BackgroundExercise-Induced Muscle Damage (EIMD) and delayed onset muscle soreness (DOMS) impact subsequent training sessions and activities of daily living (ADL) even in active individuals. In sedentary or diseased individuals, EIMD and DOMS may be even more pronounced and present even in the absence of structured exercise.MethodsThe purpose of this study was to determine the effects of oral curcumin supplementation (Longvida® 400 mg/days) on muscle & ADL soreness, creatine kinase (CK), and inflammatory cytokines (TNF-α, IL-6, IL-8, IL-10) following EMID (eccentric-only dual-leg press exercise). Subjects (N = 28) were randomly assigned to either curcumin (400 mg/day) or placebo (rice flour) and supplemented 2 days before to 4 days after EMID. Blood samples were collected prior to (PRE), and 1, 2, 3, and 4 days after EIMD to measure CK and inflammatory cytokines. Data were analyzed by ANOVA with P < 0.05.ResultsCurcumin supplementation resulted in significantly smaller increases in CK (− 48%), TNF-α (− 25%), and IL-8 (− 21%) following EIMD compared to placebo. We observed no significant differences in IL-6, IL-10, or quadriceps muscle soreness between conditions for this sample size.ConclusionsCollectively, the findings demonstrated that consumption of curcumin reduced biological inflammation, but not quadriceps muscle soreness, during recovery after EIMD. The observed improvements in biological inflammation may translate to faster recovery and improved functional capacity during subsequent exercise sessions.General significanceThese findings support the use of oral curcumin supplementation to reduce the symptoms of EIMD. The next logical step is to evaluate further the efficacy of an inflammatory clinical disease model.

KRAS-mutant colorectal cancers (CRC) are resistant to therapeutics, presenting a significant problem for ~40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in KRAS-mutant CRC. Using Kras-mutant mouse models and mouse-and patient-derived organoids we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small molecule targeting of this pathway, we acutely sensitize KRAS G12D models to rapamycin via suppression of c-MYC. We show that 45% of CRCs have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYCdependent co-targeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population who may benefit from its clinical application.

The tumour microenvironment is an important factor for colorectal cancer prognosis, affecting the patient's immune response. Immune checkpoints, which regulate the immune functions of lymphocytes, may provide prognostic power. This study aimed to investigate the prognostic value of the immune checkpoints TIM‐3, LAG‐3 and PD‐1 in patients with stage I–III colorectal cancer. Immunohistochemistry was employed to detect TIM‐3, LAG‐3, PD‐1 and PD‐L1 in 773 patients with stage I–III colorectal cancer. Immune checkpoint protein expression was assessed in tumour cells using the weighted histoscore, and in immune cells within the stroma using point counting. Scores were analysed for associations with survival and clinical factors. High tumoural LAG‐3 (hazard ratio [HR] 1.45 95% confidence interval [CI] 1.00–2.09, p = 0.049) and PD‐1 (HR 1.34 95% CI 1.00–1.78, p = 0.047) associated with poor survival, whereas high TIM‐3 (HR 0.60 95% CI 0.42–0.84, p = 0.003), LAG‐3 (HR 0.58 95% CI 0.40–0.87, p = 0.006) and PD‐1 (HR 0.65 95% CI 0.49–0.86, p = 0.002) on immune cells within the stroma associated with improved survival, while PD‐L1 in the tumour (p = 0.487) or the immune cells within the stroma (p = 0.298) was not associated with survival. Furthermore, immune cell LAG‐3 was independently associated with survival (p = 0.017). Checkpoint expression scores on stromal immune cells were combined into a Combined Immune Checkpoint Stromal Score (CICSS), where CICSS 3 denoted all high, CICSS 2 denoted any two high, and CICSS 1 denoted other combinations. CICSS 3 was associated with improved patient survival (HR 0.57 95% CI 0.42–0.78, p = 0.001). The results suggest that individual and combined high expression of TIM‐3, LAG‐3, and PD‐1 on stromal immune cells are associated with better colorectal cancer prognosis, suggesting there is added value to investigating multiple immune checkpoints simultaneously.

Background:The Glasgow Microenvironment Score (GMS) combines peritumoural inflammation and tumour stroma percentage to assess interactions between tumour and microenvironment. This was previously demonstrated to associate with colorectal cancer (CRC) prognosis, it now requires validation and assessment of interactions with adjuvant therapy.Patients and Methods: Two cohorts were utilised; 862 TNM I-III CRC validation cohort, and 2912 TNM II-III CRC adjuvant chemotherapy cohort (TransSCOT). Primary endpoints were disease-free survival (DFS) and relapse-free survival (RFS). Exploratory endpoint was adjuvant chemotherapy interaction.Results: GMS independently associated with DFS (p=0.001) and RFS (p<0.001). GMS significantly stratified RFS for both low-risk (GMS0 v GMS2: HR 3.24 95% CI 1.85-5.68, p<0.001) and high-risk disease (GMS0 v GMS2: HR 2.18 95% CI 1.39-3.41, p=0.001). In TransSCOT, chemotherapy type (p interaction =0.013), but not duration (p=0.64) was dependent on GMS. Furthermore, GMS 0 significantly associated with improved DFS in patients receiving FOLFOX compared with CAPOX p=0.012). Conclusions:This study validates the GMS as a prognostic tool for patients with stage I-III colorectal cancer, independent of TNM, with the ability to stratify both low-and high-risk disease. Furthermore, GMS 0 could be employed to identify a subset of patients that benefit from FOLFOX over CAPOX.

Over the last 15 years there has been a change in how we understand the impact of the interaction between the tumour and the host on cancer outcomes. From the simplistic view that the make-up of tumours cells largely determines their aggressiveness to a more complex view that the interaction between the products of tumour and host cell signal transduction pathways is crucial in determining whether the tumour cell is eliminated or survives in the host. Of the host cells, those with an immune/inflammatory function are most well documented to inhibit or promote tumour cell proliferation and dissemination. It is only in the last few years that there has been greater recognition of the impact of intracellular, cellular and systemic immune/inflammatory phenotypes on patient outcomes independent of current tumour staging and that these phenotypes are useful in informing oncological research and practice. In the present review we will examine the importance of inflammatory phenotypes at the intra-cellular, cellular and systemic levels on outcomes in patients with gastrointestinal cancer with focus on colorectal cancer. Based on these phenotypes we will examine and discuss the prospects for therapeutic intervention.