A 6-year-old boy presented with an acute scrotum and was found at surgical exploration to have to... more A 6-year-old boy presented with an acute scrotum and was found at surgical exploration to have torsion and infarction of an indirect hernia sac. This represents the sixth reported case of this entity in the literature. The pediatric surgical specialist and those in the acute care setting should be aware of this consideration in the differential diagnosis of the acute scrotum.
It is generally accepted that there is a risk of hypertension after renal trauma, particularly in... more It is generally accepted that there is a risk of hypertension after renal trauma, particularly in high-grade and devascularizing injuries. Hypertension following renal trauma is estimated to occur in five percent of adults, however, the incidence is unknown in the pediatric population. We performed a retrospective review of all pediatric trauma patients at Primary Children's Hospital in Salt Lake City, Utah between 2002 and 2012. We included all children age ≤17years old with American Association for Surgery of Trauma (AAST) grade 3-5 renal injury. Hypertension was defined as persistent hypertension that required anti-hypertensive medications. Our primary outcomes were incidence of hypertension during the acute trauma and in long-term follow. A total of 62 children were identified with AAST grade 3-5 renal injuries during our study period. Follow up blood pressures were recorded in 36 (58%) of these children with a median follow of 4.1years (IQR 2.1-5.1years) after trauma. Four ...
Lat1 (SLC7A5) is an amino acid transporter often required for tumor cell import of essential amin... more Lat1 (SLC7A5) is an amino acid transporter often required for tumor cell import of essential amino acids (AA) including Methionine (Met). Met is the obligate precursor of S-adenosylmethionine (SAM), the methyl donor utilized by all methyltransferases including the polycomb repressor complex (PRC2)-specific EZH2. Cell populations sorted for surface Lat1 exhibit activated EZH2, enrichment for Met-cycle intermediates, and aggressive tumor growth in mice. In agreement, EZH2 and Lat1 expression are co-regulated in models of cancer cell differentiation and co-expression is observed at the invasive front of human lung tumors. EZH2 knockdown or small-molecule inhibition leads to de-repression of RXRα resulting in reduced Lat1 expression. Our results describe a Lat1-EZH2 positive feedback loop illustrated by AA depletion or Lat1 knockdown resulting in SAM reduction and concomitant reduction in EZH2 activity. shRNA-mediated knockdown of Lat1 results in tumor growth inhibition and points to La...
Plication techniques are not a panacea for deformities associated with Peyronie's disease or ... more Plication techniques are not a panacea for deformities associated with Peyronie's disease or congenital curvature. However, they do provide certain advantages, both theoretic and real, over competing procedures such as grafting. Depending on the technique, plication procedures have minimal risk of de novo erectile dysfunction, minimal risk of injury to the dorsal neurovascular bundle, and may be used for a variety of angulation deformities, including multiplanar curvature and severe degrees of curvature. A variety of incisions may be used, including the classic circumcision with degloving but also ventral raphe, dorsal penile inversion, and penoscrotal. These may be helpful in preventing postoperative morbidity and in sparing the prepuce if desired. Plication may also be combined with procedures such as penile prosthesis for correction of residual curvature. Lastly, despite its complications, plication techniques are very well tolerated, are relatively simple to perform and resu...
Antibody-drug conjugates (ADCs) are emerging as clinically effective therapy. We hypothesized tha... more Antibody-drug conjugates (ADCs) are emerging as clinically effective therapy. We hypothesized that cancers treated with ADCs would acquire resistance mechanisms unique to immunoconjugate therapy and that changing ADC components may overcome resistance. Breast cancer cell lines were exposed to multiple cycles of anti-Her2 trastuzumab-maytansinoid ADC (TM-ADC) at IC80 concentrations followed by recovery. The resistant cells, 361-TM and JIMT1-TM, were characterized by cytotoxicity, proteomic, transcriptional, and other profiling. Approximately 250-fold resistance to TM-ADC developed in 361-TM cells, and cross-resistance was observed to other non-cleavable-linked ADCs. Strikingly, these 361-TM cells retained sensitivity to ADCs containing cleavable mcValCitPABC-linked auristatins. In JIMT1-TM cells, 16-fold resistance to TM-ADC developed, with cross-resistance to other trastuzumab-ADCs. Both 361-TM and JIMT1-TM cells showed minimal resistance to unconjugated mertansine (DM1) and other c...
The non-essential amino acid, glutamine, exerts pleiotropic effects on cell metabolism, signallin... more The non-essential amino acid, glutamine, exerts pleiotropic effects on cell metabolism, signalling and stress resistance. Here we demonstrate that short-term glutamine restriction triggers an endoplasmic reticulum (ER) stress response that leads to production of the pro-inflammatory chemokine, interleukin-8 (IL-8). Glutamine deprivation-induced ER stress triggers colocalization of autophagosomes, lysosomes and the Golgi into a subcellular structure whose integrity is essential for IL-8 secretion. The stimulatory effect of glutamine restriction on IL-8 production is attributable to depletion of tricarboxylic acid cycle intermediates. The protein kinase, mTOR, is also colocalized with the lysosomal membrane clusters induced by glutamine deprivation, and inhibition of mTORC1 activity abolishes both endomembrane reorganization and IL-8 secretion. Activated mTORC1 elicits IL8 gene expression via the activation of an IRE1-JNK signalling cascade. Treatment of cells with a glutaminase inhibitor phenocopies glutamine restriction, suggesting that these results will be relevant to the clinical development of glutamine metabolism inhibitors as anticancer agents.
We hypothesized that our compliance was low with recommended imaging for evaluation of traumatic ... more We hypothesized that our compliance was low with recommended imaging for evaluation of traumatic bladder injury, which includes either a computed tomographic (CT) cystogram or plain cystogram. We sought to determine if poor compliance impacted diagnosis, management, and outcome of patients with bladder injury. Patients with bladder injury were identified from all Level 1 hospital trauma registries in Utah from 1996 to 2010. Details including presentation, management, and outcome of bladder injury were described using descriptive statistics and bivariate and logistic regression analysis. A total of 124 patients were identified from the trauma registries with bladder injury and adequate records for review. The mean age was 35 years. Blunt trauma occurred in 110 patients (88%). Mean Injury Severity Score was 26.3. The leading concomitant injury was pelvic fracture in 98 patients (79%). Bladder injury was extraperitoneal in 75 patients (60%), intraperitoneal in 39 (31%), and both or undetermined in 10 (8%). A higher risk of death was seen in intraperitoneal with or without concomitant extraperitoneal injury compared with extraperitoneal injury only (odds ratio, 12.4; 95% confidence interval, 2.37-99.2). Management was operative in 68 (55%) patients (95% intraperitoneal, 31% extraperitoneal). Of the 124 injuries, 100 were detected with imaging: standard CT scan in 70 (56%) and cystogram or CT cystogram in 30 (24%). The remaining injuries were discovered operatively or were undocumented (n = 24, 19%). Initial imaging missed or incorrectly diagnosed bladder injury in 13 (13%) patients (nine from standard CT scan and four from CT or plain cystogram). In five cases diagnosed by standard CT scan, extraperitoneal injuries were misdiagnosed as intraperitoneal and operatively explored. There was poor compliance with imaging recommendations for evaluation of suspected bladder injury by either CT cystogram or plain cystogram at Level 1 trauma centers in Utah. We have implemented a genitourinary trauma imaging algorithm designed to minimize errors in bladder injury diagnosis. Therapeutic study, level IV.
Anterior urethral stricture disease most commonly presents as urinary obstruction. Lower urinary ... more Anterior urethral stricture disease most commonly presents as urinary obstruction. Lower urinary tract pain is not commonly reported as a presenting symptom. We prospectively characterized lower urinary tract pain in association with urethral stricture disease and assessed the effects of urethroplasty on this pain. Men (18 years old or older) with anterior urethral stricture disease were prospectively enrolled in a longitudinal, multi-institutional, urethral reconstruction outcomes study from June 2010 to January 2013 as part of TURNS (Trauma and Urologic Reconstruction Network of Surgeons). Preoperative and postoperative lower urinary tract pain was assessed by the validated CLSS. Voiding and sexual function was assessed using validated patient-reported measures, including I-PSS. Preoperatively 118 of 167 men (71%) reported urethral pain and 68 (41%) reported bladder pain. Age was the only predictor of urethral pain with men 40 years or younger reporting more pain than those 60 years old or older (81% vs 58%, p = 0.0104). Lower urinary tract pain was associated with worse quality of life and overall voiding symptoms on CLSS and I-PSS (each p <0.01). Postoperatively lower urinary tract pain completely resolved in 64% of men with urethral pain and in 73.5% with bladder pain. There were no predictive factors for changes in lower urinary tract pain after urethral reconstruction. Lower urinary tract pain is common in urethral stricture disease, especially in younger men. It is associated with worse quality of life and voiding function. In most men lower urinary tract pain resolves after urethral reconstruction.
A 6-year-old boy presented with an acute scrotum and was found at surgical exploration to have to... more A 6-year-old boy presented with an acute scrotum and was found at surgical exploration to have torsion and infarction of an indirect hernia sac. This represents the sixth reported case of this entity in the literature. The pediatric surgical specialist and those in the acute care setting should be aware of this consideration in the differential diagnosis of the acute scrotum.
It is generally accepted that there is a risk of hypertension after renal trauma, particularly in... more It is generally accepted that there is a risk of hypertension after renal trauma, particularly in high-grade and devascularizing injuries. Hypertension following renal trauma is estimated to occur in five percent of adults, however, the incidence is unknown in the pediatric population. We performed a retrospective review of all pediatric trauma patients at Primary Children's Hospital in Salt Lake City, Utah between 2002 and 2012. We included all children age ≤17years old with American Association for Surgery of Trauma (AAST) grade 3-5 renal injury. Hypertension was defined as persistent hypertension that required anti-hypertensive medications. Our primary outcomes were incidence of hypertension during the acute trauma and in long-term follow. A total of 62 children were identified with AAST grade 3-5 renal injuries during our study period. Follow up blood pressures were recorded in 36 (58%) of these children with a median follow of 4.1years (IQR 2.1-5.1years) after trauma. Four ...
Lat1 (SLC7A5) is an amino acid transporter often required for tumor cell import of essential amin... more Lat1 (SLC7A5) is an amino acid transporter often required for tumor cell import of essential amino acids (AA) including Methionine (Met). Met is the obligate precursor of S-adenosylmethionine (SAM), the methyl donor utilized by all methyltransferases including the polycomb repressor complex (PRC2)-specific EZH2. Cell populations sorted for surface Lat1 exhibit activated EZH2, enrichment for Met-cycle intermediates, and aggressive tumor growth in mice. In agreement, EZH2 and Lat1 expression are co-regulated in models of cancer cell differentiation and co-expression is observed at the invasive front of human lung tumors. EZH2 knockdown or small-molecule inhibition leads to de-repression of RXRα resulting in reduced Lat1 expression. Our results describe a Lat1-EZH2 positive feedback loop illustrated by AA depletion or Lat1 knockdown resulting in SAM reduction and concomitant reduction in EZH2 activity. shRNA-mediated knockdown of Lat1 results in tumor growth inhibition and points to La...
Plication techniques are not a panacea for deformities associated with Peyronie's disease or ... more Plication techniques are not a panacea for deformities associated with Peyronie's disease or congenital curvature. However, they do provide certain advantages, both theoretic and real, over competing procedures such as grafting. Depending on the technique, plication procedures have minimal risk of de novo erectile dysfunction, minimal risk of injury to the dorsal neurovascular bundle, and may be used for a variety of angulation deformities, including multiplanar curvature and severe degrees of curvature. A variety of incisions may be used, including the classic circumcision with degloving but also ventral raphe, dorsal penile inversion, and penoscrotal. These may be helpful in preventing postoperative morbidity and in sparing the prepuce if desired. Plication may also be combined with procedures such as penile prosthesis for correction of residual curvature. Lastly, despite its complications, plication techniques are very well tolerated, are relatively simple to perform and resu...
Antibody-drug conjugates (ADCs) are emerging as clinically effective therapy. We hypothesized tha... more Antibody-drug conjugates (ADCs) are emerging as clinically effective therapy. We hypothesized that cancers treated with ADCs would acquire resistance mechanisms unique to immunoconjugate therapy and that changing ADC components may overcome resistance. Breast cancer cell lines were exposed to multiple cycles of anti-Her2 trastuzumab-maytansinoid ADC (TM-ADC) at IC80 concentrations followed by recovery. The resistant cells, 361-TM and JIMT1-TM, were characterized by cytotoxicity, proteomic, transcriptional, and other profiling. Approximately 250-fold resistance to TM-ADC developed in 361-TM cells, and cross-resistance was observed to other non-cleavable-linked ADCs. Strikingly, these 361-TM cells retained sensitivity to ADCs containing cleavable mcValCitPABC-linked auristatins. In JIMT1-TM cells, 16-fold resistance to TM-ADC developed, with cross-resistance to other trastuzumab-ADCs. Both 361-TM and JIMT1-TM cells showed minimal resistance to unconjugated mertansine (DM1) and other c...
The non-essential amino acid, glutamine, exerts pleiotropic effects on cell metabolism, signallin... more The non-essential amino acid, glutamine, exerts pleiotropic effects on cell metabolism, signalling and stress resistance. Here we demonstrate that short-term glutamine restriction triggers an endoplasmic reticulum (ER) stress response that leads to production of the pro-inflammatory chemokine, interleukin-8 (IL-8). Glutamine deprivation-induced ER stress triggers colocalization of autophagosomes, lysosomes and the Golgi into a subcellular structure whose integrity is essential for IL-8 secretion. The stimulatory effect of glutamine restriction on IL-8 production is attributable to depletion of tricarboxylic acid cycle intermediates. The protein kinase, mTOR, is also colocalized with the lysosomal membrane clusters induced by glutamine deprivation, and inhibition of mTORC1 activity abolishes both endomembrane reorganization and IL-8 secretion. Activated mTORC1 elicits IL8 gene expression via the activation of an IRE1-JNK signalling cascade. Treatment of cells with a glutaminase inhibitor phenocopies glutamine restriction, suggesting that these results will be relevant to the clinical development of glutamine metabolism inhibitors as anticancer agents.
We hypothesized that our compliance was low with recommended imaging for evaluation of traumatic ... more We hypothesized that our compliance was low with recommended imaging for evaluation of traumatic bladder injury, which includes either a computed tomographic (CT) cystogram or plain cystogram. We sought to determine if poor compliance impacted diagnosis, management, and outcome of patients with bladder injury. Patients with bladder injury were identified from all Level 1 hospital trauma registries in Utah from 1996 to 2010. Details including presentation, management, and outcome of bladder injury were described using descriptive statistics and bivariate and logistic regression analysis. A total of 124 patients were identified from the trauma registries with bladder injury and adequate records for review. The mean age was 35 years. Blunt trauma occurred in 110 patients (88%). Mean Injury Severity Score was 26.3. The leading concomitant injury was pelvic fracture in 98 patients (79%). Bladder injury was extraperitoneal in 75 patients (60%), intraperitoneal in 39 (31%), and both or undetermined in 10 (8%). A higher risk of death was seen in intraperitoneal with or without concomitant extraperitoneal injury compared with extraperitoneal injury only (odds ratio, 12.4; 95% confidence interval, 2.37-99.2). Management was operative in 68 (55%) patients (95% intraperitoneal, 31% extraperitoneal). Of the 124 injuries, 100 were detected with imaging: standard CT scan in 70 (56%) and cystogram or CT cystogram in 30 (24%). The remaining injuries were discovered operatively or were undocumented (n = 24, 19%). Initial imaging missed or incorrectly diagnosed bladder injury in 13 (13%) patients (nine from standard CT scan and four from CT or plain cystogram). In five cases diagnosed by standard CT scan, extraperitoneal injuries were misdiagnosed as intraperitoneal and operatively explored. There was poor compliance with imaging recommendations for evaluation of suspected bladder injury by either CT cystogram or plain cystogram at Level 1 trauma centers in Utah. We have implemented a genitourinary trauma imaging algorithm designed to minimize errors in bladder injury diagnosis. Therapeutic study, level IV.
Anterior urethral stricture disease most commonly presents as urinary obstruction. Lower urinary ... more Anterior urethral stricture disease most commonly presents as urinary obstruction. Lower urinary tract pain is not commonly reported as a presenting symptom. We prospectively characterized lower urinary tract pain in association with urethral stricture disease and assessed the effects of urethroplasty on this pain. Men (18 years old or older) with anterior urethral stricture disease were prospectively enrolled in a longitudinal, multi-institutional, urethral reconstruction outcomes study from June 2010 to January 2013 as part of TURNS (Trauma and Urologic Reconstruction Network of Surgeons). Preoperative and postoperative lower urinary tract pain was assessed by the validated CLSS. Voiding and sexual function was assessed using validated patient-reported measures, including I-PSS. Preoperatively 118 of 167 men (71%) reported urethral pain and 68 (41%) reported bladder pain. Age was the only predictor of urethral pain with men 40 years or younger reporting more pain than those 60 years old or older (81% vs 58%, p = 0.0104). Lower urinary tract pain was associated with worse quality of life and overall voiding symptoms on CLSS and I-PSS (each p <0.01). Postoperatively lower urinary tract pain completely resolved in 64% of men with urethral pain and in 73.5% with bladder pain. There were no predictive factors for changes in lower urinary tract pain after urethral reconstruction. Lower urinary tract pain is common in urethral stricture disease, especially in younger men. It is associated with worse quality of life and voiding function. In most men lower urinary tract pain resolves after urethral reconstruction.
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