The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating ...mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Context
Cotadutide is a dual receptor agonist with balanced glucagon-like peptide-1 and glucagon activity.
Objective
To evaluate different doses of cotadutide and investigate underlying ...mechanisms for its glucose-lowering effects.
Design/setting
Randomized, double-blind, phase 2a study conducted in 2 cohorts at 5 clinical trial sites.
Patients
Participants were 65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs.
Intervention
Once-daily subcutaneous cotadutide or placebo for 49 days. Doses (50–300 µg) were uptitrated weekly (cohort 1) or biweekly (cohort 2).
Main outcome measures
Co-primary end points (cohort 1) were percentage changes from baseline to end of treatment in glucose (area under the curve from 0 to 4 hours AUC0–4h) post–mixed-meal tolerance test (MMTT) and weight. Exploratory measures included postprandial insulin and gastric emptying time (GET; cohort 2).
Results
Patients received cotadutide (cohort 1, n = 26; cohort 2, n = 20) or placebo (cohort 1, n = 13; cohort 2, n = 6). Significant reductions were observed with cotadutide vs placebo in glucose AUC0–4h post MMTT (least squares mean 90% CI, −21.52% −25.68, −17.37 vs 6.32% 0.45, 12.20; P < 0.001) and body weight (−3.41% −4.37, −2.44 vs −0.08% −1.45, 1.28; P = 0.002). A significant increase in insulin AUC0–4h post MMTT was observed with cotadutide (19.3 mU.h/L 5.9, 32.6; P = 0.008) and GET was prolonged on day 43 with cotadutide vs placebo (t½: 117.2 minutes vs −42.9 minutes; P = 0.0392).
Conclusion
These results suggest that the glucose-lowering effects of cotadutide are mediated by enhanced insulin secretion and delayed gastric emptying.
Trial Registration
ClinicalTrials.gov, NCT03244800.
•Affective polarization (political animosity) is rising in America and cannot be fully explained by ideological polarization.•People’s misperceptions of the ideological divide (false polarization) ...may better account for intensifying partisan dislike.•Political elites are increasingly polarized, and partisan media and social media also select for polarizing content.•Institutional polarization (political elite, media, social media) may fuel partisan false polarization and animosity.•Political and media landscape shapes partisan misperceptions contributing to a self-fulfilling cycle of rising polarization.
Political polarization is on the rise in America. Although social psychologists frequently study the intergroup underpinnings of polarization, they have traditionally had less to say about macro societal processes that contribute to its rise and fall. Recent cross-disciplinary work on the contemporary political and media landscape provides these complementary insights. In this paper, we consider the evidence for and implications of political polarization, distinguishing between ideological, affective, and false polarization. We review three key societal-level factors contributing to these polarization phenomena: the role of political elites, partisan media, and social media dynamics. We argue that institutional polarization processes (elites, media and social media) contribute to people’s misperceptions of division among the electorate, which in turn can contribute to a self-perpetuating cycle fueling animosity (affective polarization) and actual ideological polarization over time.
Background and Objective
Zibotentan, a selective endothelin A receptor antagonist, is in development for chronic liver and kidney disease. The pharmacokinetics (PK) of zibotentan were previously ...investigated in patients with either renal impairment or hepatic impairment, but the impact of both pathologies on PK was not evaluated. This study evaluated the PK and tolerability of a single oral dose of zibotentan in participants with concurrent moderate renal impairment and moderate hepatic impairment versus control participants.
Methods
Twelve participants with moderate renal and hepatic impairment and 11 healthy matched control participants with no clinically significant liver or kidney disease were enrolled in an open-label, parallel-group study design. After administration of a single oral dose of zibotentan 5 mg, blood and urine sampling was performed. Pharmacokinetic parameters were determined for each of the two cohorts and compared. Comparisons between the cohorts were based on the geometric least squares mean ratio for the primary endpoints, which were area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC
∞
) and from time zero to the time of the last measurable concentration (AUC
last
), and maximum plasma drug concentration (
C
max
) on Day 1 through 120 h post-dose. Secondary endpoints included apparent total body clearance (CL/F) on Day 1 through 120 h post-dose. Safety endpoints were assessed up to discharge.
Results
In total, 11 participants with concurrent moderate renal and hepatic impairment, and 11 controls, completed the study. Zibotentan was generally well tolerated, and no new clinically significant safety findings were observed. Total exposure (AUC
∞
and AUC
last
) was approximately 2.10-fold higher in participants with concurrent moderate renal and hepatic impairment versus controls, while
C
max
and total nonrenal body clearance were similar among all groups. A regression-based post hoc analysis, comparing exposure and CL/
F
in patients with concurrent impairment to patients with either renal or hepatic impairment alone, showed that CL/
F
with concurrent impairment was approximately half of that in controls and was positively correlated with reduction of renal function. Inclusion of the data on concurrent moderate renal and hepatic impairment in the regression analysis led to a narrower confidence interval for the predicted mean CL/
F
in participants with moderate hepatic impairment.
Conclusion
The presented findings advance the understanding of the PK of zibotentan in both renal impairment and hepatic impairment, with and without overlapping pathologies, and will thus increase the confidence of dose selection in future studies, particularly in vulnerable patient populations with concurrent renal and hepatic impairment.
Trial Registration
ClinicalTrials.gov identifier: NCT05112419.
PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α ...catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth.
Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy.
Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of -7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently.
This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk-benefit evaluations for sirolimus treatment in PROS.
Weight loss is often key in the management of obese or overweight patients with type 2 diabetes, yet few treatments for diabetes achieve clinically meaningful weight loss. We aimed to assess the ...efficacy, tolerability, and safety of treatment with MEDI0382, a balanced glucagon-like peptide-1 and glucagon receptor dual agonist developed to provide glycaemic control and weight loss, in patients with type 2 diabetes.
This randomised, placebo-controlled, double-blind, combined multiple-ascending dose (MAD) and phase 2a study was done at 11 study sites (hospitals and contract research organisations) in Germany. We enrolled patients aged 18–65 years with controlled type 2 diabetes (glycated haemoglobin A1c HbA1c levels of 6·5–8·5% at screening) and a body-mass index between 27 kg/m2 and 40 kg/m2. An interactive web-response system was used to randomly assign patients to receive MEDI0382 or placebo. Patients were randomly assigned 2:1 in cohorts A–C and 3:1 in cohorts D and E in the MAD portion of the study, and 1:1 in the phase 2a portion. Randomisation was done by a contracted third-party operator who was not involved in the clinical operations of the study. The pharmacists, participants, and study site personnel involved in treating and assessing participants were masked to treatment allocation. Patients received once-daily subcutaneous injections of the study drug at doses of no more than 300 μg for 22 days or less in the MAD portion of the study, and a dose of no more than 200 μg for 41 days or less in the phase 2a portion. The two primary endpoints of the phase 2a portion were the change from baseline to day 41 in glucose area under the curve at 0–4 h (AUC0–4 h) after a mixed-meal tolerance test (MMTT), assessed in all participants who received at least one dose of study drug and whose measurements were taken at baseline and day 41, and change from baseline in bodyweight, assessed in the intention-to-treat (ITT) population. Safety analyses were done in all participants who received any study drug analysed according to the treatment they received. This study is registered with ClinicalTrials.gov, number NCT02548585.
Patients were recruited between Dec 9, 2015, and Feb 24, 2017. 61 patients were randomly assigned to the MAD part of the study (42 to MEDI0382 and 19 to placebo). 51 patients were randomly assigned to the phase 2a part, of whom 25 were randomly assigned to MEDI0382 and 26 to placebo. In the phase 2a study, three patients in the MEDI0382 group and one in the placebo group discontinued, all as a result of adverse events. 22 (88%) patients in the MEDI0382 group and 25 (96%) in the placebo group received at least one dose and had measurements taken at baseline and day 41. Glucose AUC0–4 h post MMTT decreased significantly with MEDI0382 versus placebo (least squares LS mean −32·78% 90% CI −36·98 to −28·57 vs −10·16% –14·10 to −6·21, and the mean difference was −22·62% –28·40 to −16·85; p<0·0001). In the ITT population, reduction in bodyweight was significantly greater with MEDI0382 than with placebo (LS mean −3·84 kg 90% CI −4·55 to −3·12 vs −1·70 kg –2·40 to −1·01 and mean difference of 2·14 kg –3·13 to −1·31; p=0·0008). The proportion of patients who had a treatment-emergent adverse event (TEAE) was similar between treatment groups (22 88% of 25 in the MEDI0382 group vs 23 88% of 26 in the placebo group); gastrointestinal disorders (18 72% vs 13 40%) and decreased appetite (five 20% vs none) occurred more frequently with MEDI0382 than placebo. No participants in the MEDI0382 group had a grade 3 or worse TEAE (vs two 8% in the placebo group).
MEDI0382 has the potential to deliver clinically meaningful reductions in blood glucose and bodyweight in obese or overweight individuals with type 2 diabetes.
MedImmune.
Aim
To assess the efficacy, safety and tolerability of cotadutide in patients with type 2 diabetes mellitus and chronic kidney disease.
Materials and Methods
In this phase 2a study (NCT03550378), ...patients with body mass index 25‐45 kg/m2, estimated glomerular filtration rate 30‐59 ml/min/1.73 m2 and type 2 diabetes glycated haemoglobin 6.5‐10.5% (48‐91 mmol/mol) controlled with insulin and/or oral therapy combination, were randomized 1:1 to once‐daily subcutaneous cotadutide (50‐300 μg) or placebo for 32 days. The primary endpoint was plasma glucose concentration assessed using a mixed‐meal tolerance test.
Results
Participants receiving cotadutide (n = 21) had significant reductions in the mixed‐meal tolerance test area under the glucose concentration‐time curve (–26.71% vs. +3.68%, p < .001), more time in target glucose range on continuous glucose monitoring (+14.79% vs. –21.23%, p = .001) and significant reductions in absolute bodyweight (–3.41 kg vs. –0.13 kg, p < .001) versus placebo (n = 20). In patients with baseline micro‐ or macroalbuminuria (n = 18), urinary albumin‐to‐creatinine ratios decreased by 51% at day 32 with cotadutide versus placebo (p = .0504). No statistically significant difference was observed in mean change in estimated glomerular filtration rate between treatments. Mild/moderate adverse events occurred in 71.4% of participants receiving cotadutide and 35.0% receiving placebo.
Conclusions
We established the efficacy of cotadutide in this patient population, with significantly improved postprandial glucose control and reduced bodyweight versus placebo. Reductions in urinary albumin‐to‐creatinine ratios suggest potential benefits of cotadutide on kidney function, supporting further evaluation in larger, longer‐term clinical trials.
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