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Randomized, Double-Blind, Placebo-controlled Study of Brodalumab, a Human Anti–IL-17 Receptor Monoclonal Antibody, in Moderate to Severe Asthma
IL-17 signaling has been implicated in development and persistence of asthma. Cytokine-targeted strategies blocking IL-17 receptor signaling may be beneficial in asthma treatment.
To determine efficacy and safety of brodalumab, a human anti-IL-17 receptor A monoclonal antibody, in subjects with inadequately controlled moderate to severe asthma taking regular inhaled corticosteroids.
Three hundred two subjects were randomized to brodalumab (140, 210, or 280 mg) or placebo. Primary endpoint was change in Asthma Control Questionnaire (ACQ) score from baseline to Week 12. Secondary endpoints included FEV1, symptom scores, and symptom-free days. Prespecified subgroup analyses were conducted to identify potential responsive subpopulations. Analyses included randomized subjects receiving one or more doses of investigational product using last-observation-carried-forward imputation.
Demographics and baseline characteristics were generally balanced among groups (n = 302; n = 226 brodalumab). For the overall study population, no treatment differences were observed. Nine prespecified subgroups were examined without corrections for multiple testing. In only the high-reversibility subgroup (post-bronchodilator FEV1 improvement ≥ 20%; n = 112) was an ACQ change with nominal significance noted; ACQ responses were nominally significant in the 210-mg group (estimated treatment difference, 0.53) but not significant in the higher 280-mg group (estimated treatment difference, 0.38). Adverse events, generally balanced among groups, were most commonly asthma, upper respiratory tract infection, and injection site reaction.
Inhibition of IL-17 receptor A did not produce a treatment effect in subjects with asthma. The results of the high-reversibility subgroup analysis are of uncertain significance, requiring further study of brodalumab in this asthma subpopulation. Clinical trial registered with www.clinicaltrials.gov (NCT01199289).
Journal Article
Transcriptional and post-translational changes in the brain of mice deficient in cholesterol removal mediated by cytochrome P450 46A1 (CYP46A1)
Cytochrome P450 46A1 (CYP46A1) converts cholesterol to 24-hydroxycholesterol and thereby controls the major pathways of cholesterol removal from the brain. Cyp46a1-/- mice have a reduction in the rate of cholesterol biosynthesis in the brain and significant impairments to memory and learning. To gain insights into the mechanisms underlying Cyp46a1-/- phenotype, we used Cyp46a1-/- mice and quantified their brain sterol levels and the expression of the genes pertinent to cholesterol homeostasis. We also compared the Cyp46a1-/- and wild type brains for protein phosphorylation and ubiquitination. The data obtained enable the following inferences. First, there seems to be a compensatory upregulation in the Cyp46a1-/- brain of the pathways of cholesterol storage and CYP46A1-independent removal. Second, transcriptional regulation of the brain cholesterol biosynthesis via sterol regulatory element binding transcription factors is not significantly activated in the Cyp46a1-/- brain to explain a compensatory decrease in cholesterol biosynthesis. Third, some of the liver X receptor target genes (Abca1) are paradoxically upregulated in the Cyp46a1-/- brain, possibly due to a reduced activation of the small GTPases RAB8, CDC42, and RAC as a result of a reduced phosphorylation of RAB3IP and PAK1. Fourth, the phosphorylation of many other proteins (a total of 146) is altered in the Cyp46a1-/- brain, including microtubule associated and neurofilament proteins (the MAP and NEF families) along with proteins related to synaptic vesicles and synaptic neurotransmission (e.g., SLCs, SHANKs, and BSN). Fifth, the extent of protein ubiquitination is increased in the Cyp46a1-/- brain, and the affected proteins pertain to ubiquitination (UBE2N), cognition (STX1B and ATP1A2), cytoskeleton function (TUBA1A and YWHAZ), and energy production (ATP1A2 and ALDOA). The present study demonstrates the diverse potential effects of CYP46A1 deficiency on brain functions and identifies important proteins that could be affected by this deficiency.
Journal Article
Dry eye disease in mice activates adaptive corneal epithelial regeneration distinct from constitutive renewal in homeostasis
Many epithelial compartments undergo constitutive renewal in homeostasis but activate unique regenerative responses following injury. The clear corneal epithelium is crucial for vision and is renewed from limbal stem cells (LSCs). Using single-cell RNA sequencing, we profiled the mouse corneal epithelium in homeostasis, aging, diabetes, and dry eye disease (DED), where tear deficiency predisposes the cornea to recurrent injury. In homeostasis, we capture the transcriptional states that accomplish continuous tissue turnover. We leverage our dataset to identify candidate genes and gene networks that characterize key stages across homeostatic renewal, including markers for LSCs. In aging and diabetes, there were only mild changes with <15 dysregulated genes. The constitutive cell types that accomplish homeostatic renewal were conserved in DED but were associated with activation of cell states that comprise “adaptive regeneration.” We provide global markers that distinguish cell types in homeostatic renewal vs. adaptive regeneration and markers that specifically define DED-elicited proliferating and differentiating cell types. We validate that expression of SPARC, a marker of adaptive regeneration, is also induced in corneal epithelial wound healing and accelerates wound closure in a corneal epithelial cell scratch assay. Finally, we propose a classification system for LSC markers based on their expression fidelity in homeostasis and disease. This transcriptional dissection uncovers the dramatically altered transcriptional landscape of the corneal epithelium in DED, providing a framework and atlas for future study of these ocular surface stem cells in health and disease.
Journal Article
SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration
Leber congenital amaurosis type nine is an autosomal recessive retinopathy caused by mutations of the NAD + synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1, patients do not manifest pathologies other than retinal degeneration. Here we demonstrate that widespread NMNAT1 depletion in adult mice mirrors the human pathology, with selective loss of photoreceptors highlighting the exquisite vulnerability of these cells to NMNAT1 loss. Conditional deletion demonstrates that NMNAT1 is required within the photoreceptor. Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, highlighting an unexpected shared mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway and identifies SARM1 as a therapeutic candidate for retinopathies.
Journal Article
Combined SIRT3 and SIRT5 deletion is associated with inner retinal dysfunction in a mouse model of type 1 diabetes
Diabetic retinopathy (DR) is a major cause of blindness in working adults in the industrialized world. In addition to vision loss caused by macular edema and pathological angiogenesis, DR patients often exhibit neuronal dysfunction on electrophysiological testing, suggesting that there may be an independent neuronal phase of disease that precedes vascular disease. Given the tremendous metabolic requirements of the retina and photoreceptors in particular, we hypothesized that derangements in metabolic regulation may accelerate retinal dysfunction in diabetes. As such, we induced hyperglycemia with streptozotocin in mice with monoallelic
Nampt
deletion from rod photoreceptors, mice lacking SIRT3, and mice lacking SIRT5 and tested multiple components of retinal function with electroretinography. None of these mice exhibited accelerated retinal dysfunction after induction of hyperglycemia, consistent with normal-appearing retinal morphology in hyperglycemic
Sirt3
−/−
or
Sirt5
−/−
mice. However, mice lacking both SIRT3 and SIRT5 (
Sirt3
−/−
Sirt5
−/−
mice) exhibited significant evidence of inner retinal dysfunction after induction of hyperglycemia compared to hyperglycemic littermate controls, although this dysfunction was not accompanied by gross morphological changes in the retina. These results suggest that SIRT3 and SIRT5 may be involved in regulating neuronal dysfunction in DR and provide a foundation for future studies investigating sirtuin-based therapies.
Journal Article
The surgical resident experience in serious illness communication: A qualitative needs assessment with proposed solutions
Serious illness communication skills are important tools for surgeons, but training in residency is limited.
Thirteen senior surgical residents at an academic center were interviewed about their experiences with serious illness communication. Conventional content analysis was performed using established communication frameworks and inductive development of themes.
Residents had frequent conversations and employed known communication strategies. Three themes highlighted challenges they face. Illness severity included factors attributed to the illness that made serious illness communication more challenging: symptoms, poor prognosis, and urgency. Knowledge and feelings included the factual understanding and emotional experience of residents, patients, and families. Academic structure included hierarchy and the residents’ dual role as learners and teachers. On reflection, residents identified needing greater experiential practice, analogous to learning procedural skills.
Surgical residents regularly face serious illness conversations with little training beyond observation of role models. Dedicated training may help meet this need.
•Surgical residents face serious illness communication frequently.•Challenges arise from illness severity, knowledge and feelings, and hierarchy.•Residents receive little training besides observation of role models.•Residents find communication skills akin to procedural skills and can teach others.
Journal Article
Enhancing robotic efficiency through the eyes of robotic surgeons: sub-analysis of the expertise in perception during robotic surgery (ExPeRtS) study
BackgroundRobotic technology affords surgeons many novel and useful features, but two stereotypes continue to prevail: robotic surgery is expensive and inefficient. To identify educational opportunities and improve operative efficiency, we analyzed expert commentary on videos of robotic surgery.MethodsExpert robotic surgeons, identified through high case volumes and contributions to the surgical literature, reviewed eight anonymous video clips portraying key portions of two robotic general surgery procedures. While watching, surgeons commented on what they saw on the screen. All interactions with participants were in person, recorded, transcribed, and subsequently analyzed. Using content analysis, researchers double-coded each transcript applying a consensus developed codebook.ResultsSeventeen surgeons participated. The average participant was male (82.4%), 47 (SD = 6.6) years old, had 13.2 (SD = 8.23) years of teaching experience, worked in urban academic hospitals (64.7%) and had performed 643 (SD = 467) robotic operations at the time of interviews. Emphasis on efficiency (or lack thereof) surfaced across three main themes: overall case progression, robotic capabilities, and instrumentation. Experts verbally rewarded purposeful and “ergonomically sound” movements while language reflecting impatience with repetitive and indecisive movements was attributed to presumed inexperience. Efficient robotic capabilities included enhanced visualization, additional robotic arms to improve exposure, and wristed instruments. Finally, experts discussed instrument selection with regards to energy modality, safety features, cost, and versatility.ConclusionThis study highlights three areas for improved efficiency: case progression, robotic capabilities, and instrumentation. Development of education materials within these themes could help surgical educators overcome one of robotic technology’s persistent challenges.
Journal Article