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1.
Cureus ; 15(11): e48222, 2023 Nov.
Article in English | MEDLINE | ID: mdl-38054159

ABSTRACT

Febrile infection-related epilepsy syndrome (FIRES) is a rare epileptic syndrome characterized by new-onset refractory status epilepticus preceded by a febrile illness. Limited literature exists regarding the relationship between primary immunodeficiencies and immune-mediated epilepsy, and the relationship between new-onset refractory status epilepticus and common variable immunodeficiency (CVID) is not well-understood. We present a case of a 21-year-old female with a history of recurrent sinus infections, asthma, thrombocytopenia, atrioventricular nodal reentrant tachycardia, and neonatal seizures who presented with fever and new-onset status epilepticus. She was ultimately diagnosed with a heterozygous variant in TNFRSF13B c.311G>A (p.Cys104Tyr), which encodes for a tumor necrosis factor receptor implicated in CVID.

2.
Curr Opin Gastroenterol ; 37(4): 390-396, 2021 07 01.
Article in English | MEDLINE | ID: mdl-34059605

ABSTRACT

PURPOSE OF REVIEW: The purpose of this review is to provide the current understanding of the role of allergens/antigens, the use of allergy testing, and to elucidate the role of the allergist in the management of eosinophilic esophagitis (EoE). RECENT FINDINGS: EoE is a T2 immune disorder that is part of the atopic march. EoE patients commonly have multiple concurrent allergic disorders. Recent studies demonstrate that, like other allergic diseases, epithelial barrier dysfunction plays a key role in EoE pathogenesis. Aero- and food allergens have been identified as EoE triggers. EoE management includes the assessment and avoidance of its instigating antigens. Due to the integrated T2 immune response in an allergic individual, proper EoE care should include the control of underlying atopic disorders. EoE is a complex disease that is optimally managed by a multidisciplinary approach. SUMMARY: This review provides an update on the role of the allergist in the clinical management of EoE.


Subject(s)
Eosinophilic Esophagitis , Food Hypersensitivity , Allergens , Allergists , Eosinophilic Esophagitis/diagnosis , Eosinophilic Esophagitis/etiology , Eosinophilic Esophagitis/therapy , Food Hypersensitivity/complications , Food Hypersensitivity/therapy , Humans
3.
Onco Targets Ther ; 12: 1455-1463, 2019.
Article in English | MEDLINE | ID: mdl-30863113

ABSTRACT

Pancreatic cancer is a highly lethal disease, where the mortality closely matches increasing incidence. Pancreatic ductal adenocarcinoma (PDAC) is the most common histologic type that tends to metastasize early in tumor progression. For metastatic PDAC, gemcitabine had been the mainstay treatment for the past three decades. The treatment landscape has changed since 2010, and current first-line chemotherapy includes triplet drugs like FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin), and doublet agents like nab-paclitaxel and gemcitabine. Nanoliposomal encapsulated irinotecan (nal-IRI) was developed as a novel formulation to improve drug delivery, effectiveness, and limit toxicities. Nal-IRI, in combination with leucovorin-modulated fluorouracil (5-FU/LV), was found in a large randomized phase III clinical trial (NAPOLI-1) to significantly improve overall survival in patients who progressed on gemcitabine-based therapy. This review will focus on the value of using nal-IRI, toxicities, recent clinical experiences, and tools to improve patient outcomes in this setting.

4.
Chembiochem ; 15(8): 1131-1144, 2014 May 26.
Article in English | MEDLINE | ID: mdl-24777910

ABSTRACT

The C1 domain, which represents the recognition motif on protein kinase C for the lipophilic second messenger diacylglycerol and its ultrapotent analogues, the phorbol esters, has emerged as a promising therapeutic target for cancer and other indications. Potential target selectivity is markedly enhanced both because binding reflects ternary complex formation between the ligand, C1 domain, and phospholipid, and because binding drives membrane insertion of the C1 domain, permitting aspects of the C1 domain surface outside the binding site, per se, to influence binding energetics. Here, focusing on charged residues identified in atypical C1 domains which contribute to their loss of ligand binding activity, we showed that increasing charge along the rim of the binding cleft of the protein kinase C δ C1 b domain raises the requirement for anionic phospholipids. Correspondingly, it shifts the selectivity of C1 domain translocation to the plasma membrane, which is more negatively charged than internal membranes. This change in localization is most pronounced in the case of more hydrophilic ligands, which provide weaker membrane stabilization than do the more hydrophobic ligands and thus contributes an element to the structure-activity relations for C1 domain ligands. Coexpressing pairs of C1-containing constructs with differing charges each expressing a distinct fluorescent tag provided a powerful tool to demonstrate the effect of increasing charge in the C1 domain.


Subject(s)
Cell Membrane/metabolism , Protein Kinase C-delta/chemistry , Protein Kinase C-delta/metabolism , Amino Acid Motifs , Binding Sites , Cell Line, Tumor , Cell Membrane/chemistry , Humans , Ligands , Protein Kinase C-delta/genetics , Protein Structure, Tertiary , Static Electricity , Structure-Activity Relationship
5.
Anal Biochem ; 442(1): 97-103, 2013 Nov 01.
Article in English | MEDLINE | ID: mdl-23896461

ABSTRACT

Precise and accurate quantification of protein expression levels in a complex biological setting is challenging. Here, we describe a method for absolute quantitation of endogenous proteins in cell lysates using an automated capillary immunoassay system, the size-based Simple Western system (recently developed by ProteinSimple). The method was able to accurately measure the absolute amounts of target proteins at picogram or sub-picogram levels per nanogram of cell lysates. The measurements were independent of the cell matrix or the cell lysis buffer and were not affected by different antibody affinities for their specific epitopes. We then applied this method to quantitate absolute levels of expression of protein kinase C (PKC) isoforms in LNCaP and U937 cells, two cell lines used extensively for probing the downstream biological responses to PKC targeted ligands. Our absolute quantitation confirmed the predominance of PKCδ in both cells, supporting the important functional role of this PKC isoform in these cell lines. The method described here provides an approach to accurately quantitate levels of protein expression and correlate protein level with function. In addition to enhanced accuracy relative to conventional Western analysis, it circumvents the distortions inherent in comparison with signal intensities from different antibodies with different affinities.


Subject(s)
Immunoassay/methods , Protein Kinase C/analysis , Automation , Blotting, Western , Cell Line, Tumor , Humans , Isoenzymes/analysis , Isoenzymes/metabolism , Protein Kinase C/metabolism , Recombinant Proteins/analysis , Recombinant Proteins/metabolism
6.
J Biol Chem ; 287(16): 13137-58, 2012 Apr 13.
Article in English | MEDLINE | ID: mdl-22351766

ABSTRACT

C1 domains, the recognition motif of the second messenger diacylglycerol and of the phorbol esters, are classified as typical (ligand-responsive) or atypical (not ligand-responsive). The C1 domain of Vav1, a guanine nucleotide exchange factor, plays a critical role in regulation of Vav activity through stabilization of the Dbl homology domain, which is responsible for exchange activity of Vav. Although the C1 domain of Vav1 is classified as atypical, it retains a binding pocket geometry homologous to that of the typical C1 domains of PKCs. This study clarifies the basis for its failure to bind ligands. Substituting Vav1-specific residues into the C1b domain of PKCδ, we identified five crucial residues (Glu(9), Glu(10), Thr(11), Thr(24), and Tyr(26)) along the rim of the binding cleft that weaken binding potency in a cumulative fashion. Reciprocally, replacing these incompatible residues in the Vav1 C1 domain with the corresponding residues from PKCδ C1b (δC1b) conferred high potency for phorbol ester binding. Computer modeling predicts that these unique residues in Vav1 increase the hydrophilicity of the rim of the binding pocket, impairing membrane association and thereby preventing formation of the ternary C1-ligand-membrane binding complex. The initial design of diacylglycerol-lactones to exploit these Vav1 unique residues showed enhanced selectivity for C1 domains incorporating these residues, suggesting a strategy for the development of ligands targeting Vav1.


Subject(s)
Diglycerides/metabolism , Phorbol Esters/metabolism , Proto-Oncogene Proteins c-vav/chemistry , Proto-Oncogene Proteins c-vav/metabolism , Amino Acid Sequence , Cell Line, Tumor , Humans , Lactones/metabolism , Ligands , Male , Molecular Sequence Data , Mutagenesis, Site-Directed , Phospholipids/metabolism , Prostatic Neoplasms , Protein Binding/physiology , Protein Kinase C-delta/metabolism , Protein Structure, Tertiary , Proto-Oncogene Proteins c-vav/genetics , Signal Transduction/physiology
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