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1.
Ear Hear ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34524152

RESUMO

OBJECTIVES: Neonatal intensive care unit (NICU) patients are at high risk for congenital hearing loss. Previous studies have found sociodemographic factors associated with loss to follow-up for newborn hearing screening, but none have specifically studied the NICU population. Our objective is to determine if demographics and socioeconomic status is associated with loss to follow-up in a newborn population with extended NICU stay. DESIGN: A retrospective cohort study was conducted on 443 NICU infants with extended NICU stay utilizing data extracted from infant and maternal medical records at an urban safety-net hospital. RESULTS: Younger maternal age (adjusted odds ratio [OR] 0.95, confidence interval [CI] 0.91 to 0.99), higher gravidity (adjusted OR 1.39, CI 1.12 to 1.72), and former smoking status (adjusted OR 2.57, CI 1.07-6.18) were identified as independent predictors of loss to follow-up for NHS after conducting a multivariable logistic regression. Demographic and socioeconomic variables, such as sex, parity, birth weight, mode of birth, highest level of maternal education, maternal race/ethnicity, zip code metrics, and maternal language were not found to be associated with loss to follow-up. CONCLUSIONS: Maternal age, gravidity, and smoking status are risk factors for loss to follow-up for NHS in newborns with extended NICU stay, a group at high risk for hearing loss. Our findings demonstrate that socioeconomic and demographic factors for loss to follow-up in the extended-stay NICU population are distinct from the well-baby population. Further investigation of these patients will allow prioritization of limited resources to subgroups within the extended-stay NICU population at risk for loss to follow-up for newborn hearing screening.

2.
Thyroid ; 2021 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-34541890

RESUMO

BACKGROUND: The recurrent laryngeal nerve (RLN) can be injured during thyroid surgery, which can negatively affect a patient's quality of life. The impact of intraoperative anatomic variations of the RLN on nerve injury remains unclear. Objectives of this study were to (1) better understand the detailed surgical anatomic variability of the RLN with a world-wide perspective; (2) establish potential correlates between intraoperative RLN anatomy and electrophysiologic responses; and (3) use the information to minimize complications and assure accurate and safe intraoperative neural monitoring (IONM). METHODS: A large international registry database study with prospectively collected data was conducted through the International Neural Monitoring Study Group (INMSG) evaluating 1000 RLNs at risk during thyroid surgery using a specially designed online data repository. Monitored thyroid surgeries following standardized IONM guidelines were included. Cases with bulky lymphadenopathy, IONM failure, and failed RLN visualization were excluded. Systematic evaluation of the surgical anatomy of the RLN was performed using the International RLN Anatomic Classification System. In cases of loss of signal (LOS), the mechanism of neural injury was identified, and functional evaluation of the vocal cord was performed. RESULTS: A total of 1000 nerves at risk (NARs) were evaluated from 574 patients undergoing thyroid surgery at 17 centers from 12 countries and 5 continents. A higher than expected percentage of nerves followed an abnormal intraoperative trajectory (23%). LOS was identified in 3.5% of NARs, with 34% of LOS nerves following an abnormal intraoperative trajectory. LOS was more likely in cases of abnormal nerve trajectory, fixed splayed or entrapped nerves (including at the ligament of Berry), extensive neural dissection, cases of cancer invasion or when lateral lymph node dissection was needed. Traction injury was found to be the most common form of RLN injury and to be less recoverable than previous reports. CONCLUSIONS: Multicenter international studies enrolling diverse patient populations can help reshape our understanding of surgical anatomy during thyroid surgery. There can be significant variability in the anatomic and intraoperative characteristics of the RLN, which can impact the risk of neural injury.

3.
J Orthop Sports Phys Ther ; 51(8): CPG1-CPG102, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34338006

RESUMO

Work rehabilitation refers to the process of assisting workers to remain at work or return to work (RTW) in a safe and productive manner, while limiting the negative impact of restricted work, unemployment, and work disability. The primary purpose of this clinical practice guideline (CPG) is to systematically review available scientific evidence and provide a set of evidence-based recommendations for effective physical therapy evaluation, treatment, and management of individuals experiencing limitations in the ability to participate in work following injury or illness. J Orthop Sports Phys Ther 2021;51(8):CPG1-CPG102. doi:10.2519/jospt.2021.0303.


Assuntos
Doenças Profissionais/terapia , Saúde do Trabalhador , Traumatismos Ocupacionais/terapia , Modalidades de Fisioterapia , Retorno ao Trabalho , Avaliação da Deficiência , Humanos
4.
Cancer Res ; 81(16): 4290-4304, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34224371

RESUMO

In breast cancer, humoral immune responses may contribute to clinical outcomes, especially in more immunogenic subtypes. Here, we investigated B lymphocyte subsets, immunoglobulin expression, and clonal features in breast tumors, focusing on aggressive triple-negative breast cancers (TNBC). In samples from patients with TNBC and healthy volunteers, circulating and tumor-infiltrating B lymphocytes (TIL-B) were evaluated. CD20+CD27+IgD- isotype-switched B lymphocytes were increased in tumors, compared with matched blood. TIL-B frequently formed stromal clusters with T lymphocytes and engaged in bidirectional functional cross-talk, consistent with gene signatures associated with lymphoid assembly, costimulation, cytokine-cytokine receptor interactions, cytotoxic T-cell activation, and T-cell-dependent B-cell activation. TIL-B-upregulated B-cell receptor (BCR) pathway molecules FOS and JUN, germinal center chemokine regulator RGS1, activation marker CD69, and TNFα signal transduction via NFκB, suggesting BCR-immune complex formation. Expression of genes associated with B lymphocyte recruitment and lymphoid assembly, including CXCL13, CXCR4, and DC-LAMP, was elevated in TNBC compared with other subtypes and normal breast. TIL-B-rich tumors showed expansion of IgG but not IgA isotypes, and IgG isotype switching positively associated with survival outcomes in TNBC. Clonal expansion was biased toward IgG, showing expansive clonal families with specific variable region gene combinations and narrow repertoires. Stronger positive selection pressure was present in the complementarity determining regions of IgG compared with their clonally related IgA in tumor samples. Overall, class-switched B lymphocyte lineage traits were conspicuous in TNBC, associated with improved clinical outcomes, and conferred IgG-biased, clonally expanded, and likely antigen-driven humoral responses. SIGNIFICANCE: Tumor-infiltrating B lymphocytes assemble in clusters, undergoing B-cell receptor-driven activation, proliferation, and isotype switching. Clonally expanded, IgG isotype-biased humoral immunity associates with favorable prognosis primarily in triple-negative breast cancers.

5.
J Immunother Cancer ; 9(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34112739

RESUMO

BACKGROUND: Cancer immunotherapy with monoclonal antibodies and chimeric antigen receptor (CAR) T cell therapies can benefit from selection of new targets with high levels of tumor specificity and from early assessments of efficacy and safety to derisk potential therapies. METHODS: Employing mass spectrometry, bioinformatics, immuno-mass spectrometry and CRISPR/Cas9 we identified the target of the tumor-specific SF-25 antibody. We engineered IgE and CAR T cell immunotherapies derived from the SF-25 clone and evaluated potential for cancer therapy. RESULTS: We identified the target of the SF-25 clone as the tumor-associated antigen SLC3A2, a cell surface protein with key roles in cancer metabolism. We generated IgE monoclonal antibody, and CAR T cell immunotherapies each recognizing SLC3A2. In concordance with preclinical and, more recently, clinical findings with the first-in-class IgE antibody MOv18 (recognizing the tumor-associated antigen Folate Receptor alpha), SF-25 IgE potentiated Fc-mediated effector functions against cancer cells in vitro and restricted human tumor xenograft growth in mice engrafted with human effector cells. The antibody did not trigger basophil activation in cancer patient blood ex vivo, suggesting failure to induce type I hypersensitivity, and supporting safe therapeutic administration. SLC3A2-specific CAR T cells demonstrated cytotoxicity against tumor cells, stimulated interferon-γ and interleukin-2 production in vitro. In vivo SLC3A2-specific CAR T cells significantly increased overall survival and reduced growth of subcutaneous PC3-LN3-luciferase xenografts. No weight loss, manifestations of cytokine release syndrome or graft-versus-host disease, were detected. CONCLUSIONS: These findings identify efficacious and potentially safe tumor-targeting of SLC3A2 with novel immune-activating antibody and genetically modified cell therapies.

6.
Eur J Immunol ; 51(3): 544-556, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33450785

RESUMO

Cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and the Programmed Death Receptor 1 (PD-1) are immune checkpoint molecules that are well-established targets of antibody immunotherapies for the management of malignant melanoma. The monoclonal antibodies, Ipilimumab, Pembrolizumab, and Nivolumab, designed to interfere with T cell inhibitory signals to activate immune responses against tumors, were originally approved as monotherapy. Treatment with a combination of immune checkpoint inhibitors may improve outcomes compared to monotherapy in certain patient groups and these clinical benefits may be derived from unique immune mechanisms of action. However, treatment with checkpoint inhibitor combinations also present significant clinical challenges and increased rates of immune-related adverse events. In this review, we discuss the potential mechanisms attributed to single and combined checkpoint inhibitor immunotherapies and clinical experience with their use.


Assuntos
Anticorpos Monoclonais/imunologia , Antígeno CTLA-4/imunologia , Inibidores de Checkpoint Imunológico/imunologia , Melanoma/imunologia , Melanoma/terapia , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Animais , Humanos , Imunoterapia/métodos , Melanoma/metabolismo , Neoplasias Cutâneas/metabolismo
7.
Sci Rep ; 10(1): 8869, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483228

RESUMO

Antibody-Drug Conjugates (ADCs) developed as a targeted treatment approach to deliver toxins directly to cancer cells are one of the fastest growing classes of oncology therapeutics, with eight ADCs and two immunotoxins approved for clinical use. However, selection of an optimum target and payload combination, to achieve maximal therapeutic efficacy without excessive toxicity, presents a significant challenge. We have developed a platform to facilitate rapid and cost-effective screening of antibody and toxin combinations for activity and safety, based on streptavidin-biotin conjugation. For antibody selection, we evaluated internalization by target cells using streptavidin-linked antibodies conjugated to biotinylated saporin, a toxin unable to cross cell membranes. For payload selection, we biotinylated toxins and conjugated them to antibodies linked to streptavidin to evaluate antitumour activity and pre-clinical safety. As proof of principle, we compared trastuzumab conjugated to emtansine via streptavidin-biotin (Trastuzumab-SB-DM1) to the clinically approved trastuzumab emtansine (T-DM1). We showed comparable potency in reduction of breast cancer cell survival in vitro and in growth restriction of orthotopic breast cancer xenografts in vivo. Our findings indicate efficient generation of functionally active ADCs. This approach can facilitate the study of antibody and payload combinations for selection of promising candidates for future ADC development.


Assuntos
Antineoplásicos/química , Imunoconjugados/química , Toxinas Biológicas/química , Trastuzumab/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biotina/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Maitansina/química , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Saporinas/química , Estreptavidina/química , Transplante Heterólogo , Trastuzumab/uso terapêutico
8.
Int J Pediatr Otorhinolaryngol ; 136: 110181, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32563841

RESUMO

OBJECTIVES: Adenotonsillectomy (AT) is a common pediatric procedure performed for sleep disordered breathing (SDB) or chronic/recurrent tonsillitis. A better understanding of factors associated with clinical indications for AT would positively contribute to patient-centered care of these conditions. Our objective is to assess the relationships between race, ethnicity, and socioeconomic status (SES) and indications for adenotonsillectomy in pediatric patients. METHODS: A retrospective chart review was conducted for pediatric patients between the ages 0-18 years who underwent adenotonsillectomy between October 2012 and October 2017 at Boston Medical Center. Indication for surgery was categorized as sleep disordered breathing (SDB), tonsillitis, or other. Age, race, ethnicity, gender, language, distance to hospital and insurance type were collected as demographic variables. 9-Digit patient zip codes were matched to a corresponding area deprivation index (ADI) which combines 17 neighborhood level socioeconomic markers. Logistic regression analysis was performed to assess for association between demographic variables and indication for adenotonsillectomy. RESULTS: 1315 children were included in this study (mean age = 6.4 years, 0-18 years). African American (OR = 3.90, p-value <0.0001), Latino (OR = 2.602, p-value < 0.0001), and Asian American (OR = 4.439, p-value = 0.0146) patients were more likely to have SDB as an indication than Caucasian patients. Among children undergoing AT for SDB, patients who received pre-operative polysomnogram were more likely to be under 2 years old, African American, Asian American, or of Hispanic ethnicity and have higher BMI than patients who were diagnosed clinically prior to surgery. There was no statistically significant association between indications for adenotonsillectomy and ADI, distance to hospital, insurance status or language. Males were more likely have to have SDB as an indication than females (OR = 1.67, p-value = 0.0014). Younger patients under two years of age were more likely to have SDB as an indication for surgery when compared to older patients. CONCLUSION: We found significant relationships between indications for adenotonsillectomy and race and ethnicity as well as gender and age. Additionally, our study showed that indication for AT was not associated with either ADI or insurance status. This suggests that race and ethnicity are predictors of indication independent of SES. Knowledge of predictive factors of adenotonsillectomy indications may help to improve patient centered care.


Assuntos
Adenoidectomia , Síndromes da Apneia do Sono/cirurgia , Classe Social , Tonsilectomia , Tonsilite/cirurgia , Adolescente , Boston , Criança , Pré-Escolar , Doença Crônica , Grupos Étnicos/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Seleção de Pacientes , Polissonografia , Estudos Retrospectivos , Síndromes da Apneia do Sono/epidemiologia , Tonsilite/epidemiologia
9.
Br J Haematol ; 190(3): 450-457, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32307711

RESUMO

The pathophysiology of sickle cell disease (SCD) includes vasculopathy as well as anaemia. Elevated plasma homocysteine is a risk factor for vascular disease and may be associated with increased risk of vascular complications in SCD patients. In the present study, microvascular characteristics were assessed in the bulbar conjunctiva of 18 paediatric and 18 adult SCD patients, using the non-invasive technique of computer-assisted intravital microscopy. A vasculopathy severity index (SI) was computed to quantify the degree of microvasculopathy in each patient. Plasma homocysteine and several of its determinants [serum folate and vitamin B12, plasma pyridoxal-5'-phosphate (vitamin B6 status) and creatinine (kidney function)] were measured. Age was strongly correlated with microvasculopathy in the SCD patients, with the SI increasing about 0·1 unit per one-year increase in age (P < 0·001). After adjusting for age, gender, B-vitamin status and creatinine, homocysteine concentration was directly correlated with severity index (P < 0·05). Age and homocysteine concentration were independent predictors of microvasculopathy in SCD patients. It remains to be determined whether lowering homocysteine concentrations using appropriate B-vitamin supplements (folate and vitamins B12 and B6) - particularly if started early in life - could ameliorate microvasculopathy and its associated complications in SCD patients.


Assuntos
Anemia Falciforme/fisiopatologia , Homocisteína/sangue , Microcirculação , Microangiopatias Trombóticas/etiologia , Adolescente , Adulto , Anemia Falciforme/sangue , Criança , Pré-Escolar , Creatina/sangue , Ácido Fólico/sangue , Humanos , Microscopia Intravital , Pessoa de Meia-Idade , Fosfato de Piridoxal/sangue , Índice de Gravidade de Doença , Microangiopatias Trombóticas/sangue , Microangiopatias Trombóticas/fisiopatologia , Vitamina B 12/sangue
10.
Cancers (Basel) ; 12(4)2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32331483

RESUMO

Despite emerging targeted and immunotherapy treatments, no monoclonal antibodies or antibody-drug conjugates (ADCs) directly targeting tumor cells are currently approved for melanoma therapy. The tumor-associated antigen chondroitin sulphate proteoglycan 4 (CSPG4), a neural crest glycoprotein over-expressed on 70% of melanomas, contributes to proliferative signaling pathways, but despite highly tumor-selective expression it has not yet been targeted using ADCs. We developed a novel ADC comprising an anti-CSPG4 antibody linked to a DNA minor groove-binding agent belonging to the novel pyrridinobenzodiazepine (PDD) class. Unlike conventional DNA-interactive pyrrolobenzodiazepine (PBD) dimer payloads that cross-link DNA, PDD-based payloads are mono-alkylating agents but have similar efficacy and substantially enhanced tolerability profiles compared to PBD-based cross-linkers. We investigated the anti-tumor activity and safety of the anti-CSPG4-(PDD) ADC in vitro and in human melanoma xenografts. Anti-CSPG4-(PDD) inhibited CSPG4-expressing melanoma cell growth and colony formation and triggered apoptosis in vitro at low nanomolar to picomolar concentrations without off-target Fab-mediated or Fc-mediated toxicity. Anti-CSPG4-(PDD) restricted xenograft growth in vivo at 2 mg/kg doses. One 5 mg/kg injection triggered tumor regression in the absence of overt toxic effects or of acquired residual tumor cell resistance. This anti-CSPG4-(PDD) can deliver a highly cytotoxic DNA mono-alkylating payload to CSPG4-expressing tumors at doses tolerated in vivo.

11.
Front Immunol ; 11: 622442, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33569063

RESUMO

The contributions of the humoral immune response to melanoma are now widely recognized, with reports of positive prognostic value ascribed to tumor-infiltrating B cells (TIL-B) and increasing evidence of B cells as key predictors of patient response to treatment. There are disparate views as to the pro- and anti-tumor roles of B cells. B cells appear to play an integral role in forming tumor-associated tertiary lymphoid structures (TLSs) which can further modulate T cell activation. Expressed antibodies may distinctly influence tumor regulation in the tumor microenvironment, with some isotypes associated with strong anti-tumor immune response and others with progressive disease. Recently, B cells have been evaluated in the context of cancer immunotherapy. Checkpoint inhibitors (CPIs), targeting T cell effector functions, have revolutionized the management of melanoma for many patients; however, there remains a need to accurately predict treatment responders. Increasing evidence suggests that B cells may not be simple bystanders to CPI immunotherapy. Mature and differentiated B cell phenotypes are key positive correlates of CPI response. Recent evidence also points to an enrichment in activatory B cell phenotypes, and the contribution of B cells to TLS formation may facilitate induction of T cell phenotypes required for response to CPI. Contrastingly, specific B cell subsets often correlate with immune-related adverse events (irAEs) in CPI. With increased appreciation of the multifaceted role of B cell immunity, novel therapeutic strategies and biomarkers can be explored and translated into the clinic to optimize CPI immunotherapy in melanoma.


Assuntos
Anticorpos Antineoplásicos/uso terapêutico , Linfócitos B , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma , Linfócitos B/imunologia , Linfócitos B/patologia , Humanos , Melanoma/imunologia , Melanoma/patologia , Melanoma/terapia
12.
Otol Neurotol ; 40(8): 1047-1053, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31290804

RESUMO

OBJECTIVE: To review the demographics, treatment modalities, and survival of children with vestibular schwannomas. STUDY DESIGN: Analysis using the Surveillance, Epidemiology, and End Results (SEER) database. SUBJECTS AND METHODS: Pediatric patients from birth to 18 years in the SEER database were included from 2004 to 2014 based on a diagnosis of vestibular schwannoma using the primary site International Classification of Diseases (ICD) O-3 code of C72.4: acoustic nerve and the ICD O-3 histology codes of 9540/1: neurofibromatosis, Not Otherwise Specified (NOS); 9560/0: neurilemoma, NOS; or 9570/0: neuroma, NOS. RESULTS: One hundred forty-eight pediatric vestibular schwannomas (VSs) cases were identified. The mean age at diagnosis was 13.9 years (range, 4.0-18.0). Eighty-five (57.4%) patients were women. Seventy-seven (52.0%) patients had isolated unilateral VSs while 71 (48.0%) patients had either bilateral VSs or unilateral VSs with other brain, spinal cord, or cranial nerve tumors. Eighty two (55.4%) patients received surgical resection only, 45 (30.4%) received no treatment, 6 (4.1%) received radiation only, and 12 (8.1%) received surgery and radiation. The median tumor size for patients who received no treatment was 9.5 mm (interquartile range [IQR]: 8.0) compared with 33.5 mm (IQR: 23.0) for patients who received surgical care and 41.0 mm (IQR: 1.5) for patients who received both surgery and radiation (p < 0.001). The 5-year overall survival rate was 97%. CONCLUSION: Pediatric VSs tend to be diagnosed in adolescence. No men or women predominance was appreciated. Treatment varied according to tumor size. Survival rates for children with vestibular schwannomas are excellent. These data may assist healthcare providers when counseling children with vestibular schwannomas and their families.


Assuntos
Neuroma Acústico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Neuroma Acústico/epidemiologia , Neuroma Acústico/patologia , Neuroma Acústico/terapia , Programa de SEER
13.
Cell Rep ; 27(7): 1967-1978.e4, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31091437

RESUMO

Lymphatic vasculature is crucial for metastasis in triple-negative breast cancer (TNBC); however, cellular and molecular drivers controlling lymphovascular metastasis are poorly understood. We define a macrophage-dependent signaling cascade that facilitates metastasis through lymphovascular remodeling. TNBC cells instigate mRNA changes in macrophages, resulting in ß4 integrin-dependent adhesion to the lymphovasculature. ß4 integrin retains macrophages proximal to lymphatic endothelial cells (LECs), where release of TGF-ß1 drives LEC contraction via RhoA activation. Macrophages promote gross architectural changes to lymphovasculature by increasing dilation, hyperpermeability, and disorganization. TGF-ß1 drives ß4 integrin clustering at the macrophage plasma membrane, further promoting macrophage adhesion and demonstrating the dual functionality of TGF-ß1 signaling in this context. ß4 integrin-expressing macrophages were identified in human breast tumors, and a combination of vascular-remodeling macrophage gene signature and TGF-ß signaling scores correlates with metastasis. We postulate that future clinical strategies for patients with TNBC should target crosstalk between ß4 integrin and TGF-ß1.


Assuntos
Integrina beta4/metabolismo , Vasos Linfáticos/citologia , Vasos Linfáticos/patologia , Macrófagos/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Células Endoteliais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Humanos , Integrina beta4/genética , Metástase Linfática , Vasos Linfáticos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transdução de Sinais/genética , Fator de Crescimento Transformador beta1/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
14.
Front Immunol ; 10: 453, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941125

RESUMO

The immune system employs several checkpoint pathways to regulate responses, maintain homeostasis and prevent self-reactivity and autoimmunity. Tumor cells can hijack these protective mechanisms to enable immune escape, cancer survival and proliferation. Blocking antibodies, designed to interfere with checkpoint molecules CTLA-4 and PD-1/PD-L1 and counteract these immune suppressive mechanisms, have shown significant success in promoting immune responses against cancer and can result in tumor regression in many patients. While inhibitors to CTLA-4 and the PD-1/PD-L1 axis are well-established for the clinical management of melanoma, many patients do not respond or develop resistance to these interventions. Concerted efforts have focused on combinations of approved therapies aiming to further augment positive outcomes and survival. While CTLA-4 and PD-1 are the most-extensively researched targets, results from pre-clinical studies and clinical trials indicate that novel agents, specific for checkpoints such as A2AR, LAG-3, IDO and others, may further contribute to the improvement of patient outcomes, most likely in combinations with anti-CTLA-4 or anti-PD-1 blockade. This review discusses the rationale for, and results to date of, the development of inhibitory immune checkpoint blockade combination therapies in melanoma. The clinical potential of new pipeline therapeutics, and possible future therapy design and directions that hold promise to significantly improve clinical prognosis compared with monotherapy, are discussed.


Assuntos
Anticorpos Monoclonais/imunologia , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Melanoma/imunologia , Melanoma/terapia , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/imunologia , Antígeno CTLA-4/imunologia , Humanos , Imunoterapia/métodos
15.
Food Sci Nutr ; 7(4): 1426-1437, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31024716

RESUMO

Background: Women with polycystic ovary syndrome (PCOS) often have insulin resistance (IR) which may be worsened by obesity. The roles of dietary intake and activity are unclear. Our objectives were to determine whether (a) high caloric intake or inactivity explains obesity in PCOS, and (b) dietary composition is associated with PCOS phenotypes. Methods: Eighty-seven women with PCOS and 50 women without PCOS participated in this cohort study at a reproductive medicine center. Data collected included 3-day food and physical activity records, anthropometrics, and metabolic and hormonal assays. Results: Women with PCOS had increased body mass index (BMI) but similar caloric intake and activity to women without PCOS. There were no differences in protein, carbohydrates, fat, or glycemic load consumption, but women with PCOS consumed less fiber (medians: 19.6 vs. 24.7 g) and less magnesium (medians: 238.9 vs. 273.9 mg). In women with PCOS, those with IR consumed less fiber, less magnesium, and greater glycemic load than those without IR (medians: 18.2 vs. 22.1 g, 208.4 vs. 264.5 mg, 89.6 vs. 83.5). Fiber intake of women with PCOS was negatively correlated with IR, fasting insulin, glucose tolerance, testosterone, and dehydroepiandrosterone sulfate. Magnesium intake was negatively correlated with IR, C-reactive protein, and testosterone, but positively correlated with HDL cholesterol. Fiber intake and BMI accounted for 54.0% of the variance observed in IR. Conclusions: Obesity in women with PCOS could not be explained by overeating or inactivity. Increasing dietary fiber and magnesium intakes may assist in reducing IR and hyperandrogenemia in women with PCOS.

16.
Trials ; 19(1): 632, 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30445999

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) affects between 8 and 18% of women and is the leading cause of female anovulatory infertility. Unfortunately, common treatments for women trying to conceive can be ineffective as well as disruptive or harmful to patients' quality of life. Despite evidence that women with PCOS have expressed the need for alternative fertility treatments, lifestyle interventions incorporating a nutritional plan with supplementation, increased physical activity, and techniques for stress management have not been combined as a program and studied in this population. Literature suggests that each of these individual components can positively influence reproductive hormones and metabolic health. METHODS/DESIGN: This is a randomized controlled trial which will include 240 women diagnosed with PCOS, according to the Rotterdam criteria, who are trying to conceive. Participants will be randomized to either a comprehensive lifestyle intervention program or prescribed an oral fertility medication, letrozole. These two groups will be further randomized to consume either myo-inositol or a placebo. Participants will be between the ages of 18 and 37 years. Exclusion criteria include women who have already begun fertility treatment, who are currently using myo-inositol or have taken it within the past 3 months, or who are being treated for, or have a history of, an eating disorder. The primary outcome will be the ovulation rate, the secondary outcome will be conception. Other outcomes include miscarriage rates, validated rating measures of overall quality of life (including social, relational, mind/body and emotional sub-categories) and mental health scores (depression, anxiety, and stress). DISCUSSION: This trial will determine the effectiveness of a structured lifestyle-based comprehensive intervention program for women with PCOS experiencing infertility. In addition, it will determine whether supplementing with myo-inositol provides any further benefit. The objective of this study is to assess a possible non-pharmacological solution to ovulatory dysfunction in these patients and perhaps improve other associated features of PCOS. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02630485 . Registered on 15 December 2015.


Assuntos
Fármacos para a Fertilidade Feminina/administração & dosagem , Estilo de Vida Saudável , Infertilidade Feminina/terapia , Inositol/administração & dosagem , Letrozol/administração & dosagem , Ovulação/efeitos dos fármacos , Síndrome do Ovário Policístico/terapia , Administração Oral , Adolescente , Adulto , Dieta Saudável , Exercício Físico , Feminino , Fármacos para a Fertilidade Feminina/efeitos adversos , Humanos , Infertilidade Feminina/diagnóstico , Infertilidade Feminina/etiologia , Infertilidade Feminina/fisiopatologia , Inositol/efeitos adversos , Letrozol/efeitos adversos , Atenção Plena , Países Baixos , Educação de Pacientes como Assunto , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/fisiopatologia , Gravidez , Resultado da Gravidez , Taxa de Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto , Terapia de Relaxamento , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
17.
Clin Cancer Res ; 24(20): 5098-5111, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30068707

RESUMO

Purpose: Highly aggressive triple-negative breast cancers (TNBCs) lack validated therapeutic targets and have high risk of metastatic disease. Folate receptor alpha (FRα) is a central mediator of cell growth regulation that could serve as an important target for cancer therapy.Experimental Design: We evaluated FRα expression in breast cancers by genomic (n = 3,414) and IHC (n = 323) analyses and its association with clinical parameters and outcomes. We measured the functional contributions of FRα in TNBC biology by RNA interference and the antitumor functions of an antibody recognizing FRα (MOv18-IgG1), in vitro, and in human TNBC xenograft models.Results: FRα is overexpressed in significant proportions of aggressive basal like/TNBC tumors, and in postneoadjuvant chemotherapy-residual disease associated with a high risk of relapse. Expression is associated with worse overall survival. TNBCs show dysregulated expression of thymidylate synthase, folate hydrolase 1, and methylenetetrahydrofolate reductase, involved in folate metabolism. RNA interference to deplete FRα decreased Src and ERK signaling and resulted in reduction of cell growth. An anti-FRα antibody (MOv18-IgG1) conjugated with a Src inhibitor significantly restricted TNBC xenograft growth. Moreover, MOv18-IgG1 triggered immune-dependent cancer cell death in vitro by human volunteer and breast cancer patient immune cells, and significantly restricted orthotopic and patient-derived xenograft growth.Conclusions: FRα is overexpressed in high-grade TNBC and postchemotherapy residual tumors. It participates in cancer cell signaling and presents a promising target for therapeutic strategies such as ADCs, or passive immunotherapy priming Fc-mediated antitumor immune cell responses. Clin Cancer Res; 24(20); 5098-111. ©2018 AACR.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Receptor 1 de Folato/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/genética , Modelos Animais de Doenças , Feminino , Receptor 1 de Folato/genética , Receptor 1 de Folato/metabolismo , Expressão Gênica , Humanos , Imuno-Histoquímica , Camundongos , Modelos Biológicos , Terapia de Alvo Molecular , Neoplasia de Células Basais , Interferência de RNA , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/patologia , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Cell Rep ; 24(3): 630-641, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-30021161

RESUMO

The immunosuppressive transmembrane protein PD-L1 was shown to traffic via the multivesicular body (MVB) and to be released on exosomes. A high-content siRNA screen identified the endosomal sorting complexes required for transport (ESCRT)-associated protein ALIX as a regulator of both EGFR activity and PD-L1 surface presentation in basal-like breast cancer (BLBC) cells. ALIX depletion results in prolonged and enhanced stimulation-induced EGFR activity as well as defective PD-L1 trafficking through the MVB, reduced exosomal secretion, and its redistribution to the cell surface. Increased surface PD-L1 expression confers an EGFR-dependent immunosuppressive phenotype on ALIX-depleted cells. An inverse association between ALIX and PD-L1 expression was observed in human breast cancer tissues, while an immunocompetent mouse model of breast cancer revealed that ALIX-deficient tumors are larger and show an increased immunosuppressive environment. Our data suggest that ALIX modulates immunosuppression through regulation of PD-L1 and EGFR and may, therefore, present a diagnostic and therapeutic target for BLBC.


Assuntos
Antígeno B7-H1/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ciclo Celular/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Receptores ErbB/metabolismo , Imunossupressão , Animais , Técnicas Biossensoriais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Microambiente Celular , Exossomos/metabolismo , Exossomos/ultraestrutura , Feminino , Transferência Ressonante de Energia de Fluorescência , Humanos , Ligantes , Camundongos Endogâmicos BALB C
19.
Int J Pediatr Otorhinolaryngol ; 112: 109-112, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30055718

RESUMO

OBJECTIVE: To examine the types of pediatric middle ear tumors and review the demographics, management, and survival of pediatric patients with rhabdomyosarcoma (RMS) of the middle ear. METHODS: Pediatric patients in the Surveillance, Epidemiology, and End Results (SEER) database were included from 1973 to 2014 based on a diagnosis of middle ear tumors using the ICD O-3 code: C30.1: Middle ear primary site. Patients were included from ages 0-18 years. RESULTS: Forty pediatric middle ear tumor cases were identified. Twenty patients were female (50%). Twenty-seven (67.5%) cases were rhabdomyosarcomas (RMS). Pediatric RMS patients tended to be diagnosed in early childhood (mean age 5.30 years, standard deviation 2.9, range 1.00-13.00, 59.3% of patients were ages 5 or below). Most pediatric RMS patients received chemotherapy and radiation therapy as part of the treatment regimen (88.8%). Finally, the 5-year overall and disease-specific survival rates were 59% and 63% respectively. CONCLUSIONS: Pediatric middle ear tumors are rare. Females and male pediatric patients are both at risk for middle ear tumors. RMS is the most common malignant middle ear tumor affecting pediatric patients. Despite the use of multimodality therapies, survival rates for pediatric patients with RMS of the middle ear are low. Physicians may consider including middle ear tumors on the differential diagnosis for pediatric patients with symptoms presenting similarly to non-resolving otitis media.


Assuntos
Neoplasias da Orelha/epidemiologia , Orelha Média , Rabdomiossarcoma Embrionário/epidemiologia , Adenocarcinoma Papilar/epidemiologia , Adolescente , Distribuição por Idade , Quimiorradioterapia , Criança , Pré-Escolar , Terapia Combinada , Gerenciamento Clínico , Neoplasias da Orelha/mortalidade , Neoplasias da Orelha/terapia , Feminino , Histiocitose de Células de Langerhans/epidemiologia , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Tumores Neuroectodérmicos Primitivos Periféricos/epidemiologia , Procedimentos Cirúrgicos Otorrinolaringológicos , Prognóstico , Rabdomiossarcoma/epidemiologia , Rabdomiossarcoma/mortalidade , Rabdomiossarcoma/terapia , Rabdomiossarcoma Embrionário/mortalidade , Rabdomiossarcoma Embrionário/terapia , Programa de SEER , Distribuição por Sexo , Taxa de Sobrevida , Estados Unidos/epidemiologia
20.
J Obstet Gynaecol Can ; 40(7): 978-987, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29921434

RESUMO

OBJECTIVE: To review current non-pharmacologic and pharmacologic options for ovulation induction in women with polycystic ovary syndrome (PCOS). OPTIONS: This guideline reviews the evidence for the various options for ovulation induction in PCOS. OUTCOMES: Ovulation, pregnancy and live birth rates, risks, and side effects are the outcomes of interest. EVIDENCE: Published literature was retrieved through searches of Medline using appropriate controlled vocabulary and key words spanning from 2000 to 2016. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and of health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The evidence gathered was reviewed and evaluated by the Reproductive Endocrinology and Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada. The quality of evidence was quantified using the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS: Benefits include weight reduction and improvements in ovulation, pregnancy, and live birth rates. Potential harms include medication side effects and multiple pregnancies. VALIDATION: These guidelines have been reviewed and approved by the Reproductive Endocrinology and Infertility Committee of the SOGC. CONCLUSION: First line management of infertility once a diagnosis of PCOS is made should include weight loss and exercise with goals to below class 2 obesity (BMI <35 kg/m2) as applicable. Subsequently, first line medical therapy for ovulation induction should include aromatase inhibitors (now considered both safe and effective) and selective estrogen receptor modulators as available. Insulin sensitizers should not be used as first line therapy but as adjuncts as appropriate. Referral to a reproductive endocrinologist should be considered if there is failure or resistance to these approaches to consider ovulation induction with gonadotropins or IVF as appropriate. SPONSOR: The Society of Obstetricians and Gynaecologists of Canada.


Assuntos
Indução da Ovulação , Síndrome do Ovário Policístico , Canadá , Feminino , Ginecologia , Humanos , Obstetrícia , Gravidez , Sociedades Médicas
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