal cancer (CRC) are of particular interest in translational research to develop patient-individualized treatment strategies. Surface proteins still under debate are CD44 and CD133. The structural and functional diversity of these antigens, as well as their plasticity, has only just begun to be understood. Our study aimed to gain novel insight into the plasticity of CD133/CD44, thereby proving the hypothesis of marker-associated tumorigenic and non-tumorigenic phenotypes to be environmentally driven. CD133/CD44 profiles of 20 CRC cell lines were monitored; three models with distinct surface patterns were systematically examined. CD133/CD44 subpopulations were isolated by FACS and analyzed upon growth and/or in limiting dilution engraftment studies. The experimental setup included biomarker analyses on the protein (flow cytometry, Western blotting, immunofluorescence) and mRNA levels (RT-/qPCR) as well as CD44 gene sequencing. In general, we found that (i) the CD133/CD44 pattern never determined engraftment and (ii) the CD133/CD44 population distributions harmonized under conditions. The LS1034 cell line appeared as a unique model due to its presentation of CD44. was identified as main transcript, which was stronger expressed in primary human CRC than in normal colon tissues. Biomarker pattern of LS1034 cells reflected secondary engraftment: the tumorigenic potential was highest in CD133 /CD44 , intermediate in CD133 /CD44 and entirely lost in CD133 /CD44 subfractions. Both CD44 and CD44 LS1034 cells gave rise to tumorigenic and non-tumorigenic progeny and were convertible - but only as long as they expressed CD133 . The highly tumorigenic CD133 /CD44(v8-10) LS1034 cells were localized in well-oxygenated perivascular but not hypoxic regions. From a multitude of putative modulators, only the direct interaction with stromal fibroblasts triggered an essential, -like enhancement of CD44v8-10 presentation . Environmental conditions modulate CD133/CD44 phenotypes and tumorigenic potential of CRC subpopulations. The identification of fibroblasts as drivers of cancer-specific CD44 expression profile and plasticity sheds light on the limitation of per se dynamic surface antigens as biomarkers. It can also explain the location of putative CD133/CD44-positive CRC CSC in the perivascular niche, which is likely to comprise cancer-associated fibroblasts. The LS1034 model is a valuable tool to unravel the mechanism of stromal-induced CD44v8-10 expression and identify further therapeutically relevant, mutual interrelations between microenvironment and tumorigenic phenotype.

Purpose Profound changes of the vasculature in tumors critically impact drug delivery and therapy response. We aimed at developing a procedure to monitor morphological and functional parameters of the vasculature in subcutaneous xenograft models commonly applied for therapy testing by using probe-based confocal laser endomicroscopy. Procedures By monitoring various normal and diseased tissues, we established an experimental and analytical set-up to systematically analyze tracer extravasation from the microvasculature. Application of the approach in two xenograft models (HCT-116 and SW620) was realized consecutively throughout tumor growth. Results The incidence of dilated vessels increased with xenograft size in both models while macromolecule extravasation and tracer accumulation in the tumor tissue, respectively, was significantly reduced throughout growth. The development of dilated/ultradilated vessels correlated with tracer extravasation only in the HCT-116 but not the SW620 model. The underlying mechanisms are still ambiguous and discussed. Conclusions Our findings clearly indicate that both xenograft type and size matter for drug delivery and therapy testing.

Rare cancers are individually uncommon but collectively represent a substantial share of cancer burden, with limited systemic treatment options for many entities. Molecular profiling identifies targetable alterations, but actionable findings are limited and responses can vary despite a matched target. This motivates complementary approaches that directly assess tumor drug response. Here, we establish a biopsy-compatible ex vivo drug sensitivity testing platform optimized for low input and reproducibility. Patient-derived material was tested either directly or following ex vivo expansion. Functional profiling was performed within clinically relevant timelines across models from 126 patients with rare advanced solid tumors. Drug responses were consistent between model types. In most samples, we identified at least one potentially active compound, supporting feasibility at biopsy-scale. High in vitro sensitivity was associated with clinical benefit and progression-free survival. These findings support functional drug sensitivity testing as a complementary component in precision oncology for adults with rare cancers.Competing Interest StatementC.R.B. and I.O. received research funding from PreComb Therapeutics. C.H. received research funding and honoraria for advisory board participation from Boehringer Ingelheim and honoraria for speaking engagements from Roche and Novartis. LM: wife is an employee of Pfizer Pharma GmbH.Funder Information DeclaredBMFTR, HEROES-AYA, 01KD2207DFG, 551924272, 574708936

There is continued emphasis on increasing and improving genetics education for grades K–12, for medical professionals, and for the general public. Another critical audience is undergraduate students in introductory biology and genetics courses. To improve the learning of genetics, there is a need to first assess students' understanding of genetics concepts and their level of genetics literacy (i.e., genetics knowledge as it relates to, and affects, their lives). We have developed and evaluated a new instrument to assess the genetics literacy of undergraduate students taking introductory biology or genetics courses. The Genetics Literacy Assessment Instrument is a 31-item multiple-choice test that addresses 17 concepts identified as central to genetics literacy. The items were selected and modified on the basis of reviews by 25 genetics professionals and educators. The instrument underwent additional analysis in student focus groups and pilot testing. It has been evaluated using ∼400 students in eight introductory nonmajor biology and genetics courses. The content validity, discriminant validity, internal reliability, and stability of the instrument have been considered. This project directly enhances genetics education research by providing a valid and reliable instrument for assessing the genetics literacy of undergraduate students.

In spring, transition from a total mixed ration (TMR) to pasture requires rumen adaptions for the cow. It had been shown that transition period does not necessarily mean an increased risk for subacute ruminal acidosis (SARA). After adaption to pasture, however, supplying low amounts of concentrate did indicate increased risk, but caused no adverse effects on rumen morphology and absorption capacity. The present study aimed to investigate the effect of transition, and how a supply of 4.5 kg dry matter concentrate·cow−1 · day−1 during fulltime grazing influenced different rumen parameters. During a 12-week trial eleven rumen-cannulated dairy cows were observed during transition from confinement to pasture (PG; n = 6) and compared to cows fed TMR indoors (CG; n = 5). The CG stayed on a TMR based ration (35% corn silage, 35% grass silage, 30% concentrate; dry matter basis), whereas the PG slowly switched to a pasture-based ration (week 0 and 1 = TMR, week 2 = TMR and 3 h pasture·day−1, week 3 and 4 = TMR and 12 h pasture·day−1, and week 5 to 11 = pasture combined with 4.5 kg DM concentrate · cow−1·day−1). Papillae surface area decreased during transition and increased again during fulltime grazing, while the fractional absorption rate of volatile fatty acids (VFA) was not influenced. This suggests only a limited effect of papillae surface area on VFA absorption rate. Feeding changes resulted in different fermentation profiles of VFA. Changing ratio of starch to sugar during transition to fulltime grazing plus concentrate supply did not lead to lower rumen pH. In conclusion, the concentrate supply combined with high fermentable grass during fulltime grazing increased papillae surface area but did not affect absorption rate or rumen pH, so that risk for SARA was not increased.

With the advancement of genetic information and technologies, there is an increasing need for a genetically literate public. This study looks critically at student learning and at the current instruction of genetics in introductory non–science major biology and genetics courses at the undergraduate level. A new diagnostic tool, the Genetic Literacy Assessment Instrument, was administered pre- and postcourse to more than 300 students in six introductory nonmajor courses that emphasize genetics to varying degrees. Current data from students in these courses show a precourse average score of 43 percent correct zn the inventory. Postcourse scores increased only modestly, to an average of 49 percent. In this article, we discuss the impact of teaching methods and course content on scores, as well as student learning in the different content areas of genetics. The results suggest that further studies in genetics education are needed to better understand the effect of teaching methods on achieving genetic literacy.

In spring, the transition from a total mixed ration (TMR) to pasture requires metabolic adaptions for the cow. It had been shown that supply of low amounts of concentrate after transition to full-time grazing caused energy deficits, resulting in a lower milking performance and changes in a variety of variables indicative for energy metabolism. The present study aimed to investigate how a moderate concentrate supply (4.5 kg dry matter cow/day) after transition to pasture influences health and production indicators. Over a 12-week trial period dairy cows were observed during transition from confinement to pasture (pasture group: PG) and compared to cows fed TMR indoors (confinement group: CG). On average, the PG consumed less feed and energy than the CG and mobilized body reserves, which is mirrored in a decrease of body condition and various fat depots. These effects were paralleled by elevated serum concentrations of non-esterified fatty acids and ketone bodies as well as an increase in liver fat content. The physical activity (elevated walking, eating, decreasing rumination time) of the PG was significantly higher than that of the CG, which intensified the energy deficiency and resulted in a lower milk yield. In conclusion, the moderate concentrate supply was insufficient to counterbalance the lower energy intake from pasture during transition.