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Biomedical subjects

J R Gingrich

Publications and source records attributed to J R Gingrich.

At least 19 recordsLinked to original sources
PubMed2003

Hemorrhagic cystitis after allogeneic bone marrow transplantation in children: clinical characteristics and outcome.

Hemorrhagic cystitis (HC) is a well-documented adverse event experienced by patients undergoing hematopoietic stem cell transplantation. When severe, HC causes significant morbidity, leads to renal complications, prolongs hospitalization, increases health-care costs, and occasionally contributes to death. We retrospectively studied the medical records of 245 children undergoing an initial allogeneic bone marrow transplantation for malignant disease at St. Jude Children's Research Hospital between 1992 and 1999 to describe the clinical course of HC in all patients and to identify the risk factors for HC in this cohort. Conditioning regimens included cyclophosphamide, cytarabine, and total body irradiation. Grafts from unrelated or mismatched related donors were depleted of T lymphocytes, whereas matched sibling grafts were unmanipulated. All patients received cyclosporine as prophylaxis for graft-versus-host disease. Recipients of grafts from matched siblings also received pentoxifylline or short-course methotrexate. Severe HC developed in 27 patients (11.0%). The median duration of HC was 73 days (range, 5-619 days); 12 patients had ongoing HC at the time of death. In univariate analyses, patients were at increased risk of severe HC if they were male (P =.021) or had received T cell-depleted grafts (P =.017), grafts from unrelated donors (P =.021), a lower total nucleated cell dose (P =.032), or antithymocyte globulin (P =.0446). Multiple regression analysis revealed male sex (beta =.97; P =.027) and unrelated donor graft recipients (beta =.83; P =.039) to be significant factors.

Acute Disease↗
PubMed2002

Enforced expression of FGF-7 promotes epithelial hyperplasia whereas a dominant negative FGFR2iiib promotes the emergence of neuroendocrine phenotype in prostate glands of transgenic mice.

The minimal rat probasin (PB) promoter was used to target expression of human fibroblast growth factor-7 (FGF-7)/keratinocyte growth factor (KGF) directly to prostatic epithelium of transgenic mice, converting FGF-7 from a paracrine to an autocrine factor. Four independent lines were established that expressed the transgene (PKS) in the prostate. Upon histologic analysis, the prostatic epithelium of PKS mice was found to be hyperplastic. Many of the prostatic ducts were filled with secretory epithelial cells tightly associated with a highly enfolded basement membrane. Distortions of the ductal smooth muscle layer were also observed. Prostates from year-old PKS mice had significantly more abnormal ducts than their wild-type nontransgenic littermates. The minimal rat PB promoter was also used to target a truncated FGFR2iiib receptor to prostatic epithelium to functionally abrogate endogenous FGF-7 signaling. Three lines were established that expressed the transgene (KDNR) in the prostate. Upon dissection it was noted that all four lobes of the prostates of KDNR mice were present but smaller in size. Histologic analysis indicated that the epithelium in many of the prostatic ducts was disorganized and contained numerous rounded cytokeratin-positive cells that were not tightly associated with the basement membrane. The stroma was disorganized and did not form a tight layer of smooth muscle around the epithelial ducts. Surprisingly, abrogation of FGF signaling in KDNR mice correlated with the emergence of a neuroendocrine-like phenotype that was not observed as a consequence of enforced FGF-7 expression in the PKS mice.

Androgen-Binding Protein↗
PubMed2001

Importance of delayed imaging for blunt renal trauma.

The advent of noninvasive computed tomography of the abdomen and pelvis for evaluation of blunt renal trauma has led to the practice of expectant management for hemodynamically stable patients. Although expectant management of higher grade injuries (American Association for the Surgery of Trauma Renal Injury Scale) would intuitively result in an increased frequency of urologic complications, this has not been previously examined in a large series of patients utilizing contemporary radiologic imaging techniques. A retrospective review of patients from a single institution within a recent 4-year period revealed 4 grade I, 13 grade II, 21 grade III, 7 grade IV, and 4 grade V injuries. None of grade 1, 15% of grade II, 38% of grade III, 43% of grade IV, and 100% of grade V injuries had one or more (15 major and 11 minor) urologic complications. The incidence of urinary complications correlated significantly with increasing grade (0%, 15%, 38%, 43%, and 100% for grades I to V, respectively; r = 0.94, p = 0.0158). Of the delayed urologic complications, 50% were diagnosed on follow-up imaging studies and 33% of them required intervention. Therefore we advocate repeat imaging 2 to 4 days after trauma resulting in grade III to V blunt renal lacerations to identify delayed complications that may require intervention.

Abdominal Injuries↗
PubMed2001

Gene therapy for prostate cancer.

Basic research continues to unravel the molecular complexity of normal and abnormal biologic processes. The development of means to affect the expression level of genes that promote or contribute to cellular transformation, invasion, and metastasis has spawned the concept of gene therapy. This relatively new field seeks to reverse or suspend the pathologic progression of a variety of diseases including the malignant transformation of prostatic epithelial cells. Initial clinical trials for prostate cancer have thus far shown gene therapy to be relatively safe, although definitive evidence of durable therapeutic efficacy remains to be demonstrated. In this article, recent preclinical research, current therapeutic strategies, and recent results of gene therapy clinical trials for the treatment of prostate cancer are reviewed.

Clinical Trials as Topic↗
PubMed2001

Gene therapy for prostate cancer.

Basic research continues to unravel the molecular complexity of normal and abnormal biologic processes. The development of means to affect the expression level of genes that promote or contribute to cellular transformation, invasion, and metastasis has spawned the concept of gene therapy. This relatively new field seeks to reverse or suspend the pathologic progression of a variety of diseases including the malignant transformation of prostatic epithelial cells. Initial clinical trials for prostate cancer have thus far shown gene therapy to be relatively safe, although definitive evidence of durable therapeutic efficacy remains to be demonstrated. In this article, recent preclinical research, current therapeutic strategies, and recent results of gene therapy clinical trials for the treatment of prostate cancer are reviewed.

Genetic Therapy↗
PubMed2001

Impact of urethral injury management on the treatment and outcome of concurrent pelvic fractures.

OBJECTIVES: Multiple treatment options exist for concurrent posterior urethral trauma and pelvic fractures. Because of the increased risk of contamination, the surgical repair of fractures may be prohibited by suprapubic urologic catheters. To characterize the incidence and long-term outcomes of these management conflicts, we reviewed our experience with concomitant pelvic fractures and posterior urethral injuries. METHODS: For a 42-month period, 61 patients with concurrent lower urinary tract and pelvic trauma, including 23 with posterior urethral injuries, were retrospectively reviewed for conflicts between urologic management and optimal treatment of the associated orthopedic injuries. RESULTS: Of the 23 posterior urethral injuries identified, the management of 8 (35%) was noted to impact the decision regarding the management and outcome of the concurrent pelvic fractures. Although the overall difference in the length of hospitalization and period of immobilization was not statistically significant, of the 4 patients whose suprapubic catheter precluded surgical orthopedic fracture repair, 3 patients (75%) remain disabled because of chronic pelvic pain, and none of those who underwent early endoscopic realignment remain disabled because of their pelvic fracture. CONCLUSIONS: Endoscopic realignment for traumatic posterior urethral injuries associated with pelvic fractures, particularly acetabular fractures, should be attempted to avoid the increased morbidity associated with conservative management of the concurrent orthopedic injuries.

Accidents, Traffic↗
PubMed2000

Bcl-2 accelerates multistep prostate carcinogenesis in vivo.

The impact of bcl-2 proto-oncogene expression on the pathogenesis and progression of prostate cancer was examined in a transgenic mouse model. Probasin-bcl-2 transgenic mice were crossed with TRAMP (TRansgenic Adenocarcinoma Mouse Prostate) mice that express the SV40 early genes (T/t antigens) under probasin control. Prostate size, cell proliferation, apoptosis, and the incidence and latency of tumor formation were evaluated. The double transgenic, probasin-bcl-2 X TRAMP F1 (BxT) mice exhibited an increase in the wet weight of the prostate. This was associated with an increase in proliferation, attributable to T/t antigens, and a decrease in apoptosis attributable to bcl-2. The latency to tumor formation was also decreased in the BxT mice compared to the TRAMP mice. The incidence of metastases was identical in both the TRAMP and BxT mice. Lastly, the incidence of hormone-independent prostate cancer was reduced in the BxT mice compared to the TRAMP mice. Together, these results demonstrate that bcl-2 can facilitate multistep prostate carcinogenesis in vivo.

Adenocarcinoma↗
PubMed2000

The impact of bcl-2 expression and bax deficiency on prostate homeostasis in vivo.

Prostatic glandular epithelial cells undergo apoptosis in response to androgen-deprivation. The molecular determinants of androgen-responsiveness in these cells are incompletely understood. Recent evidence suggests that bcl-2 gene family members may be important in this context. We used the probasin promoter to target a human bcl-2 transgene specifically to the prostate in order to assess its impact on conferring resistance to androgen withdrawal in, otherwise sensitive, prostatic glandular epithelial cells in vivo. We examined the contribution of bax to mediating androgen-responsiveness in prostatic glandular epithelial cells using bax knockout mice. The histologic appearance of the prostates from probasin-bcl-2 transgenic mice or bax-/- mice did not differ from those of control littermates. There was no evidence of hyperplastic or neoplastic growth. There was no difference between probasin bcl-2 transgenic mice, bax-/- mice, and control littermates in steady-state levels of apoptosis. Following castration our findings suggest that both bax and bcl-2 may each contribute to the androgen-responsiveness of prostatic glandular epithelial cells. It is apparent from these results, however, that bax is not required to mediate cell death in prostatic glandular epithelial cells following castration. A comparison between the apoptotic indices in the ventral prostate from the probasin-bcl-2 and bax-/- mice following castration suggests that the presence of bcl-2 may be a more important indicator of androgen-sensitivity than a deficiency of bax.

Androgen-Binding Protein↗
PubMed2000

Imaging findings of hemorrhagic cystitis in pediatric oncology patients.

In pediatric oncology patients, hemorrhagic cystitis may be a life-threatening complication of bone-marrow transplantation, chemotherapy, and/or radiation therapy. The inciting agent in urine can affect the entire urothelium from the renal collecting system to the bladder, and the severity of disease can vary. The radiologist often plays a key role in the diagnosis, follow-up, and occasionally the treatment of hemorrhagic cystitis and its complications. This review discusses the imaging findings in the kidneys and bladder in patients with hemorrhagic cystitis both before and after treatment for this disease. Findings on two-dimensional sonography, color Doppler and power Doppler sonography, computed tomography, magnetic resonance imaging, antegrade pyleography, and cystography are presented.

Bone Marrow Transplantation↗
PubMed2000

Gene therapy for prostate cancer: where are we now?

PURPOSE: The ability to recombine specifically and alter DNA sequences followed by techniques to transfer these sequences or even whole genes into normal and diseased cells has revolutionized medical research and ushered the clinicians of today into the age of gene therapy. We provide urologists a review of relevant background information, outline current treatment strategies and clinical trials, and delineate current challenges facing the field of gene therapy for advanced prostate cancer. MATERIALS AND METHODS: We comprehensively reviewed the literature, including PubMed and recent abstract proceedings from national meetings, relevant to gene therapy and advanced prostate cancer. We selected for review literature representative of the principal scientific background for current gene therapy strategies and National Institutes of Health Recombinant DNA Advisory Committee approved clinical trials. RESULTS: Current prostate cancer gene therapy strategies include correcting aberrant gene expression, exploiting programmed cell death pathways, targeting critical cell biological functions, introducing toxic or cell lytic suicide genes, enhancing the immune system antitumor response and combining treatment with conventional cytotoxic chemotherapy or radiation therapy. CONCLUSIONS: Many challenges lie ahead for gene therapy, including improving DNA transfer efficiency to cells locally and at distant sites, enhancing levels of gene expression and overcoming immune responses that limit the time that genes are expressed. Nevertheless, despite these current challenges it is almost certain that gene therapy will be part of the urological armamentarium against prostate cancer in this century.

Adenoviridae↗
PubMed1999

Pathologic progression of autochthonous prostate cancer in the TRAMP model.

The ability to manipulate gene expression in specific cell types at specific times utilizing transgenic technology has allowed the development of novel mouse model systems that can mimic human disease. We have previously established the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model for prostate cancer using the rat probasin promoter to direct expression of the SV40 early genes to prostate epithelium. Male TRAMP mice exhibit consistent prostate-specific patterns of expression and develop prostatic intraepithelial neoplasia that will become invasive and metastasize primarily to the lymph nodes and lungs. In this paper we report our continued experience with this model and present a standardized histologic grading system to designate low and high grade prostatic intraepithelial neoplasia and well, moderate, and poorly differentiated prostate adenocarcinoma. In addition, we demonstrate the persistence of androgen receptor expression during pathologic progression and characterize heterogeneous cytokeratin expression in localized and metastatic prostate cancer. Finally, we report on our observations that phenotypic variability in tumor and pathologic progression in TRAMP occurs as a function of genetic background.

Journal Article↗
PubMed1999

Differential expression of C-CAM cell adhesion molecule in prostate carcinogenesis in a transgenic mouse model.

PURPOSE: The transgenic adenocarcinoma of mouse prostate (TRAMP) model, in which various grades of prostate intraepithelial neoplasia (PIN) and prostate cancer with metastases can be reproducibly generated, is a paradigm for prostate disease progression. We have previously shown that C-CAM, an adhesion molecule, can suppress the growth of prostate cancer. In this report, we describe immunohistochemical characterization of differential expression of C-CAM at various stages of prostate tumorigenesis in the TRAMP model. MATERIALS AND METHODS: We sampled prostate specimens and periaortic lymph nodes from TRAMP mice. Indirect immunohistochemical staining with a polyclonal anti-C-CAM antibody was performed on the formalin-fixed, paraffin-embedded specimens. After castration at 12 weeks of age, the TRAMP mice developed androgen-independent prostate cancer (AIPC) and lymph node metastasis at 18 to 24 weeks of age. Samples from these castrated mice were also analyzed. RESULTS: C-CAM protein was expressed in the normal prostate epithelia of non-transgenic and TRAMP mice as well as in low-grade PINs in TRAMP mice. Expression was uniform on the luminal surfaces of these epithelia. C-CAM expression was noticeably reduced and the staining pattern heterogeneous in some high-grade PINs. C-CAM staining was generally absent in prostate cancer and metastatic lymph nodes. Androgen independent prostate cancer and its metastatic tumors generated in castrated TRAMP mice were also C-CAM negative. CONCLUSIONS: C-CAM expression correlates with the differentiation states of prostate epithelia and is down regulated early in prostate tumorigenesis in the TRAMP model.

Adenosine Triphosphatases↗
PubMed1998

A gene hunting we will go!

Two general approaches toward the identification of new genes which may contribute to specific developmental, physiologic, or pathologic processes can be pursued: (1) a strategy of positional cloning or reverse genetics and linkage analysis in which affected individuals or families are studied to identify defective genes, and (2) an immediately focused approach which uses available partial information about a gene to screen cDNA libraries toward the isolation and characterization of the complete gene. The general principles that form the basis of how these two strategies aid the gene hunter in the pursuit of new genes is discussed. The modern day urologist should become familiar with these techniques and the promise they hold for the future diagnosis and treatment of urologic diseases.

Cloning, Molecular↗
PubMed1998

Inducible gene expression in the nervous system of transgenic mice.

Gene function during mammalian development is often studied by making irreversible changes to the genome. This approach has a major drawback in that the function of the gene in question must be deduced from the phenotype of animals that have been deficient for the product of the disrupted gene throughout ontogeny. Compensation for the loss of the gene product could yield an apparently unaltered phenotype. Alternatively, the changes in the regulation of other genes could yield a misleading phenotype. If the genetic manipulation results in embryonic or neonatal lethality, gene function at later stages of development cannot be analyzed. It would thus be highly advantageous if the expression of a particular gene could be restricted both temporally and spatially through the use of an inducible genetic system. This paper describes the various inducible genetic expression systems developed for use in mammalian cells, with particular emphasis on their application in the nervous system of transgenic mice.

Animals↗
PubMed1997

Androgen-independent prostate cancer progression in the TRAMP model.

We previously established the autochthonous transgenic adenocarcinoma mouse prostate (TRAMP) model to facilitate characterization of molecular mechanisms involved in the initiation and progression of prostate cancer. TRAMP mice display high grade prostatic intraepithelial neoplasia or well-differentiated prostate cancer by 10-12 weeks of age. To test the hypothesis that molecular events leading to androgen independence and metastasis can occur early in the natural history of prostate cancer yet remain silent until selective pressures such as androgen deprivation are applied, we have examined the consequences of castration on the initiation and progression to metastatic prostate cancer in TRAMP mice. Cohorts were castrated at 12 weeks of age and sacrificed at 18 (T12/18) or 24 (T12/24) weeks of age, and the development of primary cancer and metastatic disease was compared to noncastrated (T18 and T24) controls. Median T12/18 and T12/24 genitourinary (GU) weight was significantly less than T18 and T24, respectively. In addition, T12/24 GU weight was significantly greater than T12/18. Histological prostate tumors developed in 3 of 7 T12/18 and 8 of 10 T12/24 mice. All tumors that developed in castrated mice were poorly differentiated in contrast to 27% in noncastrated controls. Although castration significantly decreased GU tumor burden, overall progression to poorly differentiated and metastatic disease was not ultimately delayed. These results demonstrate that prostate cancer in the TRAMP model is heterogeneous with respect to androgen dependence as early as 12 weeks of age; therefore, early androgen ablation may have a variable impact on progression in an individual mouse. Further analysis of this prostate cancer model to identify specific molecular mechanisms that determine androgen sensitivity may facilitate future initiation of appropriate individualized hormonal therapy for the management of human prostate cancer.

Adenocarcinoma↗