Purpose
Stress-induced adrenergic signaling can suppress the immune system. In animal models, pharmacological beta-blockade stimulates CD8 + T-cell activity and improves clinical activity of immune ...checkpoint blockade (ICB) in inhibiting tumor growth. Herein, we investigated the effect of BB on clinical outcomes of patients receiving ICB in advanced solid tumors.
Methods
We retrospectively evaluated patients with solid tumors treated with ICB at our institution from January 1, 2011 to April 28, 2017. The primary clinical outcome was disease control. Secondary clinical outcomes were overall survival (OS), and duration of therapy (DoT). The primary predictor was use of BB. Association between disease control status and BB use was assessed in univariable and multivariable logistic regression. OS was calculated using hazard ratios of BB-recipient patients vs. BB non-recipient patients via Cox proportional hazards regression models. All tests were two-sided at a significance level of 0.05.
Results
Of 339 identified patients receiving ICB, 109 (32%) also received BB. In covariate-adjusted analysis, odds of disease control were significantly higher among BB recipients compared to BB-non-recipients (2.79; 1.54–5.03;
P
= 0.001). While we did not observe significant association of OS with the use of BB overall, significant association with better OS was observed for the urothelial carcinoma cohort (HR: 0.24; 0.09, 0.62;
P
= 0.0031).
Conclusions
Concurrent use of BB may enhance the clinical activity of ICB and influence overall survival, particularly in patients with urothelial carcinoma. Our findings warrant further investigation to understand the interaction of beta adrenergic signaling and antitumor immune activity and explore a combination strategy.
Background
Black women with breast cancer have a worse overall survival compared with White women; however, no difference in Oncotype DX™ (ODX) recurrence scores has been observed to explain this ...health disparity. Black women are also disproportionately affected by insulin resistance. We evaluated whether insulin resistance is associated with a higher ODX recurrence score and whether there is a difference between White and Black women to explain disparate clinical outcomes.
Methods
A subgroup analysis of patients in a multi-institutional cross-sectional study evaluating differences in insulin resistance between White and Black women was performed. Women diagnosed with a new hormone receptor-positive, HER2/neu-negative breast cancer with an ODX recurrence score were identified. Fasting blood glucose and insulin measurements were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) score, a method for assessing insulin resistance, and compared against ODX scores.
Results
Overall, 412 women (358 White women, 54 Black women) were identified. Compared with White women, Black women had a higher body mass index (30 vs. 26 kg/m
2
,
p
< 0.0001), higher HOMA-IR score (2.4 vs. 1.4,
p
= 0.004), and more high-grade tumors (30% vs. 16%,
p
= 0.01). There was a direct positive association with an increasing ODX score and HOMA-IR (
p
= 0.014). On subset analysis, this relationship was seen in White women (
p
= 0.005), but not in Black women (
p
= 0.55).
Conclusion
In women with newly diagnosed breast cancer, increasing insulin resistance is associated with a higher recurrence score; however, this association was not present in Black women. This lack of association may be due to the small number of Black women in the cohort, or possibly a reflection of a different biological disease process of the patient’s tumor.
A paradigm shift in research culture is required to ease perceived tensions between autistic people and the biomedical research community. As a group of autistic and non-autistic scientists and ...stakeholders, we contend that through participatory research, we can reject a deficit-based conceptualization of autism while building a shared vision for a neurodiversity-affirmative biomedical research paradigm.
A paradigm shift in research culture is required to ease perceived tensions between autistic people and the biomedical research community. As a group of autistic and non-autistic scientists and stakeholders, we contend that through participatory research, we can reject a deficit-based conceptualization of autism while building a shared vision for a neurodiversity-affirmative biomedical research paradigm.
The survival for breast cancer (BC) is improving but remains lower in Black women than White women. A number of factors potentially drive the racial differences in BC outcomes. The aim of our study ...was to determine if insulin resistance (defined as homeostatic model assessment for insulin resistance (HOMA-IR)), mediated part of the relationship between race and BC prognosis (defined by the improved Nottingham prognostic index (iNPI)). We performed a cross-sectional study, recruiting self-identified Black and White women with newly diagnosed primary invasive BC from 10 US hospitals between March 2013 and February 2020. Survey, anthropometric, laboratory, and tumor pathology data were gathered, and we compared the results between Black and White women. We calculated HOMA-IR as well as iNPI scores and examined the associations between HOMA-IR and iNPI. After exclusions, the final cohort was 1206: 911 (76%) White and 295 (24%) Black women. Metabolic syndrome and insulin resistance were more common in Black than White women. Black women had less lobular BC, three times more triple-negative BC, and BCs with higher stage and iNPI scores than White women (P < 0.001 for all comparisons). Fewer Black women had BC genetic testing performed. HOMA-IR mediated part of the association between race and iNPI, particularly in BCs that carried a good prognosis and were hormone receptor (HR)-positive. Higher HOMA-IR scores were associated with progesterone receptor-negative BC in White women but not Black women. Overall, our results suggest that HOMA-IR contributes to the racial disparities in BC outcomes, particularly for women with HR-positive BCs.
Teleost fish have a remarkable capacity to maintain ion homeostasis against diffusion gradients in hypo-ionic freshwater. In adult teleosts the gills are the primary site for ion uptake; however, in ...larvae, the gills are underdeveloped, and as ion-regulation is primarily cutaneous, branchial mechanisms of plasticity are not yet available. In larval rainbow trout, the gills become the primary site for Na
+
uptake at ~ 15 days post hatch (dph). To address how Na
+
uptake develops in response to differences in water Na
+
, the present study characterised the ontogeny of Na
+
uptake in rainbow trout larvae, at a time when ion regulation transitions from being a primarily cutaneous to a primarily branchial process. Results indicate that initially (0–15 dph), when ion-regulation is cutaneous, low-Na
+
reared larvae had a higher Na
+
affinity (lower
K
m
) compared to the high-Na
+
treatment. In addition, larvae reared in low-Na
+
water had a lower internal Na
+
content, despite similar Na
+
-uptake rates (
J
Na
+
in
) across treatments. But, once the gills became the dominant site for ion-regulation (> 15 dph), larvae in all treatments maintained the same Na
+
content, despite large differences in
J
Na
+
in
, indicating plasticity in those mechanisms that control Na
+
efflux (
J
Na
+
out
). The mechanisms of Na
+
uptake in larval rainbow trout showed plasticity during all stages of development. However, in young larvae that relied on cutaneous Na
+
uptake, the internal Na
+
content was significantly affected by the Na
+
in the water, perhaps revealing challenges to ion homeostasis and a period of heightened vulnerability to external stressors during early larval development.
Diabetes is a common comorbidity in patients with early-stage non-small cell lung cancer (NSCLC), a growing population due to increased LC screening. However, it is unknown if diabetes is associated ...with less aggressive NSCLC treatment and worse NSCLC outcomes. This study aimed to investigate treatment patterns and outcomes of older patients with Stage I NSCLC and diabetes.
Using national cancer registry data linked to Medicare, we identified patients ≥65 years old with Stage I NSCLC. Patients were categorized as having no diabetes, diabetes without severe complications (DM-c), or diabetes with ≥1 severe complication (DM + c). We used multinomial logistic regression to assess the association of diabetes and NSCLC treatment. The association of diabetes category with NSCLC and non-NSCLC survival was analyzed with Fine-Grey competing-risks regression.
In 25,358 patients (75% no diabetes, 12% DM-c and 13% had DM + c), adjusted analyses showed that DM-c and DM + c were associated with increased odds of receiving limited resection rather than lobectomy (odds ratio OR: 1.22, 95% confidence interval CI: 1.07–1.37 and OR 1.42, 95% CI 1.26–1.59, respectively). Competing risk regression showed diabetes was associated with increased risk of non-NSCLC death (DM-c hazard ratio HR 1.16, 95% CI: 1.08–1.25, DM + c HR 1.49, 95% CI: 1.40–1.59), but not NSCLC-specific death.
This study uncovers critical information on how diabetes is associated with less aggressive early-stage NSCLC care in older patients. This study also confirms that diabetes increases death from non-lung cancer causes and managing comorbidities is crucial to improving outcomes in older early-stage NSCLC survivors.
The Her2 oncogene is expressed in ∼25% of human breast cancers and is associated with metastatic progression and poor outcome. Epidemiological studies report that breast cancer incidence and ...mortality rates are higher in women with type 2 diabetes. Here, we use a mouse model of Her2-mediated breast cancer on a background of hyperinsulinemia to determine how elevated circulating insulin levels affect Her2-mediated primary tumor growth and lung metastasis. Hyperinsulinemic (MKR(+/+)) mice were crossed with doxycycline-inducible Neu-NT (MTB/TAN) mice to produce the MTB/TAN/MKR(+/+) mouse model. Both MTB/TAN and MTB/TAN/MKR(+/+) mice were administered doxycycline in drinking water to induce Neu-NT mammary tumor formation. In tumor tissues removed at 2, 4, and 6 weeks of Neu-NT overexpression, we observed increased tumor mass and higher phosphorylation of the insulin receptor/IGF1 receptor, suggesting that activation of these receptors in conditions of hyperinsulinemia could contribute to the increased growth of mammary tumors. After 12 weeks on doxycycline, although no further increase in tumor weight was observed in MTB/TAN/MKR(+/+) compared with MTB/TAN mice, the number of lung metastases was significantly higher in MTB/TAN/MKR(+/+) mice compared with controls (MTB/TAN/MKR(+/+) 16.41±4.18 vs MTB/TAN 5.36±2.72). In tumors at the 6-week time point, we observed an increase in vimentin, a cytoskeletal protein and marker of mesenchymal cells, associated with epithelial-to-mesenchymal transition and cancer-associated fibroblasts. We conclude that hyperinsulinemia in MTB/TAN/MKR(+/+) mice resulted in larger primary tumors, with more mesenchymal cells and therefore more aggressive tumors with more numerous pulmonary metastases.
BACKGROUND: The hallmark of Type 2 diabetes (T2D) is hyperglycemia, although there are multiple other metabolic abnormalities that occur with T2D, including insulin resistance and dyslipidemia. To ...advance T2D prevention and develop targeted therapies for its treatment, a greater understanding of the alterations in metabolic tissues associated with T2D is necessary. The aim of this study was to use microarray analysis of gene expression in metabolic tissues from a mouse model of pre-diabetes and T2D to further understand the metabolic abnormalities that may contribute to T2D. We also aimed to uncover the novel genes and pathways regulated by the insulin sensitizing agent (CL-316,243) to identify key pathways and target genes in metabolic tissues that can reverse the diabetic phenotype. METHODS: Male MKR mice on an FVB/n background and age matched wild-type (WT) FVB/n mice were used in all experiments. Skeletal muscle, liver and fat were isolated from prediabetic (3 week old) and diabetic (8 week old) MKR mice. Male MKR mice were treated with CL-316,243. Skeletal muscle, liver and fat were isolated after the treatment period. RNA was isolated from the metabolic tissues and subjected to microarray and KEGG database analysis. RESULTS: Significant decreases in the expression of mitochondrial and peroxisomal fatty acid oxidation genes were found in the skeletal muscle and adipose tissue of adult MKR mice, and the liver of pre-diabetic MKR mice, compared to WT controls. After treatment with CL-316,243, the circulating glucose and insulin concentrations in the MKR mice improved, an increase in the expression of peroxisomal fatty acid oxidation genes was observed in addition to a decrease in the expression of retinaldehyde dehydrogenases. These genes were not previously known to be regulated by CL-316,243 treatment. CONCLUSIONS: This study uncovers novel genes that may contribute to pharmacological reversal of insulin resistance and T2D and may be targets for treatment. In addition, it explains the lower free fatty acid levels in MKR mice after treatment with CL-316,243 and furthermore, it provides biomarker genes such as ACAA1 and HSD17b4 which could be further probed in a future study.
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