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PURPOSE OF REVIEW: Recent advances in hematology-oncology have pioneered cell-mediated elimination of pathologic B-cell populations employing chimeric antigen receptor (CAR) T cells. In this review, we discuss recent adoption of CAR-T treatment for severe refractory autoimmune disease. We highlight unique aspects of the autoimmune model and review current clinical data regarding treatment of rheumatologic disease. RECENT FINDINGS: To date, several CAR-Ts are FDA approved for Multiple Myeloma and B-cell malignancies and have demonstrated extraordinary clinical responses in refractory disease. Realizing the central role of B-cells in certain autoimmune diseases, CAR-T is now being explored for achieving drug-free remission induction, and potentially cure, of several rheumatologic diseases. The largest experience to date in the field of autoimmunity, building off the University Hospital Erlangen groups' earlier success treating a single patient with CD19-CAR in severe refractory SLE, Mackensen et al. enrolled five patients in a compassionate use program. Following autologous CD19-CAR T infusion, they demonstrated drug-free clinical and laboratory remission for at least 12âmonths in all five patients, with reconstitution of B cells expressing a naïve phenotype. SUMMARY: CAR-T treatment has shown striking drug-free responses in severe lupus and other autoimmune diseases, creating a need for further exploration and development.
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Artritis Reumatoide , Enfermedades Autoinmunes , Receptores Quiméricos de Antígenos , Reumatología , Humanos , Receptores Quiméricos de Antígenos/genética , Linfocitos T , Inmunoterapia Adoptiva , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
Linear porokeratosis is a rare variant of porokeratosis that is characterized by unilateral lesions along the lines of Blaschko. Like all variants of porokeratosis, linear porokeratosis is characterized by the histopathologic finding of cornoid lamellae bracketing the lesion. The underlying pathophysiology involves a two-hit post-zygotic knockdown of genes involved in mevalonate biosynthesis in embryonic keratinocytes. Although there is currently no standard or effective treatment, therapies targeted to rescue this pathway and restore keratinocyte cholesterol availability are promising. Presented here is a patient with a rare, extensive case of linear porokeratosis treated with compounded 2% lovastatin/2% cholesterol cream leading to partial resolution of the plaques.
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Poroqueratosis , Humanos , Poroqueratosis/patología , Lovastatina , Queratinocitos , ColesterolRESUMEN
Erythema ab igne is an uncommon physical dermatosis that presents with localized patches of reticulated erythema and hyperpigmentation corresponding with the underlying dermal venous plexus. The rash occurs in response to chronic heat exposure that does not meet the threshold for thermal burn of the skin. The histopathologic findings are characterized by atrophy and thinning of the epidermis, focal hyperkeratosis, and keratinocyte atypia. The dermis displays dilated capillaries, evidence of pigment incontinence, and prominent elastotic material. We report a case of a 65-year-old male who presented to his primary care physician with a 1-year history of reticular erythema and hyperpigmentation with focal ulceration on his right lateral leg. Histopathology on biopsy revealed mild hyperkeratosis and focal epidermal atrophy; however, the most striking finding was a proliferation of dermal vascular spaces lined by pleomorphic endothelial cells and numerous mitotic figures, which was morphologically compatible with angiosarcoma. However, clinicopathologic correlation and immunostaining revealed an actual diagnosis of erythema ab igne with reactive angiomatosis. Reactive angiomatosis-morphologically mimicking angiosarcoma-is a rarely reported feature of severe erythema ab igne, and dermatopathologists should be aware of this possibility to avoid misdiagnosis of erythema ab igne as angiosarcoma.
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Angiomatosis/diagnóstico , Angiomatosis/patología , Eritema Ab Igne/diagnóstico , Eritema Ab Igne/patología , Hemangiosarcoma/diagnóstico , Anciano , Diagnóstico Diferencial , Hemangiosarcoma/patología , Humanos , Masculino , Piel/patologíaRESUMEN
Treatment of verruca plana is often challenging, and multiple treatment modalities, both pharmacologic and destructive, are frequently necessary to clear lesions. We report a case of a 16-year-old girl with a 2-year history of extensive verruca plana of the forehead, temples, and upper periorbital skin, recalcitrant to monotherapy with topical tretinoin cream, that completely resolved following first dose of nonavalent human papillomavirus (HPV) immunization.
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Extramedullary hematopoiesis is the process of blood cell synthesis occurring outside the medulla of the bone marrow. During fetal development, extramedullary hematopoiesis is considered physiological; however, it is considered pathologic when occurring outside the neonatal period. Angiolymphoid hyperplasia with eosinophilia (ALHE) describes a lesion characterized histologically by plump endothelial cells associated with a mixed inflammatory infiltrate of lymphocytes, plasma cells, mast cells, and eosinophils. This report describes an adolescent boy with an isolated preauricular facial lesion. After excision, histopathology confirmed a diagnosis of ALHE with the additional finding of trilineage extramedullary hematopoiesis. To the authors' knowledge, this is the first reported case of extramedullary hematopoiesis in ALHE.
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Hiperplasia Angiolinfoide con Eosinofilia/patología , Hiperplasia Angiolinfoide con Eosinofilia/cirugía , Hematopoyesis Extramedular , Adolescente , Hiperplasia Angiolinfoide con Eosinofilia/fisiopatología , Biopsia con Aguja , Mejilla/patología , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Masculino , Enfermedades RarasRESUMEN
Hereditary angioedema is characterized by severe, episodic edema of the subcutaneous and mucosal tissue. The disease carries significant morbidity and mortality due to involvement of the gastrointestinal tract and upper airway. Recent advances in the treatment of hereditary angioedema include new techniques used to isolate and purify human-derived C1 inhibitor, the production of a recombinant form of C1 inhibitor, and the development of drugs that target the kallikrein-kinin pathway. This paper reviews the mechanisms, efficacy, and adverse reactions associated with these medications.
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Angioedemas Hereditarios/tratamiento farmacológico , Bradiquinina/análogos & derivados , Bradiquinina/uso terapéutico , Proteína Inhibidora del Complemento C1/uso terapéutico , Humanos , Péptidos/uso terapéuticoRESUMEN
Acromelic frontonasal dysostosis (AFND) is a rare disorder characterized by distinct craniofacial, brain, and limb malformations, including frontonasal dysplasia, interhemispheric lipoma, agenesis of the corpus callosum, tibial hemimelia, preaxial polydactyly of the feet, and intellectual disability. Exome sequencing of one trio and two unrelated probands revealed the same heterozygous variant (c.3487C>T [p. Arg1163Trp]) in a highly conserved protein domain of ZSWIM6; this variant has not been seen in the 1000 Genomes data, dbSNP, or the Exome Sequencing Project. Sanger validation of the three trios confirmed that the variant was de novo and was also present in a fourth isolated proband. In situ hybridization of early zebrafish embryos at 24 hr postfertilization (hpf) demonstrated telencephalic expression of zswim6 and onset of midbrain, hindbrain, and retinal expression at 48 hpf. Immunohistochemistry of later-stage mouse embryos demonstrated tissue-specific expression in the derivatives of all three germ layers. qRT-PCR expression analysis of osteoblast and fibroblast cell lines available from two probands was suggestive of Hedgehog pathway activation, indicating that the ZSWIM6 mutation associated with AFND may lead to the craniofacial, brain and limb malformations through the disruption of Hedgehog signaling.
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Proteínas de Unión al ADN/genética , Proteínas Hedgehog/genética , Disostosis Mandibulofacial/genética , Anomalías Múltiples/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Anomalías Craneofaciales , Análisis Mutacional de ADN , Exoma/genética , Cara/anomalías , Humanos , Discapacidad Intelectual , Deformidades Congénitas de las Extremidades/genética , Ratones , Datos de Secuencia Molecular , Mutación , Estructura Terciaria de Proteína/genética , Pez Cebra , Dedos de Zinc/genéticaRESUMEN
OBJECTIVE: To examine the extent to which the perception of sweet and other flavours is associated with liking and disliking of flavoured electronic cigarettes (e-cigarettes). METHODS: 31 participants (13 females/18 males; 12 sole/19 dual users) vaped 6 commercially available flavours of blu Tanks: Classic Tobacco (CT), Magnificent Menthol (MM), Cherry Crush (CC), Vivid Vanilla (VV), Piña Colada (PC) and Peach Schnapps (PS); all 'medium' strength, 12â mg/mL nicotine concentration. For each flavoured e-cigarette, participants first rated liking/disliking on the Labeled Hedonic Scale, followed by perceived intensities of sweetness, coolness, bitterness, harshness and specific flavour on the generalised version of the Labeled Magnitude Scale. The psychophysical testing was conducted individually in an environmental chamber. RESULTS: PC was perceived as sweetest and liked the most; CT was perceived as least sweet and liked the least. Across all flavours, liking was correlated with sweetness (r=0.31), coolness (r=0.25), bitterness (r=-0.25) and harshness (r=-0.29, all p<0.001). Specifically, liking was positively correlated with sweetness of PS (r=0.56, p=0.001) and PC (r=0.36, p=0.048); and with coolness of MM, CT and VV (r=0.41-0.52, p<0.05). In contrast, harshness was negatively correlated with liking for CC, PC and PS (r=0.37-0.40, p<0.05). In a multivariate model, sweetness had the greatest positive impact on liking followed by coolness; harshness had the greatest negative impact on liking. CONCLUSIONS: Our findings indicate that bitterness and harshness, most likely from nicotine, have negative impacts on the liking of e-cigarettes, but the addition of flavourants that elicit sweetness or coolness generally improves liking. The results suggest that flavours play an important role in e-cigarette preference and most likely use.
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Sistemas Electrónicos de Liberación de Nicotina/estadística & datos numéricos , Aromatizantes/administración & dosificación , Edulcorantes/administración & dosificación , Vapeo/psicología , Adulto , Femenino , Humanos , Masculino , Análisis Multivariante , Nicotina/administración & dosificación , Adulto JovenAsunto(s)
Exantema/etiología , Púrpura/etiología , Escorbuto/complicaciones , Adulto , Humanos , MasculinoRESUMEN
Chimeric antigen receptor (CAR)-T cells have demonstrated clinical potential, but current receptors still need improvements to be successful against chronic HIV infection. In this study, we address some requirements of CAR motifs for strong surface expression of a novel anti-HIV CAR by evaluating important elements in the extracellular, hinge, and transmembrane (TM) domains. When combining a truncated CD4 extracellular domain and CD8α hinge/TM, the novel CAR did not express extracellularly but was detectable intracellularly. By shortening the CD8α hinge, CD4-CAR surface expression was partially recovered and addition of the LYC motif at the end of the CD8α TM fully recovered both intracellular and extracellular CAR expression. Mutation of LYC to TTA or TTC showed severe abrogation of CAR expression by flow cytometry and confocal microscopy. Additionally, we determined that CD4-CAR surface expression could be maximized by the removal of FQKAS motif at the junction of the extracellular domain and the hinge region. CD4-CAR surface expression also resulted in cytotoxic CAR T cell killing of HIV Env+ target cells. In this study, we identified elements that are crucial for optimal CAR surface expression, highlighting the need for structural analysis studies to establish fundamental guidelines of CAR designs.
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Antígenos CD4 , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/genética , Antígenos CD4/metabolismo , Antígenos CD4/inmunología , Infecciones por VIH/inmunología , Dominios Proteicos , Células HEK293 , Antígenos CD8/inmunología , Antígenos CD8/metabolismo , Membrana Celular/metabolismo , Secuencias de Aminoácidos , VIH-1/inmunologíaRESUMEN
Chimeric antigen receptor (CAR)-T cells have demonstrated clinical potential, but current receptors still need improvements to be successful against chronic HIV infection. In this study, we address some requirements of CAR motifs for strong surface expression of a novel anti-HIV CAR by evaluating important elements in the extracellular, hinge, and transmembrane (TM) domains. When combining a truncated CD4 extracellular domain and CD8α hinge/TM, the novel CAR did not express extracellularly but was detectable intracellularly. By shortening the CD8α hinge, CD4-CAR surface expression was partially recovered and addition of the LYC motif at the end of the CD8α TM fully recovered both intracellular and extracellular CAR expression. Mutation of LYC to TTA or TTC showed severe abrogation of CAR expression by flow cytometry and confocal microscopy. Additionally, we determined that CD4-CAR surface expression could be maximized by the removal of FQKAS motif at the junction of the extracellular domain and the hinge region. CD4-CAR surface expression also resulted in cytotoxic CAR T cell killing of HIV Env+ target cells. In this study, we identified elements that are crucial for optimal CAR surface expression, highlighting the need for structural analysis studies to establish fundamental guidelines of CAR designs.
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The sonic hedgehog (SHH) inhibitors vismodegib and sonidegib are the only 2 first-line systemic medications approved for the treatment of locally aggressive basal cell carcinoma (BCC). Vismodegib is the only SHH inhibitor approved for metastatic BCC. Cemiplimab, an immune checkpoint inhibitor (ICI), is now an approved second-line therapy for locally advanced or metastatic BCC. Efficacy and adverse effect profiles of vismodegib and sonidegib appear comparable, although head-to-head clinical trials have not been conducted. Despite the remarkable efficacy demonstrated by the 2 SHH inhibitors, adverse effects are common and often lead to treatment discontinuation. Alternative dosing schedules may help to manage these side effects, with recent approval of dose interruptions of up to 8 weeks. Given the high rate of recurrence and emerging concern regarding drug resistance, maintenance dosing regimens and potential synergism with other treatment modalities, such as radiotherapy or antifungal therapy, should be further explored. The use of SHH inhibitors in the neoadjuvant setting also is warranted, as it may allow for surgical management of previously inoperable cases of BCC.
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Antineoplásicos , Carcinoma Basocelular , Neoplasias Cutáneas , Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma Basocelular/patología , Proteínas Hedgehog/uso terapéutico , Humanos , Neoplasias Cutáneas/patologíaRESUMEN
Three gene therapy strategies have received US Food and Drug Administration (FDA) approval; one includes HIV-1-based lentiviral vectors. These vectors incorporate features to provide long-term gene transfer and expression while minimizing generation of a replication-competent virus or pathogenicity. Importantly, the coding regions of viral proteins were deleted, and the cis-acting regulatory elements were retained. With the use of representative vectors developed for clinical/commercial applications, we compared the vector backbone sequences to the initial sources of the HIV-1. All vectors included required elements: 5' long terminal repeat (LTR) through the Ψ packaging signal, central polypurine tract/chain termination sequence (cPPT/CTS), Rev responsive element (RRE), and 3' LTR, including a poly(A) signal. The Ψ signaling sequence demonstrated the greatest similarity between all vectors with only minor changes. The 3' LTR was the most divergent sequence with a range of deletions. The RRE length varied between vectors. Phylogenetic analysis of the cPPT/CTS indicated multiple sources, perhaps because of its later inclusion into lentiviral vector systems, whereas other regions revealed node clusters around the HIV-1 reference genomes HXB2 and NL4-3. We examine the function of each region in a lentiviral vector, the molecular differences between vectors, and where optimization may guide development of the lentiviral delivery systems.
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IscU, the central scaffold protein in the bacterial ISC iron-sulfur (Fe-S) cluster biosynthesis system, has long been recognized to bind a Zn2+ ion at its active site. While initially regarded as an artifact, Zn2+ binding has been shown to induce stabilization of the IscU structure that may mimic a state biologically relevant to IscU's role in Fe-S cluster biosynthesis. More recent studies have revealed that SufU, a homologous protein involved in Fe-S cluster biosynthesis in Gram-positive bacteria, also binds a Zn2+ ion with structural implications. Given the widespread occurrence of the "IscU-like" protein fold, particularly among Fe-S cluster biosynthesis systems, an interesting question arises as to whether Zn2+ ion binding and the resulting structural alterations are common properties in IscU-like proteins. Interactions between IscU and specific metal ions are investigated and compared side-by-side with those of SufU from a representative Gram-positive bacterium in the phylum Firmicutes. These studies were extended with additional transition metal ions chosen to investigate the influence of coordination geometry on selectivity for binding at the active sites of IscU and SufU. Monitoring and comparing the conformational behavior and stabilization afforded by different transition metal ions upon IscU and SufU revealed similarities between the two proteins and suggest that metal-dependent conformational transitions may be characteristic of U-type proteins involved in Fe-S cluster biosynthesis.
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Proteínas Bacterianas/efectos de los fármacos , Proteínas de Escherichia coli/efectos de los fármacos , Proteínas Hierro-Azufre/efectos de los fármacos , Liasas/efectos de los fármacos , Elementos de Transición/farmacología , Zinc/farmacología , Proteínas Bacterianas/química , Dominio Catalítico , Cationes , Proteínas Hierro-Azufre/química , Unión Proteica , Conformación Proteica/efectos de los fármacosRESUMEN
Enhanced Recovery Protocols (ERPs) have been shown to lead to quicker recovery in colorectal surgery, with reduced postoperative length of stay (LOS). ERPs could potentially be improved with an expanded preoperative component reflecting current evidence. We hypothesize that an ERP with an expanded preoperative component will reduce LOS consistent with or exceeding that seen with traditional ERPs. Our ERP was implemented in June of 2014. Data was collected for two full years from July 2014 through June 2016. The protocol was employed in colorectal cases, both elective and emergent. Data from ERP cases were compared with contemporaneous controls that did not go through the ERP. Patients who underwent colorectal procedures and participated in the ERP with the expanded preoperative component had an average LOS of 5.33 days, whereas controls stayed for an average of 7.93 days (P value, <0.01). ERP cases also experienced fewer readmissions and complications, although statistical significance could not be established. The results demonstrate that an ERP with an enhanced preoperative component significantly reduces LOS and potentially decreases the rate of readmissions and total complications.
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Cirugía Colorrectal/métodos , Tiempo de Internación/estadística & datos numéricos , Cuidados Preoperatorios/métodos , Protocolos Clínicos , Humanos , Persona de Mediana Edad , Recuperación de la Función , Resultado del TratamientoRESUMEN
OBJECTIVE: Our objective was to characterize physical properties and semivolatile harmful and potentially harmful constituent yields in the mainstream smoke (MSS) of 4 popular little cigars compared to the 3R4F reference cigarette. METHODS: We used the ISO and Canadian Intense Regimen protocols to generate MSS for Cheyenne (Full Flavor and Menthol) and Swisher Sweets (Original and Sweet Cherry) little cigars; and the 3R4F. We examined physical properties such as length, tobacco filler mass, pressure drop, and ventilation for each product. Nicotine, benzo[a]pyrene, and tobacco-specific nitrosamine (TSNA) yields were determined in the MSS. RESULTS: Little cigars were longer (~15mm), contained more tobacco filler (100-200 mg), and had a higher pressure drop (~1.3X) compared to the 3R4F. Ventilation holes were found only on the filter paper of the 3R4F. Nicotine transmitted to the MSS was similar for all products under the intense smoking protocol. The highest yields of TSNAs and benzo(a)pyrene were measured for the little cigars. CONCLUSIONS: Little cigars may deliver similar levels of nicotine but higher levels of carcinogens to the MSS compared to cigarettes. Thus, previous reports on the toxicity of tobacco smoke based on cigarettes might not apply to little cigar products.
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MyoD and NeuroD2, master regulators of myogenesis and neurogenesis, bind to a "shared" E-box sequence (CAGCTG) and a "private" sequence (CAGGTG or CAGATG, respectively). To determine whether private-site recognition is sufficient to confer lineage specification, we generated a MyoD mutant with the DNA-binding specificity of NeuroD2. This chimeric mutant gained binding to NeuroD2 private sites but maintained binding to a subset of MyoD-specific sites, activating part of both the muscle and neuronal programs. Sequence analysis revealed an enrichment for PBX/MEIS motifs at the subset of MyoD-specific sites bound by the chimera, and point mutations that prevent MyoD interaction with PBX/MEIS converted the chimera to a pure neurogenic factor. Therefore, redirecting MyoD binding from MyoD private sites to NeuroD2 private sites, despite preserved binding to the MyoD/NeuroD2 shared sites, is sufficient to change MyoD from a master regulator of myogenesis to a master regulator of neurogenesis.
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Diferenciación Celular/genética , Elementos E-Box/genética , Desarrollo de Músculos/genética , Proteína MioD/metabolismo , Neuronas/citología , Neuronas/metabolismo , Secuencia de Aminoácidos , Animales , Sitios de Unión/genética , Ratones , Proteína MioD/química , Proteína MioD/genéticaRESUMEN
Filopodia are sensors which, along with microtubules, regulate the persistence of locomotion. To determine whether protrusions were involved in sensing adhesion, epithelial cells were cultured on platinum and tantalum gradients. Protrusions were defined by an unbiased statistical method of classification as factors 4 (filopodia), 5 (mass distribution), and 7 (nascent neurites). When the prevalence of protrusions was measured in zones of high (H), middle (M), and low (L) adhesiveness, the main differences were in factor 4. Its values were highest at H and declined at M and L regardless of the gradient composition. The significance of the differences was enhanced when T (top/adhesive end) and B (bottom/nonadhesive end) sides of cells were analyzed separately. Since information about sidedness increased the statistical power of the test, this result suggested that cells pointed more filopodia toward the adhesive end. Trends occurred in factors 5 and 7 only when conditions allowed for a marked trend in factor 4. The data showed that gradient sensing is proportional to the prevalence of filopodia, and filopodia are the only protrusions engaged in comparing adhesiveness across a cell. The probability (P) of the significance of a trend was then used to determine how cells sense the gradient. Binding peptides (BPs) were introduced representing sequences critical for Cdc42 docking on a specific partner. BPs for IQGAP (IQ(calmodulin-binding domain)-containing GTPase-activating protein) and ACK (Cdc42-associated kinase) reduced factor 4 values and prevented cell orientation on the gradient. Micrographs showed attenuated or stubby filopodia. These effectors may be implicated in gradient sensing. Another IQGAP BP increased filopodia prevalence and enhanced orientation on the gradient (P<0.00015). A Wiskott-Aldrich syndrome protein (WASP) BP had no effect. When sensing and orientation were abolished, they both failed at the level of filopodia, indicating that filopodia are both sensors and implementers of signals transduced by adhesion.