Lyngemosley8826
Early increase in serum tumor necrosis factor α levels, late increase in serum interleukin 6 levels and increase in tumor-infiltrating CD8+ T lymphocytes correlated more with a durable response over 60 days than with a non-durable response.
Our CD34+ humanized mouse model is the first in vivo platform for testing the long-term efficacy of anticancer immunotherapies and biomarkers, given that none of the preclinical models has ever been evaluated for such a long duration.
Our CD34+ humanized mouse model is the first in vivo platform for testing the long-term efficacy of anticancer immunotherapies and biomarkers, given that none of the preclinical models has ever been evaluated for such a long duration.
Tumor relapse constitutes a major challenge for anti-tumoral treatments, including immunotherapies. Indeed, most cancer-related deaths occur during the tumor relapse phase.
We designed a mouse model of tumor relapse in which mice transplanted with E7
TC1 tumor cells received a single therapeutic vaccination of STxB-E7+IFNα. Unlike the complete regression observed after two vaccinations, such a treatment induced a transient shrinkage of the tumor mass, followed by a rapid tumor outgrowth. To prevent this relapse, we tested the efficacy of a local administration of IFNα together with a systemic therapy with anti-PD1 Ab. The immune response was analyzed during both the tumor regression and relapse phases.
We show that, during the regression phase, tumors of mice treated with a single vaccination of STxB-E7 + IFNα harbor fewer activated CD8 T cells and monocytes than tumors doomed to fully regress after two vaccinations. In contrast, the systemic injection of an anti-PD1 Ab combined with the peri-tumoral injection of IFNα in this time frame promotes infiltration of activated CD8 T cells and myeloid cells, which, together, exert a high cytotoxicity in vitro against TC1 cells. Moreover, the IFNα and anti-PD1 Ab combination was found to be more efficient than IFNα or anti-PD1 used alone in preventing tumor relapse and was better able to prolong mice survival.
Together, these results indicate that the local increase of IFNα in combination with an anti-PD1 therapy is an effective way to promote efficient and durable innate and adaptive immune responses preventing tumor relapse.
Together, these results indicate that the local increase of IFNα in combination with an anti-PD1 therapy is an effective way to promote efficient and durable innate and adaptive immune responses preventing tumor relapse.
A single application of JV-GL1 substantially lowers non-human primate intraocular pressure (IOP) for about a week, independent of dose. This highly protracted effect does not correlate with its ocular biodisposition or correlate with the once-daily dosing regimen for other prostanoid EP
receptor agonists such as trapenepag or omidenepag. The underlying pharmacological mechanism for the multiday extended activity of JV-GL1 is highly intriguing. selleck products The present studies were intended to determine EP
receptor involvement in mediating the long-term ocular hypotensive activity of JV-GL1 by using mice genetically deficient in EP
receptors.
The protracted IOP reduction produced by JV-GL1 was investigated in C57BL/6J and EP
receptor knock-out mice (B6.129-
/J; EP
KO). Both ocular normotensive and steroid-induced ocular hypertensive (SI-OHT) mice were studied. IOP was measured tonometrically under general anaesthesia. Aqueous humour outflow facility was measured ex vivo using
in normotensive C57BL/6J mouse eyes perfused with 100 nM de-esterified JV-GL1 and in SI-OHT C57BL/6J mouse eyes that had received topical JV-GL1 (0.01%) 3 days prior.
Both the initial 1-day and the protracted multiday effects of JV-GL1 in the SI-OHT model for glaucoma were abolished by deletion of the gene encoding the EP
receptor. Thus, JV-GL1 did not lower IOP in SI-OHT EP
KO mice, but in littermate SI-OHT EP
WT control mice, JV-GL1 statistically significantly lowered IOP for 4-6 days.
Both the 1-day and the long-term effects of JV-GL1 on IOP are entirely EP
receptor dependent.
Both the 1-day and the long-term effects of JV-GL1 on IOP are entirely EP2 receptor dependent.
Polyhexamethyl biguanide (PHMB), a widely used topical treatment for
keratitis (AK), is unlicensed with no formal safety assessment. This study evaluated its safety and tolerability.
A prospective, randomised, double-masked controlled trial in 90 healthy volunteers. Subjects were treated with topical 0.04%, 0.06%, 0.08% PHMB or placebo (vehicle) 12× daily for 7days, then 6× daily for 7days. The rates of dose-limiting adverse events (DLAEs) leading to interruption of dosing, mild adverse events (AEs) (not dose limiting) and incidental AEs (unrelated to treatment) were compared. The primary outcome was the difference between treatments for DLAE rates.
5/90 subjects developed DLAE within <1-4days of starting treatment; 2/5 using PHMB 0.06% and 3/5 PHMB 0.08%. These resolved within 1-15days. There were no significant differences in DLAE between treatment groups. Mild AEs occurred in 48/90 subjects (including placebo). There was no trend for an increased incidence of any AE with increasing concentrations of PHMB, except for corneal punctate keratopathy with PHMB 0.08%, which fully resolved within 7-14days.
These findings are reassuring for PHMB 0.02% users. They also suggest that higher PHMB concentrations may show acceptable levels of tolerance and toxicity in AK subjects, whose susceptibility to AE may be greater than for the normal eyes in this study. Given the potential benefits of higher PHMB concentrations for treating deep stromal invasion in AK, we think that the use of PHMB 0.08% is justified in treatment trials.
NCT02506257.
NCT02506257.
Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is commonly prescribed to patients with type 2 diabetes. As this drug is primarily eliminated by the kidney, a reduced dose is recommended for patients with CKD. Some evidence suggests that sitagliptin is associated with a higher risk of congestive heart failure, particularly at higher doses. We compare the 1-year risk of death or hospitalization with congestive heart failure in patients with CKD newly prescribed sitagliptin at >50 versus ≤50 mg/d.
This population-based cohort study included older adults (>66 years) with type 2 diabetes and an eGFR<45 ml/min per 1.73 m
(but not receiving dialysis) who were newly prescribed sitagliptin between 2010 and 2017 in Ontario, Canada. We used inverse probability of treatment weighting on the basis of propensity scores to balance baseline characteristics. The primary composite outcome was death or hospitalization with congestive heart failure. Secondary outcomes included hospitalization with pancreatitis or hypoglycemia, all-cause hospitalization, and glycemic control.
