Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance

Although chemotherapy is designed to eradicate tumor cells, it also has significant effects on normal tissues. The platinum-induced fatty acid 16:4(n-3) (hexadeca-4,7,10,13-tetraenoic acid) induces systemic resistance to a broad range of DNA-damaging chemotherapeutics. We show that 16:4(n-3) exerts its effect by activating splenic F4/80+/CD11blow macrophages, which results in production of chemoprotective lysophosphatidylcholines (LPCs). Pharmacologic studies, together with analysis of expression patterns, identified GPR120 on F4/80+/CD11blow macrophages as the relevant receptor for 16:4(n-3). Studies that used splenocytes from GPR120-deficient mice have confirmed this conclusion. Activation of the 16:4(n-3)-GPR120 axis led to enhanced cPLA2 activity in these splenic macrophages and secretion of the resistance-inducing lipid mediator, lysophosphatidylcholine(24:1). These studies identify a novel and unexpected function for GPR120 and suggest that antagonists of this receptor might be effective agents to limit development of chemotherapy resistance.—Houthuijzen, J. M., Oosterom, I., Hudson, B. D., Hirasawa, A., Daenen, L. G. M., McLean, C. M., Hansen, S. V. F., van Jaarsveld, M. T. M., Peeper, D. S., Jafari Sadatmand, S., Roodhart, J. M. L., van de Lest, C. H. A., Ulven, T., Ishihara, K., Milligan, G., Voest, E. E. Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance

Нейроендокринний супровід поліваріантних ефектів біоактивної води Нафтуся на рівень хронічного стресу у жінок з різним оваріальним статусом

Проанализированы изменения нейроэндокринных показателен, сопутствующие поливариантным эффектам биоактивной воды Нафтуся курорта Трускавец на уровень хронического стресса у женщин детородного возраста с различным овариальным статусом. Обнаружена значительная (R=0,59) каноническая корреляционная связь между динамикой нейро-гормонального индекса стресса, с одной стороны, и вегетативной реактивности, лютеинизирующего гормона, тиреотропного гормона, тироксина и прогестерона - с другой стороны.The changes in neuroendocrine parameters, concomitant multivariate effects of bioactive water Naftussya spa Truskavets to the level of chronic stress in women of childbearing age with different ovarian status. A significant (R=0,59) canonical correlation between the dynamics of the neuro-hormonal index of stress, on the one hand, and autonomic reactivity, luteinizing hormone, thyroid-stimulating hormone, thyroxine and progesterone - the other side

Echium oil is not protective against weight loss in head and neck cancer patients undergoing curative radio(chemo)therapy: a randomised-controlled trial

Background: Therapy-induced mucositis and dysphagia puts head and neck (H&N) cancer patients at increased risk for developing cachexia. Omega-3 fatty acids (n-3 FA) have been suggested to protect against cachexia. We aimed to examine if echium oil, a plant source of n-3 FA, could reduce weight loss in H&N cancer patients undergoing radio(chemo)therapy with curative intent. Methods: In a double-blind trial, patients were randomly assigned to echium oil (intervention (I) group; 7.5 ml bis in die (b.i.d.), 235 mg/ml α-linolenic acid (ALA) + 95 mg/ml stearidonic acid (SDA) + 79 mg/ml γ-linolenic acid (GLA)) or n-3 FA deficient sunflower oil high oleic (control (C) group; 7.5 ml b.i.d.) additional to standard nutritional support during treatment. Differences in percentage weight loss between both groups were analysed according to the intention-to-treat principle. Erythrocyte FA profile, body composition, nutritional status and quality of life were collected. Results: Ninety-one eligible patients were randomised, of whom 83 were evaluable. Dietary supplement adherence was comparable in both groups (median, I: 87%, C: 81%). At week 4, the I group showed significantly increased values of erythrocyte n-3 eicosapentanoic acid (EPA, 14% vs −5%) and n-6 GLA (42% vs −20%) compared to the C group, without a significant change in n-6 arachidonic acid (AA, 2% vs −1%). Intention-to-treat analysis could not reveal a significant reduction in weight loss related to echium oil consumption (median weight loss, I: 8.9%, C: 7.6%). Also, no significant improvement was observed in the other evaluated anthropometric parameters. Conclusions: Echium oil effectively increased erythrocyte EPA and GLA FAs in H&N cancer patients. It failed however to protect against weight loss, or improve nutritional parameters. Trial registration: ClinicalTrials.gov Identifier NCT01596933

El vínculo de la innovación con la renovación estratégica como capacidad

The resource-based view (RBV) of the firm proposes that resources are mobilised by capabilities, and that both arise from ‘dynamic’ capabilities (DC). RBV research suggests that co-specialised DC’s – those which are most valuable together (CDC’s) - are particularly difficult to copy. This paper presents two corporate cases where two DC’s–innovation and strategy renewal- were successfully co-specialised as a CDC and one where it was not. Based on collaborative research, we find that CDC’s linking innovation and strategy renewal served Shell International and Nokia well, but not W.L. Gore. Our research covers a 10 year period and identifies two related themes: first, that companies investing in technological innovation can create strategy renewal opportunities in doing so, particularly by changing the order of selectors who determine if a technology has (or has not) this renewal potential. Secondly, we show that companies create several processes to sustain this CDC, to ensure the politics align with converting innovation into strategy renewal and having strategy renewal guide innovation priorities. Our research suggests that the power structures in W.L. Gore at the time of our study did not allow this CDC to work well. We conclude by summarising a set of factors that make the difference between success and failure with this CDC linking innovation and strategic renewal

NanoCMSer:a consensus molecular subtype stratification tool for fresh-frozen and paraffin-embedded colorectal cancer samples

Colorectal cancer (CRC) is a significant contributor to cancer-related mortality, emphasizing the need for advanced biomarkers to guide treatment. As part of an international consortium, we previously categorized CRCs into four consensus molecular subtypes (CMS1-CMS4), showing promise for outcome prediction. To facilitate clinical integration of CMS classification in settings where formalin-fixed paraffin-embedded (FFPE) samples are routinely used, we developed NanoCMSer, a NanoString-based CMS classifier using 55 genes. NanoCMSer achieved high accuracy rates, with 95% for fresh-frozen samples from the MATCH cohort and 92% for FFPE samples from the CODE cohort, marking the highest reported accuracy for FFPE tissues to date. Additionally, it demonstrated 96% accuracy across a comprehensive collection of 23 RNAseq-based datasets, compiled in this study, surpassing the performance of existing models. Classifying with only 55 genes, the CMS predictions were still biologically relevant, recognizing CMS-specific biology upon enrichment analysis. Additionally, we observed substantial differences in recurrence-free survival curves when comparing CMS2/3 patients in stage III versus II. Probability of recurrence after 5 years increased by 21% in CMS2 and 31% in CMS3 for patients in stage III, whereas this difference was less pronounced for CMS1 and CMS4, with 11% and 10%, respectively. We posit NanoCMSer as a robust tool for subtyping CRCs for both tumor biology and clinical practice, accessible via nanocmser r package (https://github.com/LEXORlab/NanoCMSer) and Shinyapp (https://atorang.shinyapps.io/NanoCMSer).</p

Early evaluation of the effectiveness and cost-effectiveness of ctDNA-guided selection for adjuvant chemotherapy in stage II colon cancer

Background: Current patient selection for adjuvant chemotherapy (ACT) after curative surgery for stage II colon cancer (CC) is suboptimal, causing overtreatment of high-risk patients and undertreatment of low-risk patients. Postoperative circulating tumor DNA (ctDNA) could improve patient selection for ACT. Objectives: We conducted an early model-based evaluation of the (cost-)effectiveness of ctDNA-guided selection for ACT in stage II CC in the Netherlands to assess the conditions for cost-effective implementation. Methods: A validated Markov model, simulating 1000 stage II CC patients from diagnosis to death, was supplemented with ctDNA data. Five ACT selection strategies were evaluated: the current guideline (pT4, pMMR), ctDNA-only, and three strategies that combined ctDNA status with pT4 and pMMR status in different ways. For each strategy, the costs, life years, quality-adjusted life years (QALYs), recurrences, and CC deaths were estimated. Sensitivity analyses were performed to assess the impact of the costs of ctDNA testing, strategy adherence, ctDNA as a predictive biomarker, and ctDNA test performance. Results: Model predictions showed that compared to current guidelines, the ctDNA-only strategy was less effective (+2.2% recurrences, −0.016 QALYs), while the combination strategies were more effective (−3.6% recurrences, +0.038 QALYs). The combination strategies were not cost-effective, since the incremental cost-effectiveness ratio was €67,413 per QALY, exceeding the willingness-to-pay threshold of €50,000 per QALY. Sensitivity analyses showed that the combination strategies would be cost-effective if the ctDNA test costs were lower than €1500, or if ctDNA status was predictive of treatment response, or if the ctDNA test performance improved substantially. Conclusion: Adding ctDNA to current high-risk clinicopathological features (pT4 and pMMR) can improve patient selection for ACT and can also potentially be cost-effective. Future studies should investigate the predictive value of post-surgery ctDNA status to accurately evaluate the cost-effectiveness of ctDNA testing for ACT decisions in stage II CC.</p

A review of the sensitivity of metastatic colorectal cancer patients with deficient mismatch repair to standard-of-care chemotherapy and monoclonal antibodies, with recommendations for future research

In 5% of metastatic colorectal cancer (mCRC) patients, tumours display a deficient mismatch repair (dMMR) system. Immunotherapy is beneficial in dMMR mCRC patients and has recently been approved by the Food and Drug Administration for patients with unresectable or metastatic dMMR CRC. Although dMMR and proficient MMR (pMMR) CRC tumours are biologically distinct, they are commonly treated with the same chemotherapy and monoclonal antibodies. This includes dMMR mCRC patients who did not respond to immunotherapy (20-30%). However, it is unclear if these treatments are equally beneficial in dMMR mCRC. Of note, dMMR mCRC patients have a worse prognosis compared to pMMR, which may in part be caused by a lower response to treatment. To avoid unnecessary exposure to ineffective treatments and their associated toxicity, it is important to identify which systemic treatments are most beneficial in dMMR mCRC patients, thus improving their outcome. Indeed, future treatment strategies are likely to involve combinations of immunotherapy, chemotherapy and monoclonal antibodies. In this evidence-based review, we summarize clinical trials reporting treatment efficacy of different types of chemotherapy and monoclonal antibodies in dMMR mCRC patients. We also review the biological rationale behind a potential differential benefit of chemotherapy with or without monoclonal antibodies in dMMR mCRC patients. A barrier in the interpretation of preclinical results is the choice of model systems. They largely comprise traditional models, including cell lines and xenografts, rather than more representative models, such as patient-derived organoids. We provide concrete recommendations for clinical investigators and fundamental researchers to accelerate research regarding which systemic therapy is most effective in dMMR mCRC patients