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Thomas L Jang

Publications and source records attributed to Thomas L Jang.

13 recordsLinked to original sources
PubMed2006

Infiltration of tumor-reactive transforming growth factor-beta insensitive CD8+ T cells into the tumor parenchyma is associated with apoptosis and rejection of tumor cells.

BACKGROUND: TGF-beta is a potent immunosuppressant. High levels of TGF-beta produced by cancer cells have a negative inhibition effect on surrounding host immune cells and leads to evasion of the host immune surveillance and tumor progression. In the present study, we report a distinct ability of tumor reactive, TGF-beta-insensitive CD8+ T cells to infiltrate into established tumors, secrete relevant cytokines, and induce apoptosis of tumor cells. METHODS: CD8+ T cells were isolated from the spleens of C57BL/6 mice, which were primed with irradiated mouse prostate cancer cells, the TRAMP-C2 cells. After ex vivo expansion, these tumor reactive CD8+ cells were rendered TGF-beta-insensitive by infection with a retroviral (MSCV)-mediated dominant negative TGF-beta type II receptor (TbetaRIIDN). Control CD8+ cells consist of those transfected with the GFP-only empty vector and naïve CD8+ T cells. Recipient mice were challenged with a single injection of TRAMP-C2 cells 21 days before adoptive transfer of CD8+ T cells was performed. Forty days after the adoptive transfer, all animals were sacrificed. The presence of pulmonary metastases was evaluated pathologically. Serial slides of malignant tissues were used for immunofluorescent staining for different kinds of immune cell infiltration, cytokines, and apoptosis analysis. RESULTS: Pulmonary metastases were either eliminated or significantly reduced in the group receiving adoptive transfer of tumor-reactive TGF-beta-insensitive CD8+ T cells (3 out of 12) when compared to GFP controls (9 out of 12), and naïve CD8+ T cells (12 out of 12). Results of immunofluorescent studies demonstrated that only tumor-reactive TGF-beta-insensitive CD8+ T cells were able to infiltrate into the tumor and mediate apoptosis when compared to CD4+ T cells, NK cells, and B cells. A large amount of cytokines such as perforin, nitric oxide, IFN-gamma, IL-2, TNF-alpha were secreted in tumor tissue treated with tumor-reactive TGF-beta-insensitive CD8+ T cells. No immune cells infiltration and cytokine secretion were detected in tumor tissues treated with naïve T cells and GFP controls. CONCLUSIONS: Our results demonstrate the mechanism of anti-tumor effect of tumor-reactive TGF-beta-insensitive CD8+ T cells that adoptive transfer of these CD8+ T cells resulted in infiltration of these immune cells into the tumor parenchyma, secretion of relevant cytokines, and induction of apoptosis in tumor cells. These results support the concept that tumor-reactive TGF-beta-insensitive CD8+ T cells may prove beneficial in the treatment of advanced cancer patients.

Animals↗
PubMed2006

More favorable tumor features and progression-free survival rates in a longitudinal prostate cancer screening study: PSA era and threshold-specific effects.

OBJECTIVES: To describe the changes in pathologic outcomes and progression-free survival (PFS) rates after radical retropubic prostatectomy for clinically localized prostate cancer in men whose cancers were detected in a 12-year longitudinal prostate cancer screening study. METHODS: Between 1989 and 2001, more than 36,000 men participated in a digital rectal examination-based and prostate-specific antigen (PSA)-based screening program. In 1995, the PSA cutoff for biopsy recommendation was lowered from 4.0 ng/mL to 2.6 ng/mL, and the biopsy protocol was changed from four to at least six-sector biopsies. From the screening study, 2952 men were diagnosed with cancer and 2241 of these men underwent radical retropubic prostatectomy. We analyzed the differences in clinical and pathologic stage and PFS after surgery, according to the greater PSA cutoff era (1989 to 1995) and lower PSA cutoff era (1996 to 2001). RESULTS: A significant downward clinical and pathological stage migration was found toward T1c and organ-confined disease, respectively, in men whose cancer was detected in the lower PSA cutoff era. Furthermore, men with cancer diagnosed in the lower PSA cutoff era had improved PFS rates 5 and 8 years after radical retropubic prostatectomy (P = 0.007). These changes occurred without a significant increase in the proportion of unimportant tumors (organ confined, smaller than 0.5 cm3 without a Gleason pattern of 4 or 5). CONCLUSIONS: These findings support the enhanced detection of favorable cancer and improved PFS rates with lower PSA cutoffs and more intensive biopsy regimens, although the follow-up and lead-time and length-time biases, as well as improvements in surgical technique, might also have affected these results.

Adult↗
PubMed2006

Rectourethral fistula associated with two short segment urethral strictures in the anterior and posterior urethra: single-stage reconstruction using buccal mucosa and a radial forearm fasciocutaneous free flap.

INTRODUCTION: We report a novel surgical technique used to repair a rectourethral fistula associated with two short-segment urethral strictures located in the anterior and posterior segments of the urethra in a patient with prior unsuccessful repairs. TECHNICAL CONSIDERATIONS: The anterior urethral stricture was reconstructed with a ventral onlay of buccal mucosa in the exaggerated lithotomy position. In a modified prone position, the rectourethral fistula was repaired using the transrectal transsphincteric (York-Mason) technique and the posterior urethral stricture with a radial forearm fasciocutaneous free flap which was anastomosed to the inferior gluteal artery and vein. The coexistence of a rectourethral fistula and distal urethral stricture requires simultaneous repair, because the urethral pressure from the distal obstruction may compromise fistula closure. Reconstructive efforts should be tailored to minimize disruption of the urethral blood supply in patients with previous pelvic trauma. Rectal and urethral repairs should be separated by well-vascularized tissue to prevent fistula recurrence. CONCLUSIONS: The radial fasciocutaneous flap may offer the reconstructive surgeon another surgical option for complex urethral stricture and rectourethral fistula reconstruction when the local blood supply is in question. Longer follow-up and more cases are needed to further evaluate the continued use of this technique.

Adult↗
PubMed2006

The leader sequence triggers and enhances several functions of clusterin and is instrumental in the progression of human prostate cancer in vivo and in vitro.

OBJECTIVE: To investigate the role of the leader sequence (which during clusterin biosynthesis facilitates its proper post-translational processing and secretion) in the functional activities of clusterin, a ubiquitous secretory glycoprotein with many biological functions, reported to be pro-apoptotic and anti-apoptotic in target cells, but for which the dual mechanism remains unclear. MATERIALS AND METHODS: We designed an expression vector starting from the second in-frame ATG on the full-length human clusterin cDNA that was capable of driving the expression of both the full-length and the truncated isoforms of clusterin. We established stable expression clones of the androgen-dependent prostate cancer line LNCaP expressing clusterin with and without the leader sequence. This induced expression provided an opportunity to evaluate both the in vivo and in vitro actions of clusterin expression. RESULTS: The LNCaP cells expressing clusterin with the leader sequence resisted apoptosis induced by tumour necrosis factor (TNF)-alpha, but clones with no leader sequence were highly susceptible to TNF-alpha-induced apoptosis. Furthermore, in the absence of the leader sequence, the expressed clusterin had a molecular weight consistent with that of the predicted holoprotein (40 kDa), suggesting a compromised post-translational processing with diffuse distribution throughout the cytoplasm. However, cells transfected with the full-length vector expressed clusterin of 60 and 35 kDa variants, and located exclusively in the Golgi apparatus. In vivo, only the overexpression of the full-length clusterin is anti-apoptotic and stimulates the proliferation of tumour. CONCLUSION: The leader sequence is important in determining the functions of clusterin, which include anti-apoptotic and anti-necrotic properties. The lack of the leader sequence allowed the incompletely processed clusterin to induce apoptosis in target cells; without the leader sequence, clusterin functions differently. Thus, the leader sequence is a trigger for many functions of clusterin in the progression of human prostate cancer cells.

Apoptosis↗
PubMed2006

Chronic prostatitis.

Explore the source record for details and available documents.

5-alpha Reductase Inhibitors↗
PubMed2005

Insensitivity to transforming growth factor-beta results from promoter methylation of cognate receptors in human prostate cancer cells (LNCaP).

Prostate cancers often develop insensitivity to TGF-beta to gain a growth advantage. In this study, we explored the status of promoter methylation of TGF-beta receptors (TbetaRs) in a prostate cancer cell line, LNCaP, which is insensitive to TGF-beta. Sensitivity to TGF-beta was restored in cells treated with 5-Aza-2'-deoxycytidine (5-Aza), as indicated by an increase in the expression of phosphorylated Smad-2, type I (TbetaRI), and type II (TbetaRII) TGF-beta receptors, and a reduced rate of proliferation. The same treatment did not significantly affect a benign prostate cell line, RWPE-1, which is sensitive to TGF-beta. Mapping of methylation sites was performed by screening 82 potential CpG methylation sites in the promoter of TbetaRI and 33 sites in TbetaRII using methylation-specific PCR and sequence analysis. There were six methylation sites (-365, -356, -348, -251, -244, -231) in the promoter of TbetaRI. The -244 site was located in an activator protein (AP)-2 box. There were three methylated sites (-140, +27, +32) in the TbetaRII promoter and the -140 site was located in one of the Sp1 boxes. Chromatin immunoprecipitation analysis demonstrated DNA binding activity of AP-2 in the TbetaRI promoter and of Sp1 in the TbetaRII promoter after treatment with 5-Aza. To test whether promoter methylation is present in clinical specimens, we analyzed human prostate specimens that showed negative staining for either TbetaRI or TbetaRII in a tissue microarray system. DNA samples were isolated from the microarray after laser capture microdissection. Methylation-specific PCR was performed for TbetaRI (six sites) and TbetaRII (three sites) promoters as identified in LNCaP cells. A significant number of clinical prostate cancer specimens lacked expression of either TbetaRI and/or TbetaRII, especially those with high Gleason's scores. In those specimens showing a loss of TbetaR expression, a promoter methylation pattern similar to that of LNCaP cells was a frequent event. These results demonstrate that insensitivity to TGF-beta in some prostate cancer cells is due to promoter methylation in TbetaRs.

Azacitidine↗
PubMed2005

Comparison of donor site intraoral morbidity after mucosal graft harvesting for urethral reconstruction.

OBJECTIVES: To compare postoperative intraoral morbidity after mucosal graft harvesting from the lower lip and inner cheek in men undergoing substitution urethroplasty. METHODS: From 2000 to 2004, 40 patients underwent oral mucosal graft harvesting for urethral reconstruction. Of the 40 patients, 17 underwent harvest from the lower lip (group 1), 19 from the inner cheek (group 2), and 4 from both sites (group 3). We analyzed the postoperative differences in discomfort levels, neurosensory deficits, salivary flow, complications, and overall quality of life according to harvest site. Outcomes were assessed using analog scales and a questionnaire. RESULTS: At longer term follow-up, the proportion of men with persistent postoperative discomfort, neurosensory deficits, and changes in salivary flow was greater in men whose grafts were harvested from the lower lip than in those whose grafts were harvested from the cheek. Contractures were noted in 1 (5.9%) of 17 and 5 (26.3%) of 19 men in groups 1 and 2, respectively. At the last follow-up visit, overall quality of life (measured by an analog scale of 0 [delighted] to 6 [terrible]) was not significantly different in patients with lower lip versus inner cheek harvest (1.35 versus 0.66, respectively, P = 0.079). CONCLUSIONS: Persistent postoperative discomfort, neurosensory deficits, and salivary flow changes were more common in men whose grafts were harvested from the lower lip. However, the overall quality of life in this group was not significantly different compared with men whose grafts were harvested from the inner cheek. From a morbidity standpoint, the inner cheek appears to be the preferable site of graft harvest.

Adolescent↗
PubMed2005

Histopathology of human renal tumors after laparoscopic renal cryosurgery.

PURPOSE: Laparoscopic renal cryoablation is a nephron sparing treatment alternative for selected patients with small renal tumors. The acute tumoricidal effects of cryosurgery on human renal tumors and in experimental models have been reported previously. For cryoablation to be a viable option in the treatment of renal tumors, it must induce not only acute tissue injury but also sustain permanent tissue necrosis and cellular death, in addition to affording an adequate surgical margin free of viable tumor. We report on the longer term effects of in vivo human tumor tissue destruction by cryosurgery and describe the histopathology of a cryoablated renal lesion. MATERIALS AND METHODS: Three patients in our series who were treated with laparoscopic renal cryosurgery subsequently underwent radical nephrectomy of the cryoablated renal unit. RESULTS: All patients underwent uneventful cryosurgery. Two patients were found to have positive post-cryosurgery biopsies, while a new, metachronous lesion developed in 1 patient. All 3 patients elected to undergo radical nephrectomy. Mean time from cryosurgery to nephrectomy was 275 days. The cryoablated lesions demonstrated coagulative necrosis as evidenced by numerous histiocytes, cholesterol crystals and dystrophic calcification. There was no evidence of viable tumor within the cryoablated field. CONCLUSIONS: The longer term tumoricidal effects of laparoscopic renal cryosurgery in human renal tissue have been demonstrated. However, careful patient selection with lesions less than 3.0 cm and vigilant monitoring of the iceball under strict radiographic guidance are imperative to ensure successful oncological outcomes.

Aged↗
PubMed2004

Xanthogranulomatous orchitis.

Xanthogranulomatous inflammation is an uncommon process that is usually associated with severe renal infection. We report a case of a 64-year-old man with xanthogranulomatous inflammation in the testis who presented with contralateral epididymoorchitis and a painless testicular mass. Only two prior cases of xanthogranulomatous orchitis have been reported. This case highlights the need for a broad differential diagnosis when approaching testicular masses, particularly in the setting of coincident infection.

Diagnosis, Differential↗
PubMed2003

The role of cytokines in prostatitis.

There is substantiating evidence to support the role of the immune system in the pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Inflammation of the prostate is mediated through the cytokine-induced expression of several factors such as chemokines, inducible nitric oxide synthase, and cyclooxygenase-2. The balance between the effects of proinflammatory and anti-inflammatory cytokines determines the outcome of the inflammatory process. Several proinflammatory and anti-inflammatory cytokines have been identified in CPPS patients, their roles characterized, and their inter-relationships defined. Study of this system will provide further insights into the etiology of CP/CPPS, and lead the way for the development of novel therapeutic approaches for this morbid condition.

Chronic Disease↗
PubMed2002

Pyeloureterostomy with interposition of the appendix.

PURPOSE: We describe the successful repair of a 6 cm. ureteral stricture involving the right ureteropelvic junction and proximal ureter using appendix as a ureteral substitute. MATERIALS AND METHODS: A 37-year-old man involved in a motorcycle accident presented with a retroperitoneal urinoma and a 6 cm. proximal ureteral stricture. At flank exploration we were unable to perform successfully primary pyeloureterostomy through renal descensus with ureteral mobilization. The appendix was selected to bridge the ureteral defect. The right colon and cecum were mobilized to the area of the diseased ureter and the appendix was transected across the base of the cecum. Ureteral scar tissue was resected and the appendix was interposed in an isoperistaltic orientation from renal pelvis to proximal ureter. RESULTS: Convalescence was unremarkable. Retrograde pyelography and flexible ureteroscopy 2 months postoperatively demonstrated a patent anastomosis and viable appendix. The ureteral stent was removed at that time. Excretory urography 3 months postoperatively revealed prompt enhancement of the 2 kidneys and visualization of the 2 ureters. Mercaptoacetyltriglycine-3 renal scan 5 months postoperatively confirmed no scintigraphic evidence of obstruction. The patient was asymptomatic 6 months postoperatively and renal function tests were normal. CONCLUSIONS: The appendix can be considered for proximal ureteral defects extending to the right renal pelvis.

Adult↗