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PURPOSE: The existence of cancer disparities is well known. Focus on alleviating such disparities centers on diagnosis, treatment, and mortality. This review surveyed current knowledge of health disparities that exist in the acute survivorship period (immediately following diagnosis and treatment) and their contributors, particularly for African-American breast cancer survivors (AA-BCS). METHODS: Utilizing the ASCO four components of survivorship care, we explore disparities in surveillance and effects of cancer and therapies that AA-BCS face within the acute survivorship period (the years immediately following diagnosis). A literature review of PUBMED, Scopus, and Cochrane databases was conducted to identify articles related to AA-BCS acute survivorship. The search yielded 97 articles. Of the 97 articles, 38 articles met inclusion criteria. RESULTS: AA-BCS experience disparate survivorship care, which negatively impacts quality of life and health outcomes. Challenges exist in surveillance, interventions for late effects (e.g., quality-of-life outcomes, cardiotoxicity, and cognitive changes), preventing recurrence with promotion of healthy living, and coordinating care among the healthcare team. CONCLUSIONS: This overview identified current knowledge on the challenges in survivorship among AA-BCS. Barriers to optimal survivorship care inhibit progress in eliminating breast cancer disparities. Research addressing best practices for survivorship care is needed for this population. Implementation of culturally tailored care may reduce breast cancer disparities among AA-BCS.
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Neoplasias da Mama/psicologia , Sobreviventes de Câncer/psicologia , Adulto , Negro ou Afro-Americano/etnologia , Negro ou Afro-Americano/psicologia , Assistência ao Convalescente/métodos , Antineoplásicos/efeitos adversos , Neoplasias da Mama/etnologia , Neoplasias da Mama/terapia , Transtornos Cognitivos/induzido quimicamente , Comunicação , Dieta , Exercício Físico/fisiologia , Feminino , Preservação da Fertilidade , Disparidades nos Níveis de Saúde , Cardiopatias/induzido quimicamente , Humanos , Mamoplastia/psicologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Relações Profissional-Paciente , Qualidade de Vida , Disfunções Sexuais Fisiológicas/etiologia , Disfunções Sexuais Psicogênicas/etiologia , Inquéritos e QuestionáriosRESUMO
Resistance to the human epidermal growth factor receptor (HER2)-targeted antibody trastuzumab is a major clinical concern in the treatment of HER2-positive metastatic breast cancer. Increased expression or signaling from the insulin-like growth factor-1 receptor (IGF-1R) has been reported to be associated with trastuzumab resistance. However, the specific molecular and biologic mechanisms through which IGF-1R promotes resistance or disease progression remain poorly defined. In this study, we found that the major biologic effect promoted by IGF-1R was invasion, which was mediated by both Src-focal adhesion kinase (FAK) signaling and Forkhead box protein M1 (FoxM1). Cotargeting IGF-1R and HER2 using either IGF-1R antibodies or IGF-1R short hairpin RNA in combination with trastuzumab resulted in significant but modest growth inhibition. Reduced invasion was the most significant biologic effect achieved by cotargeting IGF-1R and HER2 in trastuzumab-resistant cells. Constitutively active Src blocked the anti-invasive effect of IGF-1R/HER2 cotargeted therapy. Furthermore, knockdown of FoxM1 blocked IGF-1-mediated invasion, and dual targeting of IGF-1R and HER2 reduced expression of FoxM1. Re-expression of FoxM1 restored the invasive potential of IGF-1R knockdown cells treated with trastuzumab. Overall, our results strongly indicate that therapeutic combinations that cotarget IGF-1R and HER2 may reduce the invasive potential of cancer cells that are resistant to trastuzumab through mechanisms that depend in part on Src and FoxM1.
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Neoplasias da Mama/metabolismo , Quinase 1 de Adesão Focal/biossíntese , Fatores de Transcrição Forkhead/biossíntese , Regulação Neoplásica da Expressão Gênica , Receptor ErbB-2/biossíntese , Receptor IGF Tipo 1/biossíntese , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Proteína Forkhead Box M1 , Genes src/fisiologia , Humanos , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Transdução de Sinais/fisiologiaRESUMO
Epidermal growth factor receptor (EGFR) is a validated target for several cancers including lung, colorectal, and certain subtypes of breast cancer. Cetuximab targets ligand binding of EGFR, but major problems like high cost, short t1/2, toxicity, and emergence of resistance are associated with the drug. Immunization with EGFR B cell epitopes will train the immune system to produce specific Abs that can kill cancer cells. Also, therapy with stable, less-expensive, and nontoxic EGFR peptide mimics will block EGFR signaling and inhibit cancer growth. We designed three peptides based on the contact sites between EGF and EGFR. The B cell epitopes were synthesized alone and also linked with the measles virus T cell epitope to produce a chimeric peptide vaccine. The peptide vaccines were immunogenic in both mice and rabbits and Abs raised against the vaccine specifically bound EGFR-expressing cells and recombinant human EGFR protein. The peptide mimics and the anti-peptide Abs were able to inhibit EGFR signaling pathways. Immunization with the peptide vaccine or treatment with the B cell epitopes significantly reduced tumor growth in both transplantable breast and lung cancer models. Immunohistochemical analysis also showed significant reductions in microvascular density and actively dividing cells in the tumor sections after treatment in the FVB/n breast cancer model. The 418-435 B cell epitope was the best candidate both as a vaccine or peptide mimic because it caused significant inhibition in the two mouse models. Our results show that this novel EGFR B cell epitope has great potential to be used as a vaccine or treatment option for EGFR-expressing cancers.
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Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Receptores ErbB/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/prevenção & controle , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/prevenção & controle , Peptidomiméticos , Animais , Vacinas Anticâncer/metabolismo , Linhagem Celular Tumoral , Epitopos de Linfócito B/administração & dosagem , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito B/metabolismo , Receptores ErbB/administração & dosagem , Receptores ErbB/antagonistas & inibidores , Humanos , Ligantes , Neoplasias Pulmonares/imunologia , Neoplasias Mamárias Experimentais/imunologia , Camundongos , Fosforilação/imunologia , Ligação Proteica/imunologia , Estrutura Terciária de Proteína , Coelhos , Transdução de Sinais/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/metabolismoRESUMO
Angiogenesis, or formation of new blood vessels, is crucial to cancer tumor growth. Tumor growth, progression, and metastasis are critically influenced by the production of the pro-angiogenic vascular endothelial growth factor (VEGF). Promising anti-angiogenic drugs are currently available; however, their susceptibilities to drug resistance and long term toxicity are serious impediments to their use, thus requiring the development of new therapeutic approaches for safe and effective angiogenic inhibitors. In this work, peptides were designed to mimic the VEGF-binding site to its receptor VEGFR-2. The VEGF conformational peptide mimic, VEGF-P3(CYC), included two artificial cysteine residues, which upon cyclization constrained the peptide in a loop native-like conformation to better mimic the anti-parallel structure of VEGF. The engineered cyclic VEGF mimic peptide demonstrated the highest affinity to VEGFR-2 by surface plasmon resonance assay. The VEGF peptide mimics were evaluated as inhibitors in several in vitro assays in which VEGF-dependent signaling pathways were observed. All VEGF mimics inhibited VEGFR-2 phosphorylation with VEGF-P3(CYC) showing the highest inhibitory effects when compared with unstructured peptides. Additionally, we show in several angiogenic in vitro assays that all the VEGF mimics inhibited endothelial cell proliferation, migration, and network formation with the conformational VEGF-P3 (CYC) being the best. The VEGF-P3(CYC) also caused a significant delay in tumor development in a transgenic model of VEGF(+/-)Neu2-5(+/-). These results indicate that the structure-based design is important for the development of this peptidomimetic and for its anti-angiogenic effects.
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Inibidores da Angiogênese/farmacologia , Materiais Biomiméticos/farmacologia , Células Endoteliais/metabolismo , Peptídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Animais , Sítios de Ligação , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Camundongos , Camundongos Transgênicos , Peptídeos/síntese química , Peptídeos/química , Fosforilação/efeitos dos fármacos , Coelhos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
HER-2 is a member of the EGF receptor family and is overexpressed in 20-30% of breast cancers. HER-2 overexpression causes increased expression of VEGF at both the RNA and protein levels. HER-2 and VEGF are therefore considered good targets for cancer treatment, which has led to the development of two humanized monoclonal antibodies (mAb) pertuzumab and bevacizumab. Although passive immunotherapy with these Abs are approved for treatment of advanced breast cancer, a number of concerns exist. Treatment is expensive, has a limited duration of action, and is usually accompanied by serious side effects. We hypothesized that therapy with conformational peptide mimics aimed at blocking receptor-ligand interaction is potentially safer with little toxicity, cheaper with a longer half-life, and has greater penetrating abilities than mAbs. We designed and synthesized peptides based on the binding of HER-2 with pertuzumab and VEGF with VEGFR2. We show that treatment with the peptide mimics induces potent anti-tumor responses in vitro as determined by cell viability, proliferation, and HER2 phosphorylation assays. We also demonstrate in a transplantable BALB/c mouse tumor model that treatment with the peptide mimics resulted in a greater delay in tumor growth and development. Similarly, treatment with the peptide mimics inhibited angiogenesis in vivo as assessed by a Matrigel plug assay. To address the problem of degradability of L-amino acid peptides in vivo, we synthesized the retro-inverso D-peptide mimics that resulted in higher efficacy in treatment. Our study shows that combination treatment with HER-2 and VEGF peptide mimics provides greater efficacy than individual treatments.
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Inibidores da Angiogênese/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Materiais Biomiméticos/farmacocinética , Neoplasias Experimentais/tratamento farmacológico , Peptídeos/farmacologia , Receptor ErbB-2 , Fator A de Crescimento do Endotélio Vascular , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Peptídeos/síntese química , Peptídeos/químicaRESUMO
The ErbB family (HER-1, HER-2, HER-3 and HER-4) of receptor tyrosine kinases has been the focus of cancer immunotherapeutic strategies while antiangiogenic therapies have focused on VEGF and its receptors VEGFR-1 and VEGFR-2. Agents targeting receptor tyrosine kinases in oncology include therapeutic antibodies to receptor tyrosine kinase ligands or the receptors themselves, and small-molecule inhibitors. Many of the US FDA-approved therapies targeting HER-2 and VEGF exhibit unacceptable toxicities, and show problems of efficacy, development of resistance and unacceptable safety profiles that continue to hamper their clinical progress. The combination of different peptide vaccines and peptidomimetics targeting specific molecular pathways that are dysregulated in tumors may potentiate anticancer immune responses, bypass immune tolerance and circumvent resistance mechanisms. The focus of this review is to discuss efforts in our laboratory spanning two decades of rationally developing peptide vaccines and therapeutics for breast cancer. This review highlights the prospective benefit of a new, untapped category of therapies biologically targeted to EGF receptor (HER-1), HER-2 and VEGF with potential peptide 'blockbusters' that could lay the foundation of a new paradigm in cancer immunotherapy by creating clinical breakthroughs for safe and efficacious cancer cures.
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Vacinas Anticâncer/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Neoplasias/terapia , Vacinas de Subunidades Antigênicas/uso terapêutico , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Vacinas Anticâncer/farmacologia , Modelos Animais de Doenças , Epitopos de Linfócito B/imunologia , Receptores ErbB/química , Receptores ErbB/imunologia , Humanos , Imunoterapia , Mimetismo Molecular/imunologia , Terapia de Alvo Molecular , Neoplasias/imunologia , Neoplasias/metabolismo , Neovascularização Patológica/terapia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/química , Receptor ErbB-2/imunologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Vacinas de Subunidades Antigênicas/farmacologia , Fatores de Crescimento do Endotélio Vascular/química , Fatores de Crescimento do Endotélio Vascular/imunologiaRESUMO
Huntington's disease (HD) is a neurodegenerative dementia with a well recognised genetic cause. Alcohol misuse is a major environmental factor relevant to numerous neurological presentations, including HD. We explored the effects of alcohol intake on clinical features of HD by means of data from the Enroll-HD, which is a global registry study. A retrospective observational study making use of the Enroll-HD periodic dataset up to 2020 (in accordance with the Enroll-HD guidelines, encompassing 16,120 subjects with the HD gene (CAG expansion > 36), was carried out. This included 180 sites in 21 countries. The study looked at the association of alcohol use with the clinical presentation of HD, specifically looking into the age of first symptoms and HD severity. We also describe a specific case with manifest HD, a participant in the Enroll-HD study, whereby the patient's obsessionality was central to her pattern of high alcohol intake and to her successful avoidance of alcohol thereafter. A record of past problems with high alcohol intake was more common in the group with manifest HD (9.0%, n = 1121) when compared with the pre-manifest carriers of the HD genetic abnormality (2.3%, n = 339). Age at onset of symptoms was not significantly influenced by current alcohol misuse, or past misuse. The severity of clinical impairments in HD was influenced by alcohol. Patients who reported high alcohol intake in the past had a statistically significant increase in motor impairments, by the Unified Huntington's Disease Rating Scale total motor score (Kruskal-Wallis, post hoc Dunn's, p < 0.001), and a significantly higher burden of psychiatric symptoms by the Problem Behaviours Assessment score (Kruskal-Wallis, post hoc Dunn's, p < 0.01) compared with those not reporting high alcohol use. However, the past alcohol group did not have a lower Mini Mental State Examination score (Kruskal-Wallis, post hoc Dunn's, p > 0.05) The first symptom of HD, as determined by the assessing clinician, was more likely to be psychiatric disturbance in patients currently misusing alcohol or those with prior history of alcohol misuse (55% and 31% respectively) when compared with controls (5%). Individual case experience, such as that presented in this study, shows that HD and alcohol, two major genetic and environmental contributors to neurodegeneration, interact in producing clinical problems. However, the complexities of these interactions are difficult to define, and may require larger studies dedicated to exploring the various factors in this interaction.
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Doença de Huntington , Idade de Início , Feminino , Humanos , Doença de Huntington/epidemiologia , Doença de Huntington/genética , Sistema de Registros , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
African American (AA) women have a 42% higher breast cancer death rate compared to white women despite recent advancements in management of the disease. We examined racial differences in clinical and tumor characteristics, treatment and survival in patients diagnosed with breast cancer between 2005 and 2014 at a single institution, the James Cancer Hospital, and who were included in the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Cancer Registry in Columbus OH. Statistical analyses included likelihood ratio chi-square tests for differences in proportions, as well as univariate and multivariate Cox proportional hazards regressions to examine associations between race and overall and progression-free survival probabilities. AA women made up 10.2% (469 of 4593) the sample. Average time to onset of treatment after diagnosis was almost two times longer in AA women compared to white women (62.0 days vs 35.5 days, p < 0.0001). AA women were more likely to report past or current tobacco use, experience delays in treatment, have triple negative and late stage breast cancer, and were less likely to receive surgery, especially mastectomy and reconstruction following mastectomy. After adjustment for confounding factors (age, grade, and surgery), overall survival probability was significantly associated with race (HR = 1.33; 95% CI 1.03-1.72). These findings highlight the need for efforts focused on screening and receipt of prompt treatment among AA women diagnosed with breast cancer.
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Riso , Transtornos do Humor/diagnóstico , Doença de Parkinson/diagnóstico , Adulto , Antiparkinsonianos/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Diagnóstico Diferencial , Dopaminérgicos/uso terapêutico , Feminino , Humanos , Hipocinesia/diagnóstico , Hipocinesia/tratamento farmacológico , Hipocinesia/metabolismo , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Cintilografia , Resultado do Tratamento , Tremor/diagnóstico , Tremor/tratamento farmacológico , Tremor/metabolismoRESUMO
The human epidermal growth factor receptor 3 (HER-3/ErbB3) is a unique member of the human epidermal growth factor family of receptors, because it lacks intrinsic kinase activity and ability to heterodimerize with other members. HER-3 is frequently upregulated in cancers with epidermal growth factor receptor (EGFR/HER-1/ErbB1) or human epidermal growth factor receptor 2 (HER-2/ErBB2) overexpression, and targeting HER-3 may provide a route for overcoming resistance to agents that target EGFR or HER-2. We have previously developed vaccines and peptide mimics for HER-1, HER-2 and vascular endothelial growth factor (VEGF). In this study, we extend our studies by identifying and evaluating novel HER-3 peptide epitopes encompassing residues 99-122, 140-162, 237-269 and 461-479 of the HER-3 extracellular domain as putative B-cell epitopes for active immunotherapy against HER-3 positive cancers. We show that the HER-3 vaccine antibodies and HER-3 peptide mimics induced antitumor responses: inhibition of cancer cell proliferation, inhibition of receptor phosphorylation, induction of apoptosis and antibody dependent cellular cytotoxicity (ADCC). Two of the HER-3 epitopes 237-269 (domain II) and 461-479 (domain III) significantly inhibited growth of xenografts originating from both pancreatic (BxPC3) and breast (JIMT-1) cancers. Combined therapy of HER-3 (461-471) epitope with HER-2 (266-296), HER-2 (597-626), HER-1 (418-435) and insulin-like growth factor receptor type I (IGF-1R) (56-81) vaccine antibodies and peptide mimics show enhanced antitumor effects in breast and pancreatic cancer cells. This study establishes the hypothesis that combination immunotherapy targeting different signal transduction pathways can provide effective antitumor immunity and long-term control of HER-1 and HER-2 overexpressing cancers.
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The insulin-like growth factor-1 receptor (IGF-1R) plays a crucial role in cellular growth, proliferation, transformation, and inhibition of apoptosis. A myriad of human cancer types have been shown to overexpress IGF-1R, including breast and pancreatic adenocarcinoma. IGF-1R signaling interferes with numerous receptor pathways, rendering tumor cells resistant to chemotherapy, anti-hormonal therapy, and epidermal growth factor receptor (EGFR, also known as HER-1) and v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2, (ERBB2, best known as HER-2) -targeted therapies. Targeting the IGF:IGF-1R axis with innovative peptide inhibitors and vaccine antibodies thus represents a promising therapeutic strategy to overcome drug resistance and to provide new avenues for individualized and combinatorial treatment strategies. In this study, we designed, synthesized, and characterized several B-cell epitopes from the IGF-1:IGF-1R axis. The chimeric peptide epitopes were highly immunogenic in outbred rabbits, eliciting high levels of peptide vaccine antibodies. The IGF-1R peptide antibodies and peptide mimics inhibited cell proliferation and receptor phosphorylation, induced apoptosis and antibody-dependent cellular cytotoxicity (ADCC), and significantly inhibited tumor growth in the transplantable BxPC-3 pancreatic and JIMT-1 breast cancer models. Our results showed that the peptides and antibodies targeting residues 56-81 and 233-251 are potential therapeutic and vaccine candidates for the treatment of IGF-1R-expressing cancers, including those that are resistant to the HER-2-targeted antibody, trastuzumab. Additionally, we found additive antitumor effects for the combination treatment of the IGF-1R 56-81 epitope with HER-1-418 and HER-2-597 epitopes. Treatment with the IGF-1R/HER-1 or IGF-1R/HER-2 combination inhibited proliferation, invasion, and receptor phosphorylation, and induced apoptosis and ADCC, to a greater degree than single agents.
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A promising new era of cancer therapeutics with agents that inhibit specific growth stimulatory pathways is finding a new niche in our armamentarium in the war against cancer. Targeted cancer therapeutics, including humanized monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are amongst the major treatment options for cancer today together with cytotoxic chemotherapies. Targeted therapies are more selective for cancer cells and improve the quality of life for cancer patients undergoing treatment. Many of these drugs have been approved by the FDA, and several more are being studied in clinical trials. Although development of targeted therapeutics has improved cancer treatment significantly, the harsh reality is that the "War on Cancer" still exists. Major challenges still exist with the currently marketed inhibitors, including limitations associated with mAbs and TKIs drug types, acquired mechanisms of drug resistance that cause patient relapse, and tumor heterogeneity. Today, there is an urgent need for the development of novel anti-tumor agents that are cheaper, stable, can selectively target cancer dependent pathways without affecting normal cells, and most importantly, avoid development of resistance mechanisms. Peptide mimics have the potential benefits of being highly selective, stable, cheap, and non-toxic. The focus of this review is to discuss the disadvantages associated with the use of monoclonal antibodies and tyrosine kinase inhibitors. A special emphasis will be placed on efforts taken in our laboratory to 1) design peptide vaccines and therapeutics that target cancer dependent pathways and 2) use a combination approach that will shut down alternative mechanisms that lead to resistance.
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Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Vacinas de Subunidades Antigênicas/uso terapêutico , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/tratamento farmacológico , Peptídeos/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , RecidivaRESUMO
[This corrects the article on p. 1048 in vol. 1.].
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HER-2 and the vascular endothelial factor receptor (VEGF) represent validated targets for the therapy of multiple tumor types and inhibitors of these receptors have gained increasing importance in the clinic. In this context, novel bioactive agents associated with better therapeutic outcomes and improved safety profile are urgently required. Specifically engineered HER-2- and VEGF-derived peptides in combination with low-dose chemotherapy might provide a substantial impact on tumor metastasis and cancer progression. We tested the antitumor effects of HER-2 and VEGF peptide mimics in combination with metronomic paclitaxel in both PyMT and Balb/c murine model challenged with TUBO cells. The combination of low-dose paclitaxel and HER-2 or VEGF peptide mimics had greater inhibitory effects than either agent alone. Peptide treatment caused virtually no cardiotoxic effects, while paclitaxel and the anti-HER-2 antibody trastuzumab (Herceptin), exerted consistent cardiotoxicity. The combination regimen also promoted significant reductions in tumor burden and prolonged survival rates in both transgenic and transplantable tumor models. Tumor weights were significantly reduced in mice treated with HER-2 peptides alone, and even more in animals that received HER-2 peptide with low-dose paclitaxel, which alone had no significant effects on tumor growth in the transgenic model. Specifically engineered native peptide sequences from HER-2 and VEGF used in combination with metronomic paclitaxel demonstrate enhanced anticancer efficacy and an encouraging safety profile. This novel approach to targeted therapy may offer new avenues for the treatment of breast cancer and other solid tumors that overexpress HER-2 and VEGF.
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Overexpression of HER-2 and VEGF plays a key role in the development and metastasis of several human cancers. Many FDA-approved therapies targeting both HER-2 (Trastuzumab, Herceptin) and VEGF (Bevacizumab, Avastin) are expensive, have unacceptable toxicities and are often associated with the development of resistance. Here, we evaluate the dual antitumor effects of combining designed particular HER-2 peptide vaccine with VEGF peptide mimics. In vitro, HER-2 phosphorylation and antibody-dependent cellular toxicity were used to validate whether combining HER-2- and VEGF-targeting therapies would be effective. Moreover, a two-pronged approach was tested in vivo: (1) active immunotherapy with conformational HER-2 B-cell epitope vaccines and (2) anti-angiogenic therapy with a peptide structured to mimic VEGF. A transplantable BALB/c mouse model challenged with TUBO cells was used to test the effects of the HER-2 peptide vaccine combined with VEGF peptide mimics. Tumor sections after treatment were stained for blood vessel density and actively dividing cells. Our results show that immunization with an HER-2 peptide epitope elicits high affinity HER-2 native antibodies that are effective in inhibiting tumor growth in vivo, an effect that is enhanced by VEGF peptide mimics. We demonstrate that the combination of HER-2 and VEGF peptides induces potent anti-tumor and anti-angiogenic responses.
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Post-concussion syndrome is common after head injury. It consists of a triad of physical, cognitive and psychological symptoms that occur after a head trauma and cause significant social and occupational disability. This article examines the clinical features, epidemiology, aetiology and treatment of the condition.
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Síndrome Pós-Concussão , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Síndrome Pós-Concussão/diagnóstico , Síndrome Pós-Concussão/etiologia , Síndrome Pós-Concussão/terapia , PrognósticoRESUMO
PURPOSE To evaluate the maximum-tolerated dose (MTD), safety profile, and immunogenicity of two chimeric, B-cell epitopes derived from the human epidermal growth factor receptor (HER2) extracellular domain in a combination vaccine with a promiscuous T-cell epitope (ie, MVF) and nor-muramyl-dipeptide as adjuvant emulsified in SEPPIC ISA 720. PATIENTS AND METHODS Eligible patients with metastatic and/or recurrent solid tumors received three inoculations on days 1, 22, and 43 at doses of total peptide that ranged from 0.5 to 3.0 mg. Immunogenicity was evaluated by enzyme-linked immunosorbent assay, flow cytometry, and HER2 signaling assays. Results Twenty-four patients received three inoculations at the intended dose levels, which elicited antibodies able to recognize native HER2 receptor and inhibited both the proliferation of HER2-expressing cell lines and phosphorylation of the HER2 protein. The MTD was determined to be the highest dose level of 3.0 mg of the combination vaccine. There was a significant increase from dose level 1 (0.5 mg) to dose level 4 (3.0 mg) in HER2-specific antibodies. Four patients (one each with adrenal, colon, ovarian, and squamous cell carcinoma of unknown primary) were judged to have stable disease; two patients (one each with endometrial and ovarian cancer) had partial responses; and 11 patients had progressive disease. Patients with stable disease received 6-month boosts, and one patient received a 20-month boost. CONCLUSION The combination vaccines were safe and effective in eliciting antibody responses in a subset of patients (62.5%) and were associated with no serious adverse events, autoimmune disease, or cardiotoxicity. There was preliminary evidence of clinical activity in several patients.
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Vacinas Anticâncer/imunologia , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Receptor ErbB-2/imunologia , Adjuvantes Imunológicos , Adulto , Idoso , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/efeitos adversos , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Ensaio de Imunoadsorção Enzimática , Epitopos de Linfócito B/administração & dosagem , Epitopos de Linfócito B/efeitos adversos , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/efeitos adversos , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Receptor ErbB-2/administração & dosagem , Proteínas Recombinantes de Fusão/imunologiaRESUMO
OBJECTIVES: Numerous long-term studies of depression in psychiatric settings have shown a poor clinical outcome but little emphasis has been placed on psychosocial or functional outcome in studies to date. This article reviews published data on long-term social functioning after depression and considers why psychosocial recovery appears delayed compared with clinical recovery. METHODS: Searches were carried out of the databases MEDLINE, PSYCHLIT and EMBASE for articles published from 1980 using keywords relating to social and functional outcomes of unipolar and bipolar depression. Review articles and relevant textbooks were also searched. RESULTS: The few outcome studies published have described long-term functional impairment in the majority of patients but have been limited by methodological shortcomings. Psychosocial impairment tends to persist even after clinical remission from depression. Residual symptomatology after remission from depression may lead to enduring psychosocial impairment, as may subtle neurocognitive deficits. Axis I and II comorbidities predict a poor psychosocial outcome, but episodes of depression do not appear to lead to personality 'scarring'. CONCLUSIONS: Future outcome studies need to focus on longitudinal social functioning. Full functional recovery after an episode of depression should be the goal of treatment as enduring residual symptoms lead to long-term psychosocial impairment.
Assuntos
Transtorno Depressivo Maior/terapia , Pessoal de Saúde , Psiquiatria/métodos , Comportamento Social , Transtornos de Adaptação/epidemiologia , Transtornos de Adaptação/psicologia , Transtornos de Adaptação/terapia , Encéfalo/fisiopatologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/fisiopatologia , Comorbidade , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/epidemiologia , Humanos , Testes Neuropsicológicos , Psicologia , Psicoterapia , Indução de Remissão , Índice de Gravidade de Doença , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Fatores de TempoAssuntos
Alucinações/diagnóstico , Doença por Corpos de Lewy/diagnóstico , Idoso de 80 Anos ou mais , Feminino , Folclore , Alucinações/tratamento farmacológico , Alucinações/etnologia , Humanos , Irlanda/etnologia , Doença por Corpos de Lewy/etnologia , Doença por Corpos de Lewy/psicologia , Masculino , Mitologia/psicologiaRESUMO
Unipolar depression should be viewed as a chronic illness with multiple phases rather than as a relapsing-remitting disorder. Incomplete remission from depression is common, with approximately one third of patients continuing to have residual depression at remission. Patients who have had a depressive episode spend more time with residual depressive symptoms than with major depression long term. The presence of residual symptomatology after an episode of depression is associated with an increased risk of short-term relapse, a long-term chronic course, higher risk of suicide attempts, poor social functioning, and poor outcome of comorbid medical illnesses.