Clinical verification of body mass index and tumor immune response in patients with breast cancer receiving preoperative chemotherapy.

PURPOSE: The body mass index (BMI) is commonly used as a simple indicator of obesity; patients with early-stage breast cancer who are obese (OB) per BMI measurements have been shown to have high postoperative recurrence and low survival rates. On the other hand, it has been shown that lymphocytes present in the vicinity of malignant growths that are involved in the tumors' immune responses influence the efficacy chemotherapy. Therefore, we hypothesized that OB patients with breast cancer have a lower density of tumor-infiltrating lymphocytes (TILs), which may influence the therapeutic effect of preoperative chemotherapy (POC). In this study, we measured pretreatment BMI and TILs in patients with breast cancer who underwent POC, examined the correlations between these two factors, and retrospectively analyzed their therapeutic outcomes and prognoses. METHODS: The participants in this study were 421 patients with breast cancer who underwent surgical treatment after POC between February 2007 and January 2019. The patient's height and weight were measured before POC to calculate the BMI (weight [kg] divided by the square of the height [m2]). According to the World Health Organization categorization, patients who weighed under 18.5 kg/m2 were classified as underweight (UW), those ≥18.5 kg/m2 and > 25 kg/m2 were considered normal weight (NW), those ≥25 kg/m2 and < 30 kg/m2 were overweight (OW), and those ≥30 kg/m2 were OB. The TILs were those lymphocytes that infiltrated the tumor stroma according to the definition of the International TILs Working Group 2014. RESULTS: The median BMI was 21.9 kg/m2 (range, 14.3-38.5 kg/m2); most patients (244; 64.5%) were NW. Among all 378 patients with breast cancer, the TIL density was significantly lower in OB than in NW and OW patients (vs. NW: p = 0.001; vs. OW: p = 0.003). Furthermore, when examining patients with each breast cancer type individually, the OS of those with TNBC who had low BMIs was significantly poorer than that of their high-BMI counterparts (log rank p = 0.031). CONCLUSIONS: Our data did not support the hypothesis that obesity affects the tumor immune microenvironment; however, we showed that being UW does affect the tumor immune microenvironment.

Transient systemic inflammation in adult male mice results in underweight progeny.

PROBLEM: While the testes represent an immune-privileged organ, there is evidence that systemic inflammation is accompanied by local inflammatory responses. We therefore examined whether transient systemic inflammation caused any inflammatory and functional consequences in murine testes. METHOD OF STUDY: Using a single systemic administration of Toll-like receptor (TLR) agonists [lipopolysaccharide (LPS) or peptidoglycan (PG) or polyinosinic-polycytidylic acid (polyIC)] in young adult male mice, we assessed testicular immune-inflammatory landscape and reproductive functionality. RESULTS: Our findings demonstrated a significant induction of testicular TNF-α, IL-1ß and IL-6 transcripts within 24 h of TLR agonist injection. By day 6, these cytokine levels returned to baseline. While there was no change in caudal sperm counts at early time points, eight weeks later, twofold decrease in sperm count and reduced testicular testosterone levels were evident. When these mice were subjected to mating studies, no differences in mating efficiencies or litter sizes were observed compared with controls. Nonetheless, the neonatal weights of progeny from LPS/PG/polyIC-treated sires were significantly lower than controls. Postnatal weight gain up to three weeks was also slower in the progeny of LPS/polyIC-treated sires. Placental weights at 17.5 days post-coitum were significantly lower in females mated to LPS- and polyIC-treated males. Given this likelihood of an epigenetic effect, we found lower testicular levels of histone methyltransferase enzyme, mixed-lineage leukaemia-1, in mice given LPS/PG/polyIC 8 weeks earlier. CONCLUSION: Exposure to transient systemic inflammation leads to transient local inflammation in the testes, with persistent sperm-mediated consequences for foetal development.

Plasma endocannabinoid levels in lean, overweight, and obese humans: relationships to intestinal permeability markers, inflammation, and incretin secretion.

Intestinal production of endocannabinoid and oleoylethanolamide (OEA) is impaired in high-fat diet/obese rodents, leading to reduced satiety. Such diets also alter the intestinal microbiome in association with enhanced intestinal permeability and inflammation; however, little is known of these effects in humans. This study aimed to 1) evaluate effects of lipid on plasma anandamide (AEA), 2-arachidonyl- sn-glycerol (2-AG), and OEA in humans; and 2) examine relationships to intestinal permeability, inflammation markers, and incretin hormone secretion. Twenty lean, 18 overweight, and 19 obese participants underwent intraduodenal Intralipid infusion (2 kcal/min) with collection of endoscopic duodenal biopsies and blood. Plasma AEA, 2-AG, and OEA (HPLC/tandem mass spectrometry), tumor necrosis factor-α (TNFα), glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) (multiplex), and duodenal expression of occludin, zona-occludin-1 (ZO-1), intestinal-alkaline-phosphatase (IAP), and Toll-like receptor 4 (TLR4) (by RT-PCR) were assessed. Fasting plasma AEA was increased in obese compared with lean and overweight patients ( P < 0.05), with no effect of BMI group or ID lipid infusion on plasma 2-AG or OEA. Duodenal expression of IAP and ZO-1 was reduced in obese compared with lean ( P < 0.05), and these levels related negatively to plasma AEA ( P < 0.05). The iAUC for AEA was positively related to iAUC GIP ( r = 0.384, P = 0.005). Obese individuals have increased plasma AEA and decreased duodenal expression of ZO-1 and IAP compared with lean and overweight subjects. The relationships between plasma AEA with duodenal ZO-1, IAP, and GIP suggest that altered endocannabinoid signaling may contribute to changes in intestinal permeability, inflammation, and incretin release in human obesity.

Pre-Pregnancy Body Mass Index Is Associated with Dietary Inflammatory Index and C-Reactive Protein Concentrations during Pregnancy.

There have been a limited number of studies examining the association between pre-pregnancy body mass index (BMI) and dietary inflammation during pregnancy. Our aim is to examine the association between pre-pregnancy BMI and the Dietary Inflammatory Index (DII)™ and C-reactive protein (CRP) concentrations during pregnancy. The study included 631 pregnant American women from the National Health and Nutrition Examination Survey (NHANES) cross-sectional examinations from 2003 to 2012. Pre-pregnancy BMI was calculated based on self-reported pre-pregnancy weight and measured height. The cut-offs of <18.5 (underweight), 18.5-24.9 (normal), 25.0-29.9 (overweight), and ≥30 kg/m² (obese) were used to categorize the weight status of pregnant women prior to pregnancy. The DII, a literature-based dietary index to assess the inflammatory properties of diet, was estimated based on a one-day 24-h recall. Multivariable linear and logistic regressions were performed to estimate beta coefficients and the adjusted odds ratios (AORs) and 95% confidence intervals (95% CIs) on the association of pre-pregnancy BMI categories with the DII and CRP concentrations during pregnancy. After controlling for variables including: race/ethnicity, family poverty income ratio, education, marital status, month in pregnancy, and smoking status during pregnancy; women who were obese before pregnancy (n = 136) had increased odds for being in the highest tertile of the DII and CRP concentrations compared to women with normal weight (AORs 2.40, 95% CIs 1.01-5.71; AORs 24.84, 95% CIs 6.19-99.67, respectively). These findings suggest that women with pre-pregnancy obesity had greater odds of reporting higher DII and having elevated CRP. In conclusion, high pre-pregnancy BMI was associated with increased odds of pro-inflammatory diet and elevated CRP levels during pregnancy in the USA.

Obesity/overweight reduces the risk of active tuberculosis: a nationwide population-based cohort study in Taiwan.

BACKGROUND: Obesity affects immune function by increasing the number of T helper lymphocytes, which may reduce the risk of tuberculosis (TB) infection. However, the effect of obesity on TB development has not been extensively studied. This nationwide population-based cohort study investigated the effect of obesity on TB development in Taiwanese adults. METHODS: We included 46 028 adult participants (age ⩾18 years) from three rounds (2001, 2005 and 2009) of the Taiwan National Health Interview Survey. Obesity and overweight were defined as a body mass index (BMI) ⩾27 and 24-26.9 (kg/m2), respectively. Data on BMI and other covariates at baseline were collected by in-person interviews. Incident cases of active TB were identified from the National Health Insurance database. Multivariable logistic regression was used to estimate the associations of obesity and overweight with active TB, with adjustment for age, sex, smoking, alcohol consumption, socioeconomic status and other covariates. RESULTS: In total, 241 new cases of active TB occurred during the study period. Obesity (adjusted odds ratio [AOR], 0.43; 95% confident interval [CI], 0.28-0.67) and overweight (AOR, 0.67; 95% CI, 0.49-0.91) were associated with lower risk of incident TB, after adjusting for demographic characteristics and comorbidities. There was a linear dose-response relation of BMI with active TB incidence (AOR per unit change in BMI, 0.92; 95% CI, 0.88-0.95; P <0.001). CONCLUSION: Obesity and overweight are associated with lower risk of active TB. Future studies should investigate the underlying mechanisms and clinical and epidemiological consequences of these findings.

Oxidized low-density lipoprotein antibodies/high-density lipoprotein cholesterol ratio is linked to advanced non-alcoholic fatty liver disease lean patients.

BACKGROUND AND AIM: A small but significant proportion of patients with normal body mass index show non-alcoholic fatty liver disease (NAFLD). Oxidized low-density lipoprotein (LDL) is a powerful immunogenic molecule, which causes oxidative stress and produces antibodies (oxLDL-ab). We aimed to analyze the role of oxLDL-ab on histological features in lean-NAFLD patients. METHODS: Seventy-two biopsy-proven NAFLD patients were included. Lean patients showed body index mass of <30 kg/m(2) . Liver biopsies were assessed by one pathologist blinded to clinical data. Histological features were non-alcoholic steatohepatitis (NASH), steatosis, hepatocellular ballooning, and liver fibrosis. Metabolic and hepatic profiles were analyzed, and lipid-lowering medication was recorded. OxLDL-ab levels were measured by ELISA. OxLDL-ab-based lipid indexes analyzed: oxLDL-ab/total cholesterol ratio; oxLDL-ab/LDL-c ratio; oxLDL-ab/high-density lipoprotein cholesterol (HDL-c) ratio; and oxLDL-ab/oxLDL ratio. RESULTS: Lean-NAFLD patients presented 26.5% (9/34) of NASH. OxLDL-ab/HDL-c ratio (r = 0.570; n = 34; P = 0.001) correlated with NAS score and was the only variable associated with NASH in the multivariate analysis [odds ratio, OR, 1.10 (95% confidence interval, CI: 1.01-1.21); P = 0.039]. Severe steatosis was present in 41.2% (14/34) of lean-NAFLD patients. OxLDL-ab/HDL-c ratio was higher in patients with grade-III steatosis (54.9 (37.3-124.6)) than those with grade II (37.1 (20.2-71.1)) and grade I (17.7 (13.1-22.8)) (P = 0.018). Hepatocellular ballooning was present in 20.6% (7/34) of lean-NAFLD patients, and OxLDL-ab/HDL-c ratio (OR 1.03 [95% CI: 1.01-1.05]; P = 0.050) was independently associated with histological features. OxLDL-ab/HDL-c ratio was higher in patients with advanced fibrosis (39.8 (22.9-121.6) vs 17.7 (13.9-30.9); P = 0.025), increasing gradually with the fibrosis stage (P = 0.042) and remained in the final multivariate model [OR 1.05 (95% CI: 1.00-1.11); P = 0.05]. However, in obese-NAFLD patients, oxLDL/HDL-c ratio was not associated with histological features. CONCLUSIONS: Oxidized low-density lipoprotein antibodies/high-density lipoprotein cholesterol ratio could represent an interesting biomarker associated with NASH, hepatocellular ballooning, and liver fibrosis, in lean patients. OxLDL-ab/HDL-c could play an important role for distinguishing patients with and without NAFLD complications.

Increasing body condition score is positively associated interleukin-6 and monocyte chemoattractant protein-1 in Labrador retrievers.

The accumulation of excess body fat is a growing problem in dogs as well as people. Contrary to prior understanding of adipose tissue, fat is now considered to be an active endocrine organ that promotes a chronic low-grade inflammatory state often characterized by an increase in pro-inflammatory cytokines and chemokines. These have been implicated in several obesity-related disorders such as insulin resistance, cardiovascular disease, and neoplasia. The purpose of this study was to characterize fasting plasma cytokine concentrations in ninety-two healthy client-owned Labrador retriever dogs of various ages and body condition scores. The dogs were grouped according to body condition score (BCS) into three categories, lean, overweight and obese. The following cytokines and chemokines were evaluated; tumor necrosis factor-alpha, interleukin-2, interleukin-6, interleukin-8, and monocyte chemotactic protein-1 (TNF-α, IL-2, IL-6, IL-8, MCP-1). Our results indicated that fasting plasma IL-6 and MCP-1 concentrations are associated with increasing BCS. This data suggest that certain markers of inflammation increase with increasing body condition score, and that dogs, similar to humans, may be fostering a chronic inflammatory state due to obesity.

P65 inactivation in adipocytes and macrophages attenuates adipose inflammatory response in lean but not in obese mice.

NF-κB induces transcriptional expression of proinflammatory genes and antiapoptotic genes. The two activities of NF-κB remain to be characterized in the mechanism of chronic inflammation in obesity. To address this issue, we inactivated NF-κB in adipose tissue by knocking out p65 (RelA) in mice (F-p65-KO) and examined the inflammation in lean and obese conditions. In the lean condition, KO mice exhibited a reduced inflammation in adipose tissue with a decrease in macrophage infiltration, M1 polarization, and proinflammatory cytokine expression. In the obese condition, KO mice had elevated inflammation with more macrophage infiltration, M1 polarization, and cytokine expression. In the mechanism of enhanced inflammation, adipocytes and macrophages exhibited an increase in cellular apoptosis, which was observed with more formation of crown-like structures (CLS) in fat tissue of KO mice. Body weight, glucose metabolism, and insulin sensitivity were not significantly altered in KO mice under the lean and obese conditions. A modest but significant reduction in body fat mass was observed in KO mice on HFD with an elevation in energy expenditure. The data suggest that in the control of adipose inflammation, NF-κB exhibits different activities in the lean vs. obese condition. NF-κB is required for expression of proinflammatory genes in the lean but not in the obese condition. NF-κB is required for inhibition of apoptosis in the obese condition, in which proinflammation is enhanced by NF-κB inactivation.

Effects of epigallocatechin gallate on regulatory T cell number and function in obese v. lean volunteers.

Obesity predisposes to an increased incidence of diabetes and CVD. Also, obesity is a pro-inflammatory state. Regulatory T cells (Tregs) are essential negative regulators of inflammation and are down-regulated in pro-inflammatory states. Animal models of obesity are associated with decreased Tregs. The dietary modulation of Tregs could be used as a therapeutic strategy to control inflammation. Epigallocatechin gallate (EGCG) is a potent anti-inflammatory agent and an active ingredient of green tea and is suggested to have a role as a preventive agent in obesity, diabetes and CVD. The role of EGCG in the modulation of Tregs has, however, not been studied. Thus, the aim of the present study was to determine the effect of EGCG on the number and function of Tregs in obese and lean human subjects in vitro, and to delineate its specific regulation mechanisms. Tregs were isolated from normal-weight and obese subjects. Tregs were cultured in the absence or presence of EGCG (20 mum) for 24 h. Foxp3-expressing Tregs were enumerated using flow cytometry. Histone deacetylase (HDAC) activity and nuclear NF-kappaBp65 level were measured by ELISA and Western blots. Obese subjects had lower Tregs and IL-10 production than lean subjects. EGCG treatment significantly enhanced the number of Foxp3-expressing Tregs and IL-10 production in vitro (P < 0.05) in both groups. Also, EGCG decreased NF-kappaB activity and increased HDAC activity and HDAC-2 expression in Tregs (P < 0.05) in both groups. Thus, in part, EGCG enhances the functionality of Tregs, i.e. IL-10 production and number by suppressing the NF-kappaB signalling pathway via inducing epigenetic changes.

Peripheral but not central leptin treatment increases numbers of circulating NK cells, granulocytes and specific monocyte subpopulations in non-endotoxaemic lean and obese LEW-rats.

Leptin, a hormone mainly generated by adipocytes, acts centrally in the hypothalamus to regulate body weight and energy expenditure. However, there is strong evidence that leptin is also involved in cell-mediated immunity and cytokine crosstalk. In the present study the effects of diet-induced obesity and central and peripheral leptin treatment on leukocyte subsets and cytokine production was investigated. Leptin was injected either intravenously (i.v.) or intracerebroventricularly (i.c.v.) in male endotoxaemic or vehicle-treated healthy LEW-rats. Numbers of blood leukocyte subsets were analysed by FACS and cytokines (TNF-alpha and IL-6) by ELISA. Results showed that peripheral rather than central leptin treatment was able to significantly increase numbers of granulocytes, NK cells and monocytes. Three-colour staining revealed that the increase of ED9(+) monocytes was most likely due to the mobilization of two distinct monocyte subsets, predominantly ED9(+)CD4(-)NKR-P1A(+) and ED9(+)CD4(+)NKR-P1A(+). ELISA analysis revealed significantly elevated TNF-alpha levels in obese animals compared to their lean littermates, while IL-6 failed to show notable changes. In conclusion, the data of the present study revealed that leptin application induces a nutrition- and application-site dependent increase of circulating NK cells, granulocytes and specific monocyte subsets.

Vaccination against weight gain.

Obesity endangers the lives of millions of people worldwide, through comorbidities such as heart disease, cancers, type 2 diabetes, stroke, arthritis, and major depression. New approaches to control body weight remain a high priority. Vaccines traditionally have been used to protect against infectious diseases and, more recently, for unconventional targets such as drug addiction. Methodologies that could specifically modulate the bioavailability of an endogenous molecule that regulates energy balance might provide a new foundation for treating obesity. Here we show that active vaccination of mature rats with ghrelin immunoconjugates decreases feed efficiency, relative adiposity, and body weight gain in relation to the immune response elicited against ghrelin in its active, acylated form. Three active vaccines based on the 28-aa residue sequence of ghrelin, a gastric endocrine hormone, were used to immunize adult male Wistar rats (n = 17). Synthetic ghrelin analogs were prepared that spanned residues 1-10 [ghrelin (1-10) Ser-3(butanoyl) hapten, Ghr1], 13-28 [ghrelin (13-28) hapten, Ghr2], and 1-28 [ghrelin(1-28) Ser-3(butanoyl) hapten, Ghr3], and included n-butanoyl esters at Ser-3. Groups immunized with Ghr1 or Ghr3 showed greater and more selective plasma binding capacity for the active, Ser-3-(n-octanoyl) form of ghrelin as compared with Ghr2 or keyhole limpet hemocyanin vaccinated controls. Accordingly, they gained less body weight, with sparing of lean mass and preferential reduction of body fat, consistent with reduced circulating leptin levels. The ratio of brain/serum ghrelin levels was lower in rats with strong anti-ghrelin immune responses. Effects were not attributable to nonspecific inflammatory responses. Vaccination against the endogenous hormone ghrelin can slow weight gain in rats by decreasing feed efficiency.

Combined interleukin-6 and interleukin-1 deficiency causes obesity in young mice.

Proinflammatory cytokines including interleukin (IL)-1 and IL-6 exert pleiotropic effects on the neuro-immuno-endocrine system. Previously, we showed that IL-1 receptor antagonist-deficient (IL-1Ra(-/-)) mice show a lean phenotype due to an abnormal lipid metabolism. On the contrary, it was reported that IL-6(-/-) mice exhibit obesity after 6 months of age. This study sought to assess the roles of IL-1 and IL-6 in body weight homeostasis. We generated mice deficient in IL-6 and IL-1Ra (IL-6(-/-) IL-1Ra(-/-)) and IL-6, IL-1alpha, and IL-1beta (IL-6(-/-) IL-1(-/-)). IL-6(-/-) IL-1Ra(-/-) mice exhibited a lean phenotype, similar to IL-1Ra(-/-) mice. On the other hand, IL-6(-/-) IL-1(-/-) mice became obese as early as 10 weeks of age, while IL-1(-/-) mice and IL-6(-/-) mice were normal at this age. The daily food intake was significantly higher in IL-6(-/-) IL-1(-/-) mice than in IL-6(-/-) IL-1(+/-) mice, while energy expenditure was comparable in these two strains. Acute anorexia induced by peripheral administration of IL-1 was significantly suppressed in IL-6(-/-) IL-1(-/-) mice, but not in IL-1(-/-) mice or IL-6(-/-) mice compared with wild-type mice. These results indicate that IL-1 and IL-6 are both involved in the regulation of body fat in a redundant manner in young mice.