Citations

AbstractBackgroundWhile simultaneous pancreas kidney transplant (SPKTx) is a therapeutic option for patients with type 1 diabetes (T1DM) and renal failure, few centers offer SPKTx to “select” non‐T1DM patients. To address concerns that existing insulin resistance may limit the benefits of the pancreas allograft among non‐T1DM, we compared several indices of glucose homeostasis, in “select” non‐T1DM and T1DM patients who received SPKTx.MethodsCriteria for “select” non‐T1DM included the following: positive C‐peptide, BMI <30 kg/m2, treatment with oral agents before insulin initiation, and insulin at <1 unit/kg/d. We compared several indices of glucose homeostasis within 1 yr post‐SPKTx among seven “select” patients with non‐T1DM and nine patients with T1DM with similar age, BMI, and immunosuppression. Measurements of insulin resistance included the following: homeostatic model, insulin sensitivity index, and insulin–glucose ratio; insulin secretion measures included the following: corrected insulin response.ResultsNon‐T1DM had similar pre‐transplant metabolic (fasting glucose, HbA1c, blood pressure, and lipid) parameters to the T1DM cohort. There were no significant differences in the various measures of insulin resistance and secretion between T1DM and “select” non‐T1DM patients.ConclusionOur results suggest SPKTx should be considered in the therapeutic armamentarium among carefully select non‐T1DM with features of minimal insulin resistance; however, a larger cohort with longer follow‐up is needed to confirm our results.

Objectives To determine the association between multiple chronic conditions and risk of incident mild cognitive impairment ( MCI ) and dementia. Design Prospective cohort study. Setting Olmsted County, Minnesota. Participants Cognitively normal individuals (N = 2,176) enrolled in the Mayo Clinic Study of Aging ( MCSA ). Measurements Participants were randomly selected from the community, evaluated by a physician, and underwent neuropsychometric testing at baseline and at 15‐month intervals to assess diagnoses of MCI and dementia. Information on International Classification of Diseases, Ninth Revision codes for chronic conditions in the 5 years before enrollment was electronically captured using the Rochester Epidemiology Project medical records linkage system. Multimorbidity was defined as having two or more chronic conditions, and the association between multimorbidity and MCI and dementia was examined using Cox proportional hazards models. Results Of 2,176 cognitively normal participants (mean age ± standard deviation 78.5 ± 5.2; 50.6% male), 1,884 (86.6%) had multimorbidity. The risk of MCI or dementia was higher in persons with multimorbidity (hazard ratio ( HR ) = 1.38, 95% confidence interval ( CI ) = 1.05–1.82) than in those with one or no chronic condition. The HR was of greater magnitude in persons with four or more conditions ( HR = 1.61, 95% CI = 1.21–2.13) than in those with two or three conditions ( HR = 1.03, 95% CI = 0.76–1.39) and for men with multimorbidity( HR = 1.53, 95% CI = 1.01–2.31) than for women with multimorbidity ( HR = 1.20, 95% CI = 0.83–1.74), compared to those with one or no chronic condition. Conclusion In older adults, having multiple chronic conditions is associated with greater risk of MCI and dementia. This is consistent with the hypothesis that multiple etiologies may contribute to MCI and late‐life dementia. Preventing chronic diseases may be beneficial in delaying or preventing MCI and dementia.

Abstract Background Intra-tumor heterogeneity is the driving force behind disease progression and metastasis, drug resistance, and relapse in cancer patients. Defining personalized treatment regimens and increasing the arsenal of targeted therapies available will provide the best chance of prolonging survival and finding curative treatments. Recent work by our group and others has shed light on aberrant de novo lipogenesis as a feature of many cancers including kidney, breast, and lung cancer. Of the molecules involved in fatty acid metabolism, stearoyl-CoA desaturase 1 (SCD1) is frequently over-expressed. Targeted inhibition of SCD1 demonstrates a loss of tumor cell viability in a variety of cancer models. While there currently are specific small molecule inhibitors for SCD1 none are under investigation as anti-cancer therapeutics. In order to evaluate the efficacy of SCD1 inhibitors against ccRCC in both a preclinical and eventually a clinical setting we sought to generate unique compounds and test their biological efficacy. Methods Utilizing an innovative in silico approach, we designed new inhibitors for SCD1 via a scaffold hopping approach while searching for different “core” scaffolds. Critical interaction moieties from the chemical R-groups were held fixed, while generated cores were rapidly scanned for best-fit criteria (shape, docking, pharmacophore fit (QSAR)) into our Z-matrix. Following de novo compound generation and synthesis, we implemented iterative analog generation for the top hits. Using this method and diversity of chemical space, we pursued three divergent species of compounds into the nanomolar regime. Biological testing of the novel compounds included high-throughput proliferative-based screening, oleic acid rescue, and evaluation of the endoplasmic stress response. Enzymatic inhibition of SCD1 was evaluated by LC-MS. Preclinical pharmacokinetics was established using a range of doses administered intravenously and orally. Anti-tumor response was evaluated in an ectopic model of renal carcinoma, both as a single agent and in combination with SOC. Results A cohort of potential unique small molecule inhibitors against SCD1 were designed and synthesized. Of these, a select group of compounds demonstrated potent and selective enzyme inhibition and reduced tumor growth in in vitro and in vivo models of ccRCC. These novel inhibitors reliably reproduced activation of ER stress markers, authenticating this biological response as a harbinger for successful abrogation of SCD1 activity. Conclusions We have established an effective, expedited, and economical format for in silico modeling of novel agents based on a scaffold-hopping methodology. Our findings provide compelling evidence supporting the therapeutic benefit of SCD1 inhibitors for clinical use as broad-spectrum anti-tumor agents alone or in combination with SOC. Citation Format: Christina A. Von Roemeling, Thomas R. Caulfield, Derek C. Radisky, Ilah Bok, Laura A. Marlow, James Miller, Mojda Sidiqi, Anthony B. Pinkerton, Winston W. Tan, Amy L. Lane, Han W. Tun, John A. Copland. Accelerated drug discovery platform yields synthesis of novel stearoyl-CoA desaturase 1 inhibitors that demonstrate anti-tumor efficacy in several models of aggressive cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4459. doi:10.1158/1538-7445.AM2015-4459

OBJECT Vasopressor-induced hypertension (VIH) is an established treatment for patients with aneurysmal subarachnoid hemorrhage (SAH) who develop vasospasm and delayed cerebral ischemia (DCI). However, the safety of VIH in patients with coincident, unruptured, unprotected intracranial aneurysms is uncertain. METHODS This retrospective multiinstitutional study identified 1) patients with aneurysmal SAH and 1 or more unruptured, unprotected aneurysms who required VIH therapy (VIH group), and 2) patients with aneurysmal SAH and 1 or more unruptured, unprotected aneurysms who did not require VIH therapy (non-VIH group). All patients had previously undergone surgical or endovascular treatment for the presumed ruptured aneurysm. Comparisons between the VIH and non-VIH patients were made in terms of the patient characteristics, clinical and radiographic severity of SAH, total number of aneurysms, number of ruptured/unruptured aneurysms, aneurysm location/size, number of unruptured and unprotected aneurysms during VIH, severity of vasospasm, degree of hypervolemia, and degree and duration of VIH therapy. RESULTS For the VIH group (n = 176), 484 aneurysms were diagnosed, 231 aneurysms were treated, and 253 unruptured aneurysms were left unprotected during 1293 total days of VIH therapy (5.12 total years of VIH therapy for unruptured, unprotected aneurysms). For the non-VIH group (n = 73), 207 aneurysms were diagnosed, 93 aneurysms were treated, and 114 unruptured aneurysms were left unprotected. For the VIH and non-VIH groups, the mean sizes of the ruptured (7.2 ± 0.3 vs 7.8 ± 0.6 mm, respectively; p = 0.27) and unruptured (3.4 ± 0.2 vs 3.2 ± 0.2 mm, respectively; p = 0.40) aneurysms did not differ. The authors observed 1 new SAH from a previously unruptured, unprotected aneurysm in each group (1 of 176 vs 1 of 73 patients; p = 0.50). Baseline patient characteristics and comorbidities were similar between groups. While the degree of hypervolemia was similar between the VIH and non-VIH patients (fluid balance over the first 10 days of therapy: 3146.2 ± 296.4 vs 2910.5 ± 450.7 ml, respectively; p = 0.67), VIH resulted in a significant increase in mean arterial pressure (mean increase over the first 10 days of therapy relative to baseline: 125.1% ± 1.0% vs 98.2% ± 1.2%, respectively; p < 0.01) and systolic blood pressure (125.6% ± 1.1% vs. 104.1% ± 5.2%, respectively; p < 0.01). CONCLUSIONS For small, unruptured, unprotected intracranial aneurysms in SAH patients, the frequency of aneurysm rupture during VIH therapy is rare. The authors do not recommend withholding VIH therapy from these patients.

SummaryIt has been increasingly recognized at the basic science level that perturbations in ceramide metabolism are associated with the development and progression of many age‐related diseases. However, the translation of this work to the clinic has lagged behind. Understanding the factors longitudinally associated with plasma ceramides and dihydroceramides (DHCer) at the population level and how these lipid levels change with age, and by sex, is important for the clinical development of future therapeutics and biomarkers focused on ceramide metabolism. We, therefore, examined factors cross‐sectionally and longitudinally associated with plasma concentrations of ceramides and DHCer among Baltimore Longitudinal Study of Aging participants (n = 992; 3960 total samples), aged 55 years and older, with plasma at a mean of 4.1 visits (range 2–6). Quantitative analyses were performed on a high‐performance liquid chromatography‐coupled electrospray ionization tandem mass spectrometer. Linear mixed models were used to assess the relationships between plasma ceramide and DHCer species and demographics, diseases, medications, and lifestyle factors. Women had higher plasma concentrations of most ceramide and DHCer species and showed steeper trajectories of age‐related increases compared to men. Ceramides and DHCer were more associated with waist–hip ratio than body mass index. Plasma cholesterol and triglycerides, prediabetes, and diabetes were associated with ceramides and DHCer, but the relationship showed specificity to the acyl chain length and saturation. These results demonstrate the importance of examining the individual species of ceramides and DHCer, and of establishing whether intra‐individual age‐ and sex‐specific changes occur in synchrony to disease onset and progression.

PurposeWe compared nab-paclitaxel or ixabepilone once per week to paclitaxel with bevacizumab as first-line therapy for patients with advanced breast cancer (BC) to evaluate progression-free survival (PFS) for nab-paclitaxel or ixabepilone versus paclitaxel.Patients and MethodsEligible patients were age ≥ 18 years with chemotherapy-naive advanced BC. Patients were randomly assigned to bevacizumab with paclitaxel 90 mg/m2(arm A), nab-paclitaxel 150 mg/m2(arm B), or ixabepilone 16 mg/m2(arm C), once per week for 3 of 4 weeks. Planned enrollment was 900 patients, which would give 88% power to detect a hazard ratio of 0.73.ResultsIn all, 799 patients were enrolled, and 783 received treatment (97% received bevacizumab). Arm C was closed for futility at the first interim analysis (n = 241), and arm A (n = 267) and arm B (n = 275) were closed for futility at the second interim analysis. Median PFS for paclitaxel was 11 months, ixabepilone was inferior to paclitaxel (PFS, 7.4 months; hazard ratio, 1.59; 95% CI, 1.31 to 1.93; P < .001), and nab-paclitaxel was not superior to paclitaxel (PFS, 9.3 months; hazard ratio, 1.20; 95% CI, 1.00 to 1.45; P = .054). Results were concordant with overall survival; time to treatment failure was significantly shorter in both experimental arms v paclitaxel. Hematologic and nonhematologic toxicity, including peripheral neuropathy, was increased with nab-paclitaxel, with more frequent and earlier dose reductions.ConclusionIn patients with chemotherapy-naive advanced BC, ixabepilone once per week was inferior to paclitaxel, and nab-paclitaxel was not superior with a trend toward inferiority. Toxicity was increased in the experimental arms, particularly for nab-paclitaxel. Paclitaxel once per week remains the preferred palliative chemotherapy in this setting.