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1.
Br J Cancer ; 127(7): 1254-1262, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35869144

RESUMO

BACKGROUND: The key process of mesenchymal to amoeboid transition (MAT), which enables prostate cancer (PCa) transendothelial migration and subsequent development of metastases in red bone marrow stroma, is driven by phosphorylation of EphA2S897 by pAkt, which is induced by the omega-6 polyunsaturated fatty acid arachidonic acid. Here we investigate the influence of EphA2 signalling in PCa progression and long-term survival. METHODS: The mechanisms underpinning metastatic biopotential of altered EphA2 signalling in relation to PTEN status were assessed in vitro using canonical (EphA2D739N) and non-canonical (EphA2S897G) PC3-M mutants, interrogation of publicly available PTEN-stratified databases and clinical validation using a PCa TMA (n = 177) with long-term follow-up data. Spatial heterogeneity of EphA2 was assessed using a radical prostatectomy cohort (n = 67). RESULTS: Non-canonical EphA2 signalling via pEphA2S897 is required for PCa transendothelial invasion of bone marrow endothelium. High expression of EphA2 or pEphA2S897 in a PTENlow background is associated with poor overall survival. Expression of EphA2, pEphA2S897 and the associated MAT marker pMLC2 are spatially regulated with the highest levels found within lesion areas within 500 µm of the prostate margin. CONCLUSION: EphA2 MAT-related signalling confers transendothelial invasion. This is associated with a substantially worse prognosis in PTEN-deficient PCa.


Assuntos
Neoplasias da Próstata , Receptor EphA2 , Ácido Araquidônico , Linhagem Celular Tumoral , Humanos , Masculino , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/cirurgia , Receptor EphA2/genética , Receptor EphA2/metabolismo
2.
Rev Med Suisse ; 17(761): 2082-2085, 2021 Dec 01.
Artigo em Francês | MEDLINE | ID: mdl-34851055

RESUMO

The University Hospital of Lausanne has heavily invested in the development of interdisciplinary oncology centers to improve the quality of care, and structure research and training. By integrating specialist nurses, it follows international recommendations. These specialists' nurses rephrase the information given by the doctor and ensure patients' understanding. They assess the patient's psychosocial situation and provides guidance if necessary. They support the patient in making informed choices about treatment and coping strategies. In addition to the outpatient clinics planned in accordance with the care pathway, she can be contacted between appointments to answer questions or concerns of any kind. This article shows the added value of these nurses in the care of oncology patients.


Le CHUV s'est fortement investi dans le développement de centres interdisciplinaires en oncologie afin d'améliorer la qualité de la prise en charge, de structurer la recherche et la formation. En y intégrant des infirmières cliniciennes, il suit les recommandations internationales. Ces infirmières reprennent les informations données par le médecin et s'assurent de la compréhension du patient. Elles évaluent sa situation psychosociale et l'orientent au besoin. Elles soutiennent le patient dans ses choix de traitement ainsi que dans ses stratégies d'adaptation. Outre les entretiens planifiés en fonction du parcours de soins, elles sont joignables entre les rendez-vous pour répondre à des questions ou préoccupations de tout ordre. Cet article montre la plus-value que la présence de ces infirmières offre à la prise en charge des patients oncologiques.


Assuntos
Neoplasias da Próstata , Instituições de Assistência Ambulatorial , Humanos , Masculino , Neoplasias da Próstata/terapia
3.
BJU Int ; 116(3): 423-31, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25600712

RESUMO

OBJECTIVE: To investigate by electromyography (EMG), the presence of complex repetitive discharges (CRDs) and decelerating bursts (DBs) in the striated external urethral sphincter during the menstrual cycle in female volunteers with no urinary symptoms and complete bladder emptying. SUBJECTS AND METHODS: Healthy female volunteers aged 20-40 years, with regular menstrual cycles and no urinary symptoms were recruited. Volunteers completed a menstruation chart, urinary symptom questionnaires, pregnancy test, urine dipstick, urinary free flow and post-void ultrasound bladder scan. Exclusion criteria included current pregnancy, use of hormonal medication or contraception, body mass index of >35 kg/m(2) , incomplete voiding and a history of pelvic surgery. Eligible participants underwent an external urethral sphincter EMG, using a needle electrode in the early follicular phase and the mid-luteal phase of their menstrual cycles. Serum oestradiol and progesterone were measured at each EMG test. RESULTS: In all, 119 women enquired about the research and following screening, 18 were eligible to enter the study phase. Complete results were obtained in 15 women. In all, 30 EMG tests were undertaken in the 15 asymptomatic women. Sphincter EMG was positive for CRDs and DBs at one or both phases of the menstrual cycle in eight (53%) of the women. Three had CRDs and DBs in both early follicular and mid-luteal phases. Five had normal EMG activity in the early follicular phase and CRDs and DBs in the mid-luteal phase. No woman had abnormal EMG activity in the early follicular phase and normal activity in the luteal phase. There was no relationship between EMG activity and age, parity or serum levels of oestradiol and progesterone. CONCLUSIONS: CRDs and DB activity in the external striated urethral sphincter is present in a high proportion of asymptomatic young women. This abnormal EMG activity has been shown for the first time to change during the menstrual cycle in individual women. CRDs and DBs are more commonly found in the luteal phase of the menstrual cycle. The importance of CRDs and DBs in the aetiology of urinary retention in young women remains uncertain. The distribution and or quantity of abnormal EMG activity in the external urethral sphincter may be important. In a woman with urinary retention the finding of CRDs and DBs by needle EMG does not automatically establish Fowler's syndrome as the explanation for the bladder dysfunction. Urethral pressure profilometry may be helpful in establishing a diagnosis. Opiate use and psychological stress should be considered in young women with urinary retention.


Assuntos
Eletromiografia/métodos , Ciclo Menstrual/fisiologia , Uretra/fisiologia , Adulto , Estudos de Coortes , Estradiol/sangue , Feminino , Humanos , Progesterona/sangue , Adulto Jovem
4.
Rev Med Suisse ; 11(497): 2288-90, 2292, 2015 Dec 02.
Artigo em Francês | MEDLINE | ID: mdl-26785527

RESUMO

The adoption of multiparametric MRI within the diagnostic pathway has allowed urologists to move from random biopsy to targeted biopsy directed towards MR-visible lesions. The use of software for MR to TRUS fusion may enhance the diagnostic accuracy of targeted biopsy. To determine the eligibility for tissue-preserving approaches, further precision is required, and template prostate mapping biopsy may be offered. The employment of novel biopsy techniques provide better characterisation of the disease, and allows a tailored approach to a single subject.


Assuntos
Imageamento por Ressonância Magnética/métodos , Seleção de Pacientes , Neoplasias da Próstata/diagnóstico , Biópsia , Humanos , Masculino , Neoplasias da Próstata/patologia
5.
Rev Med Suisse ; 10(453): 2328-31, 2014 Dec 03.
Artigo em Francês | MEDLINE | ID: mdl-25626250

RESUMO

The concept of aging male is defined by an age in which might appear some clinical symptoms. These symptoms, including erectile dysfunction (ED), are sometimes similar to those met in the late onset hypogonadism. Simultaneously, cardiovascular diseases increase with age and are associated with ED. The diagnosis of ED, associated or not with late onset hypogonadism, is mostly clinical. Its management will include PDE-5 which are generally well tolerated. Early detection of late onset hypogonadism is recommended as testosterone substitution improves quality of life. Although testosterone substitution needs to be carefully monitored, there is no clear evidence of increased risk of prostate cancer or cardiovascular disease.


Assuntos
Envelhecimento/fisiologia , Disfunção Erétil/terapia , Hipogonadismo/terapia , Idade de Início , Androgênios/deficiência , Disfunção Erétil/epidemiologia , Humanos , Hipogonadismo/epidemiologia , Masculino
6.
Rev Med Suisse ; 10(453): 2316-8, 2320-1, 2014 Dec 03.
Artigo em Francês | MEDLINE | ID: mdl-25626248

RESUMO

Emergency and differed urinary stone treatment are basic challenges in daily urological practice. By proposing the complete range of treatment and by improving medical and paramedical skills, management of stone patients can be optimized. In this article, we present the latest developments in stone treatment as well as our experiences with new technologies.


Assuntos
Cálculos Urinários/cirurgia , Terapia Combinada/métodos , Humanos , Litotripsia , Nefrostomia Percutânea , Ureteroscopia/métodos
7.
Rev Med Suisse ; 10(453): 2306-10, 2014 Dec 03.
Artigo em Francês | MEDLINE | ID: mdl-25626246

RESUMO

Focal therapy is a novel treatment strategy in prostate cancer aiming to treat only the area of the gland harbouring clinically significant disease. The overall objective is to maintain the oncological benefit of active treatment while minimising treatment-related morbidity. Leading centres are currently evaluating various minimally invasive technologies in a rigorous manner. Oncological and functional results in mid-term are encouraging with low rate of urinary incontinence and erectile dysfunction. However, the oncological outcome needs to be evaluated in the long-term in the light of the prolonged natural history of the disease.


Assuntos
Prostatectomia/métodos , Neoplasias da Próstata/terapia , Criocirurgia , Humanos , Masculino , Seleção de Pacientes , Fototerapia , Neoplasias da Próstata/epidemiologia , Suíça/epidemiologia
8.
Cancers (Basel) ; 16(11)2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38893216

RESUMO

Objectives: We investigated spatial patterns between primary and recurrent tumor sites and assessed long-term toxicity after dose escalation stereotactic body radiation therapy (SBRT) to the dominant intra-prostatic nodule (DIN). Materials and methods: In 33 patients with intermediate-high-risk prostate cancer (PCa), doses up to 50 Gy were administered to the DIN. Recurrence sites were determined and compared to the original tumor development sites through multiparametric MRI and 68Ga-labeled prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (68Ga-PSMA-PET/CT) images. Overlap rates, categorized as 75% or higher for full overlap, and 25-74% for partial overlap, were assessed. Long-term toxicity is reported. Results: All patients completed treatment, with only one receiving concomitant androgen deprivation therapy (ADT). Recurrences were diagnosed after a median of 33 months (range: 17-76 months), affecting 13 out of 33 patients (39.4%). Intra-prostatic recurrences occurred in 7 patients (21%), with ≥75% overlap in two, a partial overlap in another two, and no overlap in the remaining three patients. Notably, five patients with intra-prostatic recurrences had synchronous bone and/or lymph node metastases, while six patients had isolated bone or lymph node metastasis without intra-prostatic recurrences. Extended follow-up revealed late grade ≥ 2 GU and GI toxicity in 18% (n = 6) and 6% (n = 2) of the patients. Conclusions: Among patients with intermediate-high-risk PCa undergoing focal dose-escalated SBRT without ADT, DIN recurrences were infrequent. When present, these recurrences were typically located at the original site or adjacent to the initial tumor. Conversely, relapses beyond the DIN and in extra-prostatic (metastatic) sites were prevalent, underscoring the significance of systemic ADT in managing this patient population. Advances in knowledge: Focal dose-escalated prostate SBRT prevented recurrences in the dominant nodule; however, extra-prostatic recurrence sites were frequent.

9.
Rev Med Suisse ; 9(387): 1070-5, 2013 May 22.
Artigo em Francês | MEDLINE | ID: mdl-23757912

RESUMO

The interaction between the immune system and cancer was an area of research interest for several decades. The recent U.S. Food and Drug Administration approval of sipuleucel-T and ipilimumab stimulated broader interest in manipulating immunity to fight cancer. In the context of prostate cancer, the immunotherapy strategies under development are therapeutic vaccination strategies, such as sipuleucel-T and PROSTVAC-VF, or immune checkpoint blockade of CTLA-4. Improved understanding of the immune responses generated by the development of predictive biomarkers for patient selection will guide rational combinations of these treatments and provide new treatment options in prostate cancer.


Assuntos
Imunoterapia , Neoplasias da Próstata/tratamento farmacológico , Humanos , Masculino , Neoplasias da Próstata/imunologia
10.
Rev Med Suisse ; 9(409): 2286-8, 2013 Dec 04.
Artigo em Francês | MEDLINE | ID: mdl-24416885

RESUMO

Functional disorders encounter for a large amount of the medical activity, including in urology. The decreased quality of life due to lower urinary tract symptoms requires a prompt management, with primary assessment undergone in community. Referral to a specialist is required when simple management has failed, and whenever any of these coexists: hematuria, recurrent urinary infection, and neurological condition. The specialized clinic in neurourology and functional urology aim at further investigating the underlying disorder responsible for the urinary symptoms and preventing urinary tract complications. A multidisciplinary team is the key to accurately assess patients with regards to their bother and handicap, therefore offering the most appropriate conservative, medical or surgical management.


Assuntos
Doenças Urológicas/terapia , Instituições de Assistência Ambulatorial , Humanos , Doenças do Sistema Nervoso/complicações , Neurologia , Equipe de Assistência ao Paciente , Doenças Urológicas/etiologia , Urologia
11.
Rev Med Suisse ; 9(409): 2270-2, 2274, 2013 Dec 04.
Artigo em Francês | MEDLINE | ID: mdl-24416882

RESUMO

The prostate cancer is a complex pathology involving oncological, functional and psychosocial items. The prostate's center of CHUV harmonize the know-how of urologists, oncologist, radiotherapists and clinical nurses to offer a global management to patients attempts by prostate cancer, from diagnosis to therapy and follow-up.


Assuntos
Institutos de Câncer , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/terapia , Humanos , Masculino , Equipe de Assistência ao Paciente
12.
Br J Radiol ; 96(1145): 20220803, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-36745031

RESUMO

OBJECTIVES: We conducted a phase I/II prospective trial to determine whether stereotactic dose escalation to the dominant intra-prostatic nodule (DIN) up to 50 Gy incorporating a rectal balloon spacer is safe, does not affect patient quality of life, and preserves local control in patients with intermediate-high risk PCa. METHODS: Eligible patients included males with stage ≤T3b localized disease, a prostate-specific antigen (PSA) level ≤50 , International Prostate Symptom Score (IPSS) ≤14, and a gland volume ≤70 cm3. Patients underwent perirectal spacer placement, followed by a planning MRI and were subsequently treated with SBRT doses of 36.25 Gy in five fractions to the whole prostate while simultaneously escalating doses to the magnetic resonance image visible DIN up to 50 Gy. Primary endpoint: safety. Secondary endpoints: biochemical control, quality of life (QofL), and dosimetry outcome. RESULTS: Nine patients were treated in the Phase I part of the study. Dose limiting toxicities (DLTs) were not observed. Further characterization of tolerability and efficacy was conducted in the subsequent 24 patients irradiated at the recommended Phase II dose (50 Gy, RP2D). At a median follow-up of 61 months, biochemical control is 69%. Grade 1 and 2 acute GU and GI toxicity was 57.5 and 15%, and 24.2 and 6.1%, respectively. Grade 1 and 2 late GU and GI toxicity was 66.6 and 12.1%, and 15.1 and 3%, respectively. No Grade 3 or higher toxicity was reported. QofL data confirmed physician's reported side effects. Dosimetry analysis showed adherence to the doses prescribed in the protocol. CONCLUSIONS: SBRT of the whole prostate with 36.25 Gy in 5 fractions and dose escalation to 50 Gy to the DIN, when combined with a peri-rectal balloon spacer, was tolerable and established the RP2D. QofL analysis showed minimal negative impact in GU, GI, and sexual domains. ADVANCES IN KNOWLEDGE: Extreme hypofractionated prostate radiation therapy with focal dose escalation to the DIN is well tolerated with efficacy comparable to normal fractionated radiation therapy.


Assuntos
Neoplasias da Próstata , Radiocirurgia , Masculino , Humanos , Antígeno Prostático Específico , Neoplasias da Próstata/patologia , Radiocirurgia/efeitos adversos , Radiocirurgia/métodos , Estudos Prospectivos , Qualidade de Vida
13.
Investig Clin Urol ; 62(4): 416-422, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34190436

RESUMO

PURPOSE: To compare the clinical outcome of males with low-risk and favorable intermediate-risk prostate cancer managed within a standardized modern protocol of active surveillance. MATERIALS AND METHODS: This was a prospective cohort study with strict and expanded active surveillance criteria in males with prostate cancer. Baseline assessment included multiparametric magnetic resonance imaging (mpMRI), extended systematic biopsy, and software-based MR-targeted biopsy. Follow-up included biannual prostate-specific antigen (PSA) check, mpMRI, and control biopsy once a year for the first 2 years, and afterward mpMRI every 2 years with additional tests as clinically indicated. The primary outcome was the transition rate to active treatment. RESULTS: A total of 51 patients were included: 17 (33%) and 34 (67%) followed protocols of strict (study arm 1) and expanded (study arm 2) active surveillance criteria, respectively. Median age and PSA were 65 years (IQR, 60-69 years) and 5.3 ng/mL (IQR, 4.5-7.7 ng/mL), respectively. At baseline, a median of 2 (IQR, 1-3) cores were positive out of 13 (IQR, 12-14) cores; 22 males (43%) had visible mpMRI lesions. Eight males (24%) in study arm 2 had Gleason score 3+4. After a median follow-up of 36 months (IQR, 24-48 mo), no patient in study arm 1 compared with 17 patients (33%) in arm 2 underwent active treatment (p<0.0005). CONCLUSIONS: Although expanding eligibility criteria leads to a greater transition rate to active treatment, active surveillance should be contemplated in well-selected males with favorable intermediate-risk prostate cancer as the curability window seems to be maintained.


Assuntos
Seleção de Pacientes , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Conduta Expectante , Idoso , Biópsia , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética Multiparamétrica , Gradação de Tumores , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico por imagem , Fatores de Risco
14.
Front Immunol ; 10: 622, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984190

RESUMO

The immune system plays a central role in cancer development, showing both anti-tumor and pro-tumor activities depending on the immune cell subsets and the disease context. While CD8 T cells are associated with a favorable outcome in most cancers, only T helper type 1 (Th1) CD4 T cells play a protective role, in contrast to Th2 CD4 T cells. Double positive (DP) CD4+CD8+ T cells remain understudied, although they were already described in human cancers, with conflicting data regarding their role. Here, we quantified and phenotypically/functionally characterized DP T cells in blood from urological cancer patients. We analyzed blood leukocytes of 24 healthy donors (HD) and 114 patients with urological cancers, including bladder (n = 54), prostate (n = 31), and kidney (n = 29) cancer patients using 10-color flow cytometry. As compared to HD, levels of circulating DP T cells were elevated in all urological cancer patients, which could be attributed to increased frequencies of both CD4highCD8low and CD4+CD8high DP T-cell subsets. Of note, most CD4highCD8low DP T cells show a CD8αα phenotype, whereas CD4+CD8high cells express both CD8α and CD8ß subunits. Functional properties were investigated using ex-vivo generated DP T-cell clones. DP T cells from patients were skewed toward an effector memory phenotype, along with enhanced Th2 cytokine production. Interestingly, both CD8αα and CD8αß DP T cells were able to trigger Th2 polarization of naïve CD4 T cells, while restraining Th1 induction. Thus, these data highlight a previously unrecognized immunoregulatory mechanism involving DP CD4+CD8+ T cells in urological cancers.


Assuntos
Antígenos CD4/imunologia , Antígenos CD8/imunologia , Neoplasias Renais/imunologia , Neoplasias da Próstata/imunologia , Células Th2/imunologia , Neoplasias da Bexiga Urinária/imunologia , Idoso , Idoso de 80 Anos ou mais , Antígenos CD4/sangue , Antígenos CD8/sangue , Feminino , Citometria de Fluxo , Humanos , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Células Th2/metabolismo , Células Th2/patologia , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/patologia
15.
Int J Radiat Oncol Biol Phys ; 103(2): 320-334, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30267761

RESUMO

PURPOSE: Although localized prostate cancer (PCa) is multifocal, the dominant intraprostatic nodule (DIN) is responsible for disease progression after radiation therapy. PCa expresses antigens that could be recognized by the immune system. We therefore hypothesized that stereotactic dose escalation to the DIN is safe, may increase local control, and may initiate tumor-specific immune responses. PATIENTS AND METHODS: Patients with localized PCa were treated with stereotactic extreme hypofractionated doses of 36.25 Gy in 5 fractions to the whole prostate while simultaneously escalating doses to the magnetic resonance image-visible DIN (45 Gy, 47.5 Gy, and 50 Gy in 5 fractions). The phase 1a part was designed to determine the recommended phase 1b dose in a "3 + 3" cohort-based, dose-escalation design. The primary endpoint was dose-limiting toxicities defined as ≥grade 3 gastrointestinal (GI) or genitourinary (GU) toxicity (or both) by National Cancer Institute Common Terminology Criteria for Adverse Events (version 4) up to 90 days after the first radiation fraction. The secondary endpoints were prostate-specific antigen kinetics, quality of life (QoL), and blood immunologic responses. RESULTS: Nine patients were treated in phase 1a. No dose-limiting toxicities were observed at either level, and therefore the maximum tolerated dose was not reached. Further characterization of tolerability, efficacy, and immunologic outcomes was conducted in the subsequent 11 patients irradiated at the highest dose level (50 Gy) in the phase 1b expansion cohort. Toxicity was 45% and 25% for grades 1 and 2 GU, and 20% and 5% for grades 1 and 2 GI, respectively. No grade 3 or worse toxicity was reported. The average (±standard error of the mean) of the QoL assessments at baseline and at 3-month posttreatment were 0.8 (±0.8) and 3.5 (±1.5) for the bowel (mean difference, 2.7; 95% confidence interval, 0.1-5), and 6.4 (±0.8) and 7.27 (±0.9) for the International Prostate Symptom Score (mean difference, 0.87; 95% confidence interval, 0.3-1.9), respectively. A subset of patients developed antigen-specific immune responses against prostate-specific membrane antigen (n = 2), prostatic acid phosphatase (n = 1), prostate stem cell antigen (n = 4), and prostate-specific antigen (n = 2). CONCLUSIONS: Irradiation of the whole prostate with 36.25 Gy in 5 fractions and dose escalation to 50 Gy to the DIN was tolerable and determined as the recommended phase 1b dose. This treatment has promising antitumor activity, which will be confirmed by the ongoing phase 2 part. Preliminary QoL analysis showed minimal impact in GU, GI, and sexual domains. Stereotactic irradiation induced antigen-specific immune responses in a subset of patients.


Assuntos
Próstata/efeitos da radiação , Neoplasias da Próstata/radioterapia , Radiocirurgia , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Fracionamento da Dose de Radiação , Humanos , Sistema Imunitário , Imageamento por Ressonância Magnética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Antígeno Prostático Específico , Qualidade de Vida , Radiometria , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Radioterapia de Intensidade Modulada , Linfócitos T/imunologia
16.
J Immunother Cancer ; 7(1): 257, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601268

RESUMO

BACKGROUND: Several mechanisms are present in the tumor microenvironment (TME) to impair cytotoxic T cell responses potentially able to control tumor growth. Among these, the accumulation of adenosine (Ado) contributes to tumor progression and represents a promising immunotherapeutic target. Ado has been shown to impair T cell effector function, but the role and mechanisms employed by Ado/Ado receptors (AdoRs) in modulating human peripheral and tumor-infiltrating lymphocyte (TIL) function are still puzzling. METHODS: CD8+ T cell cytokine production following stimulation was quantified by intracellular staining and flow cytometry. The cytotoxic capacity of tumor infiltrating lymphocytes (TILs) was quantified by the chromium release assay following co-culture with autologous or anti-CD3-loaded tumor cell lines. The CD8+ T cell metabolic fitness was evaluated by the seahorse assay and by the quantification of 2-NBDG uptake and CD71/CD98 upregulation upon stimulation. The expression of AdoRs was assessed by RNA flow cytometry, a recently developed technology that we validated by semiquantitative RT-PCR (qRT-PCR), while the impact on T cell function was evaluated by the use of selective antagonists and agonists. The influence of Ado/AdoR on the PKA and mTOR pathways was evaluated by phosphoflow staining of p-CREB and p-S6, respectively, and validated by western blot. RESULTS: Here, we demonstrate that Ado signaling through the A2A receptor (A2AR) in human peripheral CD8+ T cells and TILs is responsible for the higher sensitivity to Ado-mediated suppression of T central memory cells. We confirmed that Ado is able to impair peripheral and tumor-expanded T cell effector functions, and we show for the first time its impact on metabolic fitness. The Ado-mediated immunosuppressive effects are mediated by increased PKA activation that results in impairment of the mTORC1 pathway. CONCLUSIONS: Our findings unveil A2AR/PKA/mTORC1 as the main Ado signaling pathway impairing the immune competence of peripheral T cells and TILs. Thus, p-CREB and p-S6 may represent useful pharmacodynamic and efficacy biomarkers of immunotherapies targeting Ado. The effect of Ado on T cell metabolic fitness reinforces the importance of the adenosinergic pathway as a target for next-generation immunotherapy.


Assuntos
Adenosina/metabolismo , Linfócitos T CD8-Positivos/imunologia , Neoplasias/imunologia , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia , Adenosina/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Progressão da Doença , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Pessoa de Meia-Idade , Neoplasias/metabolismo , Cultura Primária de Células , Receptor A2A de Adenosina/metabolismo , Evasão Tumoral
17.
Cell Signal ; 19(10): 2201-7, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17669625

RESUMO

Islet-Brain 1 (IB1) (also called JNK-interacting protein 1; JIP1) is a scaffold protein that tethers components of the JNK mitogen-activated protein kinase pathway inducing a modulation of the activity and the target specificity of the JNK kinases. Dysfunctions in IB1 have been associated with diseases such as early type II diabetes. To gain more insight in the functions of IB1, its ability to modulate the expression levels of the various JNK proteins was assessed. Each of the three JNK genes gives rise to several splice variants encoding short or long proteins. The expression levels of the short JNK proteins, but not of the long variants, were systematically higher in rat tissues and in transformed cell lines expressing high IB1 levels compared to tissues and cells with no or low IB1 expression. HEK293 cells bearing a tetracycline-inducible IB1 construct showed a specific increase of the short JNK endogenous splice variants in the presence of tetracycline. The augmented expression level of the short JNK splice variants induced by IB1 resulted from an increased stability towards degradation. Modulation of the stability of specific JNK splice variants represents therefore a newly identified mechanism used by IB1 to regulate the JNK MAPK pathway.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Processamento Alternativo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Animais , Linhagem Celular , Linhagem Celular Transformada , Estabilidade Enzimática , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteína Quinase 8 Ativada por Mitógeno/genética , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/genética , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Ratos
18.
Rev Med Suisse ; 4(140): 166-8, 2008 Jan 16.
Artigo em Francês | MEDLINE | ID: mdl-18309882

RESUMO

The systemic treatment of kidney cancers is promising regarding the first results of the inhibiting molecules of the angiogenesis. Projections in research are encouraging for more specific and sensitive markers of the prostate cancer. For this last the intermittent hormonotherapy improves the quality of life of the patients. The overweight control in infertility allows greater chances of giving birth. The morbidity of the kidney percutaneous surgery is decreased by the use of smaller tools. Reduction rate of reobstruction thanks to new manufactoring stents. The botulinic toxin for the hyperactive bladder refunded by the health insurances.


Assuntos
Doenças Urológicas/diagnóstico , Doenças Urológicas/terapia , Antígenos de Neoplasias/análise , Toxinas Botulínicas Tipo A/uso terapêutico , Humanos , Masculino , Fármacos Neuromusculares/uso terapêutico , Stents
19.
Cell Signal ; 17(8): 929-39, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15894166

RESUMO

The scaffold protein Islet-Brain1/c-Jun amino-terminal kinase Interacting Protein-1 (IB1/JIP-1) is a modulator of the c-Jun N-terminal kinase (JNK) activity, which has been implicated in pleiotrophic cellular functions including cell differentiation, division, and death. In this study, we described the presence of IB1/JIP-1 in epithelium of the rat prostate as well as in the human prostatic LNCaP cells. We investigated the functional role of IB1/JIP-1 in LNCaP cells exposed to the proapoptotic agent N-(4-hydroxyphenyl)retinamide (4-HPR) which induced a reduction of IB1/JIP-1 content and a concomittant increase in JNK activity. Conversely, IB1/JIP-1 overexpression using a viral gene transfer prevented the JNK activation and the 4-HPR-induced apoptosis was blunted. In prostatic adenocarcinoma cells, the neuroendocrine (NE) phenotype acquisition is associated with tumor progression and androgen independence. During NE transdifferentiation of LNCaP cells, IB1/JIP-1 levels were increased. This regulated expression of IB1/JIP-1 is secondary to a loss of the neuronal transcriptional repressor neuron restrictive silencing factor (NRSF/REST) function which is known to repress IB1/JIP-1. Together, these results indicated that IB1/JIP-1 participates to the neuronal phenotype of the human LNCaP cells and is a regulator of JNK signaling pathway.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Regulação Neoplásica da Expressão Gênica , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Sistemas Neurossecretores/metabolismo , Neoplasias da Próstata/patologia , Adenocarcinoma/metabolismo , Adenoviridae/genética , Animais , Apoptose , Benzimidazóis/farmacologia , Northern Blotting , Western Blotting , Diferenciação Celular , Linhagem Celular Tumoral , Densitometria , Progressão da Doença , Ativação Enzimática , Células Epiteliais/metabolismo , Fenretinida/farmacologia , Células HeLa , Humanos , Luciferases/metabolismo , MAP Quinase Quinase 4 , Masculino , Microscopia de Fluorescência , Neoplasias/patologia , Neurônios/metabolismo , Fenótipo , Plasmídeos/metabolismo , Próstata/metabolismo , RNA/metabolismo , Ratos , Proteínas Repressoras/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sinaptofisina/metabolismo , Sais de Tetrazólio/farmacologia , Tiazóis/farmacologia , Distribuição Tecidual , Fatores de Transcrição/fisiologia , Transcrição Gênica , Regulação para Cima
20.
Can Urol Assoc J ; 10(1-2): E28-33, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26858784

RESUMO

Renal biopsy is being increasingly proposed as a diagnostic tool to characterize small renal masses (SRM). Indeed, the wide adoption of imaging in the diagnostic workup of many diseases had led to a substantial increased incidence of SRM (diameter ≤4 cm). While modern ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) techniques have high sensitivity for detecting SRM, none is able to accurately and reliably characterize them in terms of histological features. This is currently of key importance in guiding clinical decision-making in some situations, and in these cases renal biopsy should be considered. In this review, we aim to summarize the technique, diagnostic performance, and predicting factors of nondiagnostic biopsy, as well as the future perspectives.

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