PDGF receptor signal mediates the contribution of Nestin-positive cell lineage to subcutaneous fat development.

The beiging of white adipose tissue (WAT) is expected to improve systemic metabolic conditions; however, the regulation and developmental origin of this process remain insufficiently understood. In the present study, the implication of platelet-derived growth factor receptor alpha (PDGFRα) was examined in the beiging of inguinal WAT (ingWAT) of neonatal mice. Using in vivo Nestin expressing cell (Nestin+) lineage tracing and deletion mouse models, we found that, in the mice with Pdgfra gene inactivation in Nestin+ lineage (N-PRα-KO mice), the growth of inguinal WAT (ingWAT) was suppressed during neonatal periods as compared with control wild-type mice. In the ingWAT of N-PRα-KO mice, the beige adipocytes appeared earlier that were accompanied by the increased expressions of both adipogenic and beiging markers compared to control wild-type mice. In the perivascular adipocyte progenitor cell (APC) niche of ingWAT, many PDGFRα+ cells of Nestin+ lineage were recruited in Pdgfra-preserving control mice, but were largely decreased in N-PRα-KO mice. This PDGFRα+ cell depletion was replenished by PDGFRα+ cells of non-Nestin+ lineage, unexpectedly resulting in an increase of total PDGFRα+ cell number in APC niche of N-PRα-KO mice over that of control mice. These represented a potent homeostatic control of PDGFRα+ cells between Nestin+ and non-Nestin+ lineages that was accompanied by the active adipogenesis and beiging as well as small WAT depot. This highly plastic nature of PDGFRα+ cells in APC niche may contribute to the WAT remodeling for the therapeutic purpose against metabolic diseases.

X-ray-irradiated K562 feeder cells for expansion of functional CAR-T cells.

Immunotherapy, particularly CAR-T therapy has recently emerged as an innovator for cancer treatment. Gamma-irradiated K562 cells is a common and effective method to stimulated CAR-T cells prior to treatment. However, high cost and limited equipment of gamma-irradiation is drawback of this method. This requires the establishment of CAR-T-expanding alternatives, such as X-ray-irradiated K562 cells. X-ray irradiation was used to deactivate K562 cells. The post-irradiative cell survival was investigated by counting of the number of cells, staining with Trypan Blue and PI. FACS analysis was applied to detect the expression of cell surface markers. The production of CD19-CAR-T cells were executed from fresh blood donor by CD19-CAR-plasmid transfection, followed by the stimulation with X-ray-irradiated K562 feeder cells. The function of produced CAR-T cells was checked by their ability to kill Daudi cells. X-ray-irradiation inhibited the propagation and viability of K562 cells in a dose- and time-dependent manner. Interestingly, CAR-T-stimulating effectors were remained on the surface of X-ray-irradiated K562 cells. CD-19-CAR-T cells were produced successfully, suggested by number of CAR-positive cells in transfected and stimulated population, compared to un-transfected group. Lastly, our data showed that engineered CAR-T cells effectively killed Daudi cells. Our data demonstrated the efficacy of X-ray on deactivation K562 feeder cells which subsequently stimulated and expanded functional CAR-T cells. Thus, X-ray can be used as an alternative to inactivate K562 cells prior to using as a feeder of CAR-T cells.

The Correlation Between Angiopoietin-Like 3 and Metabolic Markers of Some Lipid and Glucose in Type 2 Diabetes Mellitus Patients at the First Diagnosis.

Purpose: Angiopoietin-Like3 is a protein that plays an important role in regulating plasma triglyceride concentrations by inhibiting the enzyme lipoprotein lipase. Lipid metabolism and glucose metabolism are closely related and interact with each other. ANGPTL3 may also be a factor involved in blood glucose regulation through an increase in free fatty acids generated from enhanced lipolysis in adipose tissue leading to insulin resistance. This study aimed to investigate plasma ANGPTL3 concentrations and their correlation with lipid and glucose metabolic markers in newly diagnosed type 2 Diabetes Mellitus patients. Subject and Methods: A cross-sectional descriptive study was conducted on 98 healthy subjects (control group) and 103 patients with type 2 diabetes at the first diagnosis, without any treatment (patient group). Plasma ANGPTL3 concentration was quantified by the ELISA method. The study determines the correlation of ANGPTL3 concentration with some indicators reflecting lipid and glucose metabolism. Results: The concentration of ANGPTL3 in the newly diagnosed type 2 Diabetes Mellitus patient group was lower than in the control group, the difference was statistically significant with p < 0.05. In the patient group: there was an inverse correlation between ANGPTL3 concentration and HDL-C concentration (r = -0.37; p<0.001), and a positive correlation with triglyceride concentration (r = 0.275; p < 0.05). There was no correlation between plasma ANGPTL3 levels and anthropometric indices, total cholesterol, HDL-C, glucose, HbA1C, insulin, and HOMA-IR. In the control group: there was no correlation between ANGPTL3 and any of the indicators mentioned above. Conclusion: ANGPTL3 levels in newly diagnosed type 2 diabetes mellitus patients were statistically significantly lower than in healthy subjects. Plasma ANGPTL3 was positively correlated with triglyceride levels and inversely correlated with HDL-C levels in newly diagnosed type 2 Diabetes mellitus patients.

Association of serum adiponectin and leptin levels with renal function in kidney transplant recipients with or without new-onset diabetes after transplantation.

PURPOSE: To evaluate serum adiponectin and leptin concentration in new-onset diabetes after transplantation (NODAT) and non-NODAT patients and association with renal function in kidney transplant recipients (KTRs). PATIENTS AND METHODS: A study of 314 consecutive adults KTRs divided into four groups: 236 individuals without NODAT who had renal insufficiency (RI; n = 56) or normal renal function (n = 180) and 78 patients with NODAT who had RI (n = 17) or normal renal function (n = 61). NODAT was diagnosed based on venous fasting blood glucose or HbA1c with the criteria of the American Diabetes Association. Renal insufficiency was defined according to KDOQI 2002 guidelines. RESULTS: In the NODAT group, the median level of serum adiponectin was lower than that of non-NODAT one (30 µg/ml vs 37.15 µg/ml, p < 0.001); in contrast, the median leptin concentration was higher (4.27 ng/ml vs 4.05 ng/ml, p = 0.024). In the RI group, both median serum adiponectin and leptin levels were higher than those of non-RI one (Adiponectin: 40.01 µg/ml vs 33.7 µg/ml; Leptin: 4.51 ng/ml vs 3.91 ng/ml, p < 0.001 both). We found that BMI was related to both adiponectin and leptin levels in both NODAT, non-NODAT, and all subject groups, based on univariate and multivariate linear regression analysis. CONCLUSION: New-onset diabetes after transplantation, BMI, and renal insufficiency were affected to the serum level of adiponectin and leptin in KTRs.

Reasons for Diagnostic Delay of Foot Drop Caused by Parasagittal Meningioma: Two Case Reports.

Foot drop is defined as an impaired ability or inability of dorsiflexion. Peripheral nervous system injuries are commonly considered as the cause of this condition. The central causes including parasagittal meningioma are also described in the literature but very rarely and commonly not recognized early. In this article, we report 2 patients with isolated unilateral foot drop as the first symptom of a parasagittal meningioma and discuss several reasons for delayed diagnosis. Two patients were treated with decompressive craniotomy. The histopathological findings demonstrated a fibroblastic meningioma and a meningothelial meningioma. During postoperative follow-up, the woman patient showed nearly complete recovery and the second case regained total muscle power over a period of 12 months. The rarity of the disease, the absence of upper motor neuron signs, the occurrence of peripheral pathologies and misinterpretation of F wave on nerve conduction study, and motor unit recruitment on electromyography lead to delay in diagnosis and treatment of the central foot drop due to parasagittal meningioma.

Dysregulation of Amphiregulin stimulates the pathogenesis of cystic lymphangioma.

Along with blood vessels, lymphatic vessels play an important role in the circulation of body fluid and recruitment of immune cells. Postnatal lymphangiogenesis commonly occurs from preexisting lymphatic vessels by sprouting, which is induced by lymphangiogenic factors such as vascular endothelial growth factor C (VEGF-C). However, the key signals and cell types that stimulate pathological lymphangiogenesis, such as human cystic lymphangioma, are less well known. Here, we found that mouse dermal fibroblasts that infiltrate to sponges subcutaneously implanted express VEGF-D and sushi, Von Willebrand factor type A, EGF, and pentraxin domain containing 1 (SVEP1) in response to PDGFRß signal. In vitro, Pdgfrb knockout (ß-KO) fibroblasts had reduced expression of VEGF-D and SVEP1 and overproduced Amphiregulin. Dysregulation of these three factors was involved in the cyst-like and uneven distribution of lymphatic vessels observed in the ß-KO mice. Similarly, in human cystic lymphangioma, which is one of the intractable diseases and mostly occurs in childhood, fibroblasts surrounding cystic lymphatics highly expressed Amphiregulin. Moreover, fibroblast-derived Amphiregulin could induce the expression of Amphiregulin in lymphatic endothelial cells. The dual source of Amphiregulin activated EGFR expressed on the lymphatic endothelial cells. This exacerbation cascade induced proliferation of lymphatic endothelial cells to form cystic lymphangioma. Ultimately, excessive Amphiregulin produced by fibroblasts surrounding lymphatics and by lymphatic endothelial cells per se results in pathogenesis of cystic lymphangioma and will be a fascinating therapeutic target of cystic lymphangioma.

The effect of subcutaneous injection of methylprednisolone acetate and lidocaine for refractory postherpetic neuralgia: a prospective, observational study.

BACKGROUND: Postherpetic neuralgia (PHN) is the most common and bearable complication of herpes zoster (HZ). This pain may have negative impact on the patient's all aspects of daily life and health-related quality of life (HRQOL). Despite numerous advances in treatment, many patients remain resistant to the current therapy options. It is the first time subcutaneous injection of methylprednisolone acetate and lidocaine has been used to treat refractory PHN. We report the results of this treatment evaluating pain relief and HRQOL improvement in this disorder. METHODS: A total of 43 patients with refractory PHN was enrolled in the observational study. All patients received daily subcutaneous injection of methylprednisolone acetate and lidocaine for 10 consecutive days. The severity of pain was assessed by using Visual Analog Scale (VAS), and 36-Item Short Form Survey (SF-36) was applied to evaluate HRQOL. Assessment of the pain and HRQOL was carried out at baseline and posttreatment at 4 weeks as well as 6 and 12 months. RESULTS: At baseline, all patients experienced severe PHN with average VAS scores of 8.44 ± 0.85 (minimum 7; maximum 10). At 4 weeks, 6 months, and 12 months after treatment, the pain had significantly decreased (P < .001), and all subjects showed significant improvement in all eight domains of HRQOL. No major adverse events associated with the subcutaneous injection were observed. CONCLUSIONS: Our results indicate that subcutaneous injection of methylprednisolone acetate and lidocaine can be an effective and safe treatment for PHN.

Powerful Homeostatic Control of Oligodendroglial Lineage by PDGFRα in Adult Brain.

Oligodendrocyte progenitor cells (OPCs) are widely distributed cells of ramified morphology in adult brain that express PDGFRα and NG2. They retain mitotic activities in adulthood and contribute to oligodendrogenesis and myelin turnover; however, the regulatory mechanisms of their cell dynamics in adult brain largely remain unknown. Here, we found that global Pdgfra inactivation in adult mice rapidly led to elimination of OPCs due to synchronous maturation toward oligodendrocytes. Surprisingly, OPC densities were robustly reconstituted by the active expansion of Nestin+ immature cells activated in meninges and brain parenchyma, as well as a few OPCs that escaped from Pdgfra inactivation. The multipotent immature cells were induced in the meninges of Pdgfra-inactivated mice, but not of control mice. Our findings revealed powerful homeostatic control of adult OPCs, engaging dual cellular sources of adult OPC formation. These properties of the adult oligodendrocyte lineage and the alternative OPC source may be exploited in regenerative medicine.

PDGFR-ß as a positive regulator of tissue repair in a mouse model of focal cerebral ischemia.

Although platelet-derived growth factors (PDGFs) and receptors (PDGFRs) are abundantly expressed in the central nervous system, their functions largely remain elusive. We investigated the role of PDGFR-ß in tissue responses and functional recovery after photothrombolic middle cerebral artery occlusion (MCAO). In the normal adult mouse brain, PDGFR-ß was mainly localized in neurons and in pericyte/vascular smooth muscle cells (PC/vSMCs). From 3 to 28 days after MCAO, postnatally induced systemic PDGFR-ß knockout mice (Esr-KO) exhibited the delayed recovery of body weight and behavior, and larger infarction volume than controls. In Esr-KO, PC/vSMC coverage was decreased and vascular leakage of infused fluorescent-labeled albumin was extensive within the ischemic lesion, but not in the uninjured cerebral cortex. Angiogenesis levels were comparable between Esr-KO and controls. In another PDGFR-ß conditional KO mouse (Nestin-KO), PDGFR-ß was deleted in neurons and astrocytes from embryonic day 10.5, but was preserved in PC/vSMCs. After MCAO, vascular leakage and infarction volume in Nestin-KO were worse than controls, but partly improved compared with Esr-KO. Astroglial scar formation in both Esr-KO and Nestin-KO was similarly reduced compared with controls after MCAO. These data suggested that PDGFR-ß signaling is crucial for neuroprotection, endogenous tissue repair, and functional recovery after stroke by targeting neurons, PC/vSMCs, and astrocytes.