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Cancer drug development has been riddled with high attrition rates, in part, due to poor reproducibility of preclinical models for drug discovery. Poor experimental design and lack of scientific transparency may cause experimental biases that in turn affect data quality, robustness and reproducibility. Here, we pinpoint sources of experimental variability in conventional 2D cell-based cancer drug screens to determine the effect of confounders on cell viability for MCF7 and HCC38 breast cancer cell lines treated with platinum agents (cisplatin and carboplatin) and a proteasome inhibitor (bortezomib). Variance component analysis demonstrated that variations in cell viability were primarily associated with the choice of pharmaceutical drug and cell line, and less likely to be due to the type of growth medium or assay incubation time. Furthermore, careful consideration should be given to different methods of storing diluted pharmaceutical drugs and use of DMSO controls due to the potential risk of evaporation and the subsequent effect on dose-response curves. Optimization of experimental parameters not only improved data quality substantially but also resulted in reproducible results for bortezomib- and cisplatin-treated HCC38, MCF7, MCF-10A, and MDA-MB-436 cells. Taken together, these findings indicate that replicability (the same analyst re-performs the same experiment multiple times) and reproducibility (different analysts perform the same experiment using different experimental conditions) for cell-based drug screens can be improved by identifying potential confounders and subsequent optimization of experimental parameters for each cell line.

PurposePredictive biomarkers are needed to aid the individualization of radiotherapy (RT) in breast cancer. Cancer-associated fibroblasts have been implicated in tumor radioresistance and can be identified by platelet-derived growth factor receptor-beta (PDGFRb). This study aims to analyze how PDGFRb expression affects RT benefit in a large randomized RT trial.MethodsPDGFRb was assessed by immunohistochemistry on tissue microarrays from 989 tumors of the SweBCG91RT trial, which enrolled lymph node-negative, stage I/IIA breast cancer patients randomized to RT after breast-conserving surgery. Outcomes were analyzed at 10 years for ipsilateral breast tumor recurrence (IBTR) and any recurrence and 15 years for breast cancer specific death (BCSD).ResultsPDGFRb expression correlated with estrogen receptor negativity and younger age. An increased risk for any recurrence was noted in univariable analysis for the medium (HR 1.58, CI 95% 1.11–2.23, p = 0.011) or PDGFRb high group (1.49, 1.06–2.10, p = 0.021) compared to the low group. No differences in IBTR or BCSD risk were detected. RT benefit regarding IBTR risk was significant in the PDGFRb low (0.29, 0.12–0.67, p = 0.004) and medium (0.31, 0.16–0.59, p < 0.001) groups but not the PDGFRb high group (0.64, 0.36–1.11, p = 0.110) in multivariable analysis. Likewise, risk reduction for any recurrence was less pronounced in the PDGFRb high group. No significant interaction between RT and PDGFRb-score could be detected.ConclusionA higher PDGFRb-score conferred an increased risk of any recurrence, which partly can be explained by its association with estrogen receptor negativity and young age. Reduced RT benefit was noted among patients with high PDGFRb, however without significant interaction.

BackgroundBreast-conserving surgery followed by radiotherapy is part of standard treatment for early-stage breast cancer. Hypoxia is common in cancer and may affect the benefit of radiotherapy. Cells adapt to hypoxic stress largely via the transcriptional activity of hypoxia-inducible factor (HIF)-1α. Here, we aim to determine whether tumour HIF-1α-positivity and hypoxic gene-expression signatures associated with the benefit of radiotherapy, and outcome.MethodsTumour HIF-1α-status and expression of hypoxic gene signatures were retrospectively analysed in a clinical trial where 1178 women with primary T1-2N0M0 breast cancer were randomised to receive postoperative radiotherapy or not and followed 15 years for recurrence and 20 years for breast cancer death.ResultsThe benefit from radiotherapy was similar in patients with HIF-1α-positive and -negative primary tumours. Both ipsilateral and any breast cancer recurrence were more frequent in women with HIF-1α-positive primary tumours (hazard ratio, HR0–5 yrs1.9 [1.3–2.9], p = 0.003 and HR0–5 yrs = 2.0 [1.5–2.8], p < 0.0001). Tumour HIF-1α-positivity is also associated with increased breast cancer death (HR0–10 years 1.9 [1.2–2.9], p = 0.004). Ten of the 11 investigated hypoxic gene signatures correlated positively to HIF-1α-positivity, and 5 to increased rate/risk of recurrence.ConclusionsThe benefit of postoperative radiotherapy persisted in patients with hypoxic primary tumours. Patients with hypoxic primary breast tumours had an increased risk of recurrence and breast cancer death.

Obesity increases cancer risk, whereas surgery-induced weight loss is associated with reduced risk. Risk-based patient stratification may be needed to better understand and maximize benefits of weight loss interventions in individuals with obesity. To this end, comprehensive data from high-quality studies with extended follow-up are imperative. This study examines the link between bariatric surgery and long-term cancer outcomes, focusing on patient subgroups defined by previously suggested predictors of treatment benefit, such as sex and baseline insulin levels. This post-hoc analysis used data from the Swedish Obese Subjects (SOS) study, a prospective, controlled intervention trial, designed to investigate the long-term effects of bariatric surgery-induced weight loss (ClinicalTrials.gov, NCT01479452). The study was conducted at 25 public surgical departments and 480 primary healthcare centers across Sweden. Between Sept 1, 1987, and Jan 31, 2001, 2,007 per-protocol patients with obesity who underwent bariatric surgery (gastric bypass, n = 266; gastric banding, n = 376; vertical banded gastroplasty, n = 1,365) and 2,040 matched controls, receiving standard nonsurgical obesity-related care, were recruited. Inclusion criteria were age 37-60 years and a body mass index (BMI) ≥34 kg/m2 for men and ≥38 kg/m2 for women. The primary outcome measures were cancer events and cancer-related deaths, captured through nearly complete data sourced from national Swedish health registries. Female-specific cancers were defined as gynecologic and breast cancers. Analyses were adjusted (adj) for baseline age, sagittal diameter, alcohol consumption, smoking, and serum insulin levels. The study was closed on December 31, 2022. Median follow-up was 26.8 years (interquartile range (IQR) [22.9, 29.6]) in the surgery group and 24.9 years (IQR [18.7, 28.8]) in the control group. Bariatric surgery was associated with a lower overall cancer incidence rate in women (adjusted hazard ratio (HRadj) = 0.78; 95% confidence interval (CI) [0.67, 0.90]; p = 0.001), but not in men (sex-treatment interaction p = 0.013). The HRadj for overall cancer mortality rate in women was 0.78 (95% CI [0.61, 1.00]; p = 0.050). In women, surgery was associated with a lower incidence rate of both obesity-related cancers (HRadj = 0.70; 95% CI [0.58, 0.85]; p < 0.001) and female-specific cancers (HRadj = 0.60; 95% CI [0.47, 0.75]; p < 0.001). Importantly, subgroup analyses showed that the associations between surgery and female-specific cancer incidence, as well as female-specific cancer-related mortality, were stronger in women with high baseline insulin levels (insulin-treatment interaction p = 0.021 and 0.039, respectively). The main limitation is that cancer was not a predefined study outcome. Bariatric surgery is associated with a lower risk of cancer and cancer-related mortality in women with obesity, with the strongest association observed for female-specific cancers in women with elevated baseline insulin levels. In men, bariatric surgery was not associated with overall cancer incidence or mortality. These findings support incorporating risk-based stratification to better tailor cancer prevention strategies in obesity care.

We have constructed two data sets of hourly resolution reanalyzed near-surface ozone (O3) concentrations for the period 1990–2013 for Sweden. Long-term simulations from a chemistry-transport model (CTM) covering Europe were combined with hourly ozone concentration observations at Swedish and Norwegian background measurement sites using retrospective variational data analysis. The reanalysis data sets show improved performance over the original CTM when compared to independent observations. In one of the reanalyses, we included all available hourly near-surface O3 observations, whilst in the other we carefully selected time-consistent observations. Based on the second reanalysis we investigated statistical aspects of the distribution of the near-surface O3 concentrations, focusing on the linear trend over the 24-year period. We show that high near-surface O3 concentrations are decreasing and low O3 concentrations are increasing, which is reflected in observed improvement of many health and vegetation indices (apart from those with a low threshold). Using the CTM we also conducted sensitivity simulations to quantify the causes of the observed change, focusing on three factors: change in hemispheric background concentrations, meteorology and anthropogenic emissions. The rising low concentrations of near-surface O3 in Sweden are caused by a combination of all three factors, whilst the decrease in the highest O3 concentrations is caused by European O3 precursor emissions reductions. While studying the impact of anthropogenic emissions changes, we identified systematic differences in the modeled trend compared to observations that must be caused by incorrect trends in the utilized emissions inventory or by too high sensitivity of our model to emissions changes.

Background Several cancer types have increased PFKFB3, a glycolytic enzyme for which potent inhibitors have been found. Inhibition of PFKFB3 impairs DNA repair after irradiation of cancer cells, making it a possible radiosensitization target. The SweBCG91RT trial, in which breast cancer patients were randomized to postoperative radiotherapy or not, was used to investigate PFKFB3 as a clinical marker of sensitivity to adjuvant radiotherapy. Methods Nuclear protein levels of PFKFB3 were assessed with immunohistochemistry in primary breast tumors ( n  = 970) and whole-cell RNA levels with microarray gene expression ( n  = 765). Multivariable competing risks regression analysis was employed for the effect of radiotherapy on incidence of ipsilateral breast tumor recurrence (IBTR), depending on PFKFB3 levels. Results Tumors with high levels of nuclear protein and RNA had the largest effect on incidence of IBTR of adjuvant radiotherapy, however without evidence of an interaction. PFKFB3 RNA correlated with subtype, as high levels were more common among the human epidermal growth factor receptor 2 (HER2) positive and Luminal A subtypes than Luminal B and triple negative tumors. Conclusion High PFKFB3 is associated with a larger reduction of IBTR after radiotherapy but PFKFB3 cannot reliably be used as a predictive marker of sensitivity to adjuvant radiotherapy in breast cancer. PFKFB3 expression differed with subtype, indicating that it may be a better marker among Luminal A and HER2 positive tumors, but this is yet to be investigated. Trial registration The trial has been retrospectively registered at clinicaltrials.gov 2024-10-03 (NCT06637202).

A cardiopulmonary exercise test (CPET) is a test assessing an individual’s physiological response during exercise. Results may be affected by body composition, which is best evaluated through imaging techniques like magnetic resonance imaging (MRI). The aim of this study was to assess relationships between body composition and indices obtained from CPET. A total of 234 participants (112 female), all aged 50 years, underwent CPETs and whole-body MRI scans (> 1 million voxels). Voxel-wise statistical analysis of tissue volume and fat content was carried out with a method called Imiomics and related to the CPET indices peak oxygen consumption (V̇O 2peak ), V̇O 2peak scaled by body weight (V̇O 2kg ) and by total lean mass (V̇O 2lean ), ventilatory efficiency (V̇E/V̇CO 2 -slope), work efficiency ( Δ V̇O 2 / Δ WR) and peak exercise respiratory exchange ratio (RERpeak). V̇O 2peak showed the highest positive correlation with volume of skeletal muscle. V̇O 2kg negatively correlated with tissue volume in subcutaneous fat, particularly gluteal fat. RERpeak negatively correlated with tissue volume in skeletal muscle, subcutaneous fat, visceral fat and liver. Some associations differed between sexes: in females Δ V̇O 2 / Δ WR correlated positively with tissue volume of subcutaneous fat and V̇E/V̇CO 2 -slope with tissue volume of visceral fat, and, in males, V̇O 2peak correlated positively to lung volume. In conclusion, voxel-based Imiomics provided detailed insights into how CPET indices were related to the tissue volume and fat content of different body structures.

PURPOSE: This paper aims to clarify the application of a land-use baseline in attributional life cycle assessment (ALCA) for product systems involving land use, through consideration of the fundamental purpose of ALCA. Currently, there is no clear view in the literature whether a baseline should be used when accounting for environmentally relevant physical flows related to land use. METHODS: An extensive search of literature was carried out using the key terms ‘attributional life cycle assessment’ and ‘attributional LCA’ in the Google Scholar web search engine. Approximately 700 publications were reviewed and summarised according to their type and scope, relevance of land use, key statements and references given for ALCA, and arguments for and against using a baseline in ALCA. Based on the literature review and supplementary literature references, a critical discussion on the use of a baseline and determination of the most appropriate land-use baseline in ALCA is provided. RESULTS AND DISCUSSION: A few studies clearly argued that only absolute (observable) flows without a baseline are to be inventoried in ALCA, while the majority of the studies did not make any clear statement for or against. On the other hand, a land-use baseline was explicitly applied or proposed in a minority of the studies only, despite the fact that we classified land use as highly relevant for the majority of the studies reviewed. Furthermore, the LCA guidelines reviewed give contradictory recommendations. The most cited studies for the definition of ALCA provide general rules for selecting processes based on observable flows but do not argue that observable flows necessarily describe the environmentally relevant physical flows. CONCLUSIONS: We conclude that a baseline is required to separate the studied parts of the technosphere from natural processes and to describe the impact of land use on ecosystem quality, such as carbon sequestration and biodiversity. The most coherent baseline for human-induced land-use in ALCA is natural regeneration. As the natural-regeneration baseline has typically been excluded, may vary bio-geographically and temporally, and is subject to uncertainties, case studies applying it should be performed so that implications can be studied and evaluated. This is particularly important for agricultural and forestry systems, such as food, feed, fibre, timber and biofuels.

Background Ovarian cancer is the main cause of gynecological cancer-associated death. However, 5-year survival rates differ dramatically between the five main ovarian carcinoma histotypes. Therefore, we need to have a better understanding of the mechanisms that promote histotype-specific ovarian carcinogenesis and identify novel prognostic biomarkers. Methods Here, we evaluated the prognostic role of 29 genes for early-stage (I and II) ovarian carcinomas ( n  = 206) using immunohistochemistry (IHC). Results We provide evidence of aberrant protein expression patterns for Collagen type III alpha 1 chain (COL3A1), G protein-coupled receptor 158 (GPR158) and PITH domain containing 1 (PITHD1). Kaplan-Meier survival analysis revealed that COL3A1 expression was associated with shorter overall survival in the four major histotypes of epithelial ovarian carcinoma patients ( P value = 0.026, HR = 2.99 (95% CI 1.089–8.19)). Furthermore, GPR158 and PITHD1 were shown to be histotype-specific prognostic biomarkers, with elevated GPR158 expression patterns in mucinous ovarian carcinoma patients with unfavorable overall survival ( P value = 0.00043, HR = 6.13 (95% CI 1.98–18.98)), and an association with lower PITHD1 protein expression and unfavorable overall and disease-specific survival in clear-cell ovarian carcinoma patients ( P value = 0.012, HR = 0.22 (95% CI 0.058–0.80); P value = 0.003, HR = 0.17 (95% CI 0.043–0.64)). Conclusions The novel biomarkers identified here may improve prognostication at the time of diagnosis and may assist in the development of future individualized therapeutic strategies for ovarian carcinoma patients.

Despite advances in cancer treatments, epithelial ovarian cancer (EOC) remains the leading cause of death among gynecologic cancers. EOC is stratified into five main histopathological subtypes: high-grade serous carcinoma (HGSC), low-grade serous carcinoma (LGSC), endometrioid carcinoma (EC), clear cell carcinoma (CCC), and mucinous carcinoma (MC). However, personalized treatment strategies and reliable biomarkers for all histotypes remain elusive. Building on our previous work with early-stage EOC, we aim to explore diagnostic and prognostic biomarkers in advanced-stage EOC, updated to the latest World Health Organization classification guidelines from 2020, using comprehensive transcriptomic profiling from total RNA sequencing of 146 EOCs. Differential expression analysis identified top 9 histotype-specific gene panels for HGSC, CCC, MC, and EC, including S100A1 (HGSC), ARID3A (CCC), LGALS4 (MC), and PAX9 (EC). We also identified gene candidates associated with overall survival and disease-specific survival, reflecting both favorable (e.g., OTOF , EEF1E1-BLOC1S5 , and STAC3 ) and unfavorable (e.g., SMOC1 , GDPGP1 , EPRS1 ) clinical outcome. Additionally, enrichment analysis revealed tumor progression-related pathways unique to each histotype, offering insights into the molecular mechanisms underlying disease progression and potential therapeutic targets. These findings provide valuable insights into the molecular landscape of advanced-stage EOC, paving the way for more effective diagnostic and prognostic tools across diverse histotypes.