RESUMO
We tested the effect of substituents at the (1) C3´, C3´N, (2) C10, and (3) C2-meta-benzoate positions of taxane derivatives on their activity against sensitive versus counterpart paclitaxel-resistant breast (MCF-7) and ovarian (SK-OV-3) cancer cells. We found that (1) non-aromatic groups at both C3´ and C3´N positions, when compared with phenyl groups at the same positions of a taxane derivative, significantly reduced the resistance of ABCB1 expressing MCF-7/PacR and SK-OV-3/PacR cancer cells. This is, at least in the case of the SB-T-1216 series, accompanied by an ineffective decrease of intracellular levels in MCF-7/PacR cells. The low binding affinity of SB-T-1216 in the ABCB1 binding cavity can elucidate these effects. (2) Cyclopropanecarbonyl group at the C10 position, when compared with the H atom, seems to increase the potency and capability of the derivative in overcoming paclitaxel resistance in both models. (3) Derivatives with fluorine and methyl substituents at the C2-meta-benzoate position were variously potent against sensitive and resistant cancer cells. All C2 derivatives were less capable of overcoming acquired resistance to paclitaxel in vitro than non-substituted analogs. Notably, fluorine derivatives SB-T-121205 and 121,206 were more potent against sensitive and resistant SK-OV-3 cells, and derivatives SB-T-121405 and 121,406 were more potent against sensitive and resistant MCF-7 cells. (4) The various structure-activity relationships of SB-T derivatives observed in two cell line models known to express ABCB1 favor their complex interaction not based solely on ABCB1.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP , Resistencia a Medicamentos Antineoplásicos , Humanos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células MCF-7 , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Relação Estrutura-Atividade , Taxoides/farmacologia , Taxoides/química , Linhagem Celular Tumoral , Paclitaxel/farmacologia , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Benzoatos/farmacologia , Benzoatos/química , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologiaRESUMO
INTRODUCTION: Early studies show conflicting findings regarding particulate matter ≤ 2.5 µm in diameter (PM2.5) exposure and development of head and neck cancers (HNC). We analyzed the relationship between PM2.5 exposure and various types of HNC in a nationally representative ecological sample. METHODS: We determined HNC incidence in 608 US counties from 2011 to 2019 using the Surveillance, Epidemiology and End Results (SEER) Program from the National Cancer Institute. We also collected information on sociodemographic factors from SEER and data on smoking and alcohol intake from CDC data frames (county level). PM2.5 exposure levels were estimated using satellite and meteorological data via previously validated general additive models. Flexible semi-nonparametric regression models were used to test the relationship between PM2.5 exposure levels and HNC incidence, adjusting for demographics, socioeconomic factors, and comorbidity. RESULTS: Increased PM2.5 exposure levels were associated with higher incidence-rates of oral cavity and pharyngeal cancers controlling for confounders in our primary analyses (IRR = 1.04, 95 % CI 1.01, 1.07, p = 0.02 per 1 µg/m3 increase in PM2.5). This relationship was maintained after adjusting for multiple testing (Holm s method, p = 0.04) and in ordinary least squares (OLS) regression (ß = 0.17, 95 % CI 0.01, 0.57, p = 0.01). Increased exposure was also associated with other HNC: esophagus (IRR = 1.06, 95 % CI 1.01, 1.11, p = 0.02), lip (IRR = 1.16, 95 % CI 1.03, 1.31, p = 0.01), tonsil (IRR = 1.10, 95 % CI 1.03, 1.16, p < 0.01). However, these relationships were not maintained in secondary analyses. CONCLUSIONS: This nationally representative ecological study shows that increased levels of air pollution are associated with increased incidence of overall oral cavity and pharyngeal cancers in the US.
Assuntos
Poluentes Atmosféricos , Poluição do Ar , Neoplasias de Cabeça e Pescoço , Neoplasias Faríngeas , Humanos , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Incidência , Exposição Ambiental , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Material Particulado/efeitos adversos , Material Particulado/análise , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/etiologiaRESUMO
Proper immobilization is critical for the delivery of high-quality radiation therapy. In cases when traditional immobilization is not feasible, 3-dimensional (3D) printing may provide a better-tolerated custom immobilization that is comparably effective. We present the successful treatment of a patient with inoperable oropharyngeal squamous cell carcinoma who was unable to tolerate traditional immobilization. To avoid covering the face, we created a 3D-printed cradle for the back of his head and neck. This design enabled the patient to tolerate traditional simulation scans with and without intravenous contrast and was subsequently able to undergo volumetric modulated arc therapy treatment. He successfully underwent treatment without evidence of disease more than 2 years after completion. The effect of 3D printing within the context of radiation oncology, as well as in other specialties, will undoubtedly continue to increase the variety of treatment options available to patients.
Assuntos
Neoplasias de Cabeça e Pescoço , Radioterapia de Intensidade Modulada , Masculino , Humanos , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/radioterapia , Radioterapia de Intensidade Modulada/métodos , Pescoço , Planejamento da Radioterapia Assistida por Computador/métodos , Impressão Tridimensional , ImobilizaçãoRESUMO
BACKGROUND: We aim to describe outcomes of elderly patients undergoing salvage surgery for laryngeal cancer and to characterize the interplay of age with various other factors in this growing population. METHODS: Using the National Cancer Database, we identified cases of salvage laryngectomy in patients who failed chemoradiation. An age cutoff of 70 years was used to separate subjects into two groups. Various factors were compared. RESULTS: Of the 825 patients included, 166 (20.1%) were elderly. Elderly patients had worse overall survival (p = 0.001), higher 30-day and 90-day mortality (p = 0.006, p < 0.001), and a longer length of stay (LOS) (p = 0.015). LOS over 1 week was associated with worse survival (p = 0.032). CONCLUSION: Elderly patients had worse overall perioperative survival than their younger counterparts. LOS and 30-day readmissions were associated with higher risk of mortality in this group. We provide a contemporary set of relevant information for head and neck cancer providers to consider in this growing population.
Assuntos
Neoplasias de Cabeça e Pescoço , Neoplasias Laríngeas , Humanos , Idoso , Neoplasias Laríngeas/cirurgia , Neoplasias Laríngeas/tratamento farmacológico , Estudos Retrospectivos , Neoplasias de Cabeça e Pescoço/cirurgia , Quimiorradioterapia , Tempo de Internação , Terapia de Salvação , LaringectomiaRESUMO
OPINION STATEMENT: Epidermal growth factor receptor (EGFR) is commonly overexpressed in many head and neck squamous cell carcinomas (HNSCC). With the success of EGFR inhibition in other cancer types, there was optimism for efficacy in HNSCC. Unfortunately, the clinical outcomes of EGFR-directed therapy have not provided overwhelming benefit. In the curative-intent setting, cisplatin has proven superior over cetuximab, an EGFR monoclonal antibody, in multiple large trials, and cisplatin should continue to be the treatment of choice when administered with definitive or adjuvant radiation. For cisplatin-ineligible patients, we prefer carboplatin-based treatment over cetuximab. We reserve cetuximab for a small group of patients who are eligible for radiation and systemic treatment but have contraindications to any platinum therapy. The role of EGFR inhibitors in the recurrent/metastatic setting is more robust. Although supplanted by immunotherapy as front-line treatment, cetuximab remains a meaningful second-line option for patients who have progressed on immune checkpoint inhibitors. Overall, EGFR-directed therapies have been of modest value in the treatment of both locally advanced and metastatic HNSCC. The future of EGFR-directed therapies will likely develop from exploring combination therapies, especially with immunotherapy. Early evidence suggests synergistic effects allowing for a more robust immune response, which holds promise for novel regimens in the treatment of HNSCC.
Assuntos
Cisplatino , Neoplasias de Cabeça e Pescoço , Humanos , Cetuximab/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Cisplatino/uso terapêutico , Receptores ErbB , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/etiologiaRESUMO
A limited number of studies are devoted to regulating TRIP6 expression in cancer. Hence, we aimed to unveil the regulation of TRIP6 expression in MCF-7 breast cancer cells (with high TRIP6 expression) and taxane-resistant MCF-7 sublines (manifesting even higher TRIP6 expression). We found that TRIP6 transcription is regulated primarily by the cyclic AMP response element (CRE) in hypomethylated proximal promoters in both taxane-sensitive and taxane-resistant MCF-7 cells. Furthermore, in taxane-resistant MCF-7 sublines, TRIP6 co-amplification with the neighboring ABCB1 gene, as witnessed by fluorescence in situ hybridization (FISH), led to TRIP6 overexpression. Ultimately, we found high TRIP6 mRNA levels in progesterone receptor-positive breast cancer and samples resected from premenopausal women.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP , Resistencia a Medicamentos Antineoplásicos , Proteínas com Domínio LIM , Neoplasias , Feminino , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , AMP Cíclico , Resistencia a Medicamentos Antineoplásicos/genética , Hibridização in Situ Fluorescente , Proteínas com Domínio LIM/genética , Células MCF-7 , Neoplasias/genética , Elementos de Resposta , Taxoides , Fatores de Transcrição/genéticaRESUMO
Introduction With the incorporation of modernized radiotherapy, chemotherapy, and immunotherapy, treatment outcomes have improved for patients with locally advanced, unresectable diseases. Elderly or poor performance status patients comprise more than half of non-small cell lung cancer (NSCLC) patients, but they are often underrepresented or excluded in clinical trials. Split-course concurrent chemoradiotherapy can be an effective treatment, showing good adherence and a favorable toxicity profile for unresectable, locally advanced NSCLC. Method We identified locally advanced NSCLC cancer patients via a single institution retrospective study. Patients were treated using a four-phase, split-course external beam radiotherapy approach with concurrent chemotherapy. The primary endpoints analyzed were completion rate, incidence, and severity of treatment-related toxicities, progression-free survival (PFS), and median overall survival (OS). Results Thirty-nine locally advanced lung cancer patients were treated with split-course chemoradiation (CRT). The median age at diagnosis was 73 years old. Seventeen patients had an Eastern Cooperative Oncology Group (ECOG) performance score of 2. Twenty-three patients had a clinical diagnosis of chronic obstructive pulmonary disease (COPD), and 10 patients were on home oxygen at the time of diagnosis. All patients completed 6000 centigrays (cGy) of radiation, and 95% of the patients completed at least three cycles of concurrent chemotherapy. No patients experienced grade 3 to 5 acute thoracic toxicities. Overall median survival was 12.7 months, and PFS was 7.5 months. Conclusion Our retrospective analysis of 39 poor risk and/or elderly patients with locoregional NSCLC treated with concurrent CRT via a split-course regimen suggests favorable oncologic outcomes and superb treatment completion rates and toleration.
RESUMO
BACKGROUND/AIM: There is significant variation in post-treatment surveillance imaging for sinonasal malignancies. This study examined the utility of surveillance imaging in detecting recurrence in patients treated for sinonasal malignancies. PATIENTS AND METHODS: We performed a retrospective review on an IRB-approved dataset of patients with sinonasal malignancies treated at a single institution between 2005 to 2021. Patients were categorized into groups based on the frequency of annual imaging and total number of imaging studies. We compared time-to-recurrence between the groups using log-rank test. A two-sided p-value of <0.05 was considered as the threshold for significance. RESULTS: A total of 93 patients were eligible for this study with a median follow up of 42.3 months and 25.8% (n=24) of patients had documented recurrence. Sensitivity and specificity for recurrence based on computed tomography (CT) scans within one year of treatment completion were 50.0% and 19.5%; positron emission tomography/CT was 90.0% and 19.5%; and magnetic resonance imaging was 60.0% and 61.0%, respectively. Regardless of the type of imaging, symptomatic presentation after treatment had a specificity of 91.0% with a positive likelihood ratio of recurrence of 2.95 (95%CI=1.06-8.22). The frequency of scans was not associated with the risk of recurrence (HR=0.55; 95%CI=0.23-1.29, p=0.17). Similarly, no association was noted between the total number of scans and risk of recurrence (HR=0.64; 95%CI=0.27-1.51, p=0.31). CONCLUSION: The total number of frequency of scans within the first year after treatment had no association with time to recurrence of sinonasal malignancies. Symptomatic presentation was strongly associated with recurrence and should be investigated with appropriate imaging.
Assuntos
Neoplasias Nasais , Neoplasias dos Seios Paranasais , Humanos , Neoplasias dos Seios Paranasais/diagnóstico por imagem , Neoplasias dos Seios Paranasais/terapia , Recidiva Local de Neoplasia/diagnóstico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia Computadorizada por Raios X , Estudos RetrospectivosRESUMO
Recently, we described a phenomenon whereby apoptotic cells generate and release CrkI-containing microvesicles, which stimulate proliferation in surrounding cells upon contact to compensate for their own demise. We termed these microvesicles "ACPSVs" for Apoptotic Compensatory Proliferation Signaling microvesicles. As immune cells and a majority of current cancer therapeutics destroy tumor cells primarily by apoptosis, we conducted a small pilot study to assess the possibility that ACPSVs may also be generated in squamous cell carcinomas. We first evaluated a primary and a metastatic squamous cell carcinoma cancer cell lines for their ability to produce ACPSVs under normal and apoptotic conditions. We next conducted a pilot study to assess the occurrence of ACPSVs in solid tumors extracted from 20 cancer patients with squamous cell carcinomas. Both cancer cell lines produced copious amounts of ACPSVs under apoptotic conditions. Interestingly, the metastatic squamous cell carcinoma cancer cell line also produced high levels of ACPSVs under healthy condition, suggesting that the ability to generate ACPSVs may be hijacked by these cells. Importantly, ACPSVs were also abundant in the solid tumors of all squamous cell carcinoma cancer patients. Detection of ACPSVs in cancer has potentially important ramifications in tumor biology and cancer therapeutics which warrants further investigation.
Assuntos
Carcinoma de Células Escamosas , Micropartículas Derivadas de Células , Apoptose , Biologia , Carcinoma de Células Escamosas/patologia , Micropartículas Derivadas de Células/patologia , Humanos , Projetos PilotoRESUMO
INTRODUCTION: Previous studies have evaluated stereotactic body radiotherapy (SBRT) in oligometastatic patients with NSCLC, including multimodality treatment with anti-programmed cell death protein-1 monotherapy. Questions remain regarding the timing of SBRT and immunotherapy, safety with dual checkpoint blockade, and the utility in widely metastatic patients. This randomized phase 1 trial combined nivolumab and ipilimumab with sequential or concurrent multisite SBRT in patients with stage IV NSCLC to evaluate safety and obtain preliminary activity data. METHODS: Treatment-naive patients with metastatic NSCLC were randomized to concurrent (SBRT with immunotherapy) or sequential (SBRT followed by immunotherapy) treatment. A maximum of four treatment fields received SBRT. Nivolumab and ipilimumab were continued until clinical progression, development of toxicity, or after 2 years. Dose-limiting toxicity was defined as greater than or equal to grade 3 toxicity to the relevant organ system attributed to SBRT and immunotherapy occuring within 3 months. RESULTS: A total of 37 patients were assessable. No dose-limiting toxicity occurred in the concurrent cohort (n = 18). The sequential cohort required a dose reduction in the central lung group owing to two grade 4 pneumonitis events (2 of 19). Overall best response was as follows: 5.4% (2 of 37) complete response, 40.5% (15 of 37) partial response, 16.2% (6 of 37) stable disease, and 37.8% (14 of 37) progressive disease. Median progression-free survival was 5.8 months (95% confidence interval: 3.6-11.4 mo), with median follow-up of 17.0 months. Median overall survival was not reached. CONCLUSIONS: Concurrent nivolumab, ipilimumab, and SBRT were not more toxic than sequential therapy, and multisite SBRT was well tolerated in widely metastatic patients. Multimodality therapy resulted in durable metastasis control and encouraging early overall survival.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Radiocirurgia , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Ipilimumab/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêuticoRESUMO
OBJECTIVES: We report the results of this phase I study to evaluate the maximum tolerated dose (MTD) and safety of veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin and paclitaxel induction chemotherapy (IC) for locoregionally advanced head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: In a 3 + 3 cohort design, patients with stage IVA-B human papillomavirus-negative HNSCC received 2 cycles of carboplatin (AUC 6, day 1), paclitaxel (100 mg/m2, days 1, 8, 15) and veliparib (days 1-7) every 21 days followed by standard curative-intent chemoradiotherapy. Primary endpoint: MTD and recommended phase II dose (RP2D) as determined by the first IC cycle. RESULTS: Twenty patients enrolled. Two withdrew before treatment; 18 patients were analyzed. Median age was 63 years. Primary disease sites included hypopharynx (n = 5), larynx (n = 5), oral cavity (n = 4), oropharynx (n = 3), and nasal cavity (n = 1). Through all of IC, the most common grade 3 + adverse events (AEs) were neutropenia (33%), thrombocytopenia (33%), anemia (11%), and white blood cell decrease (11%). One patient experienced a hematologic DLT at 350 mg BID. The RP2D for veliparib combined with carboplatin/paclitaxel is 350 mg BID. With 40.9 month median follow-up across dose levels for all patients, the 24-month overall and progression free survival was 77.8% (95% CI 60.8-99.6%) and 66.7% (95% CI 48.1-92.4%), respectively. Medians have not been reached. CONCLUSION: Addition of veliparib to carboplatin and paclitaxel IC was well tolerated in patients with advanced HNSCC. Hematologic toxicities were the most common AEs.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/uso terapêutico , Carboplatina/uso terapêutico , Paclitaxel/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzimidazóis/farmacologia , Carboplatina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Adulto JovemRESUMO
The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3, CPS1, and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients' poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carbamoil-Fosfato Sintase (Amônia)/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas com Domínio LIM/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Taxoides/uso terapêutico , Fatores de Transcrição/genética , Animais , Biomarcadores Tumorais/genética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Humanos , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Paclitaxel/uso terapêuticoRESUMO
BACKGROUND: There are well-documented treatment gaps in secondary prevention of coronary heart disease with a lack of clearly defined strategies to assist early physical activity after acute coronary syndromes (ACS). Smartphone technology may provide an innovative platform to close these gaps. OBJECTIVES: The primary goal of this study was to assess whether a smartphone-based, early cardiac rehabilitation program improved exercise capacity in patients with ACS. METHODS: A total of 206 patients with ACS across six tertiary Australian hospitals were included in this randomized controlled trial. Participants were randomized to usual care (UC; including referral to traditional cardiac rehabilitation), with or without an adjunctive smartphone-based cardiac rehabilitation program (S-CRP) upon hospital discharge. The primary endpoint was change in exercise capacity, measured by the change in 6-minute walk test distance at 8 weeks when compared to baseline, between groups. Secondary endpoints included uptake and adherence to cardiac rehabilitation, changes in cardiac risk factors, psychological well-being and quality of life status. RESULTS: Of the 168 patients with complete follow-up (age 56 ± 10 years; 16% females), 83 were in the S-CRP. At 8-week follow-up, the S-CRP group had a clinically significant improvement in 6-minute walk test distance (Δ117 ± 76 vs. Δ91 ± 110 m; P = 0.02). Patients in the S-CRP were more likely to participate (87% vs. 51%, P < 0.001) and adhere (72% vs. 22%, P < 0.001) to a cardiac rehabilitation program. Compared to UC, patients receiving S-CRP had similar smoking cessation rates, LDL-cholesterol levels, blood pressure reduction, depression, anxiety and quality of life measures (all P = NS). CONCLUSION: In patients with ACS, a S-CRP, as an adjunct to UC improved exercise capacity at 8 weeks in addition to participation and adherence to cardiac rehabilitation (Australian New Zealand Clinical Trials Registry; ACTRN12616000426482).
Assuntos
Síndrome Coronariana Aguda/reabilitação , Reabilitação Cardíaca , Terapia por Exercício , Exercício Físico , Qualidade de Vida , Smartphone , Síndrome Coronariana Aguda/fisiopatologia , Síndrome Coronariana Aguda/psicologia , Reabilitação Cardíaca/instrumentação , Reabilitação Cardíaca/métodos , Intervenção Médica Precoce/métodos , Exercício Físico/fisiologia , Exercício Físico/psicologia , Terapia por Exercício/instrumentação , Terapia por Exercício/métodos , Tolerância ao Exercício , Feminino , Comportamentos Relacionados com a Saúde/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Resultado do Tratamento , Teste de Caminhada/métodosRESUMO
At least half of all heart failure (CHF) patients will have a comorbidity that could be undertreated, requires additional speciality input and/or polypharmacy. These patients are then at risk of iatrogenic and disease-related complications and readmissions if not closely supervised. Common comorbidities of relevance are cardiorenal and cardiometabolic syndromes (DM, obesity, OSA), chronic airways disease, elderly age, and accompanying pharmacotherapies. The structure of community practice often leaves primary, speciality, and allied health care in silos. For example, cardiology speciality training in Australia creates excellent sub-specialists to deliver diagnostic and therapeutic advances. A casualty of this process has been the gradual alienation of general cardiology toward general internal medical specialists and primary care practitioners. The consequences are largely noticed in community practice. The issue is compounded by suboptimal communication of information. This review explores these issues from a cardiology sub-speciality lens; firstly cross speciality areas that are important for cardiologists to maintain their skill, and finally, to obtain a brief overview of disease management and identify game-changing common denominators such as endothelial dysfunction and self-management.
Assuntos
Cardiologia , Insuficiência Cardíaca , Idoso , Austrália , Comorbidade , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/terapia , Humanos , PrognósticoRESUMO
Microtubule-targeting agents (MTAs) constitute a diverse group of chemical compounds that bind to microtubules and affect their properties and function. Disruption of microtubules induces various cellular responses often leading to cell cycle arrest or cell death, the most common effect of MTAs. MTAs have found a plethora of practical applications in weed control, as fungicides and antiparasitics, and particularly in cancer treatment. Here we summarize the current knowledge of MTAs, the mechanisms of action and their role in cancer treatment. We further outline the potential use of MTAs in anti-metastatic therapy based on inhibition of cancer cell migration and invasiveness. The two main problems associated with cancer therapy by MTAs are high systemic toxicity and development of resistance. Toxic side effects of MTAs can be, at least partly, eliminated by conjugation of the drugs with various carriers. Moreover, some of the novel MTAs overcome the resistance mediated by both multidrug resistance transporters as well as overexpression of specific ß-tubulin types. In anti-metastatic therapy, MTAs should be combined with other drugs to target all modes of cancer cell invasion.
Assuntos
Microtúbulos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , HumanosAssuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mutação/genética , Inibidores de Proteínas Quinases/uso terapêutico , Circulação Sanguínea , Carcinoma Pulmonar de Células não Pequenas/genética , DNA Tumoral Circulante/análise , Análise Mutacional de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Humanos , Biópsia Líquida , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-IdadeAssuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Antineoplásicos Imunológicos/efeitos adversos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/efeitos adversos , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/enzimologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Resultado do TratamentoRESUMO
Identification of novel proteins with changed expression in resistant cancer cells could be helpful in elucidation mechanisms involved in the development of acquired resistance to paclitaxel. In this study, we carried out a 2D-PAGE using the mitochondrial-enriched fraction from paclitaxel-resistant MCF7/PacR cells compared to original paclitaxel-sensitive MCF7 breast cancer cells. Differentially expressed proteins were identified employing mass spectrometry. We found that lysosomal cathepsin D and mitochondrial abhydrolase-domain containing protein 11 (ABHD11) had decreased expression in MCF7/PacR cells. On the other hand, mitochondrial carbamoyl-phosphate synthetase 1 (CPS1) and ATPase family AAA-domain containing protein 3A and 3B (ATAD3A, ATAD3B) were overexpressed in MCF7/PacR cells. Further, we showed that there was no difference in localization of CPS1 in MCF7 and MCF7/PacR cells. We demonstrated a significant increase in the number of CPS1 positive MCF7/PacR cells, using FACS analysis, compared to the number of CPS1 positive MCF7 cells. Silencing of CPS1 expression by specific siRNA had no significant effect on the resistance of MCF7/PacR cells to paclitaxel. To summarize, we identified several novel proteins of a mitochondrial fraction whose role in acquired resistance to paclitaxel in breast cancer cells should be further assessed.