Synthetic immune checkpoint engagers protect HLA-deficient iPSCs and derivatives from innate immune cell cytotoxicity.

Immune rejection of allogeneic cell therapeutics remains a major problem for immuno-oncology and regenerative medicine. Allogeneic cell products so far have inferior persistence and efficacy when compared with autologous alternatives. Engineering of hypoimmune cells may greatly improve their therapeutic benefit.

Effect of Lactoferrin on Clinical Outcomes of Hospitalized Patients with COVID-19: The LAC Randomized Clinical Trial.

As lactoferrin is a nutritional supplement with proven antiviral and immunomodulatory abilities, it may be used to improve the clinical course of COVID-19. The clinical efficacy and safety of bovine lactoferrin were evaluated in the LAC randomized double-blind placebo-controlled trial. A total of 218 hospitalized adult patients with moderate-to-severe COVID-19 were randomized to receive 800 mg/die oral bovine lactoferrin (n = 113) or placebo (n = 105), both given in combination with standard COVID-19 therapy.

Protection of cell therapeutics from antibody-mediated killing by CD64 overexpression.

Allogeneic cell therapeutics for cancer therapy or regenerative medicine are susceptible to antibody-mediated killing, which diminishes their efficacy. Here we report a strategy to protect cells from antibody-mediated killing that relies on engineered overexpression of the IgG receptor CD64. We show that human and mouse iPSC-derived endothelial cells (iECs) overexpressing CD64 escape antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity from IgG antibodies in vitro and in ADCC-enabled mice.

Genetic activation of Nrf2 reduces cutaneous symptoms in a murine model of Netherton syndrome.

Netherton syndrome is a monogenic autosomal recessive disorder primarily characterized by the detachment of the uppermost layer of the epidermis, the It results from mutations in the gene, which codes for a kallikrein inhibitor. Uncontrolled kallikrein activity leads to premature desquamation, resulting in a severe epidermal barrier defect and subsequent life-threatening systemic infections and chronic cutaneous inflammation. Here, we show that genetic activation of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nfe2l2/Nrf2) in keratinocytes of knockout mice, a model for Netherton syndrome, significantly alleviates their cutaneous phenotype.

A Cryoinjury Model to Study Myocardial Infarction in the Mouse.

The use of animal models is essential for developing new therapeutic strategies for acute coronary syndrome and its complications. In this article, we demonstrate a murine cryoinjury infarct model that generates precise infarct sizes with high reproducibility and replicability. In brief, after intubation and sternotomy of the animal, the heart is lifted from the thorax.

De novo mutations in mitochondrial DNA of iPSCs produce immunogenic neoepitopes in mice and humans.

The utility of autologous induced pluripotent stem cell (iPSC) therapies for tissue regeneration depends on reliable production of immunologically silent functional iPSC derivatives. However, rejection of autologous iPSC-derived cells has been reported, although the mechanism underlying rejection is largely unknown. We hypothesized that de novo mutations in mitochondrial DNA (mtDNA), which has far less reliable repair mechanisms than chromosomal DNA, might produce neoantigens capable of eliciting immune recognition and rejection.

Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients.

Autologous induced pluripotent stem cells (iPSCs) constitute an unlimited cell source for patient-specific cell-based organ repair strategies. However, their generation and subsequent differentiation into specific cells or tissues entail cell line-specific manufacturing challenges and form a lengthy process that precludes acute treatment modalities. These shortcomings could be overcome by using prefabricated allogeneic cell or tissue products, but the vigorous immune response against histo-incompatible cells has prevented the successful implementation of this approach.

Sibutramine and L-carnitine compared to sibutramine alone on insulin resistance in diabetic patients.

Objective: To evaluate the effects of one year of treatment with sibutramine plus L-carnitine compared to sibutramine on body weight, glycemic control, and insulin resistance state in type 2 diabetic patients.

Methods: Two hundred and fifty-four patients with uncontrolled type 2 diabetes mellitus (T2DM) [glycated hemoglobin (HbA(1c)) >8.0%] in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomised to take sibutramine 10 mg plus L-carnitine 2 g or sibutramine 10 mg in monotherapy.

Comparison of orlistat treatment and placebo in obese type 2 diabetic patients.

Aim: To evaluate the effects of 1-year treatment with orlistat compared with placebo on different inflammatory parameters in type 2 obese diabetic patients.

Materials And Methods: Two hundred and fifty-four type 2 diabetic patients were randomized to take orlistat 120 mg three times a day or placebo for 12 months. We evaluated at baseline and after 3, 6, 9 and 12 months: leptin, tumor necrosis factor (TNF)-alpha, adiponectin (ADN), vaspin and high-sensitivity C-reactive protein (HS-CRP), body weight, waist circumference, body mass index (BMI), lipid profile, glycemic profile, fasting plasma insulin (FPI) and homeostasis model assessment insulin resistance index (HOMA-IR).

Differential effects of candesartan and olmesartan on adipose tissue activity biomarkers in type II diabetic hypertensive patients.

The aim of this study is to compare the effects of candesartan and olmesartan on insulin sensitivity-related parameters, before and after antihypertensive therapy. After a 4-week washout placebo period, 194 hypertensive (diastolic blood pressure (DBP) > or =80 mm Hg and systolic blood pressure (SBP) > or =130 mm Hg) patients with well-controlled type II diabetes were randomized to receive either 8 mg of candesartan once a day (o.d.

Effects of combination of sibutramine and L-carnitine compared with sibutramine monotherapy on inflammatory parameters in diabetic patients.

The aim of the study was to evaluate the effects of 12-month treatment with sibutramine plus L-carnitine compared with sibutramine alone on body weight, glycemic control, insulin resistance, and inflammatory state in type 2 diabetes mellitus patients. Two hundred fifty-four patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA(1c)] >8.0%) in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomized to take sibutramine 10 mg plus L-carnitine 2 g or sibutramine 10 mg in monotherapy.

Effects of a standardized oral fat load on vascular remodelling markers in healthy subjects.

The most adequate way to experimentally reproduce the post-prandial lipemia condition appears to be the administration of a standardized oral fat load (OFL) to fasting patients. We studied the effects of a standardized OFL on markers of vascular remodelling in healthy subjects. We enrolled 286 Caucasians aged >or= 18 of either sex.

Modification of vascular and inflammation biomarkers after OGTT in overweight healthy and diabetic subjects.

We evaluated the effect of an oral glucose tolerance test (OGTT) on the level of biomarkers of vascular remodelling. We enrolled 256 Caucasian overweight healthy subjects (H) and 274 overweight type 2 diabetic patients (D). All patients underwent basal measurements of blood glucose (BG), nitrites/nitrates, adiponectin (ADP), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) before and after OGTT.

Candesartan effect on inflammation in hypertension.

The aim of this study was to evaluate the effect of candesartan on inflammatory biomarkers in hypertensive patients with and without type 2 diabetes mellitus after a standardized oral fat load (OFL). A total of 219 patients were enrolled: 106 patients were assigned to the non-diabetic hypertensive (NH) group, and 113 to the diabetic hypertensive (DH) group. All patients received candesartan therapy for 6 months and underwent a standardized OFL at baseline and after 6 months of therapy.

Modulation of adipokines and vascular remodelling markers during OGTT with acarbose or pioglitazone treatment.

Adipose tissue secretes biologically active mediators as adipokines. We evaluate the effect of pioglitazone and acarbose on adipokines and vascular remodelling markers during an oral glucose tolerance test (OGTT). Height and body weight, BMI, glycemic and lipid profile, blood pressure, Nitrites/nitrates, ADP, resistin, MMP-2, and MMP-9 were evaluated at titration beginning, after 3, 6 months, and at the study end in 473 type 2 diabetic patients.

Fenofibrate, simvastatin and their combination in the management of dyslipidaemia in type 2 diabetic patients.

Objective: To evaluate the efficacy of fenofibrate, simvastatin or their combination in type 2 diabetic patients with combined dyslipidaemia.

Research Design And Methods: 241 patients, who had never previously taken lipid-lowering medications, received fenofibrate 145 mg/day, or simvastatin 40 mg/day, or fenofibrate 145 mg/day + simvastatin 40 mg/day combination for 12 months. We evaluated lipids, glycaemic, haemostatic, and inflammatory variables at baseline, and after 6 and 12 months.

Oral fat load effects on inflammation and endothelial stress markers in healthy subjects.

The aim was to study the effect of a standardized oral fat load (OFL) on different inflammatory parameters in a large sample of adult healthy subjects (n = 286) of both sexes. The fat load was given between 08:00 and 09:00 h after a 12-h fast. Blood samples were drawn before and 3, 6, 9, and 12 h after the OFL.

Direct comparison among oral hypoglycemic agents and their association with insulin resistance evaluated by euglycemic hyperinsulinemic clamp: the 60's study.

The aim of the study was to compare the long-term effect of 4 antidiabetic treatment protocols on insulin resistance evaluated by euglycemic hyperinsulinemic clamp in type 2 diabetes mellitus patients. Two hundred seventy-one type 2 diabetes mellitus patients with poor glycemic control and who were overweight were enrolled in this study. Patients were randomized and titrated to take pioglitazone, metformin, pioglitazone + metformin, or glimepiride + metformin for 15 months.

Effects of insulin therapy with continuous subcutaneous insulin infusion (CSII) in diabetic patients: comparison with multi-daily insulin injections therapy (MDI).

We compared the effects of continuous subcutaneous insulin infusion (CSII) and multi-daily insulin injections therapy (MDI) on glicemic control and on lipid profile in type 1 and type 2 diabetic patients. We divided the patients in two groups: in the first one (n=32) CSII was administered, in the second one (n=32) MDI was administered. HbA(1C) value was lower after 3, 6, 9, and 12 months with CSII compared to MDI.

Evaluation of metalloproteinase 2 and 9 levels and their inhibitors in combined dyslipidemia.

Purpose: To evaluate the distribution of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and their specific inhibitors in a sample of patients affected by mild dyslipidemia but not yet treated with antihyperlipidemic drugs.

Methods: One hundred and sixty-eight Caucasian patients aged >or=18 yr of either sex with combined dyslipidemia and who had never previously taken lipid-lowering medications were evaluated. As a control population, we enrolled 179 Caucasian healthy subjects, aged >or=18 yr of either sex.

Continuous glucose monitoring system in free-living healthy subjects: results from a pilot study.

Background And Aim: The Continuous Glucose Monitoring System (CGMS) (Medtronic Minimed, Northridge, CA) provides an opportunity to better understand abnormalities in glucose metabolism in both healthy subjects and those with diabetes. The aims of our study were to assess the reliability of CGMS compared to self-monitoring of blood glucose (BG) and to analyze the graphs obtained in a sample of healthy free-living subjects in order to establish the suitability of CGMS in physiological studies.

Methods: Eighteen healthy adults, 12 women and six men, were enrolled in this study.