Radiation morbidity and micronuclei in lymphocytes of prostate cancer patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15540-15540
Author(s):  
T. Lee ◽  
R. R. Allison ◽  
K. F. O’Brien ◽  
A. L. Wiley ◽  
R. M. Johnke ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Ex Vivo ◽  
Peripheral Blood Lymphocytes ◽  
Cytotoxic Agents ◽  
Linear Quadratic ◽  
Relative Increment ◽  
Interphase Cells ◽  
Relationship Of

15540 Background: Since formation of micronuclei (MN) in interphase cells is a reflection of DNA damage, it has been postulated that enhanced peripheral blood lymphocytes (PBL) radiosensitivity might correlate with the development of radiation morbidity. Methods: We conducted the cytokinesis-block (CB) MN assay of PBL in 54 prostate cancer (PC) patients ( mean age ± SEM: 68 ± 1.6 yrs) who had no previous exposure to cytotoxic agents. Patients received standardized pelvic radiotherapy (RT) (41.4 -50.4 Gy) with mean follow-up of 29.1± 3.3 mos. Blood samples were drawn before RT and at designated intervals after RT initiation. Gastrointestinal (GI) and genitourinary (GU) morbidity were determined using RTOG criteria. Results: Average reactors (AR, n = 14) were defined as patients who did not develop morbidity. Grade 1 (G1R, n = 19) and Grade 2 reactors (G2R, n = 21) were defined as those who developed Grade 1 or Grade 2 GI or GU morbidity, respectively. Results of the MN yield in PBL before RT indicated that (1) at baseline level (0 Gy), differences in MN yield for AR, G1R, and G2R patients were insignificant; (2) after ex vivo irradiation (1 - 4 Gy), MN yield followed a linear-quadratic polynomial trend in AR, G1R, and G2R patients; and (3) differences in MN yield in AR vs. G1R or AR vs. G2R patients were significant (P = 0.0001). After the initiation of RT, MN yields in PBL at 24 h, one week, and six weeks, the ratio of relative increment (RI) of RT-induced MN yield, i.e. MNRI = MN (RT-induced) - MN (pre-RT)/ MN (pre-RT) in both G1R and G2R patients was significantly higher than that in AR patients. Our results suggest that prediction of GI or GU morbidity in patients is potentially possible through the evaluation of both ex vivo radiation dose-response relationship of MN in PBL before the initiation of RT and the in vivo MNRI after RT. No significant financial relationships to disclose.

scholarly journals Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor Therapy in Three Subjects with the Cystic Fibrosis Genotype Phe508del/Unknown and Advanced Lung Disease

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1178
Author(s):  
Vito Terlizzi ◽  
Carmela Colangelo ◽  
Giovanni Marsicovetere ◽  
Michele D’Andria ◽  
Michela Francalanci ◽  
...  
Keyword(s):  
Drug Response ◽  
Ex Vivo ◽  
Forced Expiratory Volume ◽  
Considerable Decrease ◽  
Six Minute Walk Test ◽  
Sweat Chloride ◽  
Access Program ◽  
Minute Walk

We evaluated the effectiveness and safety of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) in three subjects carrying the Phe508del/unknown CFTR genotype. An ex vivo analysis on nasal epithelial cells (NEC) indicated a significant improvement of CFTR gating activity after the treatment. Three patients were enrolled in an ELX/TEZ/IVA managed-access program, including subjects with the highest percent predicted Forced Expiratory Volume in the 1st second (ppFEV1) < 40 in the preceding 3 months. Data were collected at baseline and after 8, 12 and 24 weeks of follow-up during treatment. All patients showed a considerable decrease of sweat chloride (i.e., meanly about 60 mmol/L as compared to baseline), relevant improvement of ppFEV1 (i.e., >8) and six-minute walk test, and an increase in body mass index after the first 8 weeks of treatment. No pulmonary exacerbations occurred during the 24 weeks of treatment and all domains of the CF Questionnaire-Revised improved. No safety concerns related to the treatment occurred. This study demonstrates the benefit from the ELX/TEZ/IVA treatment in patients with CF with the Phe508del and one unidentified CFTR variant. The preliminary ex vivo analysis of the drug response on NEC helps to predict the in vivo therapeutic endpoints.

scholarly journals Conditionally Reprogrammed Cells from Patient-Derived Xenograft to Model Neuroendocrine Prostate Cancer Development

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1398 ◽  
Author(s):  
Xinpei Ci ◽  
Jun Hao ◽  
Xin Dong ◽  
Hui Xue ◽  
Rebecca Wu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Ex Vivo ◽  
Cancer Cell Line ◽  
Marker Genes ◽  
Patient Derived Xenograft ◽  
Pdx Model ◽  
Neuroendocrine Prostate Cancer ◽  
Parental Tumor

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. It develops mainly via NE transdifferentiation of prostate adenocarcinoma in response to androgen receptor (AR)-inhibition therapy. The study of NEPC development has been hampered by a lack of clinically relevant models. We previously established a unique and first-in-field patient-derived xenograft (PDX) model of adenocarcinoma (LTL331)-to-NEPC (LTL331R) transdifferentiation. In this study, we applied conditional reprogramming (CR) culture to establish a LTL331 PDX-derived cancer cell line named LTL331_CR_Cell. These cells retain the same genomic mutations as the LTL331 parental tumor. They can be continuously propagated in vitro and can be genetically manipulated. Androgen deprivation treatment on LTL331_CR_Cells had no effect on cell proliferation. Transcriptomic analyses comparing the LTL331_CR_Cell to its parental tumor revealed a profound downregulation of the androgen response pathway and an upregulation of stem and basal cell marker genes. The transcriptome of LTL331_CR_Cells partially resembles that of post-castrated LTL331 xenografts in mice. Notably, when grafted under the renal capsules of male NOD/SCID mice, LTL331_CR_Cells spontaneously gave rise to NEPC tumors. This is evidenced by the histological expression of the NE marker CD56 and the loss of adenocarcinoma markers such as PSA. Transcriptomic analyses of the newly developed NEPC tumors further demonstrate marked enrichment of NEPC signature genes and loss of AR signaling genes. This study provides a novel research tool derived from a unique PDX model. It allows for the investigation of mechanisms underlying NEPC development by enabling gene manipulations ex vivo and subsequent functional evaluations in vivo.

Relationship of in vivo and ex vivo levels of TH1 and TH2 cytokines with viremia in HAART patients with and without opportunistic infections

2006 ◽  
Vol 78 (4) ◽  
pp. 431-439 ◽  
Author(s):  
Sardar Sindhu ◽  
Emil Toma ◽  
Paulo Cordeiro ◽  
Rasheed Ahmad ◽  
Richard Morisset ◽  
...  
Keyword(s):  
Opportunistic Infections ◽  
Ex Vivo ◽  
Th2 Cytokines ◽  
Th1 And Th2 Cytokines ◽  
Relationship Of ◽  
Th1 And Th2

Leveraging RB status to define therapy for castrate-resistant prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 96-96
Author(s):  
Renee de Leeuw ◽  
Clay de Comstock ◽  
Daniela de Pollutri ◽  
Matthew Joseph Schiewer ◽  
Stephen J Ciment ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Kinase Inhibitors ◽  
Ex Vivo ◽  
Tissue Samples ◽  
Ki67 Staining ◽  
Cell Architecture ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

96 Background: Loss of retinoblastoma (RB) tumor suppressor is overrepresented in castrate-resistant prostate cancer (CRPC) compared to primary PCa. We previously showed using analyses of human tissue and in vitro and in vivo modeling that RB constrains androgen receptor (AR) function, and that loss of RB is sufficient promote resistance to castration and AR antagonists. Thus, novel strategies are needed to treat RB-deficient tumor. By contrast, in tumors retaining RB, suppressing enhancing RB activity would be of therapeutic advantage, and may be accomplished through next-generation Cdk4/6 inhibitors. Methods: Stable isogenic pairs of prostate cancer cell lines either retaining RB or RB depleted (by shRNA) were assessed in vitro and in xenografts for response to Cdk4/6 kinase inhibitors or the cabazitaxel. In addition, using an ex vivo explant assay, fresh tumor tissue samples from radical prostatectomy were exposed to the Cdk4/6 inhibitor or cabazitaxel for up to 7 days, and evaluated by IHC for Ki67, Caspase-3, and AR. Results: Cdk4/6 inhibition blocks tumor cell proliferation dependent on RB status. This was further confirmed ex vivo, as evidenced by a marked reduction in Ki67 staining in Cdk4/6 inhibitor treated explant tissue from two prostate cancer patients. Conversely, in vitro studies revealed a modest sensitization of RB-depleted tumors to cabazitaxel that was dramatically enhanced in vivo and after castration. Cabazitaxel, like docetaxel, targets the cell architecture and induces cell death, but also induces a distinct gene expression profile that may partially explain efficacy in docetaxel-resistant tumors. Neither taxane showed affects on AR nuclear localization using in vivoor explant studies. Conclusions: These results strongly support our hypothesis that RB status can be used as a metric to define therapeutic response to cabazitaxel, as such that loss of RB function induces sensitization taxanes, whereas RB proficient tumors give an enhanced response to Cdk4/6 kinase inhibitors.

scholarly journals Apoptotic cell death, detectedex vivoin peripheral blood lymphocytes of HIV-1 infected persons

1996 ◽  
Vol 5 (5) ◽  
pp. 379-381
Author(s):  
L. F. te Velde ◽  
I. Vermes ◽  
C. Haanen ◽  
C. P. M. Reutelingsperger ◽  
C. H. H. ten Napel
Keyword(s):  
Peripheral Blood ◽  
Ex Vivo ◽  
Apoptotic Cell ◽  
Quantitative Information ◽  
Peripheral Blood Lymphocytes ◽  
Median Percentage ◽  
Blood Lymphocytes ◽  
Heterogenous Group ◽  
Hiv 1

In HIV-1 infection the ongoing depletion of CD4+ T-lymphocytes is believed, to a large extent, to be due to apoptosis. Until now quantitative information aboutin vivoapoptosis of lymphocytes in HIV-patients is scarce because of the very nature of the apoptotic process. Successful detection of apoptosisex vivorequires the recognition of the initial phase of this process, because at a later stage the cells may not remain any longer in the circulation. We measured quantitatively the amount of early apoptotic peripheral blood lymphocytes directlyex vivoin HIV-1 infected patients using a recently described flow cytometric assay. With this method we observed in an unselected heterogenous group of twelve HIV-infected individuals a median percentage of apoptotic lymphocytes to be significantly higher than in ten healthy controls. To the best of our knowledge this is the first report ofex vivoobserved increased apoptosis of peripheral blood lymphocytes in HIV-infected persons.

scholarly journals MINDIN secretion by prostate tumors induces premetastatic changes in bone via β-catenin

2020 ◽  
Vol 27 (7) ◽  
pp. 441-456
Author(s):  
Juan A Ardura ◽  
Luis Álvarez-Carrión ◽  
Irene Gutiérrez-Rojas ◽  
Peter A Friedman ◽  
Arancha R Gortázar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Tumor Cell ◽  
Ex Vivo ◽  
Prostate Tumor ◽  
Tumor Cell Adhesion ◽  
Prostate Tumors ◽  
Cell Homing

Bone metastases are common in advanced prostate cancer patients, but mechanisms by which specific pro-metastatic skeletal niches are formed before tumor cell homing are unclear. We aimed to analyze the effects of proteins secreted by primary prostate tumors on the bone microenvironment before the settlement and propagation of metastases. Here, using an in vivo pre-metastatic prostate cancer model based on the implantation of prostate adenocarcinoma TRAMP-C1 cells in immunocompetent C57BL/6 mice, we identify MINDIN as a prostate tumor secreted protein that induces bone microstructural and bone remodeling gene expression changes before tumor cell homing. Associated with these changes, increased tumor cell adhesion to the endosteum ex vivo and to osteoblasts in vitro was observed. Furthermore, MINDIN promoted osteoblast proliferation and mineralization and monocyte expression of osteoclast markers. β-catenin signaling pathway revealed to mediate MINDIN actions on osteoblast gene expression but failed to affect MINDIN-induced adhesion to prostate tumor cells or monocyte differentiation to osteoclasts. Our study evidences that MINDIN secretion by primary prostate tumors creates a favorable bone environment for tumor cell homing before metastatic spread.

scholarly journals Adoptive cell therapy targeting common p53 neoantigens in human solid cancers

2021 ◽  
Author(s):  
Sanghyun Kim ◽  
Nolan Vale ◽  
Nikolaos Zacharakis ◽  
Sri Krishna ◽  
Zhiya Yu ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Tumor Regression ◽  
Ex Vivo ◽  
Adoptive Cell Therapy ◽  
Peripheral Blood Lymphocytes ◽  
Mutant P53 ◽  
Autologous Tumor ◽  
Clinical Responses

Abstract Adoptive cell therapy (ACT) targeting neoantigens can achieve durable clinical responses in patients with cancer. Most neoantigens arise from rare mutations, requiring highly individualized treatments. To broaden the applicability of ACT targeting neoantigens, we focused on TP53 mutations commonly shared across different cancer types. Here, we describe a library of T cell receptors (TCRs) that can target TP53 mutations shared among 7.3% of patients with solid cancers. These TCRs recognized tumor cells in a TP53 mutation- and human leucocyte antigen (HLA)-specific manner both in vitro and in vivo. Patients with chemorefractory epithelial cancers treated with ex vivo-expanded autologous tumor infiltrating lymphocytes (TILs) naturally reactive with mutant p53 experienced limited clinical responses (2 PRs/12 patients), and we detected low frequencies, exhausted phenotypes, and poor persistence of the infused mutant p53-reactive TILs. Alternatively, we treated one patient with a chemorefractory breast cancer with ACT by transducing autologous peripheral blood lymphocytes with an HLA-A*02-restricted anti-p53R175H TCR. The infused cells exhibited an improved immunophenotype and prolonged persistence compared to the TIL ACT and the patient experienced an objective tumor regression (-55%) that lasted 6 months. Collectively, these data demonstrate the feasibility of off-the-shelf TCR-engineered cell therapies targeting shared p53 neoantigens to treat human cancers.

Sign in / Sign up

Export Citation Format

Share Document