Citations

PurposeTo investigate the effects on echo planar imaging (EPI) distortion of using high gradient slew rates (SR) of up to 700 T/m/s for in vivo human brain imaging, with a dedicated, head‐only gradient coil.Materials and MethodsSimulation studies were first performed to determine the expected echo spacing and distortion reduction in EPI. A head gradient of 42‐cm inner diameter and with asymmetric transverse coils was then installed in a whole‐body, conventional 3T magnetic resonance imaging (MRI) system. Human subject imaging was performed on five subjects to determine the effects of EPI on echo spacing and signal dropout at various gradient slew rates. The feasibility of whole‐brain imaging at 1.5 mm‐isotropic spatial resolution was demonstrated with gradient‐echo and spin‐echo diffusion‐weighted EPI.ResultsAs compared to a whole‐body gradient coil, the EPI echo spacing in the head‐only gradient coil was reduced by 48%. Simulation and in vivo results, respectively, showed up to 25–26% and 19% improvement in signal dropout. Whole‐brain imaging with EPI at 1.5 mm spatial resolution provided good whole‐brain coverage, spatial linearity, and low spatial distortion effects.ConclusionOur results of human brain imaging with EPI using the compact head gradient coil at slew rates higher than in conventional whole‐body MR systems demonstrate substantially improved image distortion, and point to a potential for benefits to non‐EPI pulse sequences. J. Magn. Reson. Imaging 2016;44:653–664.

ABSTRACT Using a rapid bacterial lysis method, the Check MDR CT103 and CT103 XL microarrays demonstrated accuracies of 98.1% and 94.2%, respectively, for detection of known resistance genes in 108 multidrug-resistant Gram-negative bacilli. In 45 isolates, 49 previously unrecognized extended-spectrum β-lactamase or plasmid AmpC targets were detected and confirmed by conventional PCR.

PurposeTo characterize peripheral nerve stimulation (PNS) of an asymmetric head‐only gradient coil that is compatible with a commercial high–channel‐count receive‐only array.MethodsTwo prototypes of an asymmetric head‐only gradient coil set with a 42‐cm inner diameter were constructed for brain imaging at 3T with maximum performance specifications of up to 85 mT/m and 708 T/m/s. Tests were performed in 24 volunteers to measure PNS thresholds with the transverse (x = left–right; y = anterior–posterior [A/P]) gradient coils of both prototypes. Fourteen of these 24 volunteers were also tested for the z‐gradient PNS in the second prototype and were scanned with high–slew‐rate echo planar imaging (EPI) immediately after the PNS tests.ResultsFor both prototypes, the y‐gradient PNS threshold was markedly higher than the x‐gradient threshold. The z‐gradient threshold was intermediate between those for the x‐ and y‐coils. Of the 24 volunteers, only two experienced y‐gradient PNS at 80 mT/m and 500 T/m/s. All volunteers underwent the EPI scan without PNS when the readout direction was set to A/P.ConclusionMeasured PNS characteristics of asymmetric head‐only gradient coil prototypes indicate that such coils, especially in the A/P direction, can be used for fast EPI readout in high‐performance neuroimaging scans with substantially reduced PNS concerns compared with conventional whole body gradient coils. Magn Reson Med 76:1939–1950, 2016. © 2015 International Society for Magnetic Resonance in Medicine

ABSTRACT Among 177 carbapenemase-producing Gram-negative bacilli (108 KPC, 32 NDM, 11 IMP, 8 OXA-48, 4 OXA-181, 2 OXA-232, 5 IMI, 4 VIM, and 3 SME producers), aztreonam-avibactam was active against all isolates except two NDM producers with elevated MICs of 8/4 and 16/4 mg/liter; ceftazidime-avibactam was active against all KPC-, IMI-, SME-, and most OXA-48 group-producing isolates (93%) but not metallo-β-lactamase producers. Among older and contemporary antimicrobials, the most active were colistin, tigecycline, and fosfomycin, with overall susceptibilities of 88%, 79%, and 78%, respectively.

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

AbstractThis analysis was performed to create a scoring system to estimate the survival of patients with non‐small cell lung cancer (NSCLC). Data from 1274NSCLCpatients were analyzed to create and validate a scoring system. Univariate (UV) and multivariate (MV) Cox models were used to evaluate the prognostic importance of each baseline factor. Prognostic factors that were significant on bothUVandMVanalyses were used to develop the score. These included quality of life, age, performance status, primary tumor diameter, nodal status, distant metastases, and smoking cessation. The score for each factor was determined by dividing the 5‐year survival rate (%) by 10 and summing these scores to form a total score.MVmodels and the score were validated using bootstrapping with 1000 iterations from the original samples. The score for each prognostic factor ranged from 1 to 7 points with higher scores reflective of better survival. Total scores (sum of the scores from each independent prognostic factor) of 32–37 correlated with a 5‐year survival of 8.3% (95%CI = 0–17.1%), 38–43 correlated with a 5‐year survival of 20% (95%CI = 13–27%), 44–47 correlated with a 5‐year survival of 48.3% (95%CI = 41.5–55.2%), 48–49 correlated to a 5‐year survival of 72.1% (95%CI = 65.6–78.6%), and 50–52 correlated to a 5‐year survival of 84.7% (95%CI = 79.6–89.8%). The bootstrap method confirmed the reliability of the score. Prognostic factors significantly associated with survival on bothUVandMVanalyses were used to construct a valid scoring system that can be used to predict survival ofNSCLCpatients. Optimally, this score could be used when counseling patients, and designing future trials.

BACKGROUNDThis study evaluated the 2‐year overall survival rate, adverse event rate, local control rate, and impact on pulmonary function tests for medically inoperable patients with stage IA non–small cell lung cancer (NSCLC) undergoing computed tomography (CT)–guided radiofrequency ablation (RFA) in a prospective, multicenter trial.METHODSFifty‐four patients (25 men and 29 women) with a median age of 76 years (range, 60‐89 years) were enrolled from 16 US centers; 51 patients were eligible for evaluation (they had biopsy‐proven stage IA NSCLC and were deemed medically inoperable by a board‐certified thoracic surgeon). Pulmonary function tests were performed within the 60 days before RFA and 3 and 24 months after RFA. Adverse events were recorded and categorized. Patients were followed with CT and fludeoxyglucose positron emission tomography. Local control rate and recurrence patterns were analyzed.RESULTSThe overall survival rate was 86.3% at 1 year and 69.8% at 2 years. The local tumor recurrence–free rate was 68.9% at 1 year and 59.8% at 2 years and was worse for tumors > 2 cm. In the 19 patients with local recurrence, 11 were re‐treated with RFA, 9 underwent radiation, and 3 underwent chemotherapy. There were 21 grade 3 adverse events, 2 grade 4 adverse events, and 1 grade 5 adverse event in 12 patients within the first 90 days after RFA. None of the grade 4 or 5 adverse events were attributable to RFA. There was no significant change in the forced expiratory volume in the first second of expiration or the diffusing capacity of lung for carbon monoxide after RFA. A tumor size less than 2.0 cm and a performance status of 0 or 1 were associated with statistically significant improved survival of 83% and 78%, respectively, at 2 years.CONCLUSIONSRFA is a single, minimally invasive procedure that is well tolerated in medically inoperable patients, does not adversely affect pulmonary function tests, and provides a 2‐year overall survival rate that is comparable to the rate reported after stereotactic body radiotherapy in similar patients. Cancer 2015;121:3435–43. © 2015 American Cancer Society.

The approach to the patient with acute renal failure and elevated anion and osmolal gap is difficult. Differential diagnoses include toxic alcohol ingestion, diabetic or starvation ketoacidosis, or 5-oxoproline acidosis. We present a 76-year-old female with type 2 diabetes mellitus, who was found at home in a confused state. Laboratory analysis revealed serum pH 6.84, bicarbonate 5.8 mmol/L, pCO2 29 mmHg, anion gap 22.2 mmol/L, osmolal gap 17.4 mOsm/kg, elevated beta-hydroxybutyrate (4.2 mmol/L), random blood sugar 213 mg/dL, creatinine 2.1 mg/dL, and potassium 7.5 mmol/L with no electrocardiogram (EKG) changes. Fomepizole and hemodialysis were initiated for presumed ethylene glycol or methanol ingestion. Drug screens returned negative for ethylene glycol, alcohols, and acetaminophen, but there were elevated urine levels of acetone (11 mg/dL). The acetaminophen level was negative, and 5-oxoproline was not analyzed. After 5 days in the intensive care unit (ICU), her mental status improved with supportive care. She was discharged to a nursing facility. Though a diagnosis was not established, our patient’s presentation was likely due to starvation ketosis combined with chronic acetaminophen ingestion. Acetone ingestion is less likely. Overall, our case illustrates the importance of systematically approaching an elevated osmolal and anion gap metabolic acidosis.