Parallel Profiles of Inflammatory and Effector Memory T Cells in Visceral Fat and Liver of Obesity-Associated Cancer Patients

In the midst of a worsening obesity epidemic, the incidence of obesity-associated morbidities, including cancer, diabetes, cardiac and liver disease is increasing. Insights into mechanisms underlying pathological obesity-associated inflammation are lacking. Both the omentum, the principal component of visceral fat, and liver of obese individuals are sites of excessive inflammation, but to date the T cell profiles of both compartments have not been assessed or compared in a patient cohort with obesity-associated disease. We have previously identified that omentum is enriched with inflammatory cytokines, chemokines and T cells. Here, we compared the inflammatory profile of T cells in the omentum and liver of patients with the obesity-associated malignancy oesophageal adenocarcinoma (OAC). Furthermore, we assessed the secreted cytokine profile in OAC patient serum, omentum and liver to assess systemic and local inflammation. We observed parallel T cell cytokine profiles and phenotypes in the omentum and liver of OAC patients, in particular CD69+ and inflammatory effector memory T cells. This study reflects similar processes of inflammation and T cell activation in the omentum and liver, and may suggest common targets to modulate pathological inflammation at these sites

The Microenvironment of Visceral Adipose Tissue and Liver Alter Natural Killer Cell Viability and Function

The role of NK cells in visceral adipose tissue (VAT) and liver inflammation in obesity is not fully understood. This study investigated the frequency, cytokine expression, chemokine receptor, and cytotoxicity receptor profile of NK cells in the blood, omentum, and liver of patients with the obesity-associated cancer, oesophageal adenocarcinoma (OAC). The effect of chronically inflamed tissue microenvironments on NK cell viability and function was also examined. We identified significantly lower NK cell frequencies in the liver of OAC patients compared with healthy controls and within the omentum and liver of OAC patients compared with blood, whereas IL-10-producing populations were significantly higher. Interestingly, our data suggest that reduced frequencies of NK cells in omentum and liver of OAC patients are not a result of impaired NK cell chemotaxis to these tissues. In fact, our functional data revealed that secreted factors from omentum and liver of OAC patients induce significant levels of NK cell death and lead to reduced percentages of TNF-α+ and NKP46+ NK cells and higher frequencies of IL-10-producing NK cells. Together, these data suggest that the omental and hepatic microenvironments of OAC patients alter the NK cell phenotype to a more anti-inflammatory homeostatic role

Identifying a Novel Role for Fractalkine (CX3CL1) in Memory CD8(+) T Cell Accumulation in the Omentum of Obesity-Associated Cancer Patients

The omentum is enriched with pro-inflammatory effector memory CD8+ T cells in patients with the obesity-associated malignancy, esophagogastric adenocarcinoma (EAC) and we have identified the chemokine macrophage inflammatory protein-1alpha as a key player in their active migration to this inflamed tissue. More recently, others have established that subsets of memory CD8+ T cells can be classified based on their surface expression of CX3CR1; the specific receptor for the inflammatory chemokine fractalkine. CD8+ T cells expressing intermediate levels (CX3CR1INT) are defined as peripheral memory, those expressing the highest levels (CX3CR1HI) are effector memory/terminally differentiated and those lacking CX3CR1 (CX3CR1NEG) are classified as central memory. To date, the fractalkine:CX3CR1 axis has not been examined in the context of CD8+ T cell enrichment in the omentum and here we examine this chemokines involvement in the accumulation of memory CD8+ T cells in the omentum of EAC patients. Our data show that fractalkine is significantly enriched in the omentum of EAC patients and drives migration of T cells derived from EAC patient blood. Furthermore, CX3CR1 is endocytosed specifically by CD8+ T cells upon encountering fractalkine, which is consistent with the significantly diminished frequencies of CX3CR1INT and CX3CR1HI CD8+ T cells in the fractalkine-rich environment of omentum in EAC, relative to matched blood. Fractalkine-mediated endocytosis of CX3CR1 by CD8+ T cells is sustained and is followed by enhanced surface expression of L-selectin (CD62L). These novel data align with our findings that circulating CX3CR1NEG CD8+ T cells express higher levels of L-selectin than CX3CR1INT CD8+ T cells. This is consistent with previous reports and implicates fractalkine in the conversion of CX3CR1INT CD8+ T cells to a CX3CR1NEG phenotype characterized by alterations in the migratory capacity of these T cells. For the first time, these findings identify fractalkine as a driver of T cell migration to the omentum in EAC and indicate that CD8+ T cells undergo sequenced fractalkine-mediated alterations in CX3CR1 and L-selectin expression. These data implicate fractalkine as more than a chemotactic cytokine in obesity-associated meta-inflammation and reveal a role for this chemokine in the maintenance of the CX3CR1NEG CD8+ T cell populations

Visceral Adipose Tissue Modulates Radiosensitivity in Oesophageal Adenocarcinoma

Oesophageal adenocarcinoma (OAC) is an exemplar model of obesity-associated cancer. Response to neoadjuvant chemoradiotherapy (NA CRT) is a clinical challenge. We examined if visceral adipose tissue and obesity status alter radiosensitivity in OAC. The radioresistant (OE33R) and radioresponsive (OE33P) OAC isogenic model was cultured with adipose tissue conditioned media from three patient cohorts: non-cancer patients, surgery only OAC patients and NA CRT OAC patients. Cell survival was characterised by clonogenic assay, metabolomic profiling by nuclear magnetic resonance spectroscopy and adipokine receptor gene expression by qPCR. A retrospective in vivo study compared tumour response to NA CRT in normal weight (n=53) versus overweight/obese patients (n=148). Adipose conditioned media (ACM) from all patient cohorts significantly increased radiosensitivity in radioresistant OE33R cells. ACM from the NA CRT OAC cohort increased radiosensitivity in OE33P cells. Metabolomic profiling demonstrated separation of the non-cancer and surgery only OAC cohorts and between the non-cancer and NA CRT OAC cohorts. Gene expression profiling of OE33P versus OE33R cells demonstrated differential expression of the adiponectin receptor-1 (AR1), adiponectin receptor-2 (AR2), leptin receptor (LepR) and neuropilin receptor-1 (NRP1) genes. In vivo overweight/obese OAC patients achieved an enhanced tumour response following NA CRT compared to normal weight patients. This study demonstrates that visceral adipose tissue modulates the cellular response to radiation in OA

Motivational profiles and change in physical activity during a weight loss intervention: a secondary data analysis

Background High levels of moderate-to-vigorous intensity physical activity (MVPA) are strongly associated with sustained weight loss, however the majority of adults are unsuccessful in maintaining high levels of MVPA long-term. Our goal was to identify profiles based on exercise motives, and examine the association between motivational profile and longitudinal changes in MVPA during a weight loss intervention. Methods Adults with overweight or obesity (n&thinsp;=&thinsp;169, mean&thinsp;&plusmn;&thinsp;SE; age 39&thinsp;&plusmn;&thinsp;0.7&thinsp;years, BMI 34.4&thinsp;&plusmn;&thinsp;0.3&thinsp;kg/m2, 83% female) underwent an 18-month behavioral weight loss program, including 6&thinsp;months of supervised exercise, followed by 6&thinsp;months of unsupervised exercise. Participants self-reported behavioral regulations for exercise at baseline (BREQ-2). Latent profile analysis identified subgroups from external, introjected, identified, and intrinsic regulations measured at baseline. Mean differences in device-measured total MVPA were compared across motivational profiles at baseline, after 6&thinsp;months of supervised exercise and after a subsequent 6&thinsp;months of unsupervised exercise. Results Three motivational profiles emerged: high autonomous (high identified and intrinsic, low external regulations; n&thinsp;=&thinsp;52), high combined (high scores on all exercise regulations; n&thinsp;=&thinsp;25), and moderate combined (moderate scores on all exercise regulations; n&thinsp;=&thinsp;92). Motivational profile was not associated with baseline level of MVPA or the increase in MVPA over the 6-month supervised exercise intervention (high autonomous: 21&thinsp;&plusmn;&thinsp;6&thinsp;min/d; high combined: 20&thinsp;&plusmn;&thinsp;9&thinsp;min/d; moderate combined: 33&thinsp;&plusmn;&thinsp;5&thinsp;min/d; overall P&thinsp;&gt;&thinsp;0.05). However, during the transition from supervised to unsupervised exercise, MVPA decreased, on average, within all three profiles, but the high autonomous profile demonstrated the least attenuation in MVPA (&minus;&thinsp;3&thinsp;&plusmn;&thinsp;6&thinsp;min/d) compared to the moderate combined profile (&minus;&thinsp;20&thinsp;&plusmn;&thinsp;5&thinsp;min/d; P&thinsp;=&thinsp;0.043). Conclusions Results were in alignment with the Self-Determination Theory. Adults motivated by autonomous reasons (value benefits of exercise, intrinsic enjoyment) may be more likely to sustain increases in MVPA once support is removed, whereas participants with moderate-to-high scores on all types of exercise regulations may need additional long-term support in order to sustain initial increases in MVPA.</p

Definitions of Urinary Tract Infection in Current Research: A Systematic Review

Defining urinary tract infection (UTI) is complex, as numerous clinical and diagnostic parameters are involved. In this systematic review, we aimed to gain insight into how UTI is defined across current studies. We included 47 studies, published between January 2019 and May 2022, investigating therapeutic or prophylactic interventions in adult patients with UTI. Signs and symptoms, pyuria, and a positive urine culture were required in 85%, 28%, and 55% of study definitions, respectively. Five studies (11%) required all 3 categories for the diagnosis of UTI. Thresholds for significant bacteriuria varied from 103 to 105 colony-forming units/mL. None of the 12 studies including acute cystitis and 2 of 12 (17%) defining acute pyelonephritis used identical definitions. Complicated UTI was defined by both host factors and systemic involvement in 9 of 14 (64%) studies. In conclusion, UTI definitions are heterogeneous across recent studies, highlighting the need for a consensus-based, research reference standard for UTI

Early detection and intervention evaluation for people at risk of psychosis: multisite randomised controlled trial

Objective To determine whether cognitive therapy is effective in preventing the worsening of emerging psychotic symptoms experienced by help seeking young people deemed to be at risk for serious conditions such as schizophrenia