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1.
J Exp Psychol Hum Percept Perform ; 49(8): 1158-1174, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37384518

ABSTRACT

Participants in incidental change detection studies often miss large changes to visually salient or conceptually relevant objects such as actor substitutions across video cuts, but there are competing explanations of why participants fail to detect these changes. According to an integrative processing account, object-based attention typically induces integrated representation and comparison processes sufficient to detect changes to that object. On this view, participants miss changes in incidental paradigms because those paradigms fail to elicit the level of attention necessary to trigger integrated representation and comparison processes. In contrast, a selective processing account posits that representation and comparison processes needed to detect changes do not occur by default, even for attended objects, but are only elicited in response to specific functional needs. In four experiments, we tested detection of actor substitutions when participants engaged in tasks that required actor identity processing but did not necessarily require the combination of processes necessary to detect changes. Change blindness for actor substitutions persisted when participants counted the number of actors in the video and sometimes persisted when participants were instructed to remember the substituted actor for later recall. Change blindness consistently diminished, however, when participants were shown the prechange actor before or during the video and instructed to search for that actor in the video. Our results refine the contrast between selective and integrative processing by specifying how task demands to create durable visual representations can remain independent of comparison processes, while search demands can induce integrative comparison processes in a naturalistic setting. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Subject(s)
Mental Recall , Visual Perception , Humans , Visual Perception/physiology , Attention/physiology , Blindness
2.
Cogn Sci ; 47(4): e13271, 2023 04.
Article in English | MEDLINE | ID: mdl-37071609

ABSTRACT

Written memoranda of conversations, or memcons, provide a near-contemporaneous record of what was said in conversation, and offer important insights into the activities of high-profile individuals. We assess the impact of writing a memcon on memory for conversation. Pairs of participants engaged in conversation and were asked to recall the contents of that conversation 1 week later. One participant in each pair memorialized the content of the interaction in a memcon shortly after the conversation. Participants who generated memcons recalled more details of the conversations than participants who did not, but the content of recall was equally and largely accurate for both participants. Remarkably, only 4.7% of the details of the conversation were recalled by both of the partners after a week delay. Contemporaneous note-taking appears to enhance memory for conversation by increasing the amount of information remembered but not the accuracy of that information. These findings have implications for evaluating the testimony of participants on conversations with major political or legal ramifications.


Subject(s)
Communication , Mental Recall , Humans , Writing
3.
J Pediatr Urol ; 19(1): 143-145, 2023 02.
Article in English | MEDLINE | ID: mdl-36437175
4.
J Exp Psychol Appl ; 28(4): 916-930, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36006712

ABSTRACT

Over the past decade, screen-captured instructional videos have become popular tools for learning. Viewers wanting to learn efficiently can play these videos at faster-than-normal speeds, a feature offered by hosting services such as YouTube. Although previous research suggests that moderate speeding may not lessen learning, little research has tested this form of media for speeding-induced learning impairments. Further, even if learning is not impaired by speeding, the degree to which users find speed increases taxing and/or unpleasant is unknown. We therefore created a set of screen-captured instructional videos and tested whether speeding them by up to 250% affected learning, perceived workload, and preferences. Speed increases of up to 200% minimally affected learning, but even modest 150% speed increases substantially increased perceived workload and reduced viewer preferences. However, we were able to create videos that were more selectively speeded by concentrating speeding on pauses and relatively unimportant and slow speech. These videos were just as time efficient as the 150% speeded videos, but viewers preferred them. Our findings demonstrate that speeded instructional videos have the potential to facilitate efficient learning, and they suggest techniques such as selective speeding that may be used to support efficiency while lessening viewer preference costs. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Subject(s)
Social Media , Humans , Video Recording , Learning
5.
J Urol ; 208(2): 426-433, 2022 08.
Article in English | MEDLINE | ID: mdl-35703000

ABSTRACT

PURPOSE: The thulium fiber laser is a promising new lithoptripsy technology never before studied in the pediatric population. Our center adopted the first platform in North America, the SuperPulsed thulium fiber laser (SPTF). We aimed to compare outcomes in pediatric ureteroscopy using the SPTF to those using the gold standard, low-power holmium:yttrium-aluminum-garnet (Ho:YAG) laser. MATERIALS AND METHODS: This is a retrospective, consecutive cohort study of unilateral ureteroscopy with laser lithotripsy performed in pediatric patients from 2016 to 2021 as an early adopter of the SPTF. Thirty-day complications and stone-free status, defined as the absence of a stone fragment on followup imaging within 90 days, were analyzed using logistic regression. Operative times were compared using linear regression. Propensity scores for use of SPTF were used in regression analyses to account for potential cohort imbalance. RESULTS: A total of 125 cases were performed in 109 pediatric patients: 93 with Ho:YAG and 32 with SPTF. No significant difference was noted in age (p=0.2), gender (p=0.6), stone burden (p >0.9) or stone location (p=0.1). The overall stone-free rate was 62%; 70% with SPTF and 59% with Ho:YAG. The odds of having a residual stone fragment were significantly lower with SPTF than with Ho:YAG (OR=0.39, 95% CI: 0.19-0.77, p=0.01). There was no significant difference in operative time (p=0.8). Seven (25%) complications were noted with SPTF and 19 (22%) with Ho:YAG (p=0.6). CONCLUSIONS: The SPTF laser was associated with a higher stone-free rate than the low-power Ho:YAG laser without compromising operative time and safety.


Subject(s)
Lasers, Solid-State , Lithotripsy, Laser , Child , Cohort Studies , Holmium , Humans , Lasers, Solid-State/therapeutic use , Lithotripsy, Laser/methods , Retrospective Studies , Thulium , Ureteroscopy/methods
7.
Urology ; 151: 113-117, 2021 05.
Article in English | MEDLINE | ID: mdl-32531467

ABSTRACT

OBJECTIVE: To report and compare presentation and management of Fournier's Gangrene (FG) in female vs male patients at a single tertiary care center. METHODS: Patient demographics, clinical characteristics, treatments and outcomes were summarized and compared between males and females who were treated for FG from 2011 to 2018 at a single institution. RESULTS: Of the 143 patients treated for FG at our institution, 33 (23%) were female. Female patients were predominantly white (82%), with a median (IQR) age of 55 (46, 59). Median female boby mass index (BMI) was 42.1 (32, 50.4). Female patients' wound cultures were polymicrobial mix of gram positive and gram negative organisms. Median number of debridements for females was 2 (1,3). The most common anatomic region of gangrene involvement in females was labia (76%) followed by perineum (55%) and gluteus/buttocks (42%). Mortality rate during initial admission was 6% for females. Female patients had a higher median BMI than males (42.1 vs 33.7 respectively; P = .003). FG severity index, length of hospital stay, number of debridements, and wound cultures were comparable to males. The surgical team managing initial debridements differed with females managed primarily by general surgery and males primarily by urology. Mortality rate was comparable to men (6% vs 7%, P >.05). CONCLUSION: Female patients with FG have greater BMI but similar clinical presentation, microbiologic characteristics and mortality rate compared to men. Urologists have little involvement during initial management for females at our institution.


Subject(s)
Debridement , Fournier Gangrene/microbiology , Fournier Gangrene/surgery , Body Mass Index , Buttocks/pathology , Buttocks/surgery , Female , Fournier Gangrene/mortality , Humans , Male , Middle Aged , Perineum/pathology , Perineum/surgery , Retrospective Studies , Tertiary Care Centers , Vulva/pathology , Vulva/surgery
8.
J Urol ; 204(6): 1249-1255, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32602771

ABSTRACT

PURPOSE: We evaluate the prevalent microorganisms, antibiotic sensitivity patterns and associated outcomes in patients with Fournier's gangrene. MATERIALS AND METHODS: A retrospective chart review of patients with Fournier's gangrene was conducted between October 2011 and April 2018 at our institution. Univariate analysis was performed using the independent t-test or Kruskal-Wallis H test for continuous variables and exact test for categorical variables. RESULTS: Of the 143 patients included in this study, wound culture was available in 131 (92%) patients with a median number of 3 microorganisms per wound. The most commonly grown pathogens were Staphylococcus species (66, 46%), Streptococcus species (53, 37%), Bacteroides species (34, 24%), Candida species (31, 22%), Escherichia coli (28, 20%) and Prevotella species (26, 18%). Most bacteria were sensitive to ampicillin-sulbactam, ceftriaxone, piperacillin-tazobactam, amikacin and cefepime, and resistant to ampicillin, trimethoprim-sulfamethoxazole, levofloxacin and clindamycin. Enterococcus faecalis and Streptococcus anginosus were resistant to vancomycin. The overall Fournier's gangrene mortality count was 14 (10%) patients. No association was noted between the type of infection and Fournier's gangrene severity index, length of hospital stay or mortality. CONCLUSIONS: At our institution Candida is a prevalent pathogen in the wound culture of patients with Fournier's gangrene. The resistance patterns for clindamycin and vancomycin are concerning. Addition of an antifungal agent to the empiric treatment should be considered based on clinical presentation.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/isolation & purification , Candida/isolation & purification , Fournier Gangrene/microbiology , Anti-Bacterial Agents/therapeutic use , Bacteria/drug effects , Candida/drug effects , Clindamycin/pharmacology , Clindamycin/therapeutic use , Debridement , Drug Resistance, Bacterial , Drug Resistance, Fungal , Female , Fournier Gangrene/diagnosis , Fournier Gangrene/mortality , Fournier Gangrene/therapy , Humans , Length of Stay/statistics & numerical data , Male , Microbial Sensitivity Tests/statistics & numerical data , Middle Aged , Perineum/microbiology , Perineum/surgery , Retrospective Studies , Severity of Illness Index , Tertiary Care Centers/statistics & numerical data , Vancomycin/pharmacology , Vancomycin/therapeutic use
9.
Cogn Res Princ Implic ; 4(1): 14, 2019 Apr 18.
Article in English | MEDLINE | ID: mdl-31001708

ABSTRACT

To successfully interact with software agents, people must call upon basic concepts about goals and intentionality and strategically deploy these concepts in a range of circumstances where specific entailments may or may not apply. We hypothesize that people who can effectively deploy agency concepts in new situations will be more effective in interactions with software agents. Further, we posit that interacting with a software agent can itself refine a person's deployment of agency concepts. We investigated this reciprocal relationship in one particularly important context: the classroom. In three experiments we examined connections between middle school students' concepts about agency and their success learning from a teachable-agent-based computer system called "Betty's Brain". We found that the students who made more intentional behavioral predictions about humans learned more effectively from the system. We also found that students who used the Betty's Brain system distinguished human behavior from machine behavior more strongly than students who did not. We conclude that the ability to effectively deploy agency concepts both supports, and is refined by, interactions with software agents.

10.
Urology ; 102: 43-47, 2017 Apr.
Article in English | MEDLINE | ID: mdl-27789299

ABSTRACT

OBJECTIVE: To evaluate and profile ammonium acid urate (AAU) stone formers utilizing a large contemporary cohort. MATERIALS AND METHODS: A retrospective review of all patients with documented AAU urolithiasis on stone analysis was performed from 1995 to 2013. A stone was considered AAU if it contained at least 10% of the total composition on stone analysis. RESULTS: Of 12,421 stones, a total of 111 AAU stones were identified in 89 patients. Seventy-two patients (81%) had mixed composition stones. Of the 89 AAU patients, 10 (11%) had chronic kidney disease, 12 (13%) had recurrent urinary tract infections, 8 (9%) had diabetes mellitus, 25 (28%) had a history of ileostomy or bowel resection, and 11 (12%) had significant diarrhea or inflammatory bowel disease. Additionally, 20 (22%) had prior prostate surgery with bladder neck contracture and 8 (9%) were managed with a chronic indwelling catheter. Surgical intervention was required in 74 patients (83%). At the median follow-up of 4.9 years, 19 patients (21%) had stone recurrence with a median time to recurrence of 22 months (interquartile range: 10.5-42.0). CONCLUSION: AAU stones are rare. In addition to previously described risk factors for AAU stone formation, patients with prior prostate surgery and bladder neck contracture or a surgically altered bladder may be at increased risk for formation. Furthermore, the long-term follow-up provided by this large AAU cohort demonstrates a significant risk for stone recurrence.


Subject(s)
Uric Acid/analysis , Urinary Calculi/chemistry , Adult , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Retrospective Studies
11.
Urology ; 90: 39-44, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26772639

ABSTRACT

OBJECTIVE: To describe the endoscopic characteristics of renal papillae in struvite stone formers (SFs). MATERIALS AND METHODS: From 2009 to 2014, patients undergoing percutaneous nephrolithotomy were prospectively enrolled in our study. Endoscopic analysis and biopsy of papillae were performed to demonstrate the presence and percentage surface area (SA) of Randall's plaque or ductal plug. Comparison with idiopathic calcium oxalate (CaOx) SF and non-SF controls was performed. RESULTS: We identified 29 struvite SFs to compare with 90 idiopathic CaOx SFs and 17 controls. On endoscopic mapping, 28 struvite SFs (97%) demonstrated Randall's plaque and 9 (31%) had plugging. The average mean SA of Randall's plaque in struvite SF (1.5 ± 1.4%) was less than CaOx SFs (3.7 ± 4.3%, P = .0018) and similar to controls (1.7 ± 2.7%, P = .76). Average mean plug SA was similar between struvite SFs, CaOx SFs, and controls. On metabolic assessment, 83% of struvite SFs had at least one urine abnormality, with urinary uric acid and oxalate levels significantly higher among struvite SFs compared to controls (P = .002). Despite lack of active urinary tract infection, interstitial inflammation was more prevalent in struvite SFs compared to CaOx SFs (43.5% vs 7.3%, P = .0001). CONCLUSIONS: Our findings suggest a limited role for Randall's plaque in struvite stone formation. Struvite SFs have less plaque formation than CaOx SFs, but demonstrate evidence of severe parenchymal inflammation compared to other SFs. The role of this prominent interstitial inflammation requires further study.


Subject(s)
Kidney Calculi/pathology , Magnesium Compounds , Phosphates , Aged , Female , Humans , Kidney Calculi/chemistry , Magnesium Compounds/analysis , Male , Middle Aged , Phosphates/analysis , Prospective Studies , Risk Factors , Struvite , Ureteroscopy
12.
Low Urin Tract Symptoms ; 7(3): 138-42, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26663728

ABSTRACT

OBJECTIVES: Pudendal neuralgia can cause significant voiding and pain symptoms. We explored the effects of chronic pudendal neuromodulation (CPN) and nerve blocks on pain associated with pudendal neuralgia. METHODS: Patients with pudendal neuralgia and tined lead placed at the pudendal nerve were reviewed. History and initial improvement after lead placement were collected from medical records. Demographics, symptom characteristics and changes after various treatments were assessed by mailed survey. Descriptive statistics were performed. RESULTS: Of 19 patients (mean age 54.8 years, 63% female), 6/19 (32%) had previous sacral neuromodulation. Before CPN, 18 patients had 77 nerve blocks (median six blocks per patient); most blocks (60/77; 78%) provided at least some relief. After lead placement, pain relief was complete in three patients, almost complete in three, significant/remarkable in 10, and small/slight in three. All 19 patients had a permanent generator placed. Five were ultimately explanted at (mean) 2.95 years: one had total symptom resolution, one had stopped using the device, and three lost efficacy. Survey respondents (n = 10) indicated that they had been experiencing pain for (median) 4.42 years before CPN. The most helpful pain treatment cited was medication for 6/10 and neuromodulation for 4/10; 8/9 rated neuromodulation as more helpful than nerve block, while one subject felt that the two treatments were equally helpful. Compared to sacral neuromodulation, 3/4 rated CPN as more effective for pain. Overall, 8/10 were satisfied with CPN; only 1/9 was mildly satisfied with nerve block. CONCLUSIONS: Chronic pudendal neuromodulation can improve pain in patients with pudendal neuralgia.


Subject(s)
Analgesia/methods , Electric Stimulation Therapy , Pudendal Neuralgia/therapy , Adolescent , Adult , Aged , Aged, 80 and over , Electric Stimulation Therapy/methods , Female , Humans , Male , Middle Aged , Pilot Projects , Pudendal Nerve , Young Adult
13.
J Laparoendosc Adv Surg Tech A ; 25(10): 800-3, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26421880

ABSTRACT

OBJECTIVES: Hemostatic clip migration into the lower urinary tract is a potential complication of radical prostatectomy that may cause symptoms, anxiety, and functional concern. Our objective was to evaluate initial presentation, endoscopic management, and outcomes of patients with hemostatic clip migration following radical prostatectomy. PATIENTS AND METHODS: We retrospectively identified all patients with hemostatic clip migration at our institution from 1977 to 2012. Patient records were then reviewed to identify causative factors, presentation, and long-term functional outcomes. RESULTS: Seventeen patients were identified with clip migration following radical prostatectomy. Eight (47%) patients had undergone open retropubic radical prostatectomy, and 9 (53%) had received robot-assisted radical prostatectomy. Hemostatic clip migration was diagnosed at a median of 8 (range, 1-252) months after prostatectomy. The majority of patients (n = 16, 94%) were symptomatic upon the diagnosis of clip migration. Symptoms included irritative urinary symptoms (n = 14, 82%), perineal pain (n = 3, 18%), hematuria (n = 2, 12%), and infection (n = 2, 12%). Five (29%) had concomitant bladder neck contracture. Fifteen (88%) underwent successful endoscopic clip removal, whereas 2 (13%) patients required a repeat operation for recurrent clip erosion. With a median follow-up of 1.6 years, the majority (n = 13, 87%) had complete symptom resolution after clip removal, although 2 patients had recurrent bladder neck contracture. CONCLUSIONS: Hemostatic clip migration after prostatectomy is often symptomatic with irritative voiding complaints, perineal pain, hematuria, infection, or bladder neck contracture. Fortunately, clips can be removed endoscopically with expected symptom resolution in the vast majority of patients.


Subject(s)
Contracture/etiology , Hemostasis, Surgical/instrumentation , Prostatectomy/instrumentation , Surgical Instruments/adverse effects , Urinary Bladder , Urination Disorders/etiology , Aged , Contracture/surgery , Device Removal , Dysuria/etiology , Dysuria/surgery , Endoscopy , Hematuria/etiology , Hematuria/surgery , Hemostasis, Surgical/adverse effects , Humans , Male , Middle Aged , Prostatectomy/adverse effects , Retrospective Studies , Urinary Tract Infections/etiology , Urinary Tract Infections/surgery , Urination Disorders/surgery
14.
Mol Cancer Ther ; 14(4): 931-40, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25637314

ABSTRACT

Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, ß, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 hours. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that observed with the corresponding single agents.


Subject(s)
Antineoplastic Agents/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Quinoxalines/pharmacology , Sulfonamides/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Humans , Male , Mice , Mice, Nude , Neovascularization, Pathologic/drug therapy , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Quinoxalines/administration & dosage , Ribosomal Protein S6 Kinases/metabolism , Signal Transduction/drug effects , Sulfonamides/administration & dosage , Xenograft Model Antitumor Assays
15.
BJU Int ; 115(2): 295-9, 2015 Feb.
Article in English | MEDLINE | ID: mdl-24552209

ABSTRACT

OBJECTIVES: To evaluate short-term outcomes of holmium laser enucleation of the prostate (HoLEP) and photoselective vaporisation of the prostate (PVP) in patients with benign prostatic hyperplasia (BPH) and chronic urinary retention (CUR). PATIENTS AND METHODS: A retrospective chart review was performed of all patients with CUR who underwent HoLEP or PVP at our institution over a 3-year period. CUR was defined as a persistent post-void residual urine volume (PVR) of >300 mL or refractory urinary retention requiring catheterisation. RESULTS: We identified 72 patients with CUR who underwent HoLEP and 31 who underwent PVP. Preoperative parameters including median catheterisation duration (3 vs 5 months, P = 0.71), American Urological Association Symptom Index score (AUASI; 18 vs 21, P = 0.24), and PVR (555 vs 473 mL, P = 0.096) were similar between the HoLEP and PVP groups. The HoLEP group had a larger prostate volume (88.5 vs 49 mL, P < 0.001) and higher PSA concentration (4.5 vs 2.4 ng/mL, P = 0.001). At median 6-month follow-up, 71 (99%) HoLEP patients and 23 (74%) PVP patients were catheter-free (P < 0.001). Of the voiding patients, postoperative AUASI (3 vs 4, P = 0.06), maximum urinary flow rate (23 vs 18 mL/s, P = 0.28) and PVR (56.5 vs 54 mL, P = 1.0) were improved in both groups. CONCLUSIONS: Both HoLEP and PVP are effective at improving urinary parameters in men with CUR. Despite larger prostate volumes, HoLEP had a 99% successful deobstruction rate, thus rendering patients catheter-free.


Subject(s)
Laser Therapy , Prostatic Hyperplasia/surgery , Transurethral Resection of Prostate , Urinary Retention/surgery , Humans , Lasers, Solid-State , Male , Middle Aged , Prostatic Hyperplasia/physiopathology , Quality of Life , Retrospective Studies , Transurethral Resection of Prostate/methods , Treatment Outcome , Urination
16.
Case Rep Radiol ; 2014: 239345, 2014.
Article in English | MEDLINE | ID: mdl-25093138

ABSTRACT

Lymphoma may affect the ureter in cases of retroperitoneal involvement. We present a case of an adolescent male found to have non-Hodgkin lymphoma initially presenting as ureteral stricture evident on imaging. He was treated and responded to multiagent chemotherapy with resolution of both the lymphoma and the ureteral stricture. Although rare, non-Hodgkin lymphoma should be included in the differential diagnosis of pediatric patients with noncalculous, idiopathic ureteral strictures.

17.
Mol Cancer Ther ; 13(5): 1078-91, 2014 May.
Article in English | MEDLINE | ID: mdl-24634413

ABSTRACT

Activation of the PI3K (phosphoinositide 3-kinase) pathway is a frequent occurrence in human tumors and is thought to promote growth, survival, and resistance to diverse therapies. Here, we report pharmacologic characterization of the pyridopyrimidinone derivative XL765 (SAR245409), a potent and highly selective pan inhibitor of class I PI3Ks (α, ß, γ, and δ) with activity against mTOR. Broad kinase selectivity profiling of >130 protein kinases revealed that XL765 is highly selective for class I PI3Ks and mTOR over other kinases. In cellular assays, XL765 inhibits the formation of PIP(3) in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 phosphorylation in multiple tumor cell lines with different genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL765 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL765 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of approximately 24 hours. Repeat dose administration of XL765 results in significant tumor growth inhibition in multiple human xenograft models in nude mice that is associated with antiproliferative, antiangiogenic, and proapoptotic effects.


Subject(s)
Antineoplastic Agents/pharmacology , Neoplasms/genetics , Neoplasms/metabolism , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Quinoxalines/pharmacology , Signal Transduction/drug effects , Sulfonamides/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/administration & dosage , Cell Line, Tumor , Cell Movement/drug effects , Disease Models, Animal , Humans , Inhibitory Concentration 50 , Mice , Neoplasms/drug therapy , Neoplasms/pathology , Neovascularization, Pathologic , Phosphatidylinositol Phosphates/metabolism , Phosphorylation , Protein Kinase Inhibitors/administration & dosage , Proto-Oncogene Proteins c-akt/metabolism , Quinoxalines/administration & dosage , Ribosomal Protein S6 Kinases/metabolism , Sulfonamides/administration & dosage , Xenograft Model Antitumor Assays
18.
Urology ; 82(4): 829-33, 2013 Oct.
Article in English | MEDLINE | ID: mdl-24074977

ABSTRACT

OBJECTIVE: To evaluate the outcomes after cystectomy for ulcerative interstitial cystitis (IC). METHODS: Medical records were reviewed for history, operative data, and postoperative events. A mailed survey assessed preoperative symptom severity/duration, providers seen, and symptom changes on 7-point scaled global response assessments. Descriptive statistics were performed. RESULTS: Of 10 women (mean age 64 ± 12.5 years), 9 had cystectomy with ileal conduit and 1 had a neobladder. All had previous cautery of Hunner's ulcer (median 3.0 cautery procedures). Maximum bladder capacity at first and last cautery was median 325 and 188 mL, respectively. Median operative time was 321 minutes, blood loss was 200 mL (range, 100-900), 4 of 10 were transfused, and length of stay was 8 days. During a mean follow-up of 3.9 years, 6 patients required 1 or more reoperations, including hernia repair (2), urostomy revision (2), revision of ureteroileal anastomosis (1), small bowel resection (1), and neobladder cutaneous fistula repair (1). Survey respondents (n = 9) reported having seen (mean) 5.4 ± 3.8 providers before cystectomy. Median duration of symptoms was 5 years, and day and nighttime urinary frequencies were 30 and 15 times, respectively. Postoperatively, IC pain had resolved in all patients except for one. On the global response assessments, patients had moderate/marked improvement in overall symptoms (8 of 8), pain (9 of 9), sexual function (4 of 6), and quality of life (8 of 9), 7 of 9 were very satisfied with the treatment, and 8 of 9 would make the same decision again. CONCLUSION: Despite subsequent reoperations, symptom improvements lead to high levels of satisfaction with cystectomy for IC.


Subject(s)
Cystectomy , Cystitis, Interstitial/surgery , Patient Satisfaction , Ulcer/surgery , Aged , Female , Humans , Middle Aged , Retrospective Studies , Urinary Bladder Diseases/surgery
19.
Urology ; 81(5): 1025-9, 2013 May.
Article in English | MEDLINE | ID: mdl-23465142

ABSTRACT

OBJECTIVE: To evaluate comparative safety and outcomes in patients undergoing holmium laser enucleation of the prostate (HoLEP) with and without previous transurethral prostate surgery. METHODS: We identified 37 patients who underwent HoLEP for persistent lower urinary tract symptoms (LUTS) after previous transurethral prostate surgery for benign prostatic hyperplasia (group I). Patients were then matched according to preoperative transrectal ultrasound prostate size to 74 patients without prior surgery who underwent HoLEP (group II). A retrospective chart review was performed. RESULTS: In group I, no patients had previously undergone HoLEP, and 9 (24%) had undergone >1 surgery for benign prostatic hyperplasia (BPH). There were no significant differences in age, preoperative mean urinary flow, or preoperative prostate-specific antigen (PSA) value between groups I and II. There were no significant differences in perioperative parameters, including resected tissue weight (61.7 vs 63.9 grams, P = .83) or enucleation rate (1.32 vs 1.36 g/min, P = .76). There was no significant difference in mean catheterization time or length of hospital stay. Postoperative peak flow (23.4 vs 26.9 mL/sec, P = .14) and post-void residual (PVR, 50.9 vs 50.3 mL, P = .61) were improved and similar between groups. American Urological Association Symptom Indices (AUASIs) were improved in both groups, although the primary group was significantly lower (7.52 vs 5.21, P = .0060). There was no significant difference in adverse events. All patients were urinating at last follow-up (mean 18.4 and 15.1 months, P = .16). CONCLUSION: HoLEP is safe and effective at relieving persistent LUTS after failed previous BPH surgery. Outcomes similar to those of a primary HoLEP procedure can be expected.


Subject(s)
Laser Therapy/methods , Lasers, Solid-State/therapeutic use , Lower Urinary Tract Symptoms/surgery , Prostate/surgery , Prostatic Hyperplasia/surgery , Transurethral Resection of Prostate/adverse effects , Aged , Follow-Up Studies , Humans , Lower Urinary Tract Symptoms/etiology , Male , Reoperation , Retrospective Studies , Transurethral Resection of Prostate/methods , Treatment Outcome
20.
Bioorg Med Chem Lett ; 22(17): 5396-404, 2012 Sep 01.
Article in English | MEDLINE | ID: mdl-22877636

ABSTRACT

With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/therapeutic use , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Phthalic Acids/chemistry , Phthalic Acids/therapeutic use , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Azabicyclo Compounds/pharmacokinetics , Azabicyclo Compounds/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Discovery , HSP90 Heat-Shock Proteins/metabolism , Humans , Mice , Models, Molecular , Neoplasms/metabolism , Neoplasms/pathology , Phthalic Acids/pharmacokinetics , Phthalic Acids/pharmacology
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