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Background The interdependence of cytokines and appetite‐modifying hormones implicated in cancer anorexia‐cachexia syndrome (CACS) remains unclear. This study aimed to regroup these cytokines and hormones into distinct inflammatory (or non‐inflammatory) pathways and determine whether these pathways can classify patients with CACS phenotypes. Methods Clinical characteristics of 133 patients [61.7% male; mean age = 63.4 (SD: 13.1) years] with advanced cancer prior to oncology treatments were documented, including weight loss history. Patients completed the Functional Assessment of Anorexia‐Cachexia Therapy (FAACT) questionnaire and Timed Up and Go test and had their sex‐standardized skeletal muscle index (z‐SMI) and fat mass index (z‐FMI) derived using computed tomography scans. Their plasma levels of cytokines and appetite‐modifying hormones were also determined. Date of death was recorded. Exploratory factor analysis (EFA) was used to regroup 15 cytokines and hormone into distinct inflammatory pathways (factors). For each patient, regression factor scores (RFS), which tell how strongly the patient associates with each factor, were derived. Two‐step cluster analysis on the RFS was used to classify patients into groups. CACS phenotypes were correlated with RFS and compared between groups. Groups' survival was estimated using Kaplan–Meier analysis. Results Patients had low z‐SMI (mean = −3.78 cm2/m2; SD: 8.88) and z‐FMI (mean = 0.08 kg2/m2; SD: 56.25), and 62 (46.6%) had cachexia. EFA identified three factors: (F‐1) IFN‐γ, IL‐1β, Il‐4, IL‐6, IL‐10, IL‐12, TGFβ1 (positive contribution), and IL‐18 (negative); (F‐2) IL‐8, IL‐18, MCP‐1, TGFβ1, TNF‐α (positive), and ghrelin (negative); and (F‐3) TRAIL and leptin (positive), and TGFβ1 and adiponectin (negative). RFS‐1 was associated with cachexia (P = 0.002); RFS‐2, with higher CRP (P < 0.0001) and decreased physical function (P = 0.01); and RFS‐3 with better appetite (P = 0.04), lower CRP (P = 0.002), higher z‐SMI (P = 0.04) and z‐FMI (P < 0.0001), and less cachexia characteristics (all P < 0.001). Four patient groups were identified with specific RFS clusters aligning with the CACS continuum from no cachexia to pre‐cachexia, cachexia, and terminal cachexia. Compared to the other two groups, groups 1 and 2 had higher plasma levels of IL‐18 and TRAIL. Group 1 also had lower inflammatory cytokines, adiponectin, and CRP compared to the other three groups. Group 3 had inflammatory cytokine levels similar to group 2, except for TNF‐α and leptin which were lower. Group 4 had very high inflammatory cytokines, adiponectin, and CRP compared to the other 3 groups (all P < 0.0001). Groups 3 and 4 had worse cachexia characteristics (P < 0.05) and shorter survival (log rank: P = 0.0009) than the other two groups. Conclusions This exploratory study identified three distinct pathways of inflammation, or lack thereof, characterizing different CACS phenotypes.

Background Adrenal-derived 11-oxygenated androgens (11-oxyandrogens) emerged as potential key contributors to prostate cancer (PCa) progression by activating the androgen receptor (AR). This study investigates their clinical and mechanistic role in metastatic castration-resistant prostate cancer (mCRPC) patients initiating AR pathway inhibitors (ARPI). Methods In a pilot study of 35 mCRPC patients initiating ARPI, serum steroids were quantified via mass spectrometry and correlated with survival. Functional assays assessed the proliferative effects of 11-oxyandrogens on CRPC cells and their inhibition by enzalutamide, supported by transcriptomic and proteomic profiling. Results 11-ketotestosterone (11KT) and its hydroxylated derivative, 11-hydroxytestosterone (11OHT) are the predominant potent androgens, accounting for 81% of circulating androgens. Higher baseline levels of 11KT, 11OHT, the abundant precursor 11β-hydroxyandrostenedione (11OHA4), and the downstream metabolite 11-hydroxyandrosterone (11OHAST) are linked to prolonged progression-free survival (PFS) (HR: 0.56–0.69; P  < 0.05), suggesting an enhanced treatment response. 11KT and 11OHT promoted AR-driven proliferation of CRPC cells and gene expression, which was reversed by AR antagonism, suggesting they are primarily AR-mediated. Additionally, 11-oxyandrogens display distinct effects, including the activation of AR-independent pathways. Conclusions 11-oxyandrogens are potent AR activators in mCRPC, with evidence suggesting they may exert distinct biological effects compared to canonical androgens. Their association with longer PFS and improved response to ARPI may reflect a more hormonally active tumor environment, potentially indicative of tumors with higher AR dependency and responsiveness to therapy. Their profiling may help predict ARPI response, warranting further investigation. Graphical abstract

Oxylipins are derived from enzymatic and non-enzymatic oxidation of n -3 and n -6 long-chain polyunsaturated fatty acids. They are known to be involved in inflammatory processes. The aim of this study was to describe the breast milk oxylipin profile following a docosahexaenoic acid (DHA) supplementation of mothers of preterm infants. We examined the oxylipins profile in breast milk collected at day 14 post-delivery, of 40 mothers who delivered before 29 weeks of gestation and who were supplemented with either DHA-rich algae oil (S-DHA) or a placebo (PL). These mothers were selected from the MOBYDIck cohort (NCT02371460 registered on 25/05/2015 in ClinicalTrials.gov) according to the supplementation received (S-DHA vs. PL) and the DHA content quartiles as measured in breast milk (Low vs. High) to generate four study groups. Milk oxylipins, as ng/mL of milk, were analyzed by LC-MS/MS. Ten oxylipins derived from DHA were higher in the S-DHA-High group than the other three groups (P < 0.001). The 18-HEPE, was also higher in the S-DHA-High group (0.11 ± 0.01) compared to the other groups (P = 0.0001). Compared to the PL-Low group, there was a reduction in pro-inflammatory prostaglandins found in the S-DHA-High group with lower levels of prostaglandins PGF 2α (0.21 ± 0.45 in the S-DHA-High group vs. 1.87 ± 0.44 in the PL-Low group, P = 0.03) and of PGE 2 (0.33 ± 0.26 in the S-DHA-High group vs. 1.28 ± 0.25 in the PL-Low group, P = 0.04).In sum, the DHA supplementation was linked with a predominance of anti-inflammatory oxylipins in breast milk of mothers who delivered very preterm, like 17(S)-HDHA and 18-HEPE, precursors of D and E resolvins respectively. This was also accompanied with a lower level of pro-inflammatory prostaglandins.

Preterm infants are deficient in long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), a fatty acid (FA) associated with an increase in bronchopulmonary dysplasia (BPD). In two previous randomized control trials, DHA supplementation did not reduce the risk of BPD. We examined the breast milk FA profile, collected 14 days after birth, of mothers who delivered before 29 weeks of gestation and who were supplemented with DHA-rich algae oil or a placebo within 72 h after birth as part of the MOBYDIck trial. Milk FA were analyzed by gas chromatography. The total amount of FA (mg/mL) was similar in both groups but the supplementation increased DHA (expressed as % of total FA, mean ± SD, treatment vs placebo, 0.95 ± 0.44% vs 0.34 ± 0.20%; P < 0.0001), n-6 docosapentaenoic acid (DPA) (0.275 ± 0.14% vs 0.04 ± 0.04%; P < 0.0001) and eicosapentaenoic acid (0.08 ± 0.08% vs 0.07 ± 0.07%; P < 0.0001) while decreasing n-3 DPA (0.16 ± 0.05% vs 0.17 ± 0.06%; P < 0.05). Supplementation changed the ratio of DHA to arachidonic acid (1.76 ± 1.55% vs 0.60 ± 0.31%; P < 0.0001) and n-6 to n-3 FA (0.21 ± 0.06% vs 0.17 ± 0.04%; P < 0.0001). DHA-rich algae supplementation successfully increased the DHA content of breast milk but also included secondary changes that are closely involved with inflammation and may contribute to changing clinical outcomes.

The localization, density but mostly the phenotype of tumor infiltrating lymphocytes (TIL) provide important information on the initial interaction between the host immune system and the tumor. Our objective was to assess the prognostic significance of T (CD3 ), T regulatory (T ) (FoxP3 ) and T memory (T ) (CD45RO ) infiltrating lymphocytes and of genes associated with TIL in prostate cancer (PCa). Immunohistochemistry (IHC) was used to assess the infiltration of CD3 , FoxP3 and CD45RO cells in the tumor area, tumor margin and adjacent normal-like epithelium of a series of 98 PCa samples with long clinical follow-up. Expression of a panel of 31 TIL-associated genes was analyzed by Taqman Low-Density Array (TLDA) technology in another series of 50 tumors with long clinical follow-up. Kaplan-Meier and Cox proportional hazards regression analyses were performed to determine association of these markers with biochemical recurrence (BCR), need for definitive androgen deprivation therapy (ADT) or lethal PCa. TIL subtypes were present at different densities in the tumor, tumor margin and adjacent normal-like epithelium, but their density and phenotype in the tumor area were the most predictive of clinical outcomes. In multivariate analyses, a high density of T (high FoxP3 /CD3 cell ratio) predicted a higher risk for need of definitive ADT (HR=7.69, p=0.001) and lethal PCa (HR=4.37, p=0.04). Conversely, a high density of T (high CD45RO /CD3 cell ratio) predicted a reduced risk of lethal PCa (HR=0.06, p=0.04). TLDA analyses showed that a high expression of FoxP3 was associated with a higher risk of lethal PCa (HR=5.26, p=0.02). Expression of CTLA-4, PD-1, TIM-3 and LAG-3 were correlated with that of FoxP3. Amongst these, only a high expression of TIM-3 was associated with a significant higher risk for definitive ADT in univariate Cox regression analysis (HR=3.11, p=0.01). These results show that the proportion of T and T found within the tumor area is a strong and independent predictor of late systemic progression of PCa. Our results also suggest that inhibition of TIM-3 might be a potential approach to counter the immunosuppressive functions of T in order to improve the anti-tumor immune response against PCa.

Prostate cancer (PCa) shows considerable variation in clinical outcomes between individuals with similar diseases. The initial host-tumor interaction as assessed by detailed analysis of tumor infiltrating immune cells within the primary tumor may dictate tumor evolution and late clinical outcomes. In this study, we assessed the association between clinical outcomes and dendritic cell (DC) or macrophage (MΦ) tumor infiltration as well as with expression of genes related to their functions. Infiltration and localization of immature DC, mature DC, total MΦ and M2-type MΦ was analyzed by immunohistochemistry in 99 radical prostatectomy specimens from patients with 15.5 years median clinical follow-up using antibodies against CD209, CD83, CD68 and CD163, respectively. The density of positive cells for each marker in various tumor areas was determined. In addition, expression of immune genes associated with DC and MΦ was tested in a series of 50 radical prostatectomy specimens by Taqman Low-Density Array with similarly long follow-up. Gene expression was classified as low and high after unsupervised hierarchical clustering. Numbers and ratio of positive cells and levels of gene expression were correlated with endpoints such as biochemical recurrence (BCR), need for definitive androgen deprivation therapy (ADT) or lethal PCa using Cox regression analyses and/or Kaplan-Meier curves. Positive immune cells were observed in tumor, tumor margin, and normal-like adjacent epithelium areas. CD209 and CD163 cells were more abundant at the tumor margin. Higher CD209 /CD83 cell density ratio at the tumor margin was associated with higher risk of ADT and lethal PCa while higher density of CD163 cells in the normal-like adjacent epithelium was associated with a higher risk of lethal PCa. A combination of 5 genes expressed at high levels correlated with a shorter survival without ADT and lethal PCa. Among these five genes, expression of and was correlated to each other and was associated with shorter survival without BCR and ADT/lethal PCa, respectively. A higher level of infiltration of CD209 immature DC and CD163 M2-type MΦ in the peritumor area was associated with late adverse clinical outcomes.

Background Health literacy refers to the ability of individuals to gain access to, use, and understand health information and services in order to maintain a good health. It is especially important in nephrology due to the complexity of chronic kidney disease (CKD). The present study sought to define health literacy levels in patients followed in predialysis clinic, in-center dialysis (ICHD), peritoneal dialysis (PD) and home hemodialysis (HHD). Methods This transversal monocentric observational study analysed 363 patients between October 2016 and April 2017. The Brief Health Literacy Screen (BHLS) and the Health Literacy Questionnaire (HLQ) were used to measure health literacy. Multivariate linear regressions were used to compare the mean scores on the BHLS and HLQ, across the four groups. Results Patients on PD had a significantly higher BHLS’score than patients on ICHD ( p  = 0.04). HLQ’s scores differed across the groups: patients on HHD ( p  = 0.01) and PD ( p  = 0.002) were more likely to feel understood by their healthcare providers. Compared to ICHD, patients on HHD were more likely to have sufficient information to manage their health ( p  = 0.02), and patients in the predialysis clinic were more likely to report high abilities for health information appraisal ( p  < 0.001). Conclusion In a monocentric study, there is a significant proportion of CKD patients, especially in predialysis clinic and in-centre hemodialysis, with limited health literacy. Patients on home dialysis (HHD and PD) had a higher level of health literacy compared to the other groups.

Background Perturbation of the major UGT2B17-dependent androgen catabolism pathway has the potential to affect prostate cancer (PCa) progression. The objective was to evaluate UGT2B17 protein expression in primary tumours in relation to hormone levels, disease characteristics and cancer evolution. Methods We conducted an analysis of a high-density prostate tumour tissue microarray consisting of 239 localised PCa cases treated by radical prostatectomy (RP). Cox proportional hazard ratio analysis was used to evaluate biochemical recurrence (BCR), and a linear regression model evaluated variations in circulating hormone levels measured by mass spectrometry. The transcriptome of UGT2B17 in PCa was established by using RNA-sequencing data. Results UGT2B17 expression in primary tumours was associated with node-positive disease at RP and linked to circulating levels of 3α-diol-17 glucuronide, a major circulating DHT metabolite produced by the UGT2B17 pathway. UGT2B17 was an independent prognostic factor linked to BCR after RP, and its overexpression was associated with development of metastasis. Finally, we demonstrated that distinctive alternative promoters dictate UGT2B17-dependent androgen catabolism in localised and metastatic PCa. Conclusions The androgen-inactivating gene UGT2B17 is controlled by overlooked regulatory regions in PCa. UGT2B17 expression in primary tumours influences the steroidome, and is associated with relevant clinical outcomes, such as BCR and metastasis.

To determine whether the use of a blue light-filtering intraocular lens (IOL) prevents the onset of wet age-related macular degeneration (AMD). More precisely, we examined the proportion of blue light-filtering IOL in a wet AMD patients' sample and compared it with a general North American pseudophakic population sample. Retrospective case-control study. Case patients were diagnosed and treated for wet AMD and had prior IOL implantation at least 3 years before the diagnosis of wet AMD. Control patients were randomly selected among patients who had cataract surgery at our institution. They were exempt of AMD and paired for the year of surgery, sex and age at cataract surgery. A total of 196 patients were included in each study group. Among patients with wet AMD, 62.8% had a blue light-filtering IOL compared with 63.3% among control patients (p = 0.92). Mean time between implantation and injection of anti-VEGF in AMD patients was 6.62 years (95% confidence interval (CI): 6.04-7.19) in non-blue light-filtering IOL group and 5.76 years (95% CI: 5.41-6.11) in blue light-filtering IOL group (p = 0.0120). No correlations could be established between the presence of a blue light filter in the IOL and the occurrence of wet AMD. AMD patients without blue light-filtering IOL were injected significantly later than patients with an IOL filtering blue light, which contradict the potential clinical benefit of the blue light filter.

Background Two of the most frequently deleted genes in the human genome are the UDP-glycosyltransferases UGT2B17 and UGT2B28. They encode metabolic enzymes of the glucuronidation pathway that plays a pivotal role in the maintenance of cellular homeostasis for a variety of small molecule metabolites. These deletions may impact health, yet their effects remain poorly understood. We evaluated the impact of UGT deficiency on the plasma metabolome and examined the association between altered metabolites and health outcomes. Methods The metabolomic profiles of 4262 proficient gene carriers were compared with those of 352 UGT2B17 -deficient, 97 UGT2B28 -deficient, and 20 double-gene-deficient individuals from the Canadian Longitudinal Study on Aging. Significant metabolites found in these comparisons were analyzed for their associations with common diseases. Results The unexpectedly broad molecular divergence found in UGT -deficient metabolomes, which affected > 10% of metabolites, implies their significant influence across various metabolite classes—particularly lipids and amino acids — extending beyond their known substrates. The metabolic profiles of UGT2B17 -deficient men and UGT2B28 -deficient women were most impacted, with UGT2B17 deficiency affecting various metabolites linked to metabolic diseases, arthritis, and osteoporosis. Metabolites impacted by a UGT2B28 deficiency such as amino acids, were linked to metabolic disorders in women. Conclusion The findings significantly advance our understanding of the metabolic landscape associated with these frequently deleted genes in the human genome, which may influence susceptibility to various diseases in a sex-specific manner, laying the groundwork for determining their pathological mechanisms and impact on human health.