Biomedical subjects

Javier Hernandez

Publications and source records attributed to Javier Hernandez.

24 records · Page 2Linked to original sources

PubMed2004

Diagnosis and treatment of prostate cancer.

Many controversies surround the management of prostate cancer to include screening practices, diagnosis, and treatment options. The lack of randomized prospective studies comparing the various definitive treatment modalities currently available occasionally can make the decision process challenging for patients and their providers. In this setting of controversy, the cost of treating clinically localized prostate cancer is significant. In the face of these unanswered questions, this article summarizes some important principles regarding the diagnosis and treatment of prostate cancer. This review is limited to the diagnosis and management of clinically localized disease.

Adult↗

PubMed2004

Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy.

PURPOSE: Hormonal therapy (HT) is the current mainstay of systemic treatment for prostate specific antigen (PSA) only recurrence (PSAR), however, there is virtually no published literature comparing HT to observation in the clinical setting. The goal of this study was to examine the Department of Defense Center for Prostate Disease Research observational database to compare clinical outcomes in men who experienced PSAR after radical prostatectomy by early versus delayed use of HT and by a risk stratified approach. MATERIALS AND METHODS: Of 5382 men in the database who underwent primary radical prostatectomy (RP), 4967 patients were treated in the PSA-era between 1988 and December 2002. Of those patients 1352 men who had PSAR (PSA after surgery greater than 0.2 ng/ml) and had postoperative followup greater than 6 months were used as the study cohort. These patients were further divided into an early HT group in which patients (355) received HT after PSA only recurrence but before clinical metastasis and a late HT group for patients (997) who received no HT before clinical metastasis or by current followup. The primary end point was the development of clinical metastases. Of the 1352 patients with PSAR clinical metastases developed in 103 (7.6%). Patients were also stratified by surgical Gleason sum, PSA doubling time and timing of recurrence. Univariate and multivariate Cox proportional hazard models were used to evaluate the effect of early and late HT on clinical outcome. RESULTS: Early HT was associated with delayed clinical metastasis in patients with a pathological Gleason sum greater than 7 or PSA doubling time of 12 months or less (Hazards ratio = 2.12, p = 0.01). However, in the overall cohort early HT did not impact clinical metastases. Race, age at RP and PSA at diagnosis had no effect on metastasis-free survival (p >0.05). CONCLUSIONS: The retrospective observational multicenter database analysis demonstrated that early HT administered for PSAR after prior RP was an independent predictor of delayed clinical metastases only for high-risk cases at the current followup. Further study with longer followup and randomized trials are needed to address this important issue.

Aged↗

PubMed2003

Deletion of naive CD8 T cells requires persistent antigen and is not programmed by an initial signal from the tolerogenic APC.

Activation of naive CD8 T cells in vivo requires the recognition of cognate peptide-MHC complexes on APCs. Depending upon the activation status of the APC, such recognition will promote either a vigorous immune response or T cell tolerance and deletion. Recent studies suggest that the initial signals provided by APCs are sufficient to program the proliferation of naive CD8 T cells and their differentiation into effector cells. In this study, we sought to determine whether an initial encounter with tolerogenic APCs was sufficient to program deletion of naive CD8 T cells. Surprisingly, we find that regardless of whether naive CD8 T cells were stimulated by activated or quiescent APCs, transfer of the activated T cells into an Ag-free host was sufficient to ensure survival. Thus, although the extent of clonal expansion and development of effector function is determined by the activation status of the stimulatory APC, peripheral clonal deletion requires persistent Ag and is not determined by the initial stimulatory event.

Adoptive Transfer↗

PubMed2003

A soluble single-chain T-cell receptor IL-2 fusion protein retains MHC-restricted peptide specificity and IL-2 bioactivity.

Antibody-based targeted immunotherapy has shown promise as an approach to treat cancer. However, many known tumor-associated antigens are not expressed as integral membrane proteins and cannot be utilized as targets for antibody-based therapeutics. In order to expand the limited target range of antibodies, we have constructed a soluble single-chain T-cell receptor (TCR) fusion protein designated 264scTCR/IL-2. This fusion protein is comprised of a three-domain HLA-A2-restricted TCR specific for a peptide epitope of the human p53 tumor suppressor protein, which is overexpressed in a broad range of human malignancies. The 264scTCR/IL-2 fusion protein has been expressed at high levels in mammalian cells, and milligram quantities have been purified. MHC-restricted antigen-specific binding properties are maintained in the single-chain, three-domain TCR portion of the fusion protein, and the IL-2 portion retains bioactivity similar to that of free recombinant IL-2. Moreover, this fusion protein is capable of conjugating target and effector cells, remains intact in the blood and substantially increases the half life of the IL-2 portion of the molecule. Finally, the 264scTCR/IL-2 fusion protein can be used to stain tumor cells and is capable of reducing lung metastases in an experimental model of metastasis. Thus, TCR-based fusion proteins may provide a novel class of targeted immunotherapeutics for cancer.

Amino Acid Sequence↗

PubMed2003

An animal model of abdominal aortic aneurysm created with peritoneal patch: technique and initial results.

The purpose of this study was to develop an abdominal aortic aneurysm model that more closely resembles the morphology of human aneurysms with potential for further growth of the sac. An infrarenal abdominal aortic aneurysm (AAA) model was created with a double-layered peritoneal patch in 27 domestic swine. The patch, measuring in average from 6 to 12 cm in length and from 2 to 3 cm in width, was sutured to the edge of an aortotomy. Pre- and postsurgical digital subtraction aortograms (DSA) were obtained to document the appearance and dimensions of the aneurysm. All animals were followed with DSA for up to 5 months. Laparoscopic examination enhanced by the use of laparoscopic ultrasound was also carried out in 2 animals to assess the aneurysm at 30 and 60 days following surgery. Histological examination was performed on 4 animals. All the animals that underwent the surgical creation of the AAA survived the surgical procedure. Postsurgical DSA demonstrated the presence of the AAA in all animals, defined as more than 50% increase in diameter. The aneurysmal mean diameter increased from the baseline of 10.27 +/- 1.24 to 16.69 +/- 2.29 mm immediately after surgery, to 27.6 +/- 6.59 mm at 14 days, 32.45 +/- 8.76 mm at 30 days (p < 0.01), and subsequently decreased to 25.98 +/- 3.75 mm at 60 days. A total of 15 animals died of aneurysmal rupture that occurred more frequently in the long aneurysms (> or =6 cm in length) than the short aneurysms (<6 cm in length) during the first 2 weeks after surgery (p <0.05). No rupture occurred beyond 16 days after surgery. Four animals survived and underwent 60-day angiographic follow-up. Laparoscopic follow-up showed strong pulses, a reddish external appearance and undetectable suture lines on the aneurysmal wall. On pathology, the patches were well incorporated into the aortic wall, the luminal wall appeared almost completely endothelialized, and cellular and matrix proliferation were noted in the aneurysmal wall. A reproducible technique for the creation of an infrarenal AAA model was developed using a peritoneal patch in swine. The aneurysm model proved to have potential for further growth of the sac and a tendency to rupture. Because of the growth potential, this might be a better model than those with a noncompliant aneurysmal wall for the preclinical evaluation of stent-graft devices.

Animals↗

PubMed2002

Identification of a human telomerase reverse transcriptase peptide of low affinity for HLA A2.1 that induces cytotoxic T lymphocytes and mediates lysis of tumor cells.

Telomerase reverse transcriptase (TRT) is a tumor-associated antigen expressed in the vast majority of human tumors and is presently one of the most promising target candidates for a therapeutic cancer vaccine. TRT is also expressed at low level in selected tissues and should be considered a self antigen. In the present study we sought to develop cytotoxic T lymphocytes (CTL) responses directed against human (h)TRT peptides with low relative affinity for which the available repertoire is to be preferentially spared from tolerance. This was accomplished by using analogue peptides of hTRT whose relative affinity for the MHC was increased by a targeted (-->Tyr) substitution in position one. By immunizing HLA A2.1 transgenic mice with these analogue peptides, we identified one such low relative affinity peptide (p572) that is endogenously processed and presented by HLA A2.1 in tumor cells, and is recognized by specific CTL. We used the highly immunogenic analogue peptide to successfully induce TRT-specific CTL in cancer patients and normal donors. CTL against p572-lysed human and mouse tumor cells but not activated autologous B cells. This peptide represents, therefore, an important candidate component of a cancer vaccine based on a TRT substrate and validates the strategy of targeting peptides with low affinity for the MHC for cancer immunotherapy.

Amino Acid Motifs↗