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It is known that genetic variants can affect gene expression, but it is not yet completely clear through what mechanisms genetic variation mediate this expression. We therefore compared the cis-effect of single nucleotide polymorphisms (SNPs) on gene expression between blood samples from 1,240 human subjects and four primary non-blood tissues (liver, subcutaneous, and visceral adipose tissue and skeletal muscle) from 85 subjects. We characterized four different mechanisms for 2,072 probes that show tissue-dependent genetic regulation between blood and non-blood tissues: on average 33.2% only showed cis-regulation in non-blood tissues; 14.5% of the eQTL probes were regulated by different, independent SNPs depending on the tissue of investigation. 47.9% showed a different effect size although they were regulated by the same SNPs. Surprisingly, we observed that 4.4% were regulated by the same SNP but with opposite allelic direction. We show here that SNPs that are located in transcriptional regulatory elements are enriched for tissue-dependent regulation, including SNPs at 3' and 5' untranslated regions (P = 1.84×10(-5) and 4.7×10(-4), respectively) and SNPs that are synonymous-coding (P = 9.9×10(-4)). SNPs that are associated with complex traits more often exert a tissue-dependent effect on gene expression (P = 2.6×10(-10)). Our study yields new insights into the genetic basis of tissue-dependent expression and suggests that complex trait associated genetic variants have even more complex regulatory effects than previously anticipated.

Background Metronomic chemotherapy shows potential to enhance efficacy of PD-1 antibodies but has not been assessed in gastrointestinal (GI) cancer. Immunotherapy efficacy can be affected by body composition and lipid metabolism of patients. We aimed to evaluate the feasibility of metronomic capecitabine plus camrelizumab as a salvage treatment of late-stage GI cancer and to explore the roles of body composition and lipid metabolism in this regimen. Methods This is a single-center, exploratory trial. Eligible GI cancer patients who had disease progression after standard chemotherapy were treated with metronomic capecitabine (500 mg twice daily) plus camrelizumab (200 mg on day 1 intravenously every 2 weeks). The primary endpoint was safety. Body composition indices analyzed by SliceOmatic software and lipidomics analyses using liquid chromatography-mass spectrometry were performed as exploratory investigation. Differentially expressed genes (DEGs) of C2C12 myocytes treated with metronomic dose 5-fluorouracil were detected by RNA sequencing. Results A total of 26 patients were enrolled. Treatment emergent adverse events (TEAEs) grade ≥ 3 occurred in five patients (19.2%). Objective response rate was 19.2% (5/26), including two patients with complete response. High skeletal muscle radiation attenuation (SMRA) was associated with disease control and better survival. Differential plasma lipids were identified in disease-controlled patients compared with those who showed disease progression. High levels of a 6-lipid signature composed of SM40:1;3, TG54:4-FA20:2, LPC(16:0), TG52:0-FA20:0, TG56:3-FA20:2, and PE(P-18:1/18:2) were associated with better survival. SMRA and this plasma lipid panel were both increased in disease-controlled patients after treatment. DEGs including prkg1 , adora1 , and Il15 in metronomic 5-FU treated C2C12 myocytes could be enriched into lipid metabolism pathways. Conclusions Metronomic capecitabine plus camrelizumab is well tolerated and shows promising efficacy in GI cancer. SMRA and specific plasma lipids are associated with efficacy of this regimen and indicate the modulation effect of metronomic capecitabine on lipid metabolism. Trial registrations NCT04508686 (Aug 11, 2020), NCT04510818 (Aug 12, 2020), NCT04932187 (Sep 17, 2021).

d-amino acids, the enantiomeric counterparts of l-amino acids, were long considered to be non-functional or not even present in living organisms. Nowadays, d-amino acids are acknowledged to play important roles in numerous physiological processes in the human body. The most commonly studied link between d-amino acids and human physiology concerns the contribution of d-serine and d-aspartate to neurotransmission. These d-amino acids and several others have also been implicated in regulating innate immunity and gut barrier function. Importantly, the presence of certain d-amino acids in the human body has been linked to several diseases including schizophrenia, amyotrophic lateral sclerosis, and age-related disorders such as cataract and atherosclerosis. Furthermore, increasing evidence supports a role for d-amino acids in the development, pathophysiology, and treatment of cancer. In this review, we aim to provide an overview of the various sources of d-amino acids, their metabolism, as well as their contribution to physiological processes and diseases in man, with a focus on cancer.

Clinical interest in the human intestinal microbiota has increased considerably. However, an overview of clinical studies investigating the link between the human intestinal microbiota and systemic cancer therapy is lacking. This systematic review summarizes all clinical studies describing the association between baseline intestinal microbiota and systemic cancer therapy outcome as well as therapy-related changes in intestinal microbiota composition. A systematic literature search was performed and provided 23 articles. There were strong indications for a close association between the intestinal microbiota and outcome of immunotherapy. Furthermore, the development of chemotherapy-induced infectious complications seemed to be associated with the baseline microbiota profile. Both chemotherapy and immunotherapy induced drastic changes in gut microbiota composition with possible consequences for treatment efficacy. Evidence in the field of hormonal therapy was very limited. Large heterogeneity concerning study design, study population, and methods used for analysis limited comparability and generalization of results. For the future, longitudinal studies investigating the predictive ability of baseline intestinal microbiota concerning treatment outcome and complications as well as the potential use of microbiota-modulating strategies in cancer patients are required. More knowledge in this field is likely to be of clinical benefit since modulation of the microbiota might support cancer therapy in the future.

ObjectiveObesity is a risk factor for non-alcoholic steatohepatitis (NASH). This risk has been attributed to visceral adipose tissue (vAT) expansion associated with increased proinflammatory mediators. Accumulation of CD11c+ proinflammatory adipose tissue macrophages (ATM) is an important driver of vAT inflammation. We investigated the role of ATMs in hepatic inflammation during NASH development.DesignvAT isolated from lean, obese or ATM-depleted (using clodronate liposomes) obese mice was transplanted to lean ldlr-/- acceptor mice. Systemic and hepatic inflammation was assessed either after 2 weeks on standard chow or after 8 weeks on high cholesterol diet (HCD) to induce NASH.ResultsTransplanting donor vAT from obese mice increased HCD-induced hepatic macrophage content compared with lean-transplanted mice, worsening liver damage. ATM depletion prior to vAT transplantation reduced this increased hepatic macrophage accumulation. On chow, vAT transplantation induced a more pronounced increase in circulating and hepatic neutrophil numbers in obese-transplanted than lean-transplanted mice, while ATM depletion prior to vAT transplantation reversed this effect. Microarray analysis of fluorescence-activated cell sorting of CD11c+ and CD11c− macrophages isolated from donor adipose tissue showed that obesity resulted in enhanced expression of neutrophil chemotaxis genes specifically in CD11c+ ATMs. Involvement of the neutrophil chemotaxis proteins, CXCL14 and CXCL16, was confirmed by culturing vAT. In humans, CD11c expression in vAT of obese individuals correlated with vAT expression of neutrophil chemotactic genes and with hepatic expression of neutrophil and macrophage marker genes.ConclusionATMs from obese vAT induce hepatic macrophage accumulation during NASH development, possibly by enhancing neutrophil recruitment.

Background Body composition assessment, measured using single‐slice computed tomography (CT) image at L3 level, and aerobic physical fitness, objectively measured using cardiopulmonary exercise testing (CPET), are each independently used for perioperative risk assessment. Sarcopenia (i.e. low skeletal muscle mass), myosteatosis [i.e. low skeletal muscle radiation attenuation (SM‐RA)], and impaired objectively measured aerobic fitness (reduced oxygen uptake) have been associated with poor post‐operative outcomes and survival in various cancer types. However, the association between CT body composition and physical fitness has not been explored. In this study, we assessed the association of CT body composition with selected CPET variables in patients undergoing hepatobiliary and pancreatic surgery. Methods A pragmatic prospective cohort of 123 patients undergoing hepatobiliary and pancreatic surgery were recruited. All patients underwent preoperative CPET. Preoperative CT scans were analysed using a single‐slice CT image at L3 level to assess skeletal muscle mass, adipose tissue mass, and muscle radiation attenuation. Multivariate linear regression was used to test the association between CPET variables and body composition. Main outcomes were oxygen uptake at anaerobic threshold ( V̇O2 at AT), oxygen uptake at peak exercise ( V̇O2 peak), skeletal muscle mass, and SM‐RA. Results Of 123 patients recruited [77 men (63%), median age 66.9 ± 11.7, median body mass index 27.3 ± 5.2], 113 patients had good‐quality abdominal CT scans available and were included. Of the CT body composition variables, SM‐RA had the strongest correlation with V̇O2 peak (r = 0.57, P < 0.001) and V̇O2 at AT (r = 0.45, P < 0.001) while skeletal muscle mass was only weakly associated with V̇O2 peak (r = 0.24, P < 0.010). In the multivariate analysis, only SM‐RA was associated with V̇O2 peak (B = 0.25, 95% CI 0.15–0.34, P < 0.001, R2 = 0.42) and V̇O2 at AT (B = 0.13, 95% CI 0.06–0.18, P < 0.001, R2 = 0.26). Conclusions There is a positive association between preoperative CT SM‐RA and preoperative physical fitness ( V̇O2 at AT and at peak). This study demonstrates that myosteatosis, and not sarcopenia, is associated with reduced aerobic physical fitness. Combining both myosteatosis and physical fitness variables may provide additive risk stratification accuracy and guide interventions during the perioperative period.

Background Cancer cachexia is characterized by a negative energy balance, muscle and adipose tissue wasting, insulin resistance, and systemic inflammation. Because of its strong negative impact on prognosis and its multifactorial nature that is still not fully understood, cachexia remains an important challenge in the field of cancer treatment. Recent animal studies indicate that the gut microbiota is involved in the pathogenesis and manifestation of cancer cachexia, but human data are lacking. The present study investigates gut microbiota composition, short‐chain fatty acids (SCFA), and inflammatory parameters in human cancer cachexia. Methods Faecal samples were prospectively collected in patients (N = 107) with pancreatic cancer, lung cancer, breast cancer, or ovarian cancer. Household partners (N = 76) of the patients were included as healthy controls with similar diet and environmental conditions. Patients were classified as cachectic if they lost >5% body weight in the last 6 months. Gut microbiota composition was analysed by sequencing of the 16S rRNA V4 gene region. Faecal SCFA levels were quantified by gas chromatography. Faecal calprotectin was assessed with enzyme‐linked immunosorbent assay. Serum C‐reactive protein and leucocyte counts were retrieved from medical records. Results Cachexia prevalence was highest in pancreatic cancer (66.7%), followed by ovarian cancer (25%), lung cancer (20.8%), and breast cancer (17.3%). Microbial α‐diversity was not significantly different between cachectic cancer patients (N = 33), non‐cachectic cancer patients (N = 74), or healthy controls (N = 76) (species richness P = 0.31; Shannon effective index P = 0.46). Community structure (β‐diversity) tended to differ between these groups (P = 0.053), although overall differences were subtle and no clear clustering of samples was observed. Proteobacteria (P < 0.001), an unknown genus from the Enterobacteriaceae family (P < 0.01), and Veillonella (P < 0.001) were more abundant among cachectic cancer patients. Megamonas (P < 0.05) and Peptococcus (P < 0.001) also showed differential abundance. Faecal levels of all SCFA tended to be lower in cachectic cancer patients, but only acetate concentrations were significantly reduced (P < 0.05). Faecal calprotectin levels were positively correlated with the abundance of Peptococcus, unknown Enterobacteriaceae, and Veillonella. We also identified several correlations and interactions between clinical and microbial parameters. Conclusions This clinical study provided the first insights into the alterations of gut microbiota composition and SCFA levels that occur in cachectic cancer patients and how they are related to inflammatory parameters. These results pave the way for further research examining the role of the gut microbiota in cancer cachexia and its potential use as therapeutic target.

Background Body composition alterations such as skeletal muscle (SM) loss in cancer patients are associated with poor survival. In turn, immune cell‐driven pathways have been linked to muscle wasting. We aimed to investigate the relationship between body composition, tumour‐infiltrating lymphocytes and survival in patients with advanced lung cancer. Methods We studied 200 patients with advanced lung cancer receiving immunotherapy (n = 81) or non‐immunotherapy regimens (n = 119). Body composition including SM index (SMI) at baseline and longitudinal changes were assessed using computed tomography (CT) scans at the third lumbar vertebra. Associations between body composition parameters and overall survival (OS) were evaluated using Cox regression analysis. The median value of SMI, stratified by sex, was used as the cut‐off to define groups with high and low baseline SMI. Stable SMI was defined by any increase or < 2% decrease per 100 days; loss of SMI was defined by ≥ 2% decrease per 100 days. Logistic regression analysis was applied to investigate the association between SMI and peripheral circulating immune cells. Tumour‐infiltrating lymphocytes were identified by immunohistochemistry, and their relationship with SMI was evaluated. Results SMI loss was associated with shorter OS (whole cohort: HR = 2.314, 95% CI = 1.388–3.858, p = 0.001; immunotherapy cohort: HR = 3.028, 95% CI = 1.113–8.236, p = 0.03; non‐immunotherapy cohort: HR = 2.298, 95% CI = 1.191–4.435, p = 0.013). Low baseline SMI was associated with higher CD3+ T cell abundance (OR = 1.240, 95% CI = 1.080–1.424, p = 0.002) but lower CD3+ CD8+ T cell abundance (OR = 0.862, 95% CI = 0.762–0.974, p = 0.018) in peripheral blood. Subsequent SMI loss during treatment was also significantly associated with higher CD3+ T cell counts (OR = 3.414, 95% CI = 1.301–8.961, p = 0.013) and lower CD3+ CD8+ T cell abundance (OR = 0.666, 95% CI = 0.459–0.968, p = 0.033). Patients with stable SMI had a higher number of CD8+ tumour‐infiltrating lymphocytes than patients with SMI loss (15.4% vs. 7.9%, p = 0.036). Conclusion SM loss is an independent predictor for survival in patients with advanced lung cancer and is associated with reduced peripheral and tumour‐infiltrating cytotoxic T cell abundance. An inadequate antitumour immune response may contribute to metabolic tissue wasting in cancer.

Obesity is associated with severe co-morbidities such as type 2 diabetes and nonalcoholic steatohepatitis. However, studies have shown that 10-25 percent of the severely obese individuals are metabolically healthy. To date, the identification of genetic factors underlying the metabolically healthy obese (MHO) state is limited. Systems genetics approaches have led to the identification of genes and pathways in complex diseases. Here, we have used such approaches across tissues to detect genes and pathways involved in obesity-induced disease development. Expression data of 60 severely obese individuals was accessible, of which 28 individuals were MHO and 32 were metabolically unhealthy obese (MUO). A whole genome expression profile of four tissues was available: liver, muscle, subcutaneous adipose tissue and visceral adipose tissue. Using insulin-related genes, we used the weighted gene co-expression network analysis (WGCNA) method to build within- and inter-tissue gene networks. We identified genes that were differentially connected between MHO and MUO individuals, which were further investigated by homing in on the modules they were active in. To identify potentially causal genes, we integrated genomic and transcriptomic data using an eQTL mapping approach. Both IL-6 and IL1B were identified as highly differentially co-expressed genes across tissues between MHO and MUO individuals, showing their potential role in obesity-induced disease development. WGCNA showed that those genes were clustering together within tissues, and further analysis showed different co-expression patterns between MHO and MUO subnetworks. A potential causal role for metabolic differences under similar obesity state was detected for PTPRE, IL-6R and SLC6A5. We used a novel integrative approach by integration of co-expression networks across tissues to elucidate genetic factors related to obesity-induced metabolic disease development. The identified genes and their interactions give more insight into the genetic architecture of obesity and the association with co-morbidities.

Background Sarcopenia is the loss of skeletal muscle mass and function that occurs with advancing age and certain diseases. It is thought to have a negative impact on survival in cancer patients. Routine computed tomography imaging is often used to quantify skeletal muscle in cancer patients. Sarcopenia is defined by a low skeletal muscle index (SMI). Skeletal muscle radiation attenuation (SMRA) is used to define muscle quality. The primary aim of this meta‐analysis was to study the association between sarcopenia or SMRA and overall survival (OS) or complications in patients with ovarian cancer. Methods Medline, Embase, CINAHL, and PEDro databases were searched from inception to 15 February 2019. Studies evaluating the prognostic effect of SMI and SMRA on ovarian cancer survival or surgical complications were included. Risk of bias and study quality were evaluated with the Quality in Prognosis Studies Instrument (QUIPS) according to the modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Results The search strategy yielded 4262 hits in all four databases combined. Ten and eight studies were included for qualitative and quantitative analysis, respectively. Meta‐analysis revealed a significant association between the SMI and OS [0.007; hazard ratio (HR): 1.11, 95% confidence interval (CI): 1.03–1.20]. SMRA was also significantly associated with OS (P < 0.001; HR: 1.14, 95% CI: 1.08–1.20). Association between the SMI and surgical complications had borderline statistical significance (0.05; HR: 1.23, 95% CI: 1.00–1.52). The risk of bias assessed with QUIPS was high in all studies. The quality of the evidence was very low. Conclusions Whereas our meta‐analysis indicated that a low SMI and low SMRA are associated with survival in ovarian cancer patients, the low quality of the source data precludes drawing definitive conclusions.