The intestinal extracellular matrix (ECM) helps maintain appropriate tissue barrier function and regulate host-microbial interactions. Chondroitin sulfate- and dermatan sulfate-glycosaminoglycans ...(CS/DS-GAGs) are integral components of the intestinal ECM, and alterations in CS/DS-GAGs have been shown to significantly influence biological functions. Although pathologic ECM remodeling is implicated in inflammatory bowel disease (IBD), it is unknown whether changes in the intestinal CS/DS-GAG composition are also linked to IBD in humans. Our aim was to characterize changes in the intestinal ECM CS/DS-GAG composition in intestinal biopsy samples from patients with IBD using mass spectrometry. We characterized intestinal CS/DS-GAGs in 69 pediatric and young adult patients (n = 13 control, n = 32 active IBD, n = 24 IBD in remission) and 6 adult patients. Here, we report that patients with active IBD exhibit a significant decrease in the relative abundance of CS/DS isomers associated with matrix stability (CS-A and DS) compared to controls, while isomers implicated in matrix instability and inflammation (CS-C and CS-E) were significantly increased. This imbalance of intestinal CS/DS isomers was restored among patients in clinical remission. Moreover, the abundance of pro-stabilizing CS/DS isomers negatively correlated with clinical disease activity scores, whereas both pro-inflammatory CS-C and CS-E content positively correlated with disease activity scores. Thus, pediatric patients with active IBD exhibited increased pro-inflammatory and decreased pro-stabilizing CS/DS isomer composition, and future studies are needed to determine whether changes in the CS/DS-GAG composition play a pathogenic role in IBD.
To assess practicing urologists’ attitudes and perceptions of active surveillance (AS) and other treatment options for low-risk prostate cancer.
This was a cross-sectional survey of urologists ...practicing in Michigan and Georgia. Urologists were asked about perceptions and practices pertaining to AS.
Overall, 225 urologists completed the survey; 147 (65%) were from Michigan and 78 (35%) were from Georgia. Most urologists reported they provided (99%), discussed (97%), and offered (61%) AS to all of their low-risk patients. Most believed AS is effective (97%) and underused (90%), while 80% agreed that curative therapy (surgery, radiation) is overused in the United States. Although most (79%) endorse that Black men are more likely to have aggressive low-risk disease, 89% reported feeling comfortable recommending AS to Black men. In multivariable analysis, significant provider-related predictors of AS recommendation were practice location, number of years in practice, beliefs pertaining to survival benefit of prostatectomy and effectiveness of AS, and expectation that patients are not interested in AS. The patient characteristics of race, age, life expectancy, fear of cancer progression, and fear of treatment side effects were also significant predictors of AS recommendations.
Most urologists surveyed stated that AS is effective and underused for low-risk prostate cancer . Overall, urologists are much less likely to recommend AS to younger men and slightly less to Black men. AS recommendations varied by practice location and by years in practice. These findings indicate targeted educational efforts in the US are needed to influence urologists toward greater acceptance of AS.
African Americans are often diagnosed with advanced stage cancer and experience higher mortality compared with whites in the United States. Contributing factors, like differences in access to medical ...care and the prevalence of comorbidities, do not entirely explain racial differences in outcomes.
The Detroit Research on Cancer Survivors (ROCS) pilot study was conducted to investigate factors related to short- and long-term outcomes among patients with cancer. Participants completed web-based surveys, and mailed saliva specimens were collected for future genetic studies.
We recruited 1,000 participants with an overall response rate of 68%. Thirty-one percent completed the survey without any interviewer support and the remaining participated in an interviewer-administered survey. Seventy-four percent provided a saliva specimen and 64% consented for tumor tissue retrieval. African American survivors required more interviewer support (
< 0.001); however, their response rate (69.6%) was higher than non-Hispanic whites (65.4%). African Americans reported poorer overall cancer-related quality of life compared with non-Hispanic whites, measured by FACT-G score (
< 0.001), however, this relationship was reversed after controlling for socioeconomic factors, marital status, and the presence of comorbidities.
In this pilot study, we demonstrated that a web-based survey supplemented with telephone interviews and mailed saliva kits are cost-effective methods to collect patient-reported data and DNA for large studies of cancer survivors with a high proportion of minority patients. The preliminary data collected reinforces differences by race in factors affecting cancer outcomes. Our efforts continue as we expand this unique cohort to include more than 5,000 African American cancer survivors.
Formal investigation of factors influencing adverse outcomes among African American cancer survivors will be critical in closing the racial gap in morbidity and mortality.
Background
The benefit of regular exercise in improving cancer outcomes is well established. The American Cancer Society (ACS) released a recommendation that cancer survivors should engage in at ...least 150 minutes of moderate to vigorous physical activity (PA) per week; however, few report meeting this recommendation. This study examined the patterns and correlates of meeting ACS PA recommendations in the Detroit Research on Cancer Survivors (ROCS) cohort of African American cancer survivors.
Methods
Detroit ROCS participants completed baseline and yearly follow‐up surveys to update their health and health behaviors, including PA. This study examined participation in PA by select characteristics and reported health‐related quality of life (HRQOL) as measured with the Functional Assessment of Cancer Therapy and Patient‐Reported Outcomes Measurement Information System instruments.
Results
Among the first 1500 ROCS participants, 60% reported participating in regular PA, with 24% reporting ≥150 min/wk. Although there were no differences by sex, prostate cancer survivors were the most likely to report participating in regular PA, whereas lung cancer survivors were the least likely (P = .022). Survivors who reported participating in regular PA reported higher HRQOL (P < .001) and lower depression (P = .040).
Conclusions
Just 24% of African American cancer survivors reported meeting the ACS guidelines for PA at the baseline, but it was encouraging to see increases in activity over time. Because of the established benefits of regular exercise observed in this study and others, identifying and reducing barriers to regular PA among African American cancer survivors are critical for improving outcomes and minimizing disparities.
Regular exercise is critically beneficial in improving quality of life and in reducing anxiety and depression in African American cancer survivors. Eliminating barriers to participation in physical activity will be important in reducing cancer disparities.
The extracellular matrix (ECM) of the brain comprises unique glycan “sulfation codes” that influence neurological function. Perineuronal nets (PNNs) are chondroitin sulfate‐glycosaminoglycan (CS‐GAG) ...containing matrices that enmesh neural networks involved in memory and cognition, and loss of PNN matrices is reported in patients with neurocognitive and neuropsychiatric disorders including Alzheimer's disease (AD). Using liquid chromatography tandem mass spectrometry (LC‐MS/MS), we show that patients with a clinical diagnosis of AD‐related dementia undergo a re‐coding of their PNN‐associated CS‐GAGs that correlates to Braak stage progression, hyperphosphorylated tau (p‐tau) accumulation, and cognitive impairment. As these CS‐GAG sulfation changes are detectable prior to the regional onset of classical AD pathology, they may contribute to the initiation and/or progression of the underlying degenerative processes and implicate the brain matrix sulfation code as a key player in the development of AD clinicopathology.
Racial disparities in cancer incidence and outcomes are well-documented in the US, with Black people having higher incidence rates and worse outcomes than White people. In this review, we present a ...summary of almost 30 years of research conducted by investigators at the Karmanos Cancer Institute’s (KCI’s) Population Studies and Disparities Research (PSDR) Program focusing on Black-White disparities in cancer incidence, care, and outcomes. The studies in the review focus on individuals diagnosed with cancer from the Detroit Metropolitan area, but also includes individuals included in national databases. Using an organizational framework of three generations of studies on racial disparities, this review describes racial disparities by primary cancer site, disparities associated with the presence or absence of comorbid medical conditions, disparities in treatment, and disparities in physician-patient communication, all of which contribute to poorer outcomes for Black cancer patients. While socio-demographic and clinical differences account for some of the noted disparities, further work is needed to unravel the influence of systemic effects of racism against Black people, which is argued to be the major contributor to disparate outcomes between Black and White patients with cancer. This review highlights evidence-based strategies that have the potential to help mitigate disparities, improve care for vulnerable populations, and build an equitable healthcare system. Lessons learned can also inform a more equitable response to other health conditions and crises.
The increased prevalence of inflammatory bowel disease (IBD) among patients with obesity and type 2 diabetes suggests a causal link between these diseases, potentially involving the effect of ...hyperglycemia to disrupt intestinal barrier integrity.
To investigate whether the deleterious impact of diabetes on the intestinal barrier is associated with increased IBD severity in a murine model of colitis in mice with and without diet-induced obesity.
Mice were fed chow or a high-fat diet and subsequently received streptozotocin to induce diabetic-range hyperglycemia. Six weeks later, dextran sodium sulfate was given to induce colitis. In select experiments, a subset of diabetic mice was treated with the antidiabetic drug dapagliflozin prior to colitis onset. Endpoints included both clinical and histological measures of colitis activity as well as histochemical markers of colonic epithelial barrier integrity.
In mice given a high-fat diet, but not chow-fed animals, diabetes was associated with significantly increased clinical colitis activity and histopathologic markers of disease severity. Diabetes was also associated with a decrease in key components that regulate colonic epithelial barrier integrity (colonic mucin layer content and epithelial tight junction proteins) in diet-induced obese mice. Each of these effects of diabetes in diet-induced obese mice was ameliorated by restoring normoglycemia.
In obese mice, diabetes worsened clinical and pathologic outcomes of colitis
mechanisms that are reversible with treatment of hyperglycemia. Hyperglycemia-induced intestinal barrier dysfunction offers a plausible mechanism linking diabetes to increased colitis severity. These findings suggest that effective diabetes management may decrease the clinical severity of IBD.
To investigate whether renal cell carcinoma (RCC) histologic subtypes possess different etiologies, we conducted analyses of established RCC risk factors by subtype (clear cell, papillary and ...chromophobe) in two case‐control studies conducted in the United States (1,217 cases, 1,235 controls) and Europe (1,097 cases, 1,476 controls). Histology was ascertained for 706 U.S. cases (58% of total) and 917 European cases (84%) through a central slide review conducted by a single pathologist. For the remaining cases, histology was ed from the original diagnostic pathology report. Case‐only analyses were performed to compute odds ratios (ORs) and 95% confidence intervals (CI) summarizing subtype differences by age, sex and race. Case‐control analyses were performed to compute subtype‐specific ORs for other risk factors using polytomous regression. In case‐only analyses, papillary cases (N = 237) were older (OR = 1.2, 95% CI = 1.1–1.4 per 10‐year increase), less likely to be female (OR = 0.5, 95% CI = 0.4–0.8) and more likely to be black (OR = 2.6, 95% CI = 1.8–3.9) as compared to clear cell cases (N = 1,524). In case‐control analyses, BMI was associated with clear cell (OR = 1.2, 95% CI = 1.1–1.3 per 5 kg/m2 increase) and chromophobe RCC (N = 80; OR = 1.2, 95% CI = 1.1–1.4), but not papillary RCC (OR = 1.1, 95% CI = 1.0–1.2; test versus clear cell, p = 0.006). No subtype differences were observed for associations with smoking, hypertension or family history of kidney cancer. Our findings support the existence of distinct age, sex and racial distributions for RCC subtypes, and suggest that the obesity‐RCC association differs by histology.
What's new?
Renal cell carcinoma (RCC) is the most common form of kidney cancer, which is the deadliest of all urologic malignancies. The present investigation aimed to better understand whether associations between RCC and established risk factors differed by RCC histologic subtype. Looking across two case‐control studies, the authors found that increasing body mass index was associated with clear cell and chromophobe RCC, but not papillary RCC. They also observed distinct age, sex, and racial distributions by subtype. The findings offer new insight into the relationship between obesity and RCC, and underscore the importance of subtype‐specific analyses when investigating RCC etiology.
Defective neurocircuit activity within the hypothalamic arcuate nucleus (ARC) , a crucial brain area for the regulation of metabolism, is implicated in obesity pathogenesis. Perineuronal nets (PNNs) ...are extracellular matrix structures that regulate neurocircuit activity, and PNN loss can adversely influence the activity of the enmeshed neurons. To determine if defective ARC PNNs might contribute to obesity, we first quantified PNN abundance in obese mice induced by consuming a high-fat high-sucrose diet (HFHS; Bio-Serv #F4997) 12 wk. We found that compared to chow-fed controls, HFHS diet feeding caused an 84.3% decrease (p<0.0001) in the abundance of PNNs enmeshing ARC neurons. This loss was also associated with increases of ARC microgliosis (1.5-fold; p=0.004) and astrogliosis (2.9-fold; p=0.006) , suggesting a link between ARC PNN loss and glial activation. To translate these findings to humans, we analyzed postmortem hypothalamic samples from 9 subjects (Sex, 7M/2F; Age, 22-71y) that had previously undergone quantitative T2 magnetic resonance imaging (MRI) to assess obesity-associated hypothalamic gliosis. Consistent with our findings in mice, ARC PNN content was strongly and inversely correlated with the hypothalamic gliosis score measured by T2-weighted MRI imaging (R2=0.63, p=0.01) . To assess whether this depletion of ARC PNNs might contribute to obesity, we microinjected either the PNN-digesting enzyme, ChABC, or heat-inactivated ChABC control, into the rat ARC at the onset of a 4 wk HFHS dietary intervention. We found that compared to controls, the magnitude of diet-induced hyperphagia (17%; p<0.0001) , weight gain (41%; p<0.0001) , and excess body fat accumulation (28%; p=0.01) increased following PNN digestion, driven largely by increased dark cycle food intake (24%; p=0.006) . These findings collectively identify ARC PNNs as novel participants in the central control of energy homeostasis, and implicate their loss as a potential contributor to obesity pathogenesis.
Disclosure
K.M.Alonge: None. G.J.Morton: Research Support; Novo Nordisk A/S. E.Schur: None. J.Thaler: None. M.W.Schwartz: None. M.D.Dorfman: None. J.M.Scarlett: None. S.J.Melhorn: None. Y.Ye: None. S.J.W.Hu: None. K.L.Francis: None. A.Hendrickson: None. K.Cui: None.
Funding
AG066509DK017047AG074152DK101997DK720269
Proper function of the intestinal barrier plays a crucial role to maintain normal health by selectively absorbing nutrients and keeping out pathogens. Increased gut permeability is a feature of ...several diseases, including metabolic syndrome, but whether it is a cause or a consequence is unknown. We therefore examined the impact on intestinal barrier function of streptozotocin (STZ) -induced diabetes in C57BL/6J mice that were fed either standard chow or high-fat high-sucrose (HFHS) diet for 13wk. Moderate hyperglycemia was induced by low-dose i.p. STZ injection and 12wk later, intestinal tissues were collected and processed for quantification of colonic mucin and tight junction proteins. In both HFHS- and chow-fed mice, STZ treatment resulted in significantly elevated blood glucose levels compared to vehicle-treated controls (HFHS blood glucose 249.1 mg/dL vs. 157.5 mg/dL, p=0.0008; chow 330.2 mg/dL vs. 139.7mg/dL, p=0.0005) . In HFHS-fed mice, STZ hyperglycemia was associated with reductions of both the colonic mucin layer, as measured by Alcian Blue (AB) staining (percent area 52.6 vs. 62.4, p<0.0001) , and the tight junction protein E-cadherin (percent area 34.7 vs. 55.9, p=0.0029) . In non-obese chow-fed mice, however, STZ-induced hyperglycemia had no significant impact on AB mucin staining or E-cadherin protein abundance. Similarly, levels of colonic mucins and E-cadherin were inversely correlated with blood glucose levels in HFHS-fed mice (AB R2=0.43, p=0.0116; E-cadherin R2=0.30, p=0.0439) , but not in chow-fed mice. We conclude that while the combination of hyperglycemia and diet-induced-obesity is sufficient to impair intestinal barrier function, neither obesity nor diabetes in isolation is sufficient to induce this effect. Our additional finding that the magnitude of colonic dysfunction is correlated with the degree of hyperglycemia implicates excess glucose as a potential driver of obesity-associated impairment of intestinal barrier function.
Disclosure
K.L.Francis: None. K.M.Alonge: None. S.J.W.Hu: None. B.N.Phan: None. T.P.Doan: None. C.A.Krutzsch: None. Z.Maat: None. J.M.Scarlett: None. M.W.Schwartz: None.
Funding
National Institutes of Health T32 DK007742
PDF
