The BT-40 low-grade childhood astrocytoma xenograft model expresses mutated BRAF(V600E) and is highly sensitive to the MEK inhibitor selumetinib (AZD6244). In this study, we developed and ...characterized selumetinib resistance and explored approaches to circumventing the mechanisms of acquired resistance.
BT-40 xenografts were selected in vivo for selumetinib resistance. Resistant tumors were obtained and characterized, as were tumors that reverted to sensitivity. Characterization included expression profiling, assessment of MEK signature and compensatory pathways, MEK inhibition, BRAF expression, and cytokine levels. Combination treatment of BT-40/AZD-resistant tumors with the MEK inhibitor and a STAT3 inhibitor (LLL12) was assessed.
Resistance was unstable, tumors reverting to selumetinib sensitivity when passaged in untreated mice, and MEK was equally inhibited in sensitive and resistant tumors by selumetinib. Drug resistance was associated with an enhanced MEK signature and increased interleukin (IL)-6 and IL-8 expression. Selumetinib treatment induced phosphorylation of STAT3 (Y705) only in resistant xenografts, and similar results were observed in BRAF(V600E) astrocytic cell lines intrinsically resistant to selumetinib. Treatment of BT-40-resistant tumors with selumetinib or LLL12 had no significant effect, whereas combined treatment induced complete regressions of BT-40/AZD-resistant xenografts.
Resistance to selumetinib selected in vivo in BT-40 tumor xenografts was unstable. In resistant tumors, selumetinib activated STAT3, and combined treatment with selumetinib and LLL12 induced complete responses in resistant BT-40 tumors. These results suggest dual targeting BRAF (V600E) signaling and STAT3 signaling may be effective in selumetinib-resistant tumors or may retard or prevent onset of resistance.
The objective of this study was to document pulse oximeter saturation levels achieved in the first 4 weeks of life in infants who were born at < 28 weeks' gestation, compared with the levels that ...were targeted by local policy, and examine factors that are associated with compliance with the target range.
Infants who were < 28 weeks' gestation and < or = 96 hours of age were enrolled in a prospective, multicenter cohort study. Oximetry data were collected with masked signal-extraction oximeters for a 72-hour period in each of the first 4 weeks of life. Data were compared with the pulse oximeter saturation target range prescribed by local institutional policy. Factors that were associated with intended range compliance were identified with hierarchical modeling.
Fourteen centers from 3 countries enrolled 84 infants with mean +/- SD birth weight of 863 +/- 208 g and gestational age of 26 +/- 1.4 weeks. Oxygen saturation policy limits ranged between 83% and 92% for lower limits and 92% and 98% for upper limits. For infants who received respiratory support, median pulse oximeter saturation level achieved was 95%. Center-specific medial levels were within the intended range at 12 centers. Centers maintained infants within their intended range 16% to 64% of the time but were above range 20% to 73% of the time. In hierarchical modeling, wider target ranges, higher target range upper limits, presence of a policy of setting oximeter alarms close to the target range limits, and lower gestational age were associated with improved target range compliance.
Success with maintaining the intended pulse oximeter saturation range varied substantially among centers, among patients within centers, and for individual patients over time. Most noncompliance was above the intended range. Methods for improving compliance and the effect of improved compliance on neonatal outcomes require additional research.
Objective: This study aims to appraise recommendations from an expert panel of surgical educators on optimizing surgical education and training in the setting of contemporary challenges. Background: ...The Blue Ribbon Committee (BRC II), a group of surgical educators, was convened to make recommendations to optimize surgical training considering the current changes in the landscape of surgical education. Surgical trainees were recruited to assess their impressions of the recommendations. Methods: A mixed-methods study design was employed, with a survey, followed by focus group interviews. Participating residents and fellows were recruited through a purposeful sampling approach. Descriptive statistics were applied to analyze the survey data, and a thematic data analysis on interview transcripts was employed. Results: The majority of trainee respondents (n=16) thought that all of the subcommittee recommendations should be included in the final BRC II recommendations and paper. According to the interviews, overall, the feedback from the trainees was positive, with particular excitement around work-life integration, education support and faculty development, and funding pitfalls. Some themes about concerns included a lack of clarity about the recommendations, concern about some recommendations being in conflict with one another, and a disconnect between the initial BRC II survey and the subsequent recommendations. Conclusions: The residents gathered for this focus group were encouraged by the thought, effort, and intention that gathered the surgical leaders across the country to make the recommendations. While there were areas the trainees wanted clarity on, the overall opinion was in agreement with the recommendations.
Certolizumab Pegol for the Treatment of Crohn's Disease Sandborn, William J; Feagan, Brian G; Stoinov, Simeon ...
New England journal of medicine/The New England journal of medicine,
07/2007, Letnik:
357, Številka:
3
Journal Article
Recenzirano
Odprti dostop
In this randomized trial involving 662 patients with moderate-to-severe Crohn's disease, 23% of patients who were treated with certolizumab pegol (a pegylated humanized Fab′ fragment that binds tumor ...necrosis factor) had a response at both 6 and 26 weeks, as compared with 16% of patients treated with placebo (P=0.02). Rates of remission did not differ significantly between the two study groups. Serious infections were reported in 2% of patients in the certolizumab group and in less than 1% in the placebo group.
In patients with Crohn's disease, 23% of those who were treated with certolizumab pegol had a response at both 6 and 26 weeks, as compared with 16% of those given placebo.
Tumor necrosis factor α (TNF-α) is important in the pathogenesis of Crohn's disease.
1
Accordingly, infliximab and adalimumab, IgG1 monoclonal antibodies that bind TNF, are effective therapy for patients with active Crohn's disease who have not received anti–TNF-α therapy.
2
,
3
Scheduled maintenance therapy is also effective for patients who have a response to induction therapy with these agents.
4
,
5
However, the long-term efficacy of such drugs in patients who were not selected for their response to anti-TNF therapy is unknown. Specifically, no TNF antagonist has been evaluated in an induction trial extending beyond 12 weeks in patients with active Crohn's disease. . . .
To expand our insight into cardiac development, a comparative DNA microarray analysis was performed using tissues from the atrioventricular junction (AVJ) and ventricular chambers of mouse hearts at ...embryonic day (ED) 10.5–11.0. This comparison revealed differential expression of approximately 200 genes, including cartilage link protein 1 (Crtl1). Crtl1 stabilizes the interaction between hyaluronan (HA) and versican, two extracellular matrix components essential for cardiac development. Immunohistochemical studies showed that, initially, Crtl1, versican, and HA are co-expressed in the endocardial lining of the heart, and in the endocardially derived mesenchyme of the AVJ and outflow tract (OFT). At later stages, this co-expression becomes restricted to discrete populations of endocardially derived mesenchyme. Histological analysis of the Crtl1-deficient mouse revealed a spectrum of cardiac malformations, including AV septal and myocardial defects, while expression studies showed a significant reduction in versican levels. Subsequent analysis of the hdf mouse, which carries an insertional mutation in the versican gene (CSPG2), demonstrated that haploinsufficient versican mice display septal defects resembling those seen in Crtl1−/− embryos, suggesting that reduced versican expression may contribute to a subset of the cardiac abnormalities observed in the Crtl1−/− mouse. Combined, these findings establish an important role for Crtl1 in heart development.
Mild traumatic brain injury (mTBI) remains a diagnostic challenge and therefore strategies for objective assessment of neurological function are key to limiting long-term sequelae. Current assessment ...methods are not optimal in austere environments such as athletic fields; therefore, we developed an immersive tool, the Display Enhanced Testing for Cognitive Impairment and mTBI (DETECT) platform, for rapid objective neuropsychological (NP) testing. The objectives of this study were to assess the ability of DETECT to accurately identify neurocognitive deficits associated with concussion and evaluate the relationship between neurocognitive measures and subconcussive head impacts. DETECT was used over a single season of two high school and two college football teams. Study participants were instrumented with Riddell Head Impact Telemetry (HIT) sensors and a subset tested with DETECT immediately after confirmed impacts for different combinations of linear and rotational acceleration. A total of 123 athletes were enrolled and completed baseline testing. Twenty-one players were pulled from play for suspected concussion and tested with DETECT. DETECT was 86.7% sensitive (95% confidence interval CI: 59.5%, 98.3%) and 66.7% specific (95% CI: 22.3%, 95.7%) in correctly identifying athletes with concussions (15 of 21). Weak but significant correlations were found between complex choice response time (processing speed and divided attention) and both linear (Spearman rank correlation coefficient 0.262,
p
= 0.02) and rotational (Spearman coefficient 0.254,
p
= 0.03) acceleration on a subset of 76 players (113 DETECT tests) with no concussion symptoms. This study demonstrates that DETECT confers moderate to high sensitivity in identifying acute cognitive impairment and suggests that football impacts that do not result in concussion may negatively affect cognitive performance immediately following an impact. Specificity, however, was not optimal and points to the need for additional studies across multiple neurological domains. Given the need for more objective concussion screening in triage situations, DETECT may provide a solution for mTBI assessment.
Saponins are potent and safe vaccine adjuvants, but their mechanisms of action remain incompletely understood. Here, we explored the properties of several saponin formulations, including ...immune-stimulatory complexes (ISCOMs) formed by the self-assembly of saponin and phospholipids in the absence or presence of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). We found that MPLA self-assembles with saponins to form particles physically resembling ISCOMs, which we termed saponin/MPLA nanoparticles (SMNP). Saponin-containing adjuvants exhibited distinctive mechanisms of action, altering lymph flow in a mast cell–dependent manner and promoting antigen entry into draining lymph nodes. SMNP was particularly effective, exhibiting even greater potency than the compositionally related adjuvant AS01
in mice, and primed robust germinal center B cell, T
, and HIV tier 2 neutralizing antibodies in nonhuman primates. Together, these findings shed new light on mechanisms by which saponin adjuvants act to promote the immune response and suggest that SMNP may be a promising adjuvant in the setting of HIV, SARS-CoV-2, and other pathogens.
Components of the Reelin‐signaling pathway are highly expressed in embryos and regulate neuronal positioning, whereas these molecules are expressed at low levels in adults and modulate synaptic ...plasticity. Reelin binds to Apolipoprotein E receptor 2 and Very‐low‐density lipoprotein receptors, triggers the phosphorylation of Disabled‐1 (Dab1), and initiates downstream signaling. The expression of Dab1 marks neurons that potentially respond to Reelin, yet phosphorylated Dab1 is difficult to detect due to its rapid ubiquitination and degradation. Here we used adult mice with a lacZ gene inserted into the dab1 locus to first verify the coexpression of β‐galactosidase (β‐gal) in established Dab1‐immunoreactive neurons and then identify novel Dab1‐expressing neurons. Both cerebellar Purkinje cells and spinal sympathetic preganglionic neurons have coincident Dab1 protein and β‐gal expression in dab1lacZ/+ mice. Adult pyramidal neurons in cortical layers II–III and V are labeled with Dab1 and/or β‐gal and are inverted in the dab1lacZ/lacZ neocortex, but not in the somatosensory barrel fields. Novel Dab1 expression was identified in GABAergic medial septum/diagonal band projection neurons, cerebellar Golgi interneurons, and small neurons in the deep cerebellar nuclei. Adult somatic motor neurons also express Dab1 and show ventromedial positioning errors in dab1‐null mice. These findings suggest that: (i) Reelin regulates the somatosensory barrel cortex differently than other neocortical areas, (ii) most Dab1 medial septum/diagonal band neurons are probably GABAergic projection neurons, and (iii) positioning errors in adult mutant Dab1‐labeled neurons vary from subtle to extensive.
Components of the Reelin‐signaling pathway are highly expressed in embryos and regulate neuronal positioning, whereas these molecules are expressed at low levels in adults and modulate synaptic plasticity. Dab1 expression in adult neocortex is concentrated in laminae II, III, and V, and includes the corticospinal tract neurons.
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