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Although the study of non-human primates has resulted in important advances for understanding HIV-specific immunity, a clear correlate of immune control over simian immunodeficiency virus (SIV) replication has not been found to date. In this study, CD8(+) T-cell cytotoxic capacity was examined to determine whether this function is a correlate of immune control in the rhesus macaque (RM) SIV infection model as has been suggested in chronic HIV infection. SIVmac251-infected human reverse transcriptase (hTERT)-transduced CD4(+) T-cell clone targets were co-incubated with autologous macaque effector cells to measure infected CD4(+) T-cell elimination (ICE). Twenty-three SIV-infected rhesus macaques with widely varying plasma viral RNA levels were evaluated in a blinded fashion. Nineteen of 23 subjects (83%) were correctly classified as long-term nonprogressor/elite controller (LTNP/EC), slow progressor, progressor or SIV-negative rhesus macaques based on measurements of ICE (weighted Kappa 0.75). LTNP/EC had higher median ICE than progressors (67.3% [22.0-91.7%] vs. 23.7% [0.0-58.0%], pâ=â0.002). In addition, significant correlations between ICE and viral load (râ=â-0.57, pâ=â0.01), and between granzyme B delivery and ICE (râ=â0.89, p<0.001) were observed. Furthermore, the CD8(+) T cells of LTNP/EC exhibited higher per-cell cytotoxic capacity than those of progressors (pâ=â0.004). These findings support that greater lytic granule loading of virus-specific CD8(+) T cells and efficient delivery of active granzyme B to SIV-infected targets are associated with superior control of SIV infection in rhesus macaques, consistent with observations of HIV infection in humans. Therefore, such measurements appear to represent a correlate of control of viral replication in chronic SIV infection and their role as predictors of immunologic control in the vaccine setting should be evaluated.
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Linfocitos T CD8-positivos/patología , Inmunidad , Macaca mulatta/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Linfocitos T Citotóxicos/patología , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Progresión de la Enfermedad , Interacciones Huésped-Patógeno , Macaca mulatta/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/virología , Replicación ViralRESUMEN
Nonhuman primate models are needed for evaluations of proposed strategies targeting residual virus that persists in HIV-1-infected individuals receiving suppressive combination antiretroviral therapy (cART). However, relevant nonhuman primate (NHP) models of cART-mediated suppression have proven challenging to develop. We used a novel three-class, six-drug cART regimen to achieve durable 4.0- to 5.5-log reductions in plasma viremia levels and declines in cell-associated viral RNA and DNA in blood and tissues of simian immunodeficiency virus SIVmac239-infected Indian-origin rhesus macaques, then evaluated the impact of treatment with the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA; Vorinostat) on the residual virus pool. Ex vivo SAHA treatment of CD4(+) T cells obtained from cART-suppressed animals increased histone acetylation and viral RNA levels in culture supernatants. cART-suppressed animals each received 84 total doses of oral SAHA. We observed SAHA dose-dependent increases in acetylated histones with evidence for sustained modulation as well as refractoriness following prolonged administration. In vivo virologic activity was demonstrated based on the ratio of viral RNA to viral DNA in peripheral blood mononuclear cells, a presumptive measure of viral transcription, which significantly increased in SAHA-treated animals. However, residual virus was readily detected at the end of treatment, suggesting that SAHA alone may be insufficient for viral eradication in the setting of suppressive cART. The effects observed were similar to emerging data for repeat-dose SAHA treatment of HIV-infected individuals on cART, demonstrating the feasibility, utility, and relevance of NHP models of cART-mediated suppression for in vivo assessments of AIDS virus functional cure/eradication approaches.
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Antirretrovirales/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Ácidos Hidroxámicos/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Acetilación/efectos de los fármacos , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Modelos Animales de Enfermedad , Quimioterapia Combinada , Histonas/metabolismo , Macaca mulatta , ARN Viral/sangre , ARN Viral/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Carga Viral/efectos de los fármacos , VorinostatRESUMEN
BACKGROUND: Testosterone plays an important role in collagen metabolism, transforming growth factor-ß1 expression, and wound healing, which are all critical factors in pathogenesis of Peyronie's disease. Some clinical studies have suggested an association between Peyronie's disease and hypogonadism. OBJECTIVE: We sought to investigate whether baseline total testosterone levels influence response to intralesional collagenase clostridium histolyticum in Peyronie's disease. METHODS: A retrospective review of patients receiving collagenase clostridium histolyticum injections with available total testosterone levels within 1 year of initial injection was conducted at a single institution. Baseline demographics, hypogonadal status, total testosterone, number of collagenase clostridium histolyticum cycles, and pre- and post-treatment degrees of curvature were collected. Hypogonadism was defined as total testosterone <300 ng/dL. RESULTS AND DISCUSSION: Thirty-six men were included with mean age of 58.2 years (SD 10.4) and mean body mass index 26.8 (SD 3.2). The mean total testosterone was 459.2 ng/dL (SD 144.0), and four (11.1%) were hypogonadal. Mean pre-treatment curvature was 47.6°, and mean post-treatment curvature was 27.8°, with mean improvement of 19.9° (40.1%). Hypogonadal status was not significantly associated with more severe curvature, 46.4° among hypogonadal men as to 57.5° among eugonadal men (p = 0.32). On linear regression analysis, total testosterone did not significantly predict improvement in degrees (ß = -0.02; R2 = 0.06; p = 0.14) or percent (ß = 0.0; R2 = 0.05; p = 0.18). Improvement in neither degrees nor percent differed significantly by hypogonadal status (p = 0.41 and 0.82, respectively). The cycle number did significantly predict greater improvement in curvature on both univariate and multivariate analyses (ß = 5.7; R2 = 0.34; p < 0.01). CONCLUSION: Neither total testosterone nor hypogonadism is associated with a degree of improvement after collagenase clostridium histolyticum treatment.
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Hipogonadismo , Induración Peniana , Masculino , Humanos , Persona de Mediana Edad , Colagenasa Microbiana/uso terapéutico , Induración Peniana/tratamiento farmacológico , Induración Peniana/patología , Testosterona/uso terapéutico , Resultado del Tratamiento , Inyecciones Intralesiones , Congéneres de la Testosterona , Hipogonadismo/tratamiento farmacológico , Hipogonadismo/patología , Pene/patologíaRESUMEN
The efficiency of HIV infection is greatly enhanced when the virus is delivered at conjugates between CD4+ T cells and virus-bearing antigen-presenting cells such as macrophages or dendritic cells via specialized structures known as virological synapses. Using ion abrasion SEM, electron tomography, and superresolution light microscopy, we have analyzed the spatial architecture of cell-cell contacts and distribution of HIV virions at virological synapses formed between mature dendritic cells and T cells. We demonstrate the striking envelopment of T cells by sheet-like membrane extensions derived from mature dendritic cells, resulting in a shielded region for formation of virological synapses. Within the synapse, filopodial extensions emanating from CD4+ T cells make contact with HIV virions sequestered deep within a 3D network of surface-accessible compartments in the dendritic cell. Viruses are detected at the membrane surfaces of both dendritic cells and T cells, but virions are not released passively at the synapse; instead, virus transfer requires the engagement of T-cell CD4 receptors. The relative seclusion of T cells from the extracellular milieu, the burial of the site of HIV transfer, and the receptor-dependent initiation of virion transfer by T cells highlight unique aspects of cell-cell HIV transmission.
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Células Dendríticas/virología , VIH/fisiología , Linfocitos T/virología , Virión/fisiología , Células Presentadoras de Antígenos/metabolismo , Células Presentadoras de Antígenos/ultraestructura , Células Presentadoras de Antígenos/virología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/ultraestructura , Linfocitos T CD4-Positivos/virología , Comunicación Celular , Células Dendríticas/metabolismo , Células Dendríticas/ultraestructura , Interacciones Huésped-Patógeno , Humanos , Microscopía Electrónica de Rastreo , Microscopía Electrónica de Transmisión , Microscopía Fluorescente , Linfocitos T/metabolismo , Linfocitos T/ultraestructuraRESUMEN
After a focused telehealth visit, patients can now access phosphodiesterase-5 inhibitor (PDE5 inhibitor) prescriptions through online direct-to-consumer (DTC) healthcare companies. This study seeks to quantify the cost of DTC PDE5 inhibitor treatment compared to a traditional physician visit and local pharmacy prescription. Two DTC companies, two compounding pharmacies with national reach, three online Canadian pharmacies, and sixteen American pharmacy chains were queried for prices of 90-day regimens of common PDE5 inhibitors. Prices for chains were determined using their publicly available price on GoodRx® with coupon. Cost of physician visit was determined using 2020 Center for Medicare and Medicaid Services reimbursement for a level 3 new patient visit. For sildenafil 20 mg, a physician visit and local prescription cost a low of $125.45 compared to $144.35 for compounding, $169.34 for Canadian, and $195.00 for DTC. For sildenafil 100 mg, a physician visit and local prescription cost a low of $137.16 compared to $289.35 for compounding, $200.36 for Canadian, and $900.00 for DTC. For tadalafil 5 mg, a physician visit and local prescription cost a low of $125.80 compared to $169.35 for compounding, $195.34 for Canadian, and $720.00 for DTC. For tadalafil 20 mg, a physician visit and local prescription cost a low of $161.00 compared to $289.35 for compounding, $229.00 for Canadian, and $2880.00 for DTC. Thus, local pharmacies, in conjunction with online coupons, consistently provide a markedly less-expensive option for fulfillment of PDE5 inhibitor prescriptions than online DTC services.
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Programas Nacionales de Salud , Inhibidores de Fosfodiesterasa 5 , Estados Unidos , Humanos , Anciano , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Citrato de Sildenafil/uso terapéutico , Tadalafilo/uso terapéutico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Canadá , PrescripcionesRESUMEN
Despite a well-documented increase in both the prevalence of Testosterone Deficiency (TD) and prescription of testosterone replacement therapy (TRT), few studies have investigated the preferences of patients receiving TRT and factors associated with increased treatment satisfaction. To investigate the preferences of patients receiving TRT and factors associated with improved treatment satisfaction, an open survey was completed by 140 men receiving TRT at a single institution. Survey questions investigated demographics, symptom burden of TD, TRT regimen, treatment preferences, and treatment satisfaction. 62.7% of patients were satisfied with their current TRT regimen. Those using auto-injectors (91.7%, odds ration [OR] = 9.3), subcutaneous pellets (90.0%, OR = 15.2), and intramuscular injections (67.5%, OR = 5.7), were with significantly increased satisfaction rates (p < 0.05). The majority of patients indicated that they would prefer to receive TRT injections when self-administered or administered at home. While patients noted that treatment efficacy was a significant driving factor when evaluating a TRT regimen, few patients felt that cost was the most significant factor.
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Background: Information regarding the Medicaid coverage of artificial urinary sphincter (AUS) and male suburethral slings (MS) placement in the United States (US) is not readily available. In this manuscript, we seek to elucidate the state-by-state Medicaid coverage of these two procedures in the US. Methods: State Medicaid websites were utilized to access publicly available physician fee schedules for the calendar year 2020. Fee schedules were searched for current procedural terminology (CPT) codes. CPT codes representing insertion of tandem cuff, insertion of AUS, removal of AUS, removal and replacement AUS, sling operation for correction of male stress urinary incontinence (SUI), and removal or revision of sling for male SUI were utilized. Data were recorded by the procedure for each device, including the coverage status and physician fees. Results: Of the 50 US states analyzed, 49 publish publicly accessible physician fee schedules. All 49 of these states reported coverage for removal with and without revision of the AUS, and 48 states reported coverage for insertion of an AUS, and insertion of a tandem cuff. The median reimbursement for each AUS related procedure was $624.00 ($181.84-$10,960.90) for tandem cuff, $665.54 ($199.89-$11,949.86) for AUS insertion, $528.03 ($146.90-$1,893.12) for AUS removal, and $630.29 ($208.55-$11,586.74) for AUS revision. All 49 states reported coverage for placement of MS, and 48 states reported coverage for removal or revision of MS. The median reimbursement was $652.57 ($198.00-$5,237.35) for MS placement and $554.47 ($104.27-$2,288.93) for MS revision. Conclusions: AUS and MS procedures in the Medicaid population are covered by nearly all states. Therefore, surgical treatment of SUI may be offered to Medicaid patients in most states without reimbursement concerns.
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Background: Regionalization of care for children with congenital heart disease has been proposed as a method to improve outcomes. This has raised concerns about limiting access to care. We present the details of a joint pediatric heart care program (JPHCP) which utilized regionalization and actually improved access to care. Methods: In 2017, Kentucky Children's Hospital (KCH) launched the JPHCP with Cincinnati Children's Hospital Medical Center (CCHMC). This unique satellite model was the product of several years of planning, leading to a comprehensive strategy with shared personnel, conferences, and a robust transfer system; "one program-two sites." Results: Between March 2017 and the end of June 2022, 355 operations were performed at KCH under the auspices of the JPHCP. As of the most recent published Society of Thoracic Surgeons (STS) outcome report (through the end of June 2021), for all STAT categories, the JPHCP at KCH outperformed the STS overall in postoperative length of stay, and the mortality rate was lower than expected for the case mix. Of the 355 operations, there were 131 STAT 1, 148 STAT 2, 40 STAT 3, and 36 STAT 4 operations, with two operative mortalities: an adult undergoing surgery for Ebstein anomaly, and a premature infant who died from severe lung disease many months after aortopexy. Conclusions: With a select case mix, and by affiliating with a large volume congenital heart center, the creation of the JPHCP at KCH was able to achieve excellent congenital heart surgery results. Importantly, access to care was improved for those children at the more remote location utilizing this one program-two sites model.
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Procedimientos Quirúrgicos Cardíacos , Anomalía de Ebstein , Cardiopatías Congénitas , Lactante , Recién Nacido , Adulto , Niño , Humanos , Procedimientos Quirúrgicos Cardíacos/métodos , Cardiopatías Congénitas/cirugía , Recien Nacido Prematuro , Bases de Datos Factuales , Accesibilidad a los Servicios de SaludRESUMEN
OBJECTIVES: Since the development of Kidney Donor Profile Index, outcome differences based on number of donated organs per donor have not been evaluated. MATERIALS AND METHODS: We retrospectively analyzed data from the United Network for Organ Sharing national database, which identified 176 311 adult renal transplant recipients from 2000 to 2019 with a deceased donor kidney from a kidney-only donor, from a donor of kidney and liver but no other organs, or from a multiorgan donor. Graft failure and transplant recipient survival were primary outcomes. A multivariate Cox proportional hazards model controlled for Kidney Donor Profile Index differences. RESULTS: Overall, multiorgan donors had a lower Kidney Donor Profile Index versus other donor types (odds ratio, 0.042; P < .001). Kidneys from donors with a higher Kidney Donor Profile Index were 95% less likely to be procured with other organs (P < .001). The recipient and graft survival rates for kidney transplants from kidney-only donors and from donors of kidney and liver but no other organs were 76% and 70%, respectively, whereas recipient and graft survival rates for kidney transplants from multiorgan donors were approximately 82% and 77%, respectively, at 5 years. CONCLUSIONS: After adjustment for the Kidney Donor Profile Index, the recipients of multiorgan donor grafts demonstrated superior outcomes for graft survival and mortality compared with kidney-only donors or kidney and liver only donors. The multiorgan donor status may be an additional consideration in future renal allocation calculators.
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Obtención de Tejidos y Órganos , Receptores de Trasplantes , Adulto , Supervivencia de Injerto , Humanos , Riñón , Sistema de Registros , Estudios Retrospectivos , Donantes de Tejidos , Resultado del TratamientoRESUMEN
The ability to precisely control transgene expression is essential for basic research and clinical applications. Adeno-associated viruses (AAVs) are non-pathogenic and can be used to drive stable expression in virtually any tissue, cell type, or species, but their limited genomic payload results in a trade-off between the transgenes that can be incorporated and the complexity of the regulatory elements controlling their expression. Resolving these competing imperatives in complex experiments inevitably results in compromises. Here, we assemble an optimized viral toolkit (VTK) that addresses these limitations and allows for efficient combinatorial targeting of cell types. Moreover, their modular design explicitly enables further refinements. We achieve this in compact vectors by integrating structural improvements of AAV vectors with innovative molecular tools. We illustrate the potential of this approach through a systematic demonstration of their utility for targeting cell types and querying their biology using a wide array of genetically encoded tools.
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Vectores Genéticos , Sistema Nervioso , Transducción Genética , Vectores Genéticos/genética , Transgenes/genéticaRESUMEN
Introduction: Contemporary, flexible stone baskets are unable to extract submillimeter stone fragments at the time of ureteroscopic laser lithotripsy. In this in vitro study, the feasibility of suctioning submillimeter fragments with a standard Luer Lock syringe through the working channel of a flexible ureteroscope was assessed. Materials and Methods: Phantom stones made from industrial plaster were mechanically fragmented into ≤1 and ≤0.5-mm groups. Both stone groups were divided into five preweighed trial samples. Each stone group was then mixed in a beaker filled with normal saline. A standard 10-mL Luer Lock syringe was connected to a fiber-optic ureteroscope with a 1.2-mm working channel. The syringe was then used to suction stone fragments from the beaker. The suctioned stone fragments and the stone fragments remaining in the beaker after removing the overlying solution were separated, centrifuged with supernatant removed, and dried in an incubator set at 33°C for 1 week. Dried weights were recorded. Results: Mean total weights for ≤0.5 and ≤1.0-mm stone groups at baseline were 0.807 and 0.806 g, respectively. The mean percentages of stone fragments suctioned through the ureteroscope for ≤0.5 and ≤1.0-mm groups were 86% and 86%, respectively (p = 0.973). During suctioning, 64% of stones in the ≤0.5-mm group were trapped in either the working channel of the ureteroscope or within the Luer Lock syringe compared with 78% of stones in the ≤1-mm group (p = 0.001) requiring cessation of the procedure to clear the channel. Conclusions: It is feasible to suction submillimeter stone fragments by connecting a Luer Lock syringe to the working channel of a flexible ureteroscope. The limiting factor for removing stone fragments appears to be the small working channel of flexible ureteroscopes as trapping of fragments during suctioning is common and requires time-consuming removal of the endoscope and clearing of the channel.
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Litotripsia por Láser , Cálculos Ureterales , Humanos , Succión , Cálculos Ureterales/cirugía , Ureteroscopios , UreteroscopíaRESUMEN
We report a case of contrast-induced hypothyroidism in an extremely preterm infant after percutaneous patent ductus arteriosus (PDA) device closure. Iodine-induced hypothyroidism after exposure to iodine-containing antiseptics and contrast media has been previously reported in extremely preterm infants. However, this is the first report of contrast-induced hypothyroidism in an extremely preterm infant undergoing percutaneous PDA device closure. This is timely, given percutaneous PDA device closure is more frequently utilized. Guidelines for screening thyroid function pre and post contrast-requiring procedures may be warranted. Hypothyroidism if left untreated can have detrimental effects on developing brain, especially in the preterm population. Therefore, the earlier detection and treatment of iodine-induced hypothyroidism is imperative.
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Conducto Arterioso Permeable , Hipotiroidismo , Medios de Contraste/efectos adversos , Conducto Arterioso Permeable/diagnóstico por imagen , Conducto Arterioso Permeable/cirugía , Humanos , Lactante , Recien Nacido Extremadamente Prematuro , Recién NacidoRESUMEN
OBJECTIVE: The objective of the study was to determine the clinical utility of brain natriuretic peptide (NT-proBNP) for prediction of moderate to severe bronchopulmonary dysplasia (BPD). We hypothesized that elevated NT-proBNP levels at 4 weeks of postnatal age may predict the severity of BPD in preterm infants. STUDY DESIGN: The study design was a prospective observational study. The research team enrolled and followed a cohort of 70 infants with gestational age less than or equal to 30 weeks. The plasma NT-proBNP levels were measured at the postnatal day 28th. We further followed and categorized infants into two groups. Infants with no or mild BPD (Group 1) and infants with moderate or severe BPD (Group 2). We compared plasma NT-proBNP levels at 28th day of postnatal life between Groups 1 and 2. The difference in NT-proBNP levels on day 28th between groups was used to predict the severity of BPD. RESULTS: Plasma NT-proBNP was significantly elevated in Group 2 compared with Group 1, median (IQR) of 845 pg/mL (553, 1632) compared with 726 pg/mL (391, 923), P = 0.02. NT-proBNP had a fair predictive accuracy (C statistics of 0.68) to determine moderate to severe BPD. CONCLUSION: NT-proBNP may be a useful biomarker in conjunction with clinical factors as a predictor of severe BPD. For future directions, the trend of NT-proBNP in infants with BPD may have clinical significance in monitoring of the disease.
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Displasia Broncopulmonar/sangre , Recien Nacido Prematuro/sangre , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Biomarcadores/sangre , Estudios de Cohortes , Femenino , Humanos , Recién Nacido , Masculino , Estudios ProspectivosRESUMEN
CIC-rearranged round cell sarcoma (CRS) is a rare entity that presents in various anatomical locations and involves deep soft-tissue structures and skin. Although commonly confused with and clinically similar to Ewing sarcoma (ES), investigators have recently shown that this unique condition maintains morphologic and pathologic features that are distinct from ES. In this report, we present and discuss a case of CRS of the uterus, the first of its kind to be reported in the English-language literature. We urge the scientific community to continue its investigations in elucidating the features of this entity, as young women who suffer from this condition have dismal prognoses and currently do not have access to therapeutic options for cure.
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Recent success in identifying gene-regulatory elements in the context of recombinant adeno-associated virus vectors has enabled cell-type-restricted gene expression. However, within the cerebral cortex these tools are largely limited to broad classes of neurons. To overcome this limitation, we developed a strategy that led to the identification of multiple new enhancers to target functionally distinct neuronal subtypes. By investigating the regulatory landscape of the disease gene Scn1a, we discovered enhancers selective for parvalbumin (PV) and vasoactive intestinal peptide-expressing interneurons. Demonstrating the functional utility of these elements, we show that the PV-specific enhancer allowed for the selective targeting and manipulation of these neurons across vertebrate species, including humans. Finally, we demonstrate that our selection method is generalizable and characterizes additional PV-specific enhancers with exquisite specificity within distinct brain regions. Altogether, these viral tools can be used for cell-type-specific circuit manipulation and hold considerable promise for use in therapeutic interventions.
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Dependovirus/genética , Vectores Genéticos/genética , Interneuronas/fisiología , Animales , Callithrix , Corteza Cerebral/citología , Femenino , Humanos , Macaca mulatta , Ratones , Ratones Endogámicos C57BL , Canal de Sodio Activado por Voltaje NAV1.1/genética , Neuronas , Parvalbúminas/fisiología , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Péptido Intestinal Vasoactivo/fisiologíaRESUMEN
UNLABELLED: To optimize in vivo tissue uptake kinetics and clearance of engineered monoclonal antibody (mAb) fragments for radiotherapeutic and radiodiagnostic applications, we compared the biodistribution and tumor localization of four (111)In- and (86)Y-labeled antibody formats, derived from a single antimindin/RG-1 mAb, in a prostate tumor model. The IgG, diabody, single-chain variable domain (scFv), and novel miniantibody formats, composed of the human IgE-C(H)4 and a modified IgG1 hinge linked to scFv domains, were compared. METHODS: Antibodies were first derivatized with the bifunctional chelator CHX-A''-diethylenetriamine pentaacetic acid and then bound to the radiometal to create radiolabeled immunoconjugates. Human LNCaP xenografts were grown in nude mice, and (111)In- or (86)Y-labeled antibodies were administered intravenously. Tissues were harvested at different times, and the level of antibody deposition was determined by measuring radioactivity. Whole-body small-animal PET of mice receiving (86)Y-labeled antibodies was performed at 6 time points and colocalized with simultaneous micro-CT imaging. RESULTS: The biodistributions of (111)In and (86)Y antibodies were quite similar. The blood, tumor, kidney, and liver tissues contained varying levels of radioactivity. The antibody accumulation in the tumor correlated with molecular size. The IgG steadily increased with time to 24.1 percentage injected dose per gram (%ID/g) at 48 h. The miniantibody accumulated at a similar rate to reach a lower level (14.2 %ID/g) at 48 h but with a higher tumor-to-blood ratio than the IgG. Tumor accumulation of the diabody peaked at 3 h, reaching a much lower level (3.7 %ID/g). A combination of rapid clearance and lower relative affinity of the scFv precluded deposition in the tumor. Small-animal PET results correlated well with the biodistribution results, with similar tumor localization patterns. CONCLUSION: The larger antibody formats (IgG and miniantibody) gave higher tumor uptake levels than did the smaller formats (diabody and scFv). These larger formats may be more suitable for radioimmunotherapy applications, evidenced by the preclinical efficacy previously shown by a report on the IgG format. The smaller formats were rapidly cleared from circulation, and the diabody, which accumulated in the tumor, may be more suitable for radiodiagnostic applications.
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Anticuerpos Monoclonales/farmacocinética , Neoplasias de la Próstata/metabolismo , Radiofármacos/farmacocinética , Animales , Anticuerpos Monoclonales/química , Línea Celular Tumoral , Quelantes/química , Humanos , Radioisótopos de Indio , Isotiocianatos/química , Masculino , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Ácido Pentético/análogos & derivados , Ácido Pentético/química , Tomografía de Emisión de Positrones , Radiofármacos/química , Distribución Tisular , Tomografía Computarizada por Rayos X , Trasplante Heterólogo , Radioisótopos de ItrioRESUMEN
OBJECTIVE: This investigation was performed to evaluate the registration accuracy between magnetic resonance imaging (MRI) and pathology using three-dimensional (3-D) printed molds. METHODS: Tissue-mimicking prostate phantoms were manufactured with embedded fiducials. The fiducials were used to measure and compare target registration error (TRE) between phantoms that were sliced by hand versus phantoms that were sliced within 3-D-printed molds. Subsequently, ten radical prostatectomy specimens were placed inside molds, scanned with MRI, and then sliced. The ex vivo scan was used to assess the true location of whole mount (WM) slides relative to in vivo MRI. The TRE between WM and in vivo MRI was measured using anatomic landmarks. RESULTS: Manually sliced phantoms had a 4.1-mm mean TRE, whereas mold-sliced phantoms had a 1.9-mm mean TRE. Similarly, mold-assisted slicing reduced mean angular misalignment around the left-right (LR) anatomic axis from 10.7° to 4.5°. However, ex vivo MRI revealed that excised prostates were misaligned within molds, including a mean 14° rotation about the LR axis. The mean in-plane TRE was 3.3 mm using molds alone and 2.2 mm after registration was corrected with ex vivo MRI. CONCLUSION: Patient-specific molds improved accuracy relative to manual slicing techniques in a phantom model. However, the registration accuracy of surgically resected specimens was limited by their imperfect fit within molds. This limitation can be overcome with the addition of ex vivo imaging. SIGNIFICANCE: The accuracy of 3-D-printed molds was characterized, quantifying their utility for facilitating MRI-pathology registration.
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Imagenología Tridimensional/métodos , Imagen por Resonancia Magnética/métodos , Próstata , Neoplasias de la Próstata , Marcadores Fiduciales , Humanos , Masculino , Fantasmas de Imagen , Próstata/diagnóstico por imagen , Próstata/patología , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patologíaRESUMEN
The highly polymorphic human leukocyte antigen (HLA) locus encodes cell surface proteins that are critical for immunity. HLA-A expression levels vary in an allele-dependent manner, diversifying allele-specific effects beyond peptide-binding preference. Analysis of 9763 HIV-infected individuals from 21 cohorts shows that higher HLA-A levels confer poorer control of HIV. Elevated HLA-A expression provides enhanced levels of an HLA-A-derived signal peptide that specifically binds and determines expression levels of HLA-E, the ligand for the inhibitory NKG2A natural killer (NK) cell receptor. HLA-B haplotypes that favor NKG2A-mediated NK cell licensing (i.e., education) exacerbate the deleterious effect of high HLA-A on HIV control, consistent with NKG2A-mediated inhibition impairing NK cell clearance of HIV-infected targets. Therapeutic blockade of HLA-E:NKG2A interaction may yield benefit in HIV disease.
Asunto(s)
Infecciones por VIH/inmunología , VIH/inmunología , Antígenos HLA/metabolismo , Células Asesinas Naturales/inmunología , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismo , Alelos , Recuento de Linfocito CD4 , Estudios de Cohortes , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Antígenos HLA/genética , Humanos , Ligandos , Subfamília C de Receptores Similares a Lectina de Células NK/antagonistas & inhibidores , Subfamília C de Receptores Similares a Lectina de Células NK/genética , Señales de Clasificación de Proteína , Viremia/inmunologíaRESUMEN
Amiodarone therapy is associated with several adverse effects, including hematologic ones such as pancytopenia, hemolytic anemia, and aplastic anemia. Very few cases of amiodarone-associated bone marrow granulomas have been reported. We report 2 cases of amiodarone-associated bone marrow granulomas. Patient 1 was an 81-year-old man who presented with leukopenia, thrombocytopenia, and hepatosplenomegaly after 2 years of amiodarone therapy. Patient 2 was an 80-year-old man who presented with pancytopenia 2 1/2 years after starting amiodarone treatment. Both patients had normal blood counts before amiodarone therapy. Bone marrow biopsies showed noncaseating granulomas in both patients. We reviewed the literature available on Medline for amiodarone-associated bone marrow granulomas and found 8 reported cases of amiodarone-associated bone marrow granulomas. One case also featured amiodarone-associated hepatic granulomas. Amiodarone therapy was stopped in 5 cases, with improvement of the granulomas occurring in 3 cases. We conclude that bone marrow granulomas, although rare, should be considered as a differential diagnosis for patients undergoing amiodarone therapy and presenting with cytopenias.