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Biomedical subjects

James R Porter

Publications and source records attributed to James R Porter.

11 recordsLinked to original sources
PubMed2006

Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90.

Heat shock protein 90 (Hsp90) is an emerging therapeutic target of interest for the treatment of cancer. Its role in protein homeostasis and the selective chaperoning of key signaling proteins in cancer survival and proliferation pathways has made it an attractive target of small molecule therapeutic intervention. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), the most studied agent directed against Hsp90, suffers from poor physical-chemical properties that limit its clinical potential. Therefore, there exists a need for novel, patient-friendly Hsp90-directed agents for clinical investigation. IPI-504, the highly soluble hydroquinone hydrochloride derivative of 17-AAG, was synthesized as an Hsp90 inhibitor with favorable pharmaceutical properties. Its biochemical and biological activity was profiled in an Hsp90-binding assay, as well as in cancer-cell assays. Furthermore, the metabolic profile of IPI-504 was compared with that of 17-AAG, a geldanamycin analog currently in clinical trials. The anti-tumor activity of IPI-504 was tested as both a single agent as well as in combination with bortezomib in myeloma cell lines and in vivo xenograft models, and the retention of IPI-504 in tumor tissue was determined. In conclusion, IPI-504, a potent inhibitor of Hsp90, is efficacious in cellular and animal models of myeloma. It is synergistically efficacious with the proteasome inhibitor bortezomib and is preferentially retained in tumor tissues relative to plasma. Importantly, it was observed that IPI-504 interconverts with the known agent 17-AAG in vitro and in vivo via an oxidation-reduction equilibrium, and we demonstrate that IPI-504 is the slightly more potent inhibitor of Hsp90.

Animals↗
PubMed2006

Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90.

17-Allylamino-17-demethoxygeldanamycin (17-AAG)1 is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.

Animals↗
PubMed2006

Urethral and bladder neck injury associated with pelvic fracture in 25 female patients.

PURPOSE: We describe the presentation, diagnostic evaluation, management and outcome of female urethral trauma. MATERIALS AND METHODS: All female patients treated at Harborview Medical Center between 1985 and 2001 with urethral injury were identified by International Classification of Diseases 9th revision code. Approval of the Human Subject Division was obtained and patient charts were reviewed. The Urogenital Distress Inventory Short Form, the Incontinence Impact Questionnaire Short Form and the Female Sexual Function Index were sent to the patients. RESULTS: A total of 25 patients (13 adults, 12 children) with a mean age of 22 years (range 4 to 67) met inclusion criteria. All had pelvic fracture related to blunt trauma. They represented 6% of all female patients treated in the same review period with pelvic fracture. Blood was seen at the introitus in 15 patients and 19 had gross hematuria. Of the injuries 9 were avulsions, 15 were longitudinal lacerations and 1 was not further specified. Primary repair was performed in 21 patients and 4 were treated nonoperatively. There were 5 patients who required secondary procedures including fistula repair in 4 and continent urinary diversion in 1. At a mean followup of 7.3 years (range 1.6 to 14.4) 9 of 21 patients (43%) had moderate or severe lower urinary tract symptoms and 8 of 13 (38%) had sexual dysfunction (FSFI score less than 26.55). CONCLUSIONS: Female urethral and bladder neck injury occurs with pelvic fracture, presents with gross hematuria and/or blood at the introitus, and requires operative repair for avulsions and longitudinal lacerations. These patients are at risk for significant sexual and lower urinary tract dysfunction.

Adolescent↗
PubMed2006

Laparoscopic ureterolysis: technical alternatives.

BACKGROUND AND PURPOSE: We describe our technique for laparoscopic ureterolysis for idiopathic retroperitoneal fibrosis. Various options for tissue interposition are discussed, including management of bilateral disease. PATIENTS AND METHODS: Patients found to have retroperitoneal fibrosis were offered laparoscopic ureterolysis with the option of treatment with anti-inflammatory medications preoperatively. The obstructed renal collecting system was decompressed preopeatively with a nephrostomy tube or Double-J stent to stabilize renal function. A four-port transperitoneal approach was used. Patients with bilateral obstruction were offered bilateral ureterolysis in the same operative session. RESULTS: Case 1 was a 57-year-old man with right-ureteral obstruction in a solitary kidney, the left kidney having been lost to retroperitoneal fibrosis. The patient had right laparoscopic ureterolysis with omental interposition. Case 2 was a 45-year-old man with left-flank pain and left-sided hydronephrosis. He underwent laparoscopic ureterolysis with an omental wrap through a mesenteric window. Case 3 was a 56-year-old woman with a retroperitoneal mass causing bilateral hydronephrosis. The patient had left laparoscopic ureterolysis with omental interposition through a mesenteric window. In the same sitting, the patient was repositioned for right laparoscopic ureterolysis with interposition of a peritoneal flap. CONCLUSIONS: The treatment of retroperitoneal fibrosis can be performed in a safe and effective manner through the laparoscopic approach. Interposition of omentum or peritoneum can be accomplished laparoscopically. Moreover, bilateral disease can be managed in a single session using this approach.

Female↗
PubMed2005

Renal artery pseudoaneurysm after laparoscopic partial nephrectomy.

Delayed bleeding from a renal artery pseudoaneurysm is a rare occurrence after partial nephrectomy. We present 2 cases of renal artery pseudoaneurysm after laparoscopic partial nephrectomy. One patient presented with gross hematuria and flank pain and the other presented with flank pain and a decreasing hematocrit. The patients were treated with selective angioembolization of the pseudoaneurysm. The etiology and management of this potentially life-threatening condition are discussed.

Aneurysm, False↗
PubMed2005

Robotic versus conventional laparoscopic skill acquisition: implications for training.

BACKGROUND AND PURPOSE: Despite the growing interest in surgical robotics, very little study has been done regarding the acquisition of the skills needed to perform robotic surgery safely. The purpose of this study was to determine whether skills are transferred between conventional laparoscopy and robotically assisted surgery. SUBJECTS AND METHODS: Intracorporeal knot tying was used for evaluating laparoscopic skills for time and error performance. Twenty medical students without any laparoscopic experience were randomized into two groups. Group A initially performed knot tying with conventional laparoscopic instruments, were trained with the daVinci Robotic System, and then performed knot tying with conventional laparoscopy. Group B performed knot tying with robotics, trained with standard laparoscopy, and completed post-training knot tying with robotics. Pretraining and post-training tasks were videotaped and analyzed using a detailed scoring system by one independent referee, who was blinded to the subjects' experience. RESULTS: Pre-training knot tying was faster with robotics (4.4 v 9.9 minutes; P < 0.001). The mean composite scores were 27.4 for group A and 57.4 for group B (P = 0.09), and the error scores were 57.1 and 42.1 (P = 0.29), respectively. Post-training time for knot completion decreased to 6.7 minutes and 3.4 minutes for groups A and B, respectively. Composite scores increased significantly, from 27.4 to 66.1 for group A and 57.4 to 81.8 for group B. Error scores decreased to 32.9 for group A (P = 0.1) and 16.2 in group B (P = 0.02). CONCLUSIONS: There appears to be reciprocal transfer of skills between conventional laparoscopy and robotically assisted surgery. However, this transference is incomplete. Our results suggest that training with either technique or conventional laparoscopy is superior to training with robotics alone.

Clinical Competence↗
PubMed2005

Laparoscopic partial nephrectomy: comparison of transperitoneal and retroperitoneal approaches.

PURPOSE: Laparoscopic partial nephrectomy has become an effective alternative for small renal tumors. Previous reports include transperitoneal and retroperitoneal approaches but to our knowledge the indications for when to apply the techniques have not been defined. We report our experience with comparing the 2 techniques. MATERIALS AND METHODS: A retrospective review of 51 laparoscopic partial nephrectomies was performed. Patients were analyzed based on the surgical approach, operative parameters and postoperative recovery. The 2 approaches used similar operative techniques to control parenchymal bleeding and collecting system entry. RESULTS: There were 32 retroperitoneal and 19 transperitoneal partial nephrectomies. Mean operative time (3.5 vs 5.4 hours, p = 0.000001) and blood loss (192 vs 403 cc, p = 0.002) was significantly less for the retroperitoneal approach. Renal vessel clamping was performed in 81% of retroperitoneal and 63% of transperitoneal operations. Warm ischemia time was not significantly different between the groups. Patients undergoing the retroperitoneal approach had a statistically significant decrease in time to tolerating a regular diet (1.2 vs 1.7 days, p = 0.02), catheter removal (1.4 vs 2.5 days, p = 0.004) and discharge home (2.3 vs 3.6 days, p = 0.0008). CONCLUSIONS: Based on tumor location as the selection criteria the retroperitoneal approach was associated with shorter operative time, less blood loss, more rapid return of bowel function and shorter hospitalization compared with those in patients selected for the transperitoneal technique. Based on our experience we believe that the decision on the approach should be based on the tumor location on the kidney surface. For polar or posterolateral masses the retroperitoneal approach is preferred. The transperitoneal approach is best suited to anterior and medial lesions.

Blood Loss, Surgical↗
PubMed2003

Renal injury and operative management in the United States: results of a population-based study.

BACKGROUND: To evaluate the extent to which nonoperative renal trauma management has been adopted, we determined the incidence of renal injury and the rate of operative management across the United States. METHODS: International Classification of Diseases, Ninth Revision diagnosis and procedure codes identified patients with renal injuries in an 18-state administrative database representing 62% of the U.S. population. RESULTS: Of 523,870 patients hospitalized for trauma in 1997 or 1998, 6,231 (1.2%) had renal injuries (4.89 per 100,000 population). Sixty-four percent of patients with injuries that were classified had contusions/hematomas, 26.3% had lacerations, 5.3% had parenchymal disruption, and 4% had vascular injuries. Eleven percent of renal trauma patients required surgical management of their kidney injuries, of whom 61%, or 7% of patients with renal injuries overall, underwent nephrectomy. Injury Severity Score, mechanism, and renal injury severity were independent predictors of nephrectomy. CONCLUSION: The nephrectomy rate in community and academic centers reflects renal and global injury severity. Prospective trials are indicated to determine whether, in the traumatized patient with severe kidney injury, renal preservation could lead to improved outcomes compared with nephrectomy.

Adolescent↗
PubMed2002

Intramolecular cycloadditions of cyclobutadiene with olefins.

Intramolecular cycloadditions between cyclobutadiene and olefins can provide highly functionalized cyclobutene-containing products. The outcome of the reaction depends on the nature of the tether connecting the two reactive partners in the cycloaddition. Electronically unactivated olefins attached to cyclobutadiene through a three-atom, heteroatom-containing tether yield successfully the desired cycloadducts, whereas the corresponding substrates without a heteroatom linkage or with a longer tether are less prone to undergo the intramolecular cycloaddition. Calculations were used to help uncover some of the factors that influence the course of the cycloaddition. Successful intramolecular reactions usually require either electronic activation of the dienophile, conformational restriction of the tether, or a slower oxidation protocol. In general, a facile intermolecular dimerization of cyclobutadiene is the major process that competes with the intramolecular cycloaddition.

Alkenes↗