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PURPOSE: Few studies have examined the long-term impact of communication skills training for oncologists. We developed a year-long communication skills curriculum for medical oncology fellows with the primary goals of fostering life-long learning of patient-centered communication skills and internalization of associated attitudes and beliefs. We engaged learners through reflection, narrative methods, and action methods, thereby creating a non-threatening, team-based environment. The purpose of the current study was to determine whether learners perceived that they had acquired enduring skills, attitudes, and knowledge years after they participated. METHODS: Former fellows completed an online cross-sectional survey from June to July 2019 that included demographic information, 21 items on a numerical scale, and 3 narrative prompts. Survey items pertained to 4 domains, including skills, attitudes, confidence with specific scenarios, and overall impressions. The numerical scale ranged from "strongly agree" = 1 to "strongly disagree" = 5. RESULTS: A total of 114 fellows, including 27 teaching assistants, participated in the communication skills training over 8 years. The average time between the end of the training program and completion of the survey was 5.2 years. The response rate was 68/114 (64%). Forty-one (60%, 95% CI: 49.3-73.8) fellows agreed or strongly agreed that the curriculum profoundly impacted their practice of medicine. Forty-three (64%, 95% CI: 51.5-75.5) fellows strongly agreed or agreed that they often found themselves informally sharing lessons they learned during the series. Overall average domain scores were 1.89 (SD = 0.84) for skills, 2.16 (0.79) for attitudes, 2.05 (0.81) for confidence with specific challenges, and 2.38 (0.94) for lasting impressions. Results were significantly more favorable for teaching assistants than for others. CONCLUSION: Engaging, interactive, safe, and learner-centered communication skills training has an enduring and favorable impact on oncologists' self-perceived skills, confidence with specific challenges, and attitudes.
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Comunicação , Oncologistas , Humanos , Estudos Transversais , Currículo , Oncologia/educaçãoRESUMO
BACKGROUND: The role of neuroleptics for terminal agitated delirium is controversial. We assessed the effect of three neuroleptic strategies on refractory agitation in patients with cancer with terminal delirium. METHODS: In this single-centre, double-blind, parallel-group, randomised trial, patients with advanced cancer, aged at least 18 years, admitted to the palliative and supportive care unit at the University of Texas MD Anderson Cancer Center (Houston, TX, USA), with refractory agitation, despite low-dose haloperidol, were randomly assigned to receive intravenous haloperidol dose escalation at 2 mg every 4 h, neuroleptic rotation with chlorpromazine at 25 mg every 4 h, or combined haloperidol at 1âmg and chlorpromazine at 12·5 mg every 4 h, until death or discharge. Rescue doses identical to the scheduled doses were administered at inception, and then hourly as needed. Permuted block randomisation (block size six; 1:1:1) was done, stratified by baseline Richmond Agitation Sedation Scale (RASS) scores. Research staff, clinicians, patients, and caregivers were masked to group assignment. The primary outcome was change in RASS score from time 0 to 24 h. Comparisons among group were done by modified intention-to-treat analysis. This completed study is registered with ClinicalTrials.gov, NCT03021486. FINDINGS: Between July 5, 2017, and July 1, 2019, 998 patients were screened for eligibility, with 68 being enrolled and randomly assigned to treatment; 45 received the masked study interventions (escalation n=15, rotation n=16, combination n=14). RASS score decreased significantly within 30 min and remained low at 24 h in the escalation group (n=10, mean RASS score change between 0 h and 24 h -3·6 [95% CI -5·0 to -2·2]), rotation group (n=11, -3·3 [-4·4 to -2·2]), and combination group (n=10, -3·0 [-4·6 to -1·4]), with no difference among groups (p=0·71). The most common serious toxicity was hypotension (escalation n=6 [40%], rotation n=5 [31%], combination n=3 [21%]); there were no treatment-related deaths. INTERPRETATION: Our data provide preliminary evidence that the three strategies of neuroleptics might reduce agitation in patients with terminal agitation. These findings are in the context of the single-centre design, small sample size, and lack of a placebo-only group. FUNDING: National Institute of Nursing Research.
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Antipsicóticos/uso terapêutico , Delírio/tratamento farmacológico , Haloperidol/uso terapêutico , Neoplasias/complicações , Cuidados Paliativos , Agitação Psicomotora/tratamento farmacológico , Idoso , Delírio/etiologia , Delírio/patologia , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/psicologia , Neoplasias/terapia , Prognóstico , Agitação Psicomotora/etiologia , Agitação Psicomotora/patologiaRESUMO
Oncology training focuses primarily on biomedical content rather than psychosocial content, which is not surprising in light of the enormous volume of technical information that oncology fellows assimilate in a short time. Nonetheless, the human connection, and specifically communication skills, remains as important as ever in caring for highly vulnerable patients with cancer. We previously described a year-long communication skills curriculum for oncology fellows that consisted of monthly 1-hour seminars with role play as the predominant teaching method (Epner and Baile, Acad Med. 89:578-84, 2014). Over several years, we adapted the curriculum based on learner feedback and reflection by faculty and teaching assistants and consolidated sessions into quarterly 3-4-hour workshops. We now describe integrating stories into the curriculum as a way of building empathy and warming fellows to the arduous task of dealing with highly emotional content, such as conversations with young patients about transitioning off disease-directed therapy. Learners read and discussed published, medically themed stories; discussed their own patient care stories; and completed brief writing reflections and discussions. They then worked in small groups facilitated by faculty and upper level fellows who functioned as teaching assistants to work on applying specific skills and strategies to scenarios that they chose. Fellows completed anonymous surveys on which they rated the curriculum highly for relevance, value, organization, content, and teaching methods, including storytelling aspects. We conclude that sharing stories can help highly technical learners build reflective ability, mindfulness, and empathy, which are all critical ingredients of the art of medicine.
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Comunicação , Currículo/normas , Bolsas de Estudo/métodos , Oncologia/educação , Narração , Neoplasias/psicologia , Estudantes de Medicina/psicologia , Empatia , Humanos , Ensino , Revelação da VerdadeRESUMO
BACKGROUND: Patients with advanced cancer who progress on standard therapy are potential candidates for phase I clinical trials. Due to their aggressive disease and complex comorbid conditions, these patients often need inpatient admission. This study assessed the outcomes of such patients after they were discharged to hospice care. PATIENTS AND METHODS: We performed a retrospective analysis of patients with solid tumor malignancies who were discharged to hospice care from the inpatient service. RESULTS: One hundred thirty-three patients were included in the study cohort. All patients had metastatic disease and an Eastern Cooperative Oncology Group performance status ≥3. The median survival after discharge to hospice from an inpatient setting was 16 days, with a survival rate of 5% at 3 months after discharge. The median survival after the last cancer treatment was 46 days, with survival of 17% at 3 months, and 5% at 6 months. Patients with lactate dehydrogenase (LDH) >618 IU/L had a median post-discharge survival of 11 days versus 20 days for patients with LDH ≤618 IU/L. CONCLUSIONS: Patients with metastatic cancer participating in phase I trials who have poor performance status and require inpatient admission have a very short survival after discharge to hospice. A high LDH level predicts an even shorter survival.
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Ensaios Clínicos Fase I como Assunto/estatística & dados numéricos , Neoplasias/mortalidade , Neoplasias/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Cuidados Paliativos na Terminalidade da Vida/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida , Texas/epidemiologia , Adulto JovemRESUMO
Importance: The use of benzodiazepines to control agitation in delirium in the last days of life is controversial. Objective: To compare the effect of lorazepam vs placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium in the setting of advanced cancer. Design, Setting, and Participants: Single-center, double-blind, parallel-group, randomized clinical trial conducted at an acute palliative care unit at MD Anderson Cancer Center, Texas, enrolling 93 patients with advanced cancer and agitated delirium despite scheduled haloperidol from February 11, 2014, to June 30, 2016, with data collection completed in October 2016. Interventions: Lorazepam (3 mg) intravenously (n = 47) or placebo (n = 43) in addition to haloperidol (2 mg) intravenously upon the onset of an agitation episode. Main Outcomes and Measures: The primary outcome was change in Richmond Agitation-Sedation Scale (RASS) score (range, -5 [unarousable] to 4 [very agitated or combative]) from baseline to 8 hours after treatment administration. Secondary end points were rescue neuroleptic use, delirium recall, comfort (perceived by caregivers and nurses), communication capacity, delirium severity, adverse effects, discharge outcomes, and overall survival. Results: Among 90 randomized patients (mean age, 62 years; women, 42 [47%]), 58 (64%) received the study medication and 52 (90%) completed the trial. Lorazepam + haloperidol resulted in a significantly greater reduction of RASS score at 8 hours (-4.1 points) than placebo + haloperidol (-2.3 points) (mean difference, -1.9 points [95% CI, -2.8 to -0.9]; P < .001). The lorazepam + haloperidol group required less median rescue neuroleptics (2.0 mg) than the placebo + haloperidol group (4.0 mg) (median difference, -1.0 mg [95% CI, -2.0 to 0]; P = .009) and was perceived to be more comfortable by both blinded caregivers and nurses (caregivers: 84% for the lorazepam + haloperidol group vs 37% for the placebo + haloperidol group; mean difference, 47% [95% CI, 14% to 73%], P = .007; nurses: 77% for the lorazepam + haloperidol group vs 30% for the placebo + haloperidol group; mean difference, 47% [95% CI, 17% to 71%], P = .005). No significant between-group differences were found in delirium-related distress and survival. The most common adverse effect was hypokinesia (3 patients in the lorazepam + haloperidol group [19%] and 4 patients in the placebo + haloperidol group [27%]). Conclusions and Relevance: In this preliminary trial of hospitalized patients with agitated delirium in the setting of advanced cancer, the addition of lorazepam to haloperidol compared with haloperidol alone resulted in a significantly greater reduction in agitation at 8 hours. Further research is needed to assess generalizability and adverse effects. Trial Registration: clinicaltrials.gov Identifier: NCT01949662.
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Ansiolíticos/administração & dosagem , Antipsicóticos/administração & dosagem , Delírio/tratamento farmacológico , Haloperidol/administração & dosagem , Lorazepam/administração & dosagem , Neoplasias/complicações , Cuidados Paliativos , Adulto , Idoso , Idoso de 80 Anos ou mais , Ansiolíticos/efeitos adversos , Antipsicóticos/efeitos adversos , Delírio/etiologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Haloperidol/efeitos adversos , Hospitalização , Humanos , Lorazepam/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neoplasias/psicologia , Neoplasias/terapiaRESUMO
BACKGROUND: Body image is a critical psychosocial issue for patients with cancer because they often undergo significant changes to appearance and functioning. The primary purpose of this review article was to identify empirically-supported approaches to treat body image difficulties of adult cancer patients that can be incorporated into high-quality comprehensive cancer care. METHODS: An overview was provided of theoretical models of body image relevant to cancer patients, and findings were presented from published literature on body image and cancer from 2003 to 2013. These data were integrated with information from the patient-doctor communication literature to delineate a practical approach for assessing and treating body image concerns of adult cancer patients. RESULTS: Body image difficulties were found across patients with diverse cancer sites, and were most prevalent in the immediate postoperative and treatment period. Age, body mass index, and specific cancer treatments have been identified as potential risk factors for body image disturbance in cancer patients. Current evidence supports the use of time-limited cognitive-behavioral therapy interventions for addressing these difficulties. Other intervention strategies also show promise but require further study. Potential indicators of body image difficulties were identified to alert health care professionals when to refer patients for psychosocial care, and a framework was proposed for approaching conversations about body image that can be used by the oncologic treatment team. CONCLUSIONS: Body image issues affect a wide array of cancer patients. Providers can use available evidence combined with information from the health care communication literature to develop practical strategies for treating body image concerns of patients with cancer.
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Imagem Corporal/psicologia , Neoplasias/psicologia , Neoplasias/terapia , Atenção à Saúde , Humanos , Modelos Psicológicos , Relações Médico-Paciente , Psicoterapia , PesquisaRESUMO
BACKGROUND: Body image is a critical psychosocial issue for patients with cancer because they often undergo significant changes to appearance and functioning. The primary purpose of this review article was to identify empirically-supported approaches to treat body image difficulties of adult cancer patients that can be incorporated into high-quality comprehensive cancer care. METHODS: An overview was provided of theoretical models of body image relevant to cancer patients, and findings were presented from published literature on body image and cancer from 2003 to 2013. These data were integrated with information from the patient-doctor communication literature to delineate a practical approach for assessing and treating body image concerns of adult cancer patients. RESULTS: Body image difficulties were found across patients with diverse cancer sites, and were most prevalent in the immediate postoperative and treatment period. Age, body mass index, and specific cancer treatments have been identified as potential risk factors for body image disturbance in cancer patients. Current evidence supports the use of time-limited cognitive behavioral therapy interventions for addressing these difficulties. Other intervention strategies also show promise but require further study. Potential indicators of body image difficulties were identified to alert health care professionals when to refer patients for psychosocial care, and a framework was proposed for approaching conversations about body image that can be used by the oncologic treatment team. CONCLUSIONS: Body image issues affect a wide array of cancer patients. Providers can use available evidence combined with information from the health care communication literature to develop practical strategies for treating body image concerns of patients with cancer.
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Transtornos Dismórficos Corporais/etiologia , Transtornos Dismórficos Corporais/terapia , Imagem Corporal , Neoplasias/psicologia , Estresse Psicológico/etiologia , Estresse Psicológico/terapia , Adaptação Psicológica , Imagem Corporal/psicologia , Terapia Cognitivo-Comportamental , Comunicação , Feminino , Humanos , Masculino , Neoplasias/complicações , Neoplasias/terapia , Estudos Observacionais como Assunto , Equipe de Assistência ao Paciente , Educação de Pacientes como Assunto , Aptidão Física , Resolução de Problemas , Ensaios Clínicos Controlados Aleatórios como Assunto , Autoimagem , AutoeficáciaRESUMO
Importance: There are few robust evaluations of disease-specific question prompt sheets (QPS) in patient-physician communication among patients with advanced cancer. Objective: To compare the patient perception of helpfulness, global evaluation, and preference for the QPS vs a general information sheet (GIS), and to examine the effect of the QPS on participants' anxiety, participants' speaking time, number of questions asked, and length of the clinical encounter. Design, Setting, and Participants: This controlled, double-blind randomized clinical trial was conducted at an outpatient palliative and supportive care clinic in a cancer center in the US. Eligible patients were 18 years or older, had a cancer diagnosis, and were undergoing their first outpatient consultation visit with a palliative care physician from September 1, 2017, to May 31, 2019. Data analysis used a modified intention-to-treat design. Data were analyzed from May 18 to June 27, 2022. Intervention: QPS, a 25-item list of questions developed by expert palliative care clinicians using a Delphi process and tested among ambulatory advanced cancer patients. The control was GIS, generic information material given routinely to patients seen at the supportive care clinic. Main Outcomes and Measures: The main outcome was patient perception of helpfulness. Secondary outcomes included global evaluation and preference of QPS compared with GIS immediately after the encounter. Results: A total of 130 patients (mean [SD] age, 58.6 [13.3] years; 79 [60.8%] female) were randomized to receive either QPS (67 patients [51.5%]) or GIS (63 patients [48.5%]). Patients considered QPS and GIS equally helpful, with no statistically significant difference (mean [SD] helpfulness score, 7.2 [2.3] points vs 7.1 [2.7] points; P = .79). The QPS group, compared with the GIS group, had a higher global positive view of the material (mean [SD] global perception score, 7.1 [1.3] vs 6.5 [1.7]; P = .03) and felt it prompted them more to generate new questions (mean [SD] rating, 7.0 [2.9] vs 5.3 [3.5]; P = .005). Of 47 patients asked their preference between the items, more participants preferred the QPS to the GIS in communicating with their physicians (24 patients [51.1%] vs 7 patients [14.9%]; P = .01) at the 4-week follow-up. No significant differences between the QPS and GIS groups were observed regarding participant anxiety, speaking time, number of questions asked, or consultation length (eg, mean [SD] anxiety rating, 2.3 [3.7] vs 1.6 [2.7]; P = .19). Conclusions and Relevance: In this randomized clinical trial, participants perceived both QPS and GIS as equally helpful, but they had a more positive global view of and preferred the QPS. QPS facilitated generation of new questions without increasing patient anxiety nor prolonging the consultation. The findings provide support for increased adoption and integration of QPS into routine oncologic care. Trial Registration: ClinicalTrials.gov Identifier: NCT03287492.
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Neoplasias , Médicos , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Comunicação , Neoplasias/terapia , Neoplasias/diagnóstico , Pacientes Ambulatoriais , OncologiaRESUMO
CONTEXT: Levorphanol is a potent opioid agonist and NMDA receptor blocker with minimal drug interactions, and there are few reports of its use in cancer patients. OBJECTIVES: We aimed to determine the frequency of successful opioid rotation (OR) to levorphanol and the median opioid rotation ratio (ORR) from Morphine Equivalent Daily Dose (MEDD). METHODS: This is a prospective, single-group, interventional study. Cancer outpatients requiring an OR and receiving a MEDD of 60-300 mg were rotated to levorphanol using a ratio of 10:1 and assessed daily for 10-day. Successful OR was defined as a 2-point improvement in the Edmonton Symptom Assessment System (ESAS) pain score on day 10 or achieving the personalized pain goal between days 3-10 in patients with uncontrolled pain or resolution of opioid side effects (OSE) in those undergoing OR for OSE alone. The ORR to levorphanol was calculated using net-MEDD (MEDD before OR minus the MEDD of the breakthrough opioid used along with levorphanol after OR). RESULTS: Forty patients underwent OR to levorphanol, and uncontrolled pain 35/40 (87.5%) was the most common indication. The median net-MEDD and levorphanol doses were 95 and 10 mg, respectively, and 33/40 (82.5%) had a successful OR with a median (IQR) ORR of 8.56 (7.5-10). Successful OR was associated with significant improvement in ESAS and OSE scale scores. There was a strong association between MEDD and levorphanol dose. CONCLUSION: This study provided preliminary data that cancer patients could be successfully rotated to levorphanol using an ORR of 8.5. Levorphanol was associated with improved pain and symptom control and was well- tolerated.
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Analgésicos Opioides , Neoplasias , Humanos , Analgésicos Opioides/uso terapêutico , Levorfanol/uso terapêutico , Morfina/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/complicações , Pacientes Ambulatoriais , Dor/tratamento farmacológico , Dor/complicações , Estudos ProspectivosRESUMO
PURPOSE: Patients with serious illness derive a sense of security by forming strong, healing relationships with their providers. These bonds are particularly strong in life-threatening illnesses, such as cancer, which carry the stigma of death and suffering. These strong relationships create expectations in patients that are not necessarily shared by their clinicians. Providers often focus on treating disease and emphasize technically excellent, "evidence-based" practice while failing to fully appreciate the power of the patient-provider relationship. In contrast, vulnerable patients expect much more than technical competence, including open and clear communication, security, continuity, and access. Patients are often left feeling abandoned when their providers do not meet their expectations, even when their care is technically sound. METHODS/RESULTS: In this paper, we describe scenarios that can lead to feelings of abandonment and discuss strategies to avoid and respond to them. CONCLUSIONS: These strategies can help us maintain healing relationships with our patients by maintaining their trust, confidence, and satisfaction. Cultivating relational aspects of medical practice requires an interchange and takes time. Experienced doctors know this and continue to do so because being present and staying with the patient during difficult times is a pillar of moral and ethical training and a fundamental attribute of a good physician.
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Família/psicologia , Neoplasias/psicologia , Relações Médico-Paciente , Comunicação , Continuidade da Assistência ao Paciente , Acessibilidade aos Serviços de Saúde , Humanos , Satisfação do Paciente , Recusa em Tratar , ConfiançaRESUMO
BACKGROUND: John Wooden, the legendary college basketball coach, created the "Pyramid of Success", which he constructed from 14 timeless character traits and interpersonal skills that are critical to competitive greatness. Wooden's pyramid is a powerful symbol that he and others have used for several decades as an educational tool to promote leadership and teamwork. AIM: This article proposes the "Pyramid of Relational Excellence (PRE)", patterned after Wooden's pyramid, as a mnemonic-based educational symbol for communication skills training. METHOD: Literature review, personal reflection. RESULTS: The PRE is constructed of four tiers with a total of 12 building blocks, with each successive tier built upon the one beneath it. The building blocks represent fundamental elements that are known to be critical to successful communication. CONCLUSIONS: The PRE is process oriented rather than task oriented and focuses exclusively on the face-to-face encounter. It therefore complements established communications curricula, such as the UK communication wheel and others, which are more comprehensive and task oriented. The PRE is constructed of timeless, fundamental principles. It is therefore particularly well suited for training medical students and residents.
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Comunicação , Educação Médica , Competência Profissional/normas , Humanos , Relações Médico-PacienteRESUMO
Palliative care is seeing cancer patients earlier in the disease trajectory with a multitude of chronic issues. Chronic non-malignant pain (CNMP) in cancer patients is under-studied. In this prospective study, we examined the prevalence and management of CNMP in cancer patients seen at our supportive care clinic for consultation. We systematically characterized each pain type with the Brief Pain Inventory (BPI) and documented current treatments. The attending physician made the pain diagnoses according to the International Association for the Study of Pain (IASP) task force classification. Among 200 patients (mean age 60 years, 69% metastatic disease, 1-year survival of 77%), the median number of pain diagnosis was 2 (IQR 1-2); 67 (34%, 95% CI 28-41%) had a diagnosis of CNMP; 133 (67%) had cancer-related pain; and 52 (26%) had treatment-related pain. In total, 12/31 (39%) patients with only CNMP and 21/36 (58%) patients with CNMP and other pain diagnoses were on opioids. There was a total of 94 CNMP diagnoses among 67 patients, including 37 (39%) osteoarthritis and 20 (21%) lower back pain; 30 (32%) were treated with opioids. In summary, CNMP was common in the timely palliative care setting and many patients were on opioids. Our findings highlight the need to develop clinical guidelines for CNMP in cancer patients to standardize its management.
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The purpose of this study is to investigate the role of PI3K-Akt signaling in prostate cancer cell growth and androgen receptor (AR)-mediated gene expression. Androgen-dependent LNCaP cells and their androgen-independent counterpart, LNCaP-AI cells, were used. We found that PI3K-Akt signaling is elevated in LNCaP-AI cells compared to that in LNCaP cells and is involved in androgen-independent growth. More importantly, PI3K-Akt signaling enhances AR activity and is involved in the induction of AR target genes, such as p21(WAF/CIP), a gene with anti-apoptosis activity and associated with androgen-independent growth in human prostate cancer. A receptor tyrosine kinase inhibitor also inhibits the PI3K-Akt signaling and compromises AR activity and cell growth. These findings suggest that the PI3K-Akt cell growth survival pathway and its downstream-regulated gene, p21(WAF/CIP), are targets for developing novel therapies against prostate cancer, especially those androgen-independent diseases.
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Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Fosfatidilinositol 3-Quinases/fisiologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Androgênios/fisiologia , Sobrevivência Celular , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/fisiologia , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Proteínas Proto-Oncogênicas c-akt/fisiologia , Receptores Androgênicos/fisiologia , Transdução de Sinais , Células Tumorais CultivadasRESUMO
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional enzyme overexpressed in many tumors and induced by hypoxia in normal and malignant cells. The degree to which hypoxia transcriptionally activates GAPDH is cell type specific. The GAPDH promoter region contains a hypoxia responsive element (HRE) consisting of a hypoxia inducible factor-1 (HIF-1) consensus binding site plus adjacent sequence [Graven et al. (1999) Biochim. Biophys. Acta 1447, 208-218]. Using transient transfection experiments with the GAPDH promoter region linked to a luciferase reporter gene, we found that GAPDH was transcriptionally activated by hypoxia in each of three human prostate cancer cell lines tested, with the greatest level of induction in the most differentiated cell line. Using sequence analysis of the GAPDH promoter region, we identified a novel HRE distinct from the previously characterized one that consists of two consensus HIF-1 sites arranged as inverted repeats separated by 5 bp. Hypoxia transcriptionally activated a promoter construct in which the previously characterized HRE was mutated and the novel HRE remained intact. Heterologous promoter constructs containing only one or two copies of the novel HRE plus a minimal promoter consisting of a TATA box drove hypoxia inducible expression of the luciferase reporter gene in transient transfection assays. Mutation of HIF-1 sites within the novel HRE resulted in complete loss of function.
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Hipóxia Celular/genética , Gliceraldeído-3-Fosfato Desidrogenases/genética , Neoplasias da Próstata/genética , Elementos de Resposta , Sequência de Bases , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Gliceraldeído-3-Fosfato Desidrogenases/biossíntese , Humanos , Masculino , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Neoplasias da Próstata/enzimologia , Ativação Transcricional , Transfecção , Células Tumorais CultivadasRESUMO
Anorexia and weight loss are negative prognostic factors in patients with cancer. Although total ghrelin levels are increased in energy-negative states, levels of the biologically active octanoylated ghrelin and the anorexigenic peptide YY (PYY) have not been reported in patients with cancer-induced cachexia. We hypothesized that abnormal ghrelin and/or PYY levels contribute to cancer-induced cachexia. We evaluated 21 patients with cancer-induced cachexia; 24 cancer patients without cachexia; and 23 age-, sex-, race-, and BMI-matched subjects without cancer. Active ghrelin levels and the active to total ghrelin ratio were significantly increased in subjects with cancer-induced cachexia, compared with cancer and noncancer controls. PYY levels were similar among groups. Appetite measured by a visual analog scale was not increased in subjects with cachexia. The increase in active ghrelin levels is likely to be a compensatory response to weight loss. Cachexia may be a state of ghrelin resistance because appetite does not correlate with ghrelin levels. Changes in the active to total ghrelin ratio suggest that a mechanism other than increased secretion must be responsible for the increase in active ghrelin levels. PYY is unlikely to play an important role in cancer-induced cachexia.
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Caquexia/sangue , Neoplasias/complicações , Hormônios Peptídicos/sangue , Idoso , Apetite , Caquexia/etiologia , Grelina , Humanos , Resistência à Insulina , Fator de Crescimento Insulin-Like I/análise , Interleucina-6/sangue , Pessoa de Meia-Idade , Neoplasias/sangue , Peptídeo YY/sangue , Albumina Sérica/análise , Fator de Necrose Tumoral alfa/análiseRESUMO
Tumors are relatively more sensitive to methionine restriction than corresponding normal tissues, a phenomenon known as methionine auxotrophy. The current studies were undertaken to elucidate the molecular mechanisms for methionine auxotrophy of prostate cancer cells. We found that the activity of c-Jun N-terminal kinase 1 (JNK1) increased dramatically in response to methionine restriction. Over expression of wild type JNK1 by transient transfection enhanced apoptosis in response to methionine restriction, whereas over expression of a kinase inactive mutant of JNK1 protected PC-3 human prostate cancer cells from apoptosis. We conclude that JNK1 plays a critical role in signaling cancer cells to undergo apoptosis in response to methionine restriction.