Acute Homeostatic Responses to Increased Fat Consumption in MCH1R Knockout Mice

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide which has been shown to regulate energy homeostasis. Using genetic knockout mice lacking the MCH1 receptor (MCH1R), we investigated how these mice adapt to metabolic changes caused by excessive caloric consumption. We show that the MCH system is one of the players mediating behavioral and metabolic responses upon increased caloric consumption. MCH1R knockout mice showed decreased tendency of food intake upon exposure to a high-fat diet. They also are resistant to gain weight upon high-fat diet by increasing fat metabolism. Therefore, the MCH system is important in regulating metabolic responses upon various environmental stimuli such as high-fat diet

Chemokine (C-C Motif) Ligand 2 (CCL2) in Sera of Patients with Type 1 Diabetes and Diabetic Complications

Chemokine (C-C motif) ligand 2 (CCL2), commonly known as monocyte chemoattractant protein-1 (MCP-1), has been implicated in the pathogenesis of many diseases characterized by monocytic infiltration. However, limited data have been reported on MCP-1 in type 1 diabetes (T1D) and the findings are inconclusive and inconsistent.In this study, MCP-1 was measured in the sera from 2,472 T1D patients and 2,654 healthy controls using a Luminex assay. The rs1024611 SNP in the promoter region of MCP-1 was genotyped for a subset of subjects (1764 T1D patients and 1323 controls) using the TaqMan-assay.Subject age, sex or genotypes of MCP-1 rs1024611SNP did not have a major impact on serum MCP-1 levels in either healthy controls or patients. While hemoglobin A1c levels did not have a major influence on serum MCP-1 levels, the mean serum MCP-1 levels are significantly higher in patients with multiple complications (mean = 242 ng/ml) compared to patients without any complications (mean = 201 ng/ml) (p = 3.5×10(-6)). Furthermore, mean serum MCP-1 is higher in controls (mean = 261 ng/ml) than T1D patients (mean = 208 ng/ml) (p<10(-23)). More importantly, the frequency of subjects with extremely high levels (>99(th) percentile of patients or 955 ng/ml) of serum MCP-1 is significantly lower in the T1D group compared to the control group (odds ratio = 0.11, p<10(-33)).MCP-1 may have a dual role in T1D and its complications. While very high levels of serum MCP-1 may be protective against the development of T1D, complications are associated with higher serum MCP-1 levels within the T1D group

Current and future roles of biosimilars in oncology practice (Review)

Biologics have been used increasingly in the treatment and supportive care of cancer; however, their high cost places a significant burden on healthcare systems. The expiration of patents for biologics has led to the development of biosimilars, with the aim of reducing cost and increasing accessibility to novel treatments, which are affordable for a greater number of patients. Biosimilars are highly similar but not identical to the reference products; therefore, strict regulatory requirements have been formed for their approval. This ensures that there are no clinically meaningful differences compared with respective biologics, with regard to purity, safety and efficacy. In 2003, a regulatory framework for the approval of biosimilars was established in Europe, whereas the USA did not implement a framework until 2009, when the Biologics Price Competition and Innovation Act was formed. A number of biosimilars have currently been approved in oncology and the number is expected to rise in the near future. More than 10 years of evidence has revealed that biosimilars are safe and effective; however healthcare professionals need to be further educated to eliminate potential misconceptions and integrate biosimilars into routine clinical practice. The present review aims to provide an overview of the biosimilars used in Europe and the USA, present their main benefits and challenges, and discuss their current and future roles in medical oncology. © 2020 Spandidos Publications. All rights reserved

Sex-Differences in Hepatic Fatty-Acid Uptake Reflect a Greater Affinity of the Transport-System in Females

In this study, we examined the hypothesis that the reported sex difference in hepatic free fatty acid (FFA) uptake involves the putative FFA transport system, the plasma membrane fatty acid binding protein (FABP(pm)). In hepatocytes isolated from both male and female rats, initial [H-3]oleate uptake velocity reflected transmembrane influx and not subsequent metabolism and was a saturable function of the unbound oleate concentration. Although V(max) values were similar (61 +/-2 vs. 65 +/- 5 pmol.min-1.5 x 10(4) cells-1 for females and males, respectively), the apparent K(m) was significantly smaller in females (40 +/- 4 vs. 90 +/- 11 nM; P < 0.05), reflecting faster influx velocities in female cells over a range of unbound oleate concentrations. The oleate efflux rate constant was also greater in females (0.280 +/- 0.014 vs. 0.198 +/- 0.020 min-1; P < 0.05) despite their greater hepatic content of cytosolic FABP. Finally, despite the greater rates of transmembrane FFA flux in female hepatocytes, the surface expression of FABP(pm) was virtually identical in the two sexes (2.5 +/- 0.5 vs. 2.4 +/- 0.4 mug/10(6) cells). Collectively, these data indicate that at FFA-to-albumin ratios occurring in vivo the plasma membrane of female hepatocytes transports oleate bidirectionally at a greater rate than that of male hepatocytes. A sex-related difference in the functional affinity of FABP(pm) for FFA appears the most likely explanation for the greater oleate uptake in females

Role of acid sphingomyelinase bioactivity in human CD4+ T-cell activation and immune responses

Acid sphingomyelinase (ASM), a lipid hydrolase enzyme, has the potential to modulate various cellular activation responses via the generation of ceramide and by interaction with cellular receptors. We have hypothesized that ASM modulates CD4+ T-cell receptor activation and impacts immune responses. We first observed interactions of ASM with the intracellular domains of both CD3 and CD28. ASM further mediates T-cell proliferation after anti-CD3/CD28 antibody stimulation and alters CD4+ T-cell activation signals by generating ceramide. We noted that various pharmacological inhibitors of ASM or knockdown of ASM using small hairpin RNA inhibit CD3/CD28-mediated CD4+ T-cell proliferation and activation. Furthermore, such blockade of ASM bioactivity by biochemical inhibitors and/or molecular-targeted knockdown of ASM broadly abrogate T-helper cell responses. In conclusion, we detail immune, pivotal roles of ASM in adaptive immune T-cell responses, and propose that these pathways might provide novel targets for the therapy of autoimmune and inflammatory diseases

Diagnosis of Gulf War Illness Using Laser-Induced Spectra Acquired from Blood Samples

Gulf War illness (GWI) is a chronic illness with no known validated biomarkers that affects the lives of hundreds of thousands of people. As a result, there is an urgent need for the development of an untargeted and unbiased method to distinguish GWI patients from non-GWI patients. We report on the application of laser-induced breakdown spectroscopy (LIBS) to distinguish blood plasma samples from a group of subjects with GWI and from subjects with chronic low back pain as controls. We initially obtained LIBS data from blood plasma samples of four GWI patients and four non-GWI patients. We used an analytical method based on taking the difference between a mean LIBS spectrum obtained with those of GWI patients from the mean LIBS spectrum of those of the control group, to generate a “difference” spectrum for our classification model. This model was cross-validated using different numbers of differential LIBS emission peaks. A subset of 17 of the 82 atomic and ionic transitions that provided 70% of correct diagnosis was selected test in a blinded fashion using 10 additional samples and was found to yield 90% classification accuracy, 100% sensitivity, and 83.3% specificity. Of the 17 atomic and ionic transitions, eight could be assigned unambiguously to species of Na, K, and Fe

Lung cancer patients’ journey from first symptom to treatment: Results from a Greek registry

Background: To map the patients’ journey from symptoms onset to treatment initiation for the most frequent histological types of lung cancer in Greece and describe the initial treatment that patients receive. Methods: The primary data source was a Greek hospital-based registry. Demographic, anthropometric, lifestyle, and diagnostic-related characteristics as well as treatment-related data were extracted from the registry for patients diagnosed with Adenocarcinoma, Squamous and Small Cell Lung Cancer (SCLC). The time intervals from symptoms onset to diagnosis (StD), diagnosis to treatment initiation (DtT), symptoms onset to treatment initiation (StT) and surgery to post–surgery treatment (SRGtT) were estimated. Results: 231, 120 and 122 patients were diagnosed with Adenocarcinoma, SCLC and Squamous, respectively. The percentage of patients diagnosed at stage III/IV ranged from 75% in Adenocarcinoma to 97.5% in SCLC (p &lt; 0.001). The median (IQR) StD was 52 (28–104) days and no difference was detected across the three histological types (p = 0.301). Cough as first symptom was the only determinant of StD (p = 0.001). The median (IQR) DtT was 23 (13–36) days, with this time interval being shorter among patients with SCLC compared to patients with Adenocarcinoma and Squamous (p &lt; 0.001). The median (IQR) StT was 81 (51–139) days. Almost one third of patients with Adenocarcinoma and Squamous were subjected first to surgery and the median (IQR) SRGtT was 42 (34–55) days. Conclusions: Our results indicate that time interval from symptoms onset to treatment initiation in Greece is substantially prolonged, highlighting the need for strategies to expedite lung cancer diagnosis and access to evidence-based treatment. © 2019 Elsevier Lt