Statin Type and Cancer Outcomes in Patients with Diabetes Type 2 and Solid Tumors.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) affects 10% of Americans and is associated with an increased incidence of cancer. Statins are first-line cholesterol-lowering medications in the treatment of hyperlipidemia. Several studies have demonstrated a relationship between statin use and reduced cancer incidence. We examined the cancer benefits of statin subtypes, with specific attention to disease-free survival (DFS) and overall survival (OS). METHODS: This retrospective review included adults with T2DM diagnosed with solid tumors at Roswell Park Cancer Institute in Buffalo, NY, USA (2003-2010). Individuals with gestational diabetes, incomplete records, or diagnosed with rare solid tumors were excluded. Follow-up began at the date of diagnosis and ended with the first confirmed recurrence, death, or loss of contact. Demographics were assessed by Chi-square, Kaplan-Meier survival analyses, and Cox proportional hazards regression. FINDINGS: Overall, 1102 patients met inclusion criteria, 52.1% of the study participants were female, and 578 participants (52.5%) died during the follow-up period which ranged from 0 to 156 months. Hydrophilic statin use was associated with improved DFS at 5-year follow-up (41.0% vs. 36.9%, P = 0.0077) compared to lipophilic statin use. Multivariate regression revealed that hydrophilic statins were associated with improved DFS (hazard ratio [HR]: 0.706, 95% confidence interval [CI]: 0.526-0.947) and OS (HR: 0.685, 95% CI: 0.503-0.934). Pravastatin was associated with improved OS (HR: 0.674, 95% CI: 0.471-0.964). CONCLUSION: In patients with T2DM and cancer, hydrophilic statins, and pravastatin in particular, are associated with improved DFS as well as OS. Further research examining the cancer-specific effects of hydrophilic and lipophilic statins is needed to better understand their beneficial effects.

Denitrification using permeable reactive barriers with organic substrate or zero-valent iron fillers: controlling mechanisms, challenges, and future perspectives.

Nitrate as a diffusive agricultural contaminant has been causing substantial groundwater quality deterioration worldwide. In situ groundwater remediation techniques using permeable reactive barriers (PRBs) have attracted increasing interest. Particularly, PRBs based on biological denitrification, using the organic substrate as a biostimulator, and chemical nitrate reduction, using zero-valent iron (ZVI) as a reductant, are two major PRB approaches for groundwater denitrification. This review paper analyzed the published studies over the past 10 years (2010-2020) using laboratory, modeling, and field-scale approaches to explore the performance and mechanisms of these two types of PRBs. Important factors affecting the denitrification efficiencies as well as the influential mechanisms were discussed. Several research gaps have been identified and further research needs are discussed in the end.

Missing the Benefit of Metformin in Acute Myeloid Leukemia: A Problem of Contrast?

OBJECTIVE: To evaluate whether metformin's cancer-related benefits reported in patients with solid tumors (ST) are also present in acute myeloid leukemia (AML) patients. METHODS: Baseline demographic and clinical history for all diabetes mellitus patients newly diagnosed with AML or cancer of the breast, ovary, prostate, gastrointestinal tract, lung, or kidney at Roswell Park Cancer Institute in Buffalo, NY (January 2003-December 2010, n = 924) was collected. Overall survival (OS) and disease-free survival (DFS) were assessed by Kaplan-Meier (KM) analysis and Cox proportional hazards regression (hazard ratio [HR]). FINDINGS: Baseline metformin use provided significant OS and DFS benefit in ST but not in AML (KM: PST-OS= 0.003; PST-DFS= 0.002; PAML-OS= 0.961; PAML-DFS= 0.943). AML median survival was slightly better with metformin use, but users derived no relapse benefit. In ST, metformin nonusers had shorter median survival, 57.7 versus 86 months, and poorer outcomes (HRST-OS= 1.33; PST-OS= 0.002; HRST-DFS= 1.32; PST-DFS= 0.002). These findings remained significant in age-adjusted models (HRST-OS= 1.21; PST-OS= 0.039; HRST-DFS= 1.23; PST-DFS= 0.02) but not fully adjusted models (HRST-OS= 0.96; PST-OS= 0.688; HRST-DFS= 1.0; PST-DFS= 0.94). Higher mortality was noted in AML patients taking insulin versus oral diabetes pharmacotherapy at baseline (HRAML-OS= 2.03; PAML-OS= 0.04). CONCLUSION: Lack of metformin benefit in AML could be due to advanced age at cancer diagnosis. Metformin substitution with insulin before computed tomography scans with contrast - a frequent AML assessment practice - may also explain the lack of subsequent benefit despite taking metformin at baseline. A temporary metformin substitution is recommended by the package insert due to a possible drug interaction with the contrast dye. Our data suggest that metformin substitution was permanent in many patients. Nonetheless, the observed benefit in other malignancies warrants further investigation of metformin use in AML.

Dataset on granulopoiesis- and lymphopoiesis-stimulating cytokine levels in insulin secretagogue users with incident breast cancer.

GM-CSF and G-CSF are widely used for their benefit in reducing chemotherapy-associated neutropenia. However, whether GM- or G-CSF administration could have tumorigenic or pro-metastatic effects or whether insulin resistance could negatively impact such effects is not known. Their ability to stimulate monocyte production at the same time with the highly sought after neutrophils' production, enables an enhanced potential for activation of tumor-associated macrophages. At the same time, IL-7 remains the main driver of B and T cell differentiation and maturation, a process linked to the development of insulin resistance and response to diabetes pharmacotherapy. Insulin secretagogues have the potential to interfere with the hematopoiesis process, respectively with the formation of lineages that may lead to a tumorigenic or pro-metastatic phenotype, but this relationship has not been yet investigated. The data presented here shows the relationship between pre-existing use of insulin secretagogues in women diagnosed with breast cancer and type 2 diabetes mellitus, the GM-CSF, G-CSF and IL-7 cytokine profiles at the time of breast cancer diagnosis, and subsequent cancer outcomes. A Pearson correlation analysis evaluating the relationship between investigated cytokines stratified by secretagogue use and controls, and interferon is also provided.

TH1 and TH2 cytokines dataset in insulin users with diabetes mellitus and newly diagnosed breast cancer.

Exogenous insulin use may interfere with the T helper cells' cytokine production. This dataset presents the relationship between pre-existing use of injectable insulin in women diagnosed with breast cancer and type 2 diabetes mellitus, the T-helper 1 and 2 produced cytokine profiles at the time of breast cancer diagnosis, and subsequent cancer outcomes. A Pearson correlation analysis evaluating the relationship between T-helper cytokines stratified by of insulin use and controls is also provided.

Insulin use, hormone receptor status and hematopoietic cytokines׳ circulation in women with diabetes mellitus and breast cancer.

Granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) are cytokines of particular interest in oncology from the perspective of neutropenia management (Mehta et al., 2015 [1]) and also as indirect activators of tumor-associated macrophages and modifiers of tumor microenvironment. Associated with poor breast cancer survival and unfavorable hormone receptor status (Wintrob et al., 2017 [2]), insulin may also influence hematopoiesis, thus interfering with colony stimulating factor production. Although G-CSF has been linked to exacerbating insulin resistance (Ordelheide et al., 2016 [3]), thus far no study linked insulin treatment and hematopoietic cytokines production. Additionally, IL-7 is the primary driver of T and B cell differentiation, maturation, and response (Corfe and Paige, 2012 [4]) and its elevated levels have been associated with poor prognosis in breast cancer. The data presented here is among the first to show a relationship between pre-existing use of injectable insulin in women diagnosed with breast cancer and type 2 diabetes mellitus, hematopoietic cytokine profiles at time of breast cancer diagnosis, and subsequent cancer outcomes. A Pearson correlation analysis evaluating the relationship between G-CSF, GM-CSF, and IL-7 stratified by insulin use, controls, as well as by estrogen and progesterone receptor status is also provided.

Insulin secretagogue use and circulating inflammatory C-C chemokine levels in breast cancer patients.

Monocytes' infiltration into the tumor tissue and their activation to tumor-associated macrophages is an essential step in tumor development, also playing a critical role in an eventual metastasis. Stimulation of endogenous insulin production by oral insulin secretagogue treatment has the potential to interfere with the production and release of C-C chemokines, a group of potent inflammatory cytokines acting as monocyte chemo-attractants and influencing their behavior in the tumor microenvironment. Studied plasma samples were collected under a previously reported study design involving a population of women diagnosed with breast cancer presenting with or without type 2 diabetes mellitus at the time of breast cancer diagnosis (Wintrob et al., 2017, 2016) [1,2]. The data presented here shows the relationship between pre-existing use of insulin secretagogue, the inflammatory C-C chemokine profiles at the time of breast cancer diagnosis, and subsequent cancer outcomes. A Pearson correlation analysis stratified by secretagogue use and controls was implemented to evaluate the relationship between the investigated biomarkers and respectively each of these biomarkers and the other relevant reported cytokine datasets derived from the same patient population (Wintrob et al., 2017, 2016) [1,2].

TH1 and TH2 cytokine data in insulin secretagogues users newly diagnosed with breast cancer.

Stimulation of insulin production by insulin secretagogue use may impact T helper cells' cytokine production. This dataset presents the relationship between baseline insulin secretagogues use in women diagnosed with breast cancer and type 2 diabetes mellitus, the T-helper 1 and 2 produced cytokine profiles at the time of breast cancer diagnosis, and subsequent cancer outcomes. A Pearson correlation analysis evaluating the relationship between T-helper cytokines stratified by of insulin secretagogues use and controls is also provided.

Data report on inflammatory C-C chemokines among insulin-using women with diabetes mellitus and breast cancer.

Injectable insulin use may interfere with pro-inflammatory cytokines' production and, thus, play a role in the activation of tumor-associated macrophages - a process mainly influenced by inflammatory C-C chemokines. The data presented shows the relationship between pre-existing use of injectable insulin in women diagnosed with breast cancer and type 2 diabetes mellitus, the inflammatory C-C chemokine profiles at the time of breast cancer diagnosis, and subsequent cancer outcomes. A Pearson correlation analysis stratified by insulin use and controls is also provided. We present the observed relationship between the investigated C-C chemokines and between each of these biomarkers and previously reported adipokines levels in this study population [1].

Circulating growth factors data associated with insulin secretagogue use in women with incident breast cancer.

Oral drugs stimulating insulin production may impact growth factor levels. The data presented shows the relationship between pre-existing insulin secretagogues use, growth factor profiles at the time of breast cancer diagnosis and subsequent cancer outcomes in women diagnosed with breast cancer and type 2 diabetes mellitus. A Pearson correlation analysis evaluating the relationship between growth factors stratified by diabetes pharmacotherapy and controls is also provided.

Dataset on growth factor levels and insulin use in patients with diabetes mellitus and incident breast cancer.

Growth factor profiles could be influenced by the utilization of exogenous insulin. The data presented shows the relationship between pre-existing use of injectable insulin in women diagnosed with breast cancer and type 2 diabetes mellitus, the growth factor profiles at the time of breast cancer diagnosis, and subsequent cancer outcomes. A Pearson correlation analysis evaluating the relationship between growth factors stratified by of insulin use and controls is also provided.

Synergistic Benefit of Statin and Metformin in Gastrointestinal Malignancies.

OBJECTIVES: To evaluate whether statin use influences gastrointestinal cancer prognosis in patients with diabetes mellitus (DM). METHODS: We reviewed all DM patients diagnosed at Roswell Park Cancer Institute with emergent gastrointestinal malignancy (January 2003 to December 2010) (N = 222). Baseline demographic, clinical history, and cancer outcomes were documented. Overall survival (OS) and disease-free survival (DFS) comparisons across various treatment groups were assessed by Kaplan-Meier and Cox proportional hazards. RESULTS: Use of statin, alone or in combination, was associated with improved OS and DFS (hazard ratio [HR] = 0.65, P = .06; HR = 0.60, P < .02). We report similar OS and DFS advantage among users of mono- or combined metformin therapy (HR = 0.55, P < .01; HR = 0.63, P < .02). Concomitant use of metformin and statin provided a synergistic OS and DFS benefit (HR = 0.42, P < .01; HR = 0.44, P < .01). Despite significant tobacco and alcohol use history, patients with upper gastrointestinal cancers derived enhanced cancer outcomes from this combination (HR = 0.34, P < .01; HR = 0.43, P < .02), while receiving a statin without metformin or metformin without a statin did not provide significant cancer-related benefits. CONCLUSION: Use of statin and metformin provides a synergistic improvement in gastrointestinal malignancies outcomes.

Circulating adipokines data associated with insulin secretagogue use in breast cancer patients.

Oral drugs stimulating endogenous insulin production (insulin secretagogues) may have detrimental effects on breast cancer outcomes. The data presented shows the relationship between pre-existing insulin secretagogues use, adipokine profiles at the time of breast cancer (BC) diagnosis and subsequent cancer outcomes in women diagnosed with BC and type 2 diabetes mellitus (T2DM). The Pearson correlation analysis evaluating the relationship between adipokines stratified by T2DM pharmacotherapy and controls is also provided. This information is the extension of the data presented and discussed in "Insulin use, adipokine profiles and breast cancer prognosis" (Wintrob et al., in press) [1].

Insulin use, adipokine profiles and breast cancer prognosis.

BACKGROUND: Type-2 diabetes mellitus (T2DM) and breast cancer (BC) share common cytokine signaling changes resultant from adipose tissue dysfunction. This modified adipokine signaling was shown to be directly associated with changes in the body mass index (BMI) and diet and it is expected to also be influenced by T2DM pharmacotherapy. We evaluated the relationship between pre-existing diabetes treatment, circulating adipokine levels at cancer diagnosis, and long-term outcomes. METHODS: All incident BC cases were reviewed (01/01/2003-12/31/2009, N=2194). Each of the subjects with baseline T2DM (cases) was matched with two other subjects without T2DM (controls) based on the following criteria: age, BMI, ethnicity, menopausal status and tumor stage. All cases and controls with available baseline plasma and tumor biopsies, and being surgery and BC treatment naïve, were included (N1=97, N2=194). Clinical history and vital status were documented. Adipokine levels (adiponectin, leptin, TNF-α, CRP, IL-1ß, IL-1Ra, IL-6, and C-peptide) were assessed by either ELISA or Luminex® assays. Cancer outcomes were assessed by Kaplan-Meier analysis; associations between categorical variables were assessed by Fisher's exact test, categorical and continuous variables by Kruskal-Wallis or Wilcoxon Rank-Sum test, where appropriate. Multivariate adjustments (MVP, multivariate p-value) were performed accounting for age, tumor stage, BMI, estrogen receptor (ER) status and cumulative comorbidity. All biomarker correlations were assessed by the Pearson method. Utilization of insulin and insulin secretagogues was associated with ER (-) phenotype (p=0.008, p=0.043) and poorer BC outcomes (p=0.012, p=0.033). Insulin users were found to have lower C-peptide and higher IL-6, TNF-α and CRP levels, of which elevated CRP and TNF-α were associated with poorer BC outcomes (p=0.003, MVP=0.210). Insulin remarked by higher leptin levels as compared to controls (p=0.052), but did not differ significantly from non-users. Although lower adiponectin levels were observed among non-insulin users as compared to controls (p<0.001, MVP=0.006), insulin use seemed to have restored adiponectin production. C-peptide levels were lower among insulin users as compared to non-users (p<0.001, MVP<0.001) and approached levels comparable with those of the controls. In the overall dataset, C-peptide lower than 0.75ng/ml were strongly associated with poorer survival (p=0.007, MVP=0.002). Among insulin users, C-peptide levels were inversely correlated with IL-1ß and IL-1Ra levels only after full adjustment (p=0.012, p=0.030); the correlation was unremarkable in other groups. CONCLUSION: Insulin use is associated with elevated leptin, CRP, TNFα, and lower C-peptide and also linked to poor BC outcomes. More research is needed to verify these findings; however, we are among the first to correlate pharmacotherapy use, measures of adipose tissue dysfunction and cancer outcomes.

Arabidopsis thaliana mitochondrial glyoxalase 2-1 exhibits beta-lactamase activity.

In an effort to determine the physiological role of Arabidopsis thaliana Glx2-1, we attempted to uncover a substrate for the enzyme. Glx2-1 did not effectively process 192 diverse substrates found in a commercial screen used for microorganism identification or exhibit arylsulfatase, lactonase, or phosphotriesterase activities. However, Glx2-1 does exhibit beta-lactamase activity with k(cat)/KM values from 10(3) to 10(5) M(-1) s(-1). Glx2-1 can hydrolyze cephalosporins and carbapenems, albeit with rate constants slower than those of most metallo-beta-lactamases. The potential role of a beta-lactamase in the mitochondria of plant cells is briefly discussed.

Dietary cholesterol plays a role in CD36-mediated atherogenesis in LDLR-knockout mice.

OBJECTIVE: CD36 has been shown to play a role in atherosclerosis in the apolipoprotein E-knockout (apoE(o)) mouse. We observed no difference in aortic lesion area between Western diet (WD)-fed LDLR(o) and LDLR(o)/CD36(o) mice. The objective was to understand the mechanism of CD36-dependent atherogenesis. METHODS AND RESULTS: ApoE(o) mice transplanted with bone marrow from LDLR(o)/CD36(o) mice had significantly less aortic lesion compared with those transplanted with LDLR(o) marrow. Reciprocal macrophage transfer into hyperlipidemic apoE(o) and LDLR(o) animals showed that foam cell formation induced by in vivo modified lipoproteins was dependent on the lipoprotein, not macrophage type. LDLR(o) and LDLR(o)/CD36(o) mice were fed a cholesterol-enriched diet (HC), and we observed significant lesion inhibition in LDLR(o)/CD36(o) mice. LDL/plasma isolated from HC-fed LDLR(o) mice induced significantly greater jnk phosphorylation, cytokine release, and reactive oxygen species secretion than LDL/plasma from WD-fed LDLR(o) mice, and this was CD36-dependent. HC-fed LDLR(o) mice had higher circulating levels of cytokines than WD-fed mice. CONCLUSIONS: These data support the hypothesis that CD36-dependent atherogenesis is contingent on a proinflammatory milieu that promotes the creation of specific CD36 ligands, not solely hypercholesterolemia, and may explain the greater degree/accelerated rate of atherosclerosis observed in syndromes associated with inflammatory risk.

Absence of CD36 protects against atherosclerosis in ApoE knock-out mice with no additional protection provided by absence of scavenger receptor A I/II.

AIMS: The role of scavenger receptors in atherogenesis is controversial as a result of conflicting reports and a recent hypothesis suggesting that scavenger receptor absence would enhance the pro-inflammatory, pro-atherogenic milieu. This study addresses the effect of combined absence of scavenger receptors CD36 and SRA I/II on atherosclerosis lesion development in the apolipoprotein E knock-out (apoE degrees ) model. METHODS: We created background-related strains of apoE degrees , scavenger receptor A I/II knock-out (SRA degrees )/apoE degrees , CD36 knock-out (CD36 degrees )/apoE degrees , and CD36 degrees /SRA degrees /apoE degrees mice that were >99% C57Bl/6. Four-week-old mice were fed a Western diet for 12 weeks and were assessed for lesion burden/morphology, risk factors for atherosclerosis, inflammatory mediators, and macrophage function. RESULTS: There was a 61 and 74% decrease in total aortic lesion area in CD36 degrees /apoE degrees males and females, respectively, compared with apoE degrees controls. The absence of SRA was protective (32% decrease in lesion) in female mice. The combined absence of CD36 and SRA provided no further protection in either gender. Macrophages from mice lacking CD36 had decreased pro-inflammatory characteristics and less migration to a pro-inflammatory stimulus. Plasma levels of cytokines/chemokines showed that CD36 degrees /apoE degrees and CD36 degrees /SRA degrees /apoE degrees mice had a less pro-inflammatory phenotype compared with apoE degrees and SRA degrees /apoE degrees mice. Oblivious mice in the apoE degrees background ruled out potential 'passenger gene' effects in the case of CD36. CONCLUSION: These results provide new insights into the pro-atherogenic mechanisms of CD36 by implicating processes other than modified lipoprotein uptake.