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1.
Front Immunol ; 14: 1212190, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37559725

RESUMO

Infection-induced T cell responses must be properly tempered and terminated to prevent immuno-pathology. Using transgenic mice, we demonstrate that T cell intrinsic STAT1 signaling is required to curb inflammation during acute infection with Toxoplasma gondii. Specifically, we report that mice lacking STAT1 selectively in T cells expel parasites but ultimately succumb to lethal immuno-pathology characterized by aberrant Th1-type responses with reduced IL-10 and increased IL-13 production. We also find that, unlike STAT1, STAT3 is not required for induction of IL-10 or suppression of IL-13 during acute toxoplasmosis. Each of these findings was confirmed in vitro and ChIP-seq data mining showed that STAT1 and STAT3 co-localize at the Il10 locus, as well as loci encoding other transcription factors that regulate IL-10 production, most notably Maf and Irf4. These data advance basic understanding of how infection-induced T cell responses are managed to prevent immuno-pathology and provide specific insights on the anti-inflammatory properties of STAT1, highlighting its role in shaping the character of Th1-type responses.

2.
J Appl Clin Med Phys ; 24(11): e14090, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37464581

RESUMO

PURPOSE: To evaluate the clinical feasibility of the Siemens Healthineers AI-Rad Companion Organs RT VA30A (Organs-RT) auto-contouring algorithm for organs at risk (OARs) of the pelvis, thorax, and head and neck (H&N). METHODS: Computed tomography (CT) datasets from 30 patients (10 pelvis, 10 thorax, and 10 H&N) were collected. Four sets of OARs were generated on each scan, one set by Organs-RT and the others by three experienced users independently. A physician (expert) then evaluated each contour by assigning a score from the following scale: 1-Must Redo, 2-Major Edits, 3-Minor Edits, 4-Clinically usable. Using the highest-scored OAR from the human users as a reference, the contours generated by Organs-RT were evaluated via Dice Similarity Coefficient (DSC), Hausdorff Distance (HDD), Mean Distance to Agreement (mDTA), Volume comparison, and visual inspection. Additionally, each human user recorded the time to delineate each structure set and time-saving efficiency was measured. RESULTS: The average DSC obtained for the pelvic OARs ranged between (0.81 ± 0.06)Rectum and (0.94 ± 0.03)Bladder . (0.75 ± 0.09)Esophagus to ( 0.96 ± 0.02 ) Rt . Lung ${( {0.96 \pm 0.02} )}_{{\mathrm{Rt}}.{\mathrm{\ Lung}}}$ for the thoracic OARs and (0.66 ± 0.07)Lips to (0.83 ± 0.04)Brainstem for the H&N. The average HDD in cm for the pelvis cohort ranged between (0.95 ± 0.35)Bladder to (3.62 ± 2.50)Rectum , (0.42 ± 0.06)SpinalCord to (2.09 ± 2.00)Esophagus for the thoracic set and ( 0.53 ± 0.22 ) Cerv _ SpinalCord ${( {0.53 \pm 0.22} )}_{{\mathrm{Cerv}}\_{\mathrm{SpinalCord}}}$ to (1.50 ± 0.50)Mandible for the H&N region. The time-saving efficiency was 67% for H&N, 83% for pelvis, and 84% for thorax. 72.5%, 82%, and 50% of the pelvis, thorax, and H&N OARs were scored as clinically usable by the expert, respectively. CONCLUSIONS: The highest agreement registered between OARs generated by Organs-RT and their respective references was for the bladder, heart, lungs, and femoral heads, with an overall DSC≥0.92. The poorest agreement was for the rectum, esophagus, and lips, with an overall DSC⩽0.81. Nonetheless, Organs-RT serves as a reliable auto-contouring tool by minimizing overall contouring time and increasing time-saving efficiency in radiotherapy treatment planning.


Assuntos
Aprendizado Profundo , Humanos , Estudos de Viabilidade , Planejamento da Radioterapia Assistida por Computador/métodos , Algoritmos , Pescoço , Órgãos em Risco
4.
Sci Rep ; 12(1): 10985, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35768540

RESUMO

Subcellular organelles have long been an interest in biochemical research and drug development as the isolation of those organelles can help to probe protein functions and elucidate drug disposition within the cell. Usually, the purity of isolated subcellular organelle fractions was determined using immunoblot analysis of subcellular organelle marker proteins, which can be labor-intensive and lack reproducibility due to antibody batch-to-batch variability. As such, a higher throughput and more robust method is needed. Here, a UPLC-MRM-based targeted proteomic method was developed for a panel of human organelle marker proteins and used to profile a series of sucrose fractions isolated from the protein extract of human liver tissues. The method was validated by comparing to the traditional immunoblot and determining subcellular localization of three case study proteins (CYP3A4, FcRn, and ß2M) pertaining to the disposition of small molecule and biologic drugs. All three case study proteins were co-enriched with their corresponding subcellular protein marker, and complete recoveries were achieved from isolated fractions. This newly developed MRM method for the panel of human organelle marker proteins can potentially accelerate future intracellular drug disposition analysis and facilitate subcellular organelle quality assessment.


Assuntos
Organelas , Proteômica , Biomarcadores/metabolismo , Humanos , Fígado/metabolismo , Organelas/metabolismo , Proteínas/metabolismo , Proteômica/métodos , Reprodutibilidade dos Testes , Frações Subcelulares/metabolismo
5.
Int J Pharm Pract ; 30(3): 268-272, 2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-35532379

RESUMO

INTRODUCTION: Pharmacists traditionally work in either hospital or community settings and increasingly in primary care. As demands on health care continue to rise, pharmacists need a well-rounded understanding of the patient journey and transfer of care and be capable of working in any setting. In response, Health Education and Improvement Wales (HEIW) launched a multi-sector pre-registration pharmacy training programme. Trainees experience all three pharmacy settings throughout the year, in contrast to the traditional, single-sector programmes. OBJECTIVES: To explore the views of the now-qualified pharmacists, their tutors and line managers on the multi-sector programme and how it prepares pharmacists for practice. METHODS: This longitudinal study followed pharmacists through the multi-sector programme, to approximately 1 year post-registration. Data were collected via interviews (n = 27) with pharmacists, tutors and line managers. All data were pattern coded and analysed thematically. KEY FINDINGS: Pharmacists maintained that they benefited from the multi-sector training programme and would choose this option again. Pharmacists, tutors and line managers considered that the programme provided a more holistic perspective of pharmacy than single-sector programmes and a greater understanding of patient journeys and transfer of care. Nonetheless, there remains a lack of consensus on how the programme is best structured, and there is scope to increase the hands-on experience in primary care settings. CONCLUSIONS: Greater communication across sectors and smoother transfer of patient care benefit employers and patients as well as the pharmacists. Recommendations for future multi-sector programmes are suggested.


Assuntos
Serviços Comunitários de Farmácia , Assistência Farmacêutica , Farmácias , Humanos , Estudos Longitudinais , Farmacêuticos , Papel Profissional
6.
Implement Sci Commun ; 2(1): 111, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34579790

RESUMO

BACKGROUND: Implementation science frameworks aided the development of a new, evidence-based clinical physical therapy program. The purpose of this report is to describe the process of sustaining a clinical program in practice for over 4 years. We present a framework for integrating tools for sustainability with the Knowledge-to-Action model in the context of a proactive physical therapy (PAPT) program for individuals with early-stage Parkinson's disease. METHODS: Sustainability of implementation strategies was addressed using the Dynamic Sustainability Framework and sustainability assessment tools. Repeated retrospective medical record reviews and phone interviews were used to evaluate the reach and adoption of the PAPT over 4 years. Characteristics of those who engaged with PAPT, implementation fidelity, and clinical effectiveness were assessed for year 1 and year 3. Sustainability was measured using RE-AIM, NHS Sustainability Model, and Clinical Sustainability Assessment Tool. RESULTS: Reach increased from 28 to 110 total patients per year and spread occurred from one to three sites. PAPT user age, sex, Hoehn and Yahr rating, time since diagnosis, and type of insurance were similar in year 1 and year 3 (p > 0.05). The program sustained its effect to help participants increase or maintain self-reported exercise (Y1, 95%; Y3, 100%). However, upon evaluation PAPT users in year 3 had longer time since symptom onset and worse UPDRS motor scores compared to the PAPT users in year 1 (p < 0.05). All sites sustained the core intervention components, with sustainability scores of 71/100 (± 9.9) on the NHS Sustainability Model and 6.1/7 (± 0.9) on the Clinical Sustainability Assessment Tool. CONCLUSIONS: Integrating multiple sustainability models and assessments supported continued effectiveness, spread, and sustainment of PAPT for 4 years. Effective planning, anticipating common healthcare changes, and addressing sustainability determinants early in program implementation were essential aspects of long-term success.

7.
Cureus ; 13(2): e13354, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33747655

RESUMO

Background The COVID-19 pandemic challenges our ability to safely treat breast cancer patients and requires revisiting current techniques to evaluate optimal strategies. Potential long-term sequelae of breast radiation have been addressed by deep inspiration breath-hold (DIBH), prone positioning, and four-dimensional computed tomography (4DCT) average intensity projection (AveIP)-based planning techniques. Dosimetric comparisons to determine the optimal technique to minimize the normal tissue dose for left-sided breast cancers have not been performed. Methods Ten patients with left-sided, early-stage breast cancer undergoing whole breast radiation were simulated in the prone position, supine with DIBH, and with a free-breathing 4DCT scan. The target and organs at risk (OAR) contours were delineated in all scans. Target volume coverage and OAR doses were assessed. One-way analysis of variance (ANOVA) and Kruskal-Wallis one-way ANOVA were used to detect differences in dosimetric parameters among the different treatment plans. Significance was set as p < 0.05. Results We demonstrate differences in heart and lung dose by the simulation technique. The mean heart doses in the prone, DIBH, and AveIP plans were 129 cGy, 154 cGy, and 262 cGy, respectively (p=0.02). The lung V20 in the prone, DIBH, and AveIP groups was 0.5%, 10.3% and 9.5%, respectively (p <0.001). Regardless of technique, lumpectomy planning target volume (PTV) coverage did not differ between the three plans with 95% of the lumpectomy PTV volume covered by 100.4% in prone plans, 98.5% in AveIP plans, and 99.3% in DIBH plans (p=0.7). Conclusions Prone positioning provides dosimetric advantages as compared to DIBH. When infection risks are considered as in the current coronavirus disease 2019 (COVID-19) pandemic, prone plans have advantages in reducing the risk of disease transmission. In instances where prone positioning is not feasible, obtaining an AveIP simulation may be useful in more accurately assessing heart and lung toxicity and informing a risk/benefit discussion of DIBH vs free breath-hold techniques.

8.
J Hematol Oncol ; 13(1): 160, 2020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33256806

RESUMO

BACKGROUND: Signal regulatory protein α (SIRPα) is a myeloid-lineage inhibitory receptor that restricts innate immunity through engagement of its cell surface ligand CD47. Blockade of the CD47-SIRPα interaction synergizes with tumor-specific antibodies and T-cell checkpoint inhibitors by promoting myeloid-mediated antitumor functions leading to the induction of adaptive immunity. Inhibition of the CD47-SIRPα interaction has focused predominantly on targeting CD47, which is expressed ubiquitously and contributes to the accelerated blood clearance of anti-CD47 therapeutics. Targeting SIRPα, which is myeloid-restricted, may provide a differential pharmacokinetic, safety, and efficacy profile; however, SIRPα polymorphisms and lack of pan-allelic and species cross-reactive agents have limited the clinical translation of antibodies against SIRPα. Here, we report the development of humanized AB21 (hAB21), a pan-allelic anti-SIRPα antibody that binds human, cynomolgus monkey, and mouse SIRPα alleles with high affinity and blocks the interaction with CD47. METHODS: Human macrophages derived from donors with various SIRPα v1 and v2 allelic status were used to assess the ability of hAB21 to enhance phagocytosis. HAB21_IgG subclasses were evaluated for targeted depletion of peripheral blood mononuclear cells, phagocytosis and in vivo efficacy in xenograft models. Combination therapy with anti-PD1/anti-PD-L1 in several syngeneic models was performed. Immunophenotyping of tissues from MC38 tumor-bearing mice treated with AB21 and anti-PD-1 was evaluated. PK, PD and tolerability of hAB21 were evaluated in cynomolgus monkeys. RESULTS: SIRPα blockade with hAB21 promoted macrophage-mediated antibody-dependent phagocytosis of tumor cells in vitro and improved responses to rituximab in the Raji human tumor xenograft mouse model. Combined with PD-1/PD-L1 blockade, AB21 improved response rates by facilitating monocyte activation, dendritic cell activation, and T cell effector functions resulting in long term, durable antitumor immunity. In cynomolgus monkeys, hAB21 has a half-life of 5.3 days at 10 mg/kg and complete target occupancy with no hematological toxicity or adverse findings at doses up to 30 mg/kg. CONCLUSIONS: The in vitro and in vivo antitumor activity of hAB21 broadly recapitulates that of CD47 targeted therapies despite differences in ligand expression, binding partners, and function, validating the CD47-SIRPα axis as a fundamental myeloid checkpoint pathway and its blockade as promising therapeutic intervention for treatment of human malignancies.


Assuntos
Imunidade Adaptativa , Antineoplásicos Imunológicos/uso terapêutico , Antígeno CD47/imunologia , Neoplasias/terapia , Receptores Imunológicos/antagonistas & inibidores , Animais , Antígenos de Diferenciação/imunologia , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Imunoterapia , Macaca fascicularis , Macrófagos/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Fagocitose , Receptores Imunológicos/imunologia
9.
Brachytherapy ; 19(3): 282-289, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32217038

RESUMO

PURPOSE: High dose-rate (HDR) brachytherapy is commonly administered as a boost to external beam radiation therapy (EBRT). Our purpose was to compare toxicity with increasingly hypofractionated EBRT in combination with a single 15 Gy HDR boost for men with intermediate-risk prostate cancer. METHODS AND MATERIALS: Forty-two men were enrolled on this phase IB clinical trial to one of three EBRT dose cohorts: 10 fractions, seven fractions, or five fractions. Patients were followed prospectively for safety, efficacy, and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition. RESULTS: With a median follow up of 36 months, the biochemical disease-free survival was 95.5%. One man developed metastatic disease at 5 years. There was no significant minimally important difference in EPIC PRO for either urinary, bowel, or sexual domains. There was one acute Grade 3 GI and GU toxicity, but no late Grade 3 GU or GI toxicities. CONCLUSION: Fifteen gray HDR brachytherapy followed by a five fraction SBRT approach results in high disease control rates and low toxicity similar to previously reported HDR protocols with significant improvement in patient convenience and resource savings. While mature results with longer follow up are awaited, this treatment approach may be considered a safe and effective option for men with intermediate-risk disease.


Assuntos
Braquiterapia/efeitos adversos , Neoplasias da Próstata/radioterapia , Lesões por Radiação/etiologia , Radiocirurgia/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Braquiterapia/métodos , Intervalo Livre de Doença , Seguimentos , Humanos , Enteropatias/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Qualidade de Vida , Hipofracionamento da Dose de Radiação , Radiocirurgia/métodos , Disfunções Sexuais Fisiológicas/etiologia , Doenças Urológicas/etiologia
10.
Artigo em Inglês | MEDLINE | ID: mdl-31685474

RESUMO

Miltefosine is an alkylphosphocholine compound that is used primarily for treatment of leishmaniasis and demonstrates in vitro and in vivo antiamebic activity against Acanthamoeba species. Recommendations for treatment of amebic encephalitis generally include miltefosine therapy. Data indicate that treatment with an amebicidal concentration of at least 16 µg/ml of miltefosine is required for most Acanthamoeba species. Although there is a high level of mortality associated with amebic encephalitis, a paucity of data regarding miltefosine levels in plasma and cerebrospinal fluid in vivo exists in the literature. We found that despite aggressive dosing (oral miltefosine 50 mg every 6 h) and therapeutic plasma levels, the miltefosine concentration in cerebrospinal fluid was negligible in a patient with AIDS and Acanthamoeba encephalitis.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Amebíase/tratamento farmacológico , Amebicidas/sangue , Amebicidas/líquido cefalorraquidiano , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Encefalite Infecciosa/tratamento farmacológico , Fosforilcolina/análogos & derivados , Infecções Oportunistas Relacionadas com a AIDS/sangue , Infecções Oportunistas Relacionadas com a AIDS/líquido cefalorraquidiano , Acanthamoeba/efeitos dos fármacos , Acanthamoeba/isolamento & purificação , Adulto , Amebíase/sangue , Amebíase/líquido cefalorraquidiano , Amebicidas/administração & dosagem , Encéfalo/parasitologia , Infecções Protozoárias do Sistema Nervoso Central/sangue , Infecções Protozoárias do Sistema Nervoso Central/líquido cefalorraquidiano , Humanos , Encefalite Infecciosa/sangue , Encefalite Infecciosa/líquido cefalorraquidiano , Masculino , Fosforilcolina/administração & dosagem , Fosforilcolina/sangue , Fosforilcolina/líquido cefalorraquidiano
11.
J Contemp Brachytherapy ; 11(3): 221-226, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31447900

RESUMO

PURPOSE: Permanent seed implant cesium-131 (131Cs) brachytherapy provides highly localized radiation for patients with recurrent head and neck cancer (HNC), who may be ineligible for external beam radiation therapy due to a high-risk of toxicity. As carotid blowout is a concern in the setting of re-irradiation, a dose to the carotid artery was examined for 131Cs brachytherapy implants. MATERIAL AND METHODS: Eleven patients were implanted with 131Cs adjacent to carotid at the time of resection for recurrent HNC. Vascularized tissue flaps were used in some patients. The carotid artery was contoured on the post-implant brachytherapy treatment plan, and the maximum carotid point dose and minimum carotid-seed distances are reported. The incidence of carotid blowout in the follow-up period was also measured. RESULTS: The maximum carotid dose was 77 ±52 Gy (range, 3-158 Gy). The closest seed to the carotid artery was 0.8 ±0.8 cm (range, 0.2-2.6 cm). One patient without a flap experienced carotid blowout, which was attributed to a non-healing wound rather than to high radiation doses. CONCLUSIONS: Carotid artery doses from 131Cs are reported. Vascularized tissue flaps should be considered when planning 131Cs brachytherapy.

12.
J Contemp Brachytherapy ; 11(3): 227-234, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31435429

RESUMO

PURPOSE: Permanent interstitial brachytherapy is an appealing treatment modality for patients with locoregional recurrent, resectable head and neck carcinoma (HNC), having previously received radiation. Cesium-131 (131Cs) is a permanent implant brachytherapy isotope, with a low average photon energy of 30 keV and a short half-life of 9.7 days. Exposure to medical staff and family members is low; patient isolation and patient room shielding are not required. This work presents a single institution's implementation process of utilizing an intraoperative, permanent 131Cs implant for patients with completely resected recurrent HNC. MATERIAL AND METHODS: Fifteen patients receiving 131Cs permanent seed brachytherapy were included in this analysis. The process of pre-planning, selecting the dose prescription, seed ordering, intraoperative procedures, post-implant planning, and radiation safety protocols are described. RESULTS: Tumor volumes were contoured on the available preoperative PET/CT scans and a pre-implant treatment plan was created using uniform source strength and uniform 1 cm seed spacing. Implants were performed intraoperatively, following tumor resection. In five of the fifteen cases, intraoperative findings necessitated a change from the planned number of seeds and recalculation of the pre-implant plan. The average prescription dose was 56.1 ±6.6 Gy (range, 40-60 Gy). The average seed strength used was 2.2 ±0.2 U (3.5 ±0.3 mCi). Patients returned to a recovery room on a standard surgical floor and remained inpatients, without radiation safety restrictions, based on standard surgical recovery protocols. A post-implant treatment plan was generated based on immediate post-operative CT imaging to verify the seed distribution and confirm delivery of the prescription dose. Patients were provided educational information regarding radiation safety recommendations. CONCLUSIONS: Cesium-131 interstitial brachytherapy is feasible and does not pose major radiation safety concerns; it should be considered as a treatment option for previously irradiated patients with recurrent, resectable HNC.

13.
Cells ; 8(7)2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31311206

RESUMO

The use of extracellular vesicles, specifically exosomes, as carriers of biomarkers in extracellular spaces has been well demonstrated. Despite their promising potential, the use of exosomes in the clinical setting is restricted due to the lack of standardization in exosome isolation and analysis methods. The purpose of this review is to not only introduce the different types of extracellular vesicles but also to summarize their differences and similarities, and discuss different methods of exosome isolation and analysis currently used. A thorough understanding of the isolation and analysis methods currently being used could lead to some standardization in the field of exosomal research, allowing the use of exosomes in the clinical setting to become a reality.


Assuntos
Fracionamento Celular/métodos , Exossomos/química , Animais , Exossomos/metabolismo , Exossomos/ultraestrutura , Humanos , Proteômica/métodos
14.
MAbs ; 11(6): 1036-1052, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257988

RESUMO

Targeting the CD47-signal-regulatory protein α (SIRPα) pathway represents a novel therapeutic approach to enhance anti-cancer immunity by promoting both innate and adaptive immune responses. Unlike CD47, which is expressed ubiquitously, SIRPα expression is mainly restricted to myeloid cells and neurons. Therefore, compared to CD47-targeted therapies, targeting SIRPα may result in differential safety and efficacy profiles, potentially enabling lower effective doses and improved pharmacokinetics and pharmacodynamics. The development of effective SIRPα antagonists is restricted by polymorphisms within the CD47-binding domain of SIRPα, necessitating pan-allele reactive anti-SIRPα antibodies for therapeutic intervention in diverse patient populations. We immunized wild-type and human antibody transgenic chickens with a multi-allele and multi-species SIRPα regimen in order to discover pan-allelic and pan-mammalian reactive anti-SIRPα antibodies suitable for clinical translation. A total of 200 antibodies were isolated and screened for SIRPα reactivity from which approximately 70 antibodies with diverse SIRPα binding profiles, sequence families, and epitopes were selected for further characterization. A subset of anti-SIRPα antibodies bound to both human SIRPα v1 and v2 alleles with high affinity ranging from low nanomolar to picomolar, potently antagonized the CD47/SIRPα interaction, and potentiated macrophage-mediated antibody-dependent cellular phagocytosis in vitro. X-ray crystal structures of five anti-SIRPα antigen-binding fragments, each with unique epitopes, in complex with SIRPα (PDB codes 6NMV, 6NMU, 6NMT, 6NMS, and 6NMR) are reported. Furthermore, some of the anti-SIRPα antibodies cross-react with cynomolgus SIRPα and various mouse SIRPα alleles (BALB/c, NOD, BL/6), which can facilitate preclinical to clinical development. These properties provide an attractive rationale to advance the development of these anti-SIRPα antibodies as a novel therapy for advanced malignancies. Abbreviations: ADCC: antibody-dependent cellular cytotoxicity; ADCP: antibody-dependent cellular phagocytosis; CFSE: carboxyfluorescein succinimidyl ester; Fab: fragment antigen binding; Fc: fragment crystallizable; FcγR: Fcγ receptor; Ig: immunoglobulin; IND: investigational new drug; MDM⊘: monocyte-derived macrophage; NOD: non-obese diabetic; scFv: single chain fragment variable; SCID: severe combined immunodeficiency; SIRP: signal-regulatory protein.


Assuntos
Anticorpos Monoclonais , Especificidade de Anticorpos , Antígenos de Diferenciação , Receptores Imunológicos , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Antígenos de Diferenciação/química , Antígenos de Diferenciação/imunologia , Antígeno CD47/imunologia , Galinhas , Cristalografia por Raios X , Epitopos/química , Epitopos/genética , Epitopos/imunologia , Feminino , Humanos , Imunoterapia , Masculino , Neoplasias/imunologia , Neoplasias/terapia , Domínios Proteicos , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/química , Receptores Imunológicos/imunologia
16.
J Contemp Brachytherapy ; 11(1): 91-98, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30911315

RESUMO

PURPOSE: Intraoperatively implanted Cesium-131 (131Cs) permanent seed brachytherapy is used to deliver highly localized re-irradiation in recurrent head and neck cancers. A single planar implant of uniform air kerma strength (AKS) seeds and 10 mm seed-to-seed spacing is used to deliver the prescribed dose to a point 5 mm or 10 mm perpendicular to the center of the implant plane. Nomogram tables to quickly determine the required AKS for rectangular and irregularly shaped implants were created and dosimetrically verified. By eliminating the need for a full treatment planning system plan, nomogram tables allow for fast dose calculation for intraoperative re-planning and for a second check method. MATERIAL AND METHODS: TG-43U1 recommended parameters were used to create a point-source model in MATLAB. The dose delivered to the prescription point from a single 1 U seed at each possible location in the implant plane was calculated. Implant tables were verified using an independent seed model in MIM Symphony LDR™. Implant tables were used to retrospectively determine seed AKS for previous cases: three rectangular and three irregular. RESULTS: For rectangular implants, the percent difference between required seed AKS calculated using MATLAB and MIM was at most 0.6%. For irregular implants, the percent difference between MATLAB and MIM calculations for individual seed locations was within 1.5% with outliers of less than 3.1% at two distal locations (10.6 cm and 8.8 cm), which have minimal dose contribution to the prescription point. The retrospectively determined AKS for patient implants using nomogram tables agreed with previous calculations within 5% for all six cases. CONCLUSIONS: Nomogram tables were created to determine required AKS per seed for planar uniform AKS 131Cs implants. Comparison with the treatment planning system confirms dosimetric accuracy that is acceptable for use as a second check or for dose calculation in cases of intraoperative re-planning.

17.
J Contemp Brachytherapy ; 10(5): 454-462, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30479623

RESUMO

PURPOSE: To review brachytherapy use in recurrent head and neck carcinoma (RHNC) with focus on its efficacy and complication rates. MATERIAL AND METHODS: A literature search of PubMed, Ovid, Google Scholar, and Scopus was conducted from 1990 to 2017. Publications describing treatment of RHNC with brachytherapy with or without surgery were included. The focus of this review is on oncologic outcomes and the safety of brachytherapy in the recurrent setting. RESULTS: Thirty studies involving RHNC treatment with brachytherapy were reviewed. Brachytherapy as adjunctive treatment to surgical resection appears to be associated with an improved local regional control and overall survival, when compared with the published rates for re-irradiation utilizing external beam radiotherapy (RT) or brachytherapy alone. Safety data remains variable with different isotopes and dose rates with implantable brachytherapy demonstrating a tolerable side effect profile. CONCLUSIONS: Although surgery remains a mainstay treatment for RHNC, intraoperative interstitial brachytherapy delivery as adjunctive therapy may improve the treatment outcome and may be associated with fewer complication rates as compared to reirradiation using external beam radiotherapy. Further investigations are required to elucidate the role of brachytherapy for RHNC.

18.
Bioorg Med Chem Lett ; 28(19): 3197-3201, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30170943

RESUMO

Utilizing the already described 3,4-bi-aryl pyridine series as a starting point, incorporation of a second ring system with a hydrogen bond donor and additional hydrophobic contacts yielded the azaindole series which exhibited potent, picomolar RSK2 inhibition and the most potent in vitro target modulation seen thus far for a RSK inhibitor. In the context of the more potent core, several changes at the phenol moiety were assessed to potentially find a tool molecule appropriate for in vivo evaluation.


Assuntos
Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Animais , Cromatografia Líquida , Desenho de Fármacos , Humanos , Espectrometria de Massas , Fenóis/farmacologia , Inibidores de Proteínas Quinases/química , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-Atividade
19.
PLoS One ; 13(8): e0201832, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30133535

RESUMO

CD47 is a widely expressed cell surface protein that functions as an immune checkpoint in cancer. When expressed by tumor cells, CD47 can bind SIRPα on myeloid cells, leading to suppression of tumor cell phagocytosis and other innate immune functions. CD47-SIRPα signaling has also been implicated in the suppression of adaptive antitumor responses, but the relevant cellular functions have yet to be elucidated. Therapeutic blockade of the CD47 pathway may stimulate antitumor immunity and improve cancer therapy. To this end, a novel CD47-blocking molecule, ALX148, was generated by fusing a modified SIRPα D1 domain to an inactive human IgG1 Fc. ALX148 binds CD47 from multiple species with high affinity, inhibits wild type SIRPα binding, and enhances phagocytosis of tumor cells by macrophages. ALX148 has no effect on normal human blood cells in vitro or on blood cell parameters in rodent and non-human primate studies. Across several murine tumor xenograft models, ALX148 enhanced the antitumor activity of different targeted antitumor antibodies. Additionally, ALX148 enhanced the antitumor activity of multiple immunotherapeutic antibodies in syngeneic tumor models. These studies revealed that CD47 blockade with ALX148 induces multiple responses that bridge innate and adaptive immunity. ALX148 stimulates antitumor properties of innate immune cells by promoting dendritic cell activation, macrophage phagocytosis, and a shift of tumor-associated macrophages toward an inflammatory phenotype. ALX148 also stimulated the antitumor properties of adaptive immune cells, causing increased T cell effector function, pro-inflammatory cytokine production, and a reduction in the number of suppressive cells within the tumor microenvironment. Taken together, these results show that ALX148 binds and blocks CD47 with high affinity, induces a broad antitumor immune response, and has a favorable safety profile.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Antineoplásicos Imunológicos/farmacologia , Antígeno CD47/antagonistas & inibidores , Imunidade Inata/efeitos dos fármacos , Fragmentos Fc das Imunoglobulinas/farmacologia , Neoplasias/tratamento farmacológico , Animais , Linhagem Celular , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Macaca fascicularis , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Transplante de Neoplasias , Neoplasias/imunologia , Fagocitose/efeitos dos fármacos , Primatas , Ratos
20.
Arch Phys Med Rehabil ; 99(1): 82-90, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28928025

RESUMO

OBJECTIVE: To examine the use and effect of the Battery of Rehabilitation Assessments and Interventions on evidence-based practice (EBP) over 6 years. DESIGN: Successive independent samples study. SETTING: Large rehabilitation system. PARTICIPANTS: Successive samples of allied health clinicians (N=372) in 2009 (n=136), 2012 (n=115), and 2015 (n=121). INTERVENTIONS: The Battery of Rehabilitation Assessments and Interventions includes 2 components: (1) a process to synthesize, adapt, and make recommendations about the application of evidence; and (2) a process to implement the recommended practices in 3 levels of care. MAIN OUTCOME MEASURES: To assess the effect of the project, surveys on EBP perspectives, use, and barriers were conducted before Battery of Rehabilitation Assessments and Interventions implementation and 3 and 6 years after implementation. Questions about effect of the project on clinical practice were included 3 and 6 years postimplementation. RESULTS: Survey data indicate the Battery of Rehabilitation Assessments and Interventions resulted in a significant increase in use of EBPs to make clinical decisions and justify care. As a result of the project, survey participants reported a substantial increase in use of outcome measures in 2012 (74%) and 2015 (91%) and evidence-based interventions in 2012 (62%) and 2015 (82%). In 2012, significant differences (P≤.01) in effect of the Battery of Rehabilitation Assessments and Interventions on practice were identified between therapists who were directly involved in the project and Interventions compared with uninvolved therapists. In 2015, no significant differences existed between involved and uninvolved therapists. CONCLUSIONS: After 6 years of sustained implementation efforts, the Battery of Rehabilitation Assessments and Interventions expedited the adoption of EBPs throughout a large system of care in rehabilitation.


Assuntos
Prática Clínica Baseada em Evidências , Terapia Ocupacional , Modalidades de Fisioterapia , Reabilitação , Patologia da Fala e Linguagem , Pesquisa Translacional Biomédica/métodos , Tomada de Decisão Clínica , Humanos , Análise de Séries Temporais Interrompida , Avaliação de Resultados em Cuidados de Saúde , Desenvolvimento de Programas , Avaliação de Programas e Projetos de Saúde , Inquéritos e Questionários
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