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Vantictumab is a monoclonal antibody that binds to frizzled (FZD) receptors and inhibits canonical WNT signaling. This phase Ib dose escalation study enrolled patients with locally recurrent or metastatic HER2-negative breast cancer who were treated with weekly paclitaxel in combination with escalating doses of vantictumab.

Patients were enrolled in dose escalation cohorts treated with weekly paclitaxel 90mg/m

on days 1, 8 and 15 in combination with vantictumab 3.5-14mg/kg days 1 and 15 or 3-8mg/kg day 1 of every 28-day cycle. Primary endpoints were safety, dose-limiting toxicities (DLTs). Secondary endpoints included pharmacokinetics, efficacy and an exploratory biomarker analysis.

Forty-eight female patients with a mean age of 54 were enrolled. The majority (66.6%) received prior chemotherapy for recurrent or metastatic disease; 45.8% were hormone receptor (HR)-positive, HER2-negative and 54.2% triple-negative. The most frequent adverse events related to any study treatment were nausea (54.2%), alopecia (52.1%), fatigue (47.9%), and peripheral neuropathy (43.8%). No DLTs occurred; however, 6 patients experienced fractures outside of the DLT window. The overall response rate was 31.3% and the clinical benefit rate was 68.8%. A 6-gene WNT pathway signature showed significant association with progression-free survival (PFS) and overall survival (OS) for the biomarker high versus biomarker low groups (PFS p = 0.029 and OS p = 0.00045, respectively).

The combination of vantictumab and weekly paclitaxel was generally well tolerated with promising efficacy; however, the incidence of fractures limits future clinical development of this particular WNT inhibitor in metastatic breast cancer.

ClinicalTrials.gov registration NCT01973309.

ClinicalTrials.gov registration NCT01973309.Increasingly compelling data link chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) to cardiovascular complications independent of known comorbidities. It remains unclear whether the association is amplified in the presence of both conditions. The aims of this study are to assess the prevalence of atrial fibrillation (AF) in overlap syndrome (OS) and to identify risk factors predisposing to this atrial arrhythmia. We conducted a retrospective cohort study of 268 adults without past or current AF who were referred for an initial diagnostic polysomnogram from 2012 to 2019. A logistic regression analysis was performed to identify risk factors for incident AF. Incident AF occurred in 64 subjects [cumulative probability 24%, 95% confidence interval (CI) 19-29]. selleck screening library Independent predictors of incident AF were age-adjusted Charlson index [Odds ratio (OR) 1.62; 95% confidence interval (CI) 1.3-2.0], percentage of time spent with O2 saturation below 90% (CT90) (OR 3.72, 95% CI 1.18-11.71), and CPAP adherence (OR 0.32, 95% CI 0.13-0.71). OS patients with AF experienced higher hospitalization rates (OR 1.25, 95% CI 1.03-2.37) and worse mortality rates (OR 1.92, 95% CI 1.04-3.54). In multivariate Cox proportional regression, age-adjusted Charlson Index, severity of airflow obstruction, and CPAP adherence were independent predictors of mortality. The burden of hypoxemia and severity of comorbidities are independent factors for incident AF in individuals with OS. CPAP adherence may mitigate the risk of AF and reduce the rate of mortality in this population.The present study was aimed to evaluate the anticonvulsant activity of acteoside and explore its mechanism of action. Initially, the acteoside was evaluated in maximal electroshock (MES) and pentylenetetrazole (PTZ)-induced convulsions, and later it was evaluated against N-methyl-D-aspartic acid (NMDA)-induced mortality in Swiss albino mice. Based on the response in these models, further evaluations were performed to explore the mechanism of action. In the results, the acteoside (10, 25, and 50 mg/kg) has shown significant anticonvulsant activity in the PTZ model (p  less then  0.01 for all doses); however, there was no protection observed in MES and NMDA models. Therefore, further mechanism-based studies were performed on the PTZ model, and the outcomes have revealed that there was a significant reduction in GABA (p  less then  0.01 for both regions) and elevation of glutamate (p  less then  0.01 for both regions) in the cortex and hippocampus regions of PTZ-treated animals. Further, the antioxidant levels (SOD, catalase, GPx, GR, GSH, LPO) were altered significantly (p  less then  0.01 for all parameters), with reduced GABAA mRNA levels (p  less then  0.01) in the PTZ control compared with the normal control. Interestingly, co-administration of acteoside (25 mg/kg) (p  less then  0.01 for all parameters) has restored all the PTZ-induced alterations compared to PTZ-control. Moreover, the anti-PTZ action of acteoside was completely blocked in the presence of flumazenil, and thus confirmed the GABAergic mechanism behind the anticonvulsant activity of acteoside. Besides, actophotometer and rotarod tests have confirmed that the acteoside is free from central side effects like motor incoordination and locomotor deficits.Exercise exerts helpful effects in Parkinson's disease. link2 In this study, the 6-hydroxydopamine (6-OHDA) injection was used to investigate the effect of exercise on apomorphine-induced rotation and neurorestoration. Rats (n = 32) were divided into four groups (1) Saline+Noexercise (Sham); (2) 6-OHDA+Noexercise (6-OHDA); (3) Saline+Exercise (S+EXE), and (4) 6-OHDA+Exercise (6-OHDA+EXE). The rats were administered 8 μg 6-OHDA by injection into the right medial forebrain bundle. After 2 weeks, the exercise group was run (14 consecutive days, 30 min per day). One month after the surgery, following the injection of apomorphine, the 6-OHDA group displayed a significant increase in rotation and the 6-OHDA+EXE group showed a significant reduction of rotational asymmetry (P less then 0.001). 6-OHDA injection reduced the mRNA and protein expression of the AMP-activated protein kinase, brain-derived neurotropic factor, and tyrosine hydroxylase in relation to the Sham group and exercise increased these levels. Expression of the silent information regulator 2 homolog 1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha was unexpectedly enhanced in the 6-OHDA groups in relation to the Sham group. These findings suggest that the 6-OHDA injection increased the neurodegeneration and mitochondrial and behavioral dysfunctions and the treadmill running attenuated these disorders in the ipsilateral striatum of the 6-OHDA+EXE group.

This study's purpose was to develop a better understanding of the experiences of parents of children with achondroplasia and to provide qualitative evidence to support the development of a patient-reported outcome (PRO) measure of parent impacts.

Concept elicitation (CE) individual/focus group interviews were conducted with parents of children aged 2 to < 12years with achondroplasia in the United States and Spain. The qualitative analysis informed the PRO measure development. Cognitive debriefing (CD) interviews were conducted to ensure parent understanding and item relevance.

Thirty-six parents participated in individual/focus group CE interviews. The analysis identified parent impacts in four domains, including caretaking responsibilities, emotional well-being, family, and work, and results informed the development of the Achondroplasia Parent Experience Measure (APEM). Caretaking responsibilities included managing child's medical care (92%), helping child with self-care (67%), advocating for childalidate the measure.

The KLIK Patient-Reported Outcome Measure (PROM) portal is an evidence-based intervention implemented in clinical practice in > 25 Dutch hospitals for patients (children and adults) who regularly visit the outpatient clinic. Implementation science frameworks can be used to understand why implementation succeeded or failed, to structure barriers and enablers, and to develop implementation strategies to overcome barriers. This paper aimed to (A) retrospectively describe determinants of successful KLIK PROM implementation using the Consolidated Framework for Implementation Research (CFIR), and (B) identify current barriers and match implementation strategies.

(A) The KLIK implementation process was described retrospectively based on literature and experience, using the 39 CFIR constructs organized in five general domains intervention characteristics, outer setting, inner setting, characteristics of individuals, and implementation process. (B) The CFIR-Expert Recommendations for Implementing Change (ERIC) nsight into possible enablers and barriers.Primary immunodeficiencies (PIDs) are heterogeneous disorders, characterized by variable clinical and immunological features. National PID registries offer useful insights on the epidemiology, diagnosis, and natural history of these disorders. In 1999, the Italian network for primary immunodeficiencies (IPINet) was established. We report on data collected from the IPINet registry after 20 years of activity. A total of 3352 pediatric and adult patients affected with PIDs are registered in the database. In Italy, a regional distribution trend of PID diagnosis was observed. Based on the updated IUIS classification of 2019, PID distribution in Italy showed that predominantly antibody deficiencies account for the majority of cases (63%), followed by combined immunodeficiencies with associated or syndromic features (22.5%). The overall age at diagnosis was younger for male patients. The minimal prevalence of PIDs in Italy resulted in 5.1 per 100.000 habitants. Mortality was similar to other European registries (4.2%). Immunoglobulin replacement treatment was prescribed to less than one third of the patient cohort. Collectively, this is the first comprehensive description of the PID epidemiology in Italy.Embryonic development is of great importance because it determines congenital anomalies and influences their severity. However, little is known about the actual probabilities of success or failure and about the nature of early embryonic defects. Here, we propose that the analysis of embryonic mortality as a function of post-fertilization time provides a simple way to identify major defects. By reviewing the literature, we show that even small initial defects, e.g., spatial cellular asymmetries or irregularities in the timing of development, carry with them lethal effects in subsequent stages of embryogenesis. Although initially motivated by human study, in this contribution, we review the few embryonic mortality data available for farm animals and highlight zebrafish as a particularly suited organism for such a kind of study because embryogenesis can be followed from its very beginning and observed easily thanks to eggshell transparency. link3 In line with the few other farm animals for which data are available, we provide empirical evidence that embryonic mortality in zebrafish has a prominent peak shortly after fertilization. Indeed, we show how subsequent mortality rates decay according to a power law, supporting the role of the early embryonic mortality peak as a screening process rapidly removing defective embryos.