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"Thomas, Sherry (Sherry M.)"
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The immortal heights
When Bane, the monstrous tyrant who bestrides the entire mage world, demands that Titus hand over Iolanthe or watch as his entire realm is destroyed in a deadly rampage, Iolanthe and Titus decide to infiltrate Bane's crypt, the most ferociously guarded fortress in Atlantis.
Book
Cancer Regression and Autoimmunity Induced by Cytotoxic T Lymphocyte-Associated Antigen 4 Blockade in Patients with Metastatic Melanoma
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical immunoregulatory molecule (expressed on activated T cells and a subset of regulatory T cells) capable of down-regulating T cell activation. Blockade of CTLA-4 has been shown in animal models to improve the effectiveness of cancer immunotherapy. We thus treated 14 patients with metastatic melanoma by using serial i.v. administration of a fully human anti-CTLA-4 antibody (MDX-010) in conjunction with s.c. vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-288(288V). This blockade of CTLA-4 induced grade III/IV autoimmune manifestations in six patients (43%), including dermatitis, enterocolitis, hepatitis, and hypophysitis, and mediated objective cancer regression in three patients (21%; two complete and one partial responses). This study establishes CTLA-4 as an important molecule regulating tolerance to \"self\" antigens in humans and suggests a role for CTLA-4 blockade in breaking tolerance to human cancer antigens for cancer immunotherapy.
Journal Article
The burning sky
\"A young elemental mage named Iaolanthe Seabourne discovers her shocking power and destiny when she is thrown together with a deposed prince to lead a rebellion against a tyrant\"-- Provided by publisher.
Book
Cellular Senescence Is a Central Driver of Cognitive Disparities in Aging
Cognitive function in aging is heterogeneous: while some older individuals develop significant impairments and dementia, others remain resilient and retain cognitive function throughout their lifespan. The molecular mechanisms that underlie these divergent cognitive trajectories, however, remain largely unresolved. Here, we utilized a high‐resolution home‐cage‐based cognitive testing paradigm to delineate mechanisms that contribute to age‐related cognitive heterogeneity. We cognitively stratified aged C57Bl/6N male mice by cognitive performance into intact (resilient) or impaired subgroups based on young performance benchmarks. Cognitively impaired males exhibited marked reactive gliosis in the hippocampus, characterized by microglial activation, increased astrocyte arborization, and elevated transcriptional expression of reactivity markers. These changes were accompanied by increased markers of cellular senescence and the associated senescence‐associated secretory phenotype (SASP) in impaired animals, including p16INK4a, SASP factors (e.g., Il‐6, Il‐1b, Mmp3), and SA‐β‐gal staining in the hippocampus. Notably, clearance of senescent cells using senolytic agents dasatinib and quercetin ameliorated the heterogeneity in cognitive performance observed with age and attenuated impairment‐associated gliosis, senescence markers, and mitochondrial dysfunction. Aged female mice could not be stratified into subgroups yet showed increased neuroinflammation with age that was not resolved with senolytics. Collectively, our findings implicate cellular senescence as a central driver of sex‐specific neuroinflammation that drives divergent cognitive trajectories in aging. Thus, we demonstrate that senolytic treatment is an effective therapeutic strategy to mitigate cognitive impairment by reducing neuroinflammation and associated metabolic disturbances. The molecular underpinnings of divergent cognitive trajectories in aging remain unresolved. Using high‐resolution behavioral testing to cognitively stratify aged male mice into ‘intact’ and ‘impaired’ subgroups, we show that reactive gliosis and cellular senescence are key determinants of disparities in cognitive function with age.
Journal Article
The art of theft
\"As \"Sherlock Holmes, consulting detective,\" Charlotte Holmes has solved murders and found missing individuals. But she has never stolen a priceless artwork--or rather, made away with the secrets hidden behind a much-coveted canvas. But Mrs. Watson is desperate to help her old friend recover those secrets and Charlotte finds herself involved in a fever-paced scheme to infiltrate a glamorous Yuletide ball where the painting is one handshake away from being sold and the secrets a bare breath from exposure. Her dear friend Lord Ingram, her sister Livia, Livia's admirer Stephen Marbleton--everyone pitches in to help and everyone has a grand time. But nothing about this adventure is what it seems and disaster is biding time on the grounds of a glittering French chateau, waiting only for Charlotte to make a single mistake\"-- Provided by publisher.
Book
Delta-like 4 is required for pulmonary vascular arborization and alveolarization in the developing lung
The molecular mechanisms by which endothelial cells (ECs) regulate pulmonary vascularization and contribute to alveolar epithelial cell development during lung morphogenesis remain unknown. We tested the hypothesis that delta-like 4 (DLL4), an EC Notch ligand, is critical for alveolarization by combining lung mapping and functional studies in human tissue and DLL4-haploinsufficient mice ( Dll4 +/lacz ). DLL4 expressed in a PECAM-restricted manner in capillaries, arteries, and the alveolar septum from the canalicular to alveolar stage in mice and humans. Dll4 haploinsufficiency resulted in exuberant, nondirectional vascular patterning at E17.5 and P6, followed by smaller capillaries and fewer intermediate blood vessels at P14. Vascular defects coincided with polarization of lung EC expression toward JAG1-NICD-HES1 signature and decreased tip cell-like ( Car4 ) markers. Dll4 +/lacZ mice had impaired terminal bronchiole development at the canalicular stage and impaired alveolarization upon lung maturity. We discovered that alveolar type I cell ( Aqp5 ) markers progressively decreased in Dll4 +/lacZ mice after birth. Moreover, in human lung EC, DLL4 deficiency programmed a hypersprouting angiogenic phenotype cell autonomously. In conclusion, DLL4 is expressed from the canalicular to alveolar stage in mice and humans, and Dll4 haploinsufficiency programs dysmorphic microvascularization, impairing alveolarization. Our study reveals an obligate role for DLL4-regulated angiogenesis in distal lung morphogenesis.
Journal Article
The hollow of fear
\"Under the cover of 'Sherlock Holmes, consulting detective,' Charlotte Holmes puts her extraordinary powers of deduction to good use. Aided by the capable Mrs. Watson, Charlotte draws those in need to her and makes it her business to know what other people don't. When the estranged wife of her dear friend Lord Ingram is discovered dead on his estate, all signs point to him as the murderer. With Scotland Yard closing in, Charlotte goes under disguise to find out the truth\"-- Provided by publisher.
Book
Efficacy and safety after cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib (MK-0859) in patients with primary hypercholesterolemia or mixed hyperlipidemia
This report describes the lipid and safety data collected during an off-drug period that followed 8 weeks of treatment with the cholesteryl ester transfer protein inhibitor, anacetrapib (ANA). A total of 589 patients with primary hypercholesterolemia or mixed hyperlipidemia were randomized to placebo, atorvastatin (ATV) 20 mg, and varying doses of ANA, provided as monotherapy or coadministered with ATV 20 mg daily. Patients were treated for 8 weeks, followed by an 8-week follow-up period, during which ANA was switched to placebo. At week 16 (8 weeks after ANA was stopped), persistent reductions in low-density lipoprotein cholesterol (LDL-C) were evident for the monotherapy groups receiving ANA 150 and 300 mg (−9.3% and −15.3%, respectively), and residual increases in high-density lipoprotein cholesterol (HDL-C) were observed for the monotherapy groups receiving ANA 40 mg (18.6%), 150 mg (40.5%), and 300 mg (43.4%). The effects on apolipoprotein B and apolipoprotein A-I were consistent with the changes observed for LDL-C and HDL-C, respectively. Corresponding residual changes in LDL-C and HDL-C were also noted in the ATV coadministration groups at the similar doses of ANA compared with ATV 20 mg alone. Residual plasma drug levels accompanied by reductions in cholesteryl ester transfer protein activity were observed at week 16 and may account for the alterations in plasma lipids 8 weeks after cessation of ANA.
Journal Article
A study in scarlet women
\"USA Today bestselling author Sherry Thomas turns the story of the renowned Sherlock Holmes upside down... With her inquisitive mind, Charlotte Holmes has never felt comfortable with the demureness expected of the fairer sex in upper class society. But she never thought that she would become a social pariah, an outcast fending for herself on the mean streets of London. When the city is struck by a trio of unexpected deaths and suspicion falls on her sister and her father, Charlotte is desperate to find the true culprits and clear the family name. She'll have help from friends new and old--a kind-hearted widow, a police inspector, and a man who has long loved her. But in the end, it will be up to Charlotte, under the assumed name Sherlock Holmes, to challenge society's expectations and match wits against an unseen mastermind\"-- Provided by publisher.
Book
Guidelines for Neuroprognostication in Comatose Adult Survivors of Cardiac Arrest
Background
Among cardiac arrest survivors, about half remain comatose 72 h following return of spontaneous circulation (ROSC). Prognostication of poor neurological outcome in this population may result in withdrawal of life-sustaining therapy and death. The objective of this article is to provide recommendations on the reliability of select clinical predictors that serve as the basis of neuroprognostication and provide guidance to clinicians counseling surrogates of comatose cardiac arrest survivors.
Methods
A narrative systematic review was completed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Candidate predictors, which included clinical variables and prediction models, were selected based on clinical relevance and the presence of an appropriate body of evidence. The Population, Intervention, Comparator, Outcome, Timing, Setting (PICOTS) question was framed as follows: “When counseling surrogates of comatose adult survivors of cardiac arrest, should [predictor, with time of assessment if appropriate] be considered a reliable predictor of poor functional outcome assessed at 3 months or later?” Additional full-text screening criteria were used to exclude small and lower-quality studies. Following construction of the evidence profile and summary of findings, recommendations were based on four GRADE criteria: quality of evidence, balance of desirable and undesirable consequences, values and preferences, and resource use. In addition, good practice recommendations addressed essential principles of neuroprognostication that could not be framed in PICOTS format.
Results
Eleven candidate clinical variables and three prediction models were selected based on clinical relevance and the presence of an appropriate body of literature. A total of 72 articles met our eligibility criteria to guide recommendations. Good practice recommendations include waiting 72 h following ROSC/rewarming prior to neuroprognostication, avoiding sedation or other confounders, the use of multimodal assessment, and an extended period of observation for awakening in patients with an indeterminate prognosis, if consistent with goals of care. The bilateral absence of pupillary light response > 72 h from ROSC and the bilateral absence of N20 response on somatosensory evoked potential testing were identified as reliable predictors. Computed tomography or magnetic resonance imaging of the brain > 48 h from ROSC and electroencephalography > 72 h from ROSC were identified as moderately reliable predictors.
Conclusions
These guidelines provide recommendations on the reliability of predictors of poor outcome in the context of counseling surrogates of comatose survivors of cardiac arrest and suggest broad principles of neuroprognostication. Few predictors were considered reliable or moderately reliable based on the available body of evidence.
Journal Article