Search

Abstract Introduction The transcription factor MYC is overexpressed in 30% of small cell lung cancer (SCLC) tumors and is known to modulate the balance between two major pathways of metabolism: glycolysis and mitochondrial respiration. This duality of MYC underscores the importance of further investigation into its role in SCLC metabolism and could lead to insights into metabolic targeting approaches. Methods We investigated differences in metabolic pathways in transcriptional and metabolomics datasets based on cMYC expression in patient and cell line samples. Metabolic pathway utilization was evaluated by flow cytometry and Seahorse extracellular flux methodology. Glycolysis inhibition was evaluated in vitro and in vivo using PFK158, a small molecular inhibitor of PFKFB3. Results MYC-overexpressing SCLC patient samples and cell lines exhibited increased glycolysis gene expression directly mediated by MYC. Further, MYC-overexpressing cell lines displayed enhanced glycolysis consistent with the Warburg effect, while cell lines with low MYC expression appeared more reliant on oxidative metabolism. Inhibition of glycolysis with PFK158 preferentially attenuated glucose uptake, ATP production, and lactate in MYC-overexpressing cell lines. Treatment with PFK158 in xenografts delayed tumor growth and decreased glycolysis gene expression. Conclusions Our study highlights an in-depth characterization of SCLC metabolic programming and presents glycolysis as a targetable mechanism downstream of MYC that could offer therapeutic benefit in a subset of SCLC patients.

Background: To investigate the association between serum bilirubin (BIL) levels and the progression of albuminuria in type 2 diabetic Taiwanese. Methods: Longitudinal data from January 2001 to June 2015 were retrospectively reviewed from Chang Gung Memorial Hospital in Taiwan. A total of 2877 type 2 diabetic patients with normal total BIL levels were divided into 4 groups according to BIL, with the highest BIL in the fourth group. The urinary albumin/creatinine ratio (UACR) trend and progression, as well as other laboratory measurements, were evaluated among the four groups. The cumulative incidence and Cox proportional hazard model analysis were performed to examine the relationship between BIL and the risk of albuminuria progression (AUPr). Results: The mean duration of follow-up was 1.5 years (±1.37 years). The mean patient age, glycosylated hemoglobin level, and duration of diabetes were 62.52 years, 7.9%, and 3.94 years, respectively. A significant correlation was observed between BIL and both the UACR at baseline (P

Efficient accurate Gaussian localization is an important topic in many applications, e.g. localization based super-resolution microscopy and image scanning microscopy, which requires large-scale Gaussian patterns localization for accurate super-resolution image reconstruction. Existing Gaussian localization methods usually require high signal-to-noise image and the existing standard fitting algorithm usually requires manually inputting a good initial value for all parameters, which could be not convenient to use and difficult to guarantee high robustness for large-scale Gaussian localizations with a computer. It would be even more challenge to detect all the Gaussian patterns with high-dynamic-range of amplitudes, as well as to estimate a good initial value for all parameters for efficient Gaussian fitting and guarantee high robustness of the localization algorithm for low signal-to-noise ratio image data with strong background. In this paper, we propose an efficient Gaussian patterns detection technique and a robust Gaussian fitting method for accurate Gaussian fitting without initial estimation. In our technique, a fast Pearson correlation algorithm is proposed to improve the efficiency of the calculation of normalized cross correlation for large scale object detection with template matching. By introducing blind background estimation, a modified iterative least-squares Gaussian fitting algorithm without initials estimation is proposed for robust Gaussian fitting with noisy data with strong background. The simulation shows that the performance of the proposed detection technique is high for low SNR image and an efficiency improvement of 27% can be achieved; the proposed Gaussian fitting algorithm is capable of calculating all parameters without initial estimation, and the resulting fitting accuracy is very close to exiting standard methods, which indicates that image signal-to-noise ratio higher than 10dB is required to obtain subpixel accuracy.

Summary: lncRNA taurine-upregulated gene 1 (Tug1) is a promising therapeutic target in the progression of diabetic nephropathy (DN), but the molecular basis of its protection remains poorly understood. Here, we generate a triple-mutant diabetic mouse model coupled with metabolomic profiling data to interrogate whether Tug1 interaction with peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) is required for mitochondrial remodeling and progression of DN in vivo. We find that, compared with diabetic conditional deletion of Pgc1α in podocytes alone (db/db; Pgc1αPod-f/f), diabetic Pgc1α knockout combined with podocyte-specific Tug1 overexpression (db/db; TugPodTg; Pgc1αPod-f/f) reverses the protective phenotype of Tug1 overexpression, suggesting that PGC1α is required for the renoprotective effect of Tug1. Using unbiased metabolomic profiling, we find that altered urea cycle metabolites and mitochondrial arginase 2 play an important role in Tug1/PGC1α-induced mitochondrial remodeling. Our work identifies a functional role of the Tug1/PGC1α axis on mitochondrial metabolic homeostasis and urea cycle metabolites in experimental models of diabetes.

Background: This study compared event rates of diabetic ketoacidosis (DKA) and severe hypoglycemia, as well as glycemic control, among children, adolescents, and young adults with type 1 diabetes mellitus (T1DM) receiving basal-bolus or premixed insulin therapy. Methods: A total of 825 individuals aged ≤ 20 years with T1DM, using either basal-bolus or premixed insulin regimens, were retrospectively recruited from 2001 to 2015. Rates of DKA after diagnosis, severe hypoglycemia, and the level of glycated hemoglobin A1c (HbA1c) improvement during the follow-up period were analyzed. Results: Of the 825 patients, 226 receiving a premixed regimen were matched to the same number of patients receiving a basal-bolus regimen. In the matched cohort, DKA (10.62% vs. 5.31%; p = 0.037) and severe hypoglycemic episodes (25.22% vs. 10.62%; p

Accurate segmented mirror wavefront sensing and control is essential for next-generation large aperture telescope system design. In this paper, a direct tip–tilt and piston error detection technique based on model-based phase retrieval with multiple defocused images is proposed for segmented mirror wavefront sensing. In our technique, the tip–tilt and piston error are represented by a basis consisting of three basic plane functions with respect to the x, y, and z axis so that they can be parameterized by the coefficients of these bases; the coefficients then are solved by a non-linear optimization method with the defocus multi-images. Simulation results show that the proposed technique is capable of measuring high dynamic range wavefront error reaching 7λ, while resulting in high detection accuracy. The algorithm is demonstrated as robust to noise by introducing phase parameterization. In comparison, the proposed tip–tilt and piston error detection approach is much easier to implement than many existing methods, which usually introduce extra sensors and devices, as it is a technique based on multiple images. These characteristics make it promising for the application of wavefront sensing and control in next-generation large aperture telescopes.

Thyroid radiofrequency ablation and microwave ablation are widely adopted minimally invasive treatments for diverse thyroid conditions worldwide. Fundamental skills such as the trans-isthmic approach and the moving shot technique are crucial for performing thyroid ablation, and advanced techniques, including hydrodissection and vascular ablation, improve safety and efficacy and reduce complications. Given the learning curve associated with ultrasound-guided therapeutic procedures, operators need training and experience. While training models exist, limited attention has been given to ultrasound maneuvers in ablation needle manipulation. This article introduces two essential maneuvers, the zigzag moving technique and the alienate maneuver, while also reviewing the latest ultrasound techniques in thyroid ablation, contributing valuable insights into this evolving field.

Asparagine is a non-essential amino acid since it can either be taken up via the diet or synthesized by asparagine synthetase. Acute lymphoblastic leukemia (ALL) cells do not express asparagine synthetase or express it only minimally, which makes them completely dependent on extracellular asparagine for their growth and survival. This dependency makes ALL cells vulnerable to treatment with L-asparaginase, an enzyme that hydrolyzes asparagine. To date, all clinically approved L-asparaginases have significant L-glutaminase co-activity, associated with non-immune related toxic side effects observed during therapy. Therefore, reduction of L-glutaminase co-activity with concomitant maintenance of its anticancer L-asparaginase effect may effectively improve the tolerability of this unique drug. Previously, we designed a new alternative variant of Erwinia chrysanthemi (ErA; Erwinaze) with decreased L-glutaminase co-activity, while maintaining its L-asparaginase activity, by the introduction of three key mutations around the active site (ErA-TM). However, Erwinaze and our ErA-TM variant have very short half-lives in vivo. Here, we show that the fusion of ErA-TM with an albumin binding domain (ABD)-tag significantly increases its in vivo persistence. In addition, we evaluated the in vivo therapeutic efficacy of ABD-ErA-TM in a B-ALL xenograft model of SUP-B15. Our results show a comparable long-lasting durable antileukemic effect between the standard-of-care pegylated-asparaginase and ABD-ErA-TM L-asparaginase, but with fewer co-glutaminase-related acute side effects. Since the toxic side effects of current L-asparaginases often result in treatment discontinuation in ALL patients, this novel ErA-TM variant with ultra-low L-glutaminase co-activity and long in vivo persistence may have great clinical potential.