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1.
Commun Biol ; 6(1): 1276, 2023 12 18.
Article in English | MEDLINE | ID: mdl-38110506

ABSTRACT

Iron-sulfur clusters are essential for life and defects in their biosynthesis lead to human diseases. The mechanism of cluster assembly and delivery to cytosolic and nuclear client proteins via the cytosolic iron-sulfur cluster assembly (CIA) pathway is not well understood. Here we report cryo-EM structures of the HEAT-repeat protein Met18 from Saccharomyces cerevisiae, a key component of the CIA targeting complex (CTC) that identifies cytosolic and nuclear client proteins and delivers a mature iron-sulfur cluster. We find that in the absence of other CTC proteins, Met18 adopts tetrameric and hexameric states. Using mass photometry and negative stain EM, we show that upon the addition of Cia2, these higher order oligomeric states of Met18 disassemble. We also use pulldown assays to identify residues of critical importance for Cia2 binding and recognition of the Leu1 client, many of which are buried when Met18 oligomerizes. Our structures show conformations of Met18 that have not been previously observed in any Met18 homolog, lending support to the idea that a highly flexible Met18 may be key to how the CTC is able to deliver iron-sulfur clusters to client proteins of various sizes and shapes, i.e. Met18 conforms to the dimensions needed.


Subject(s)
Hot Temperature , Iron-Sulfur Proteins , Humans , Iron-Sulfur Proteins/chemistry , Cytosol/metabolism , Nuclear Proteins/metabolism , Saccharomyces cerevisiae/metabolism , Iron/metabolism , Sulfur/metabolism
2.
Urology ; 169: 134-140, 2022 11.
Article in English | MEDLINE | ID: mdl-36049631

ABSTRACT

OBJECTIVE: To assess the reliability of peer-review of TURBT videos as a means to evaluate surgeon skill and its relationship to detrusor sampling. METHODS: Urologists from an academic health system submitted TURBT videos in 2019. Ten blinded peers evaluated each surgeon's performance using a 10-item scoring instrument to quantify surgeon skill. Normalized composite skill scores for each surgeon were calculated using peer ratings. For surgeons submitting videos, we retrospectively reviewed all TURBT pathology results (2018-2019) to assess surgeon-specific detrusor sampling. A hierarchical logistic regression model was fit to evaluate the association between skill and detrusor sampling, adjusting for patient and surgeon factors. RESULTS: Surgeon skill scores and detrusor sampling rates were determined for 13 surgeons performing 245 TURBTs. Skill scores varied from -6.0 to 5.1 [mean: 0; standard deviation (SD): 2.40]. Muscle was sampled in 72% of cases, varying considerably across surgeons (mean: 64.5%; SD: 30.7%). Among 8 surgeons performing >5 TURBTs during the study period, adjusted detrusor sampling rate was associated with sending separate deep specimens (odds ratio [OR]: 1.97; 95% confidence interval [CI]: 1.02-3.81, P = .045) but not skill (OR: 0.81; 95% CI: 0.57-1.17, P = .191). CONCLUSION: Surgeon skill was not associated with detrusor sampling, suggesting there may be other drivers of variability of detrusor sampling in TURBT.


Subject(s)
Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/surgery , Urinary Bladder Neoplasms/pathology , Retrospective Studies , Reproducibility of Results , Cystectomy/methods , Muscle, Smooth/pathology
3.
Urol Pract ; 9(2): 166-172, 2022 Mar.
Article in English | MEDLINE | ID: mdl-37145692

ABSTRACT

INTRODUCTION: We evaluated educational outcomes and satisfaction following institution of a novel, flexible and urology-driven resident curriculum. METHODS: A new urology resident curriculum was instituted at Northwestern University in 2006. Rotation schedules and resident electives were recorded annually. Operative case logs and American Urological Association In-Service Examination scores were collected prospectively. Residents and faculty rated satisfaction with the residency program on a 5-point Likert scale from "poor" to "outstanding." Differences in cases logged, In-Service Examination scores and satisfaction ratings under the new and prior curricula were compared. RESULTS: Curriculum changes included full 5-year urology oversight of the residency curriculum by the program director, 8 months of urology rotations in the first postgraduate year and 2 months of general surgery during the second postgraduate year. General surgery rotations were modified annually based on educational rationale and feedback. Cases logged per resident and In-Service Examination scores were comparable between old and new curricula groups. All residents matriculating under the new curriculum took and passed their written boards. The percentage of faculty and residents describing the program as "outstanding" increased from 50% in 2004‒2005 to 82% in 2017‒2018. Program satisfaction increased significantly when comparing the first and last 6 years (percent rating "outstanding": 56.1±2.1% vs 71.6±10.0%, p=0.028). CONCLUSIONS: After 13 years with the novel curriculum, resident case numbers and In-Service Examination scores remained similar while faculty/resident satisfaction increased. Direct control of general surgery rotations enabled adjustments based on educational rationale. These results demonstrate that a urology-directed and flexible residency program can be instituted without compromising learner outcomes.

4.
Prostate Cancer Prostatic Dis ; 25(3): 463-471, 2022 09.
Article in English | MEDLINE | ID: mdl-34035460

ABSTRACT

BACKGROUND: Inflammatory bowel disease (IBD) has been implicated as a risk factor for prostate cancer, however, the mechanism of how IBD leads to prostate tumorigenesis is not known. Here, we investigated whether chronic intestinal inflammation leads to pro-inflammatory changes associated with tumorigenesis in the prostate. METHODS: Using clinical samples of men with IBD who underwent prostatectomy, we analyzed whether prostate tumors had differences in lymphocyte infiltrate compared to non-IBD controls. In a mouse model of chemically-induced intestinal inflammation, we investigated whether chronic intestinal inflammation could be transferred to the wild-type mouse prostate. In addition, mouse prostates were evaluated for activation of pro-oncogenic signaling and genomic instability. RESULTS: A higher proportion of men with IBD had T and B lymphocyte infiltration within prostate tumors. Mice with chronic colitis showed significant increases in prostatic CD45 + leukocyte infiltration and elevation of three pro-inflammatory cytokines-TIMP-1, CCL5, and CXCL1 and activation of AKT and NF-kB signaling pathways. Lastly, mice with chronic colitis had greater prostatic oxidative stress/DNA damage, and prostate epithelial cells had undergone cell cycle arrest. CONCLUSIONS: These data suggest chronic intestinal inflammation is associated with an inflammatory-rich, pro-tumorigenic prostatic phenotype which may explain how gut inflammation fosters prostate cancer development in men with IBD.


Subject(s)
Colitis , Inflammatory Bowel Diseases , Prostatic Neoplasms , Animals , Carcinogenesis , Colitis/chemically induced , Colitis/metabolism , Colitis/pathology , Dextran Sulfate/adverse effects , Disease Models, Animal , Humans , Inflammation , Inflammatory Bowel Diseases/complications , Inflammatory Bowel Diseases/genetics , Male , Mice , Mice, Inbred C57BL , Prostate/pathology , Prostatic Neoplasms/genetics
6.
Urology ; 153: 138, 2021 07.
Article in English | MEDLINE | ID: mdl-34311907
7.
Cancer ; 127(18): 3354-3360, 2021 09 15.
Article in English | MEDLINE | ID: mdl-34081322

ABSTRACT

BACKGROUND: Despite consensus guidelines, many men with low-grade prostate cancer are not managed with active surveillance. Patient perception of the nomenclature used to describe low-grade prostate cancers may partly explain this discrepancy. METHODS: A randomized online survey was administered to men without a history of prostate cancer, presenting a hypothetical clinical scenario in which they are given a new diagnosis of low-grade prostate cancer. The authors determined whether diagnosis nomenclature was associated with management preference and diagnosis-related anxiety using ratings given on a scale from 1 to 100, adjusting for participant characteristics through multivariable linear regression. RESULTS: The survey was completed by 718 men. Compared with Gleason 6 out of 10 prostate cancer, the term grade group 1 out of 5 prostate cancer was associated with lower preference for immediate treatment versus active surveillance (ß = -9.3; 95% CI, -14.4, -4.2; P < .001), lower diagnosis-related anxiety (ß = -8.3; 95% CI, -12.8, -3.8; P < .001), and lower perceived disease severity (ß = -12.3; 95% CI, -16.5, -8.1; P < .001) at the time of initial diagnosis. Differences decreased as participants received more disease-specific education. Indolent lesion of epithelial origin, a suggested alternative term for indolent tumors, was not associated with differences in anxiety or preference for active surveillance. CONCLUSIONS: Within a hypothetical clinical scenario, nomenclature for low-grade prostate cancer affects initial perception of the disease and may alter subsequent decision making, including preference for active surveillance. Disease-specific education reduces the differential impact of nomenclature use, reaffirming the importance of comprehensive counseling and clear communication between the clinician and patient.


Subject(s)
Prostatic Neoplasms , Anxiety/epidemiology , Anxiety/etiology , Anxiety Disorders , Humans , Male , Neoplasm Grading , Prostate-Specific Antigen , Prostatic Neoplasms/pathology , Surveys and Questionnaires , Watchful Waiting
8.
Urology ; 153: 132-138, 2021 07.
Article in English | MEDLINE | ID: mdl-33482131

ABSTRACT

OBJECTIVES: To evaluate patient, provider, and facility factors associated with variation in opioid prescribing after endoscopic procedures for benign prostatic hyperplasia across a large academic health system to drive improvement efforts. METHODS: Opioids prescribed at discharge for patients who underwent an endoscopic prostate procedure March 2018-November 2019 were analyzed. Multivariable logistic and linear regression were used to evaluate the relationship between patient, provider, and facility factors and the receipt of any opioid prescription and the quantity prescribed. RESULTS: We included 724 patients who had surgery with one of 26 urologists across five facilities. 222 (30.7%) received an opioid prescription, and the average morphine milligram equivalents (MMEs) prescribed was 97.9±33.5. We found wide variation in the proportion of patients who received an opioid prescription across surgeons (range 0%-88.9%) and facilities (range 19.9%-66.7%) and the average MMEs prescribed (range 25-188.5). Outpatient surgery (OR 2.32; 95% confidence interval [CI] 1.22-4.40, P = .010) and preoperative opioid use (OR 15.04; CI 9.65-23.45, P < .001) were associated with higher rates of opioid prescribing, while prescribing decreased with increasing patient age (OR 0.97; CI 0.95-0.99, P = 0.016). Multivariable linear regression analysis demonstrated an association between surgery at satellite facilities, having a surgeon in practice for at least 20 years, and higher surgeon volume with increased MMEs prescribed. CONCLUSIONS: Opioid prescribing following endoscopic prostate procedures varied widely. Targeted interventions tailored to younger patients, those taking opioids preoperatively, recipients of outpatient surgery and those undergoing surgery at satellite facilities may be particularly high yield given the association between these factors and increased postoperative prescribing.


Subject(s)
Analgesics, Opioid/administration & dosage , Pain, Postoperative/drug therapy , Prostatic Hyperplasia , Surgeons/statistics & numerical data , Urologic Surgical Procedures, Male/adverse effects , Academic Medical Centers/statistics & numerical data , Aged , Ambulatory Surgical Procedures/statistics & numerical data , Analgesics, Opioid/classification , Chicago/epidemiology , Humans , Male , Pain, Postoperative/diagnosis , Pain, Postoperative/epidemiology , Patient Discharge/statistics & numerical data , Practice Patterns, Physicians' , Prostatic Hyperplasia/epidemiology , Prostatic Hyperplasia/surgery , Retrospective Studies , Urologic Surgical Procedures, Male/methods , Urologic Surgical Procedures, Male/statistics & numerical data
9.
Prostate Cancer Prostatic Dis ; 24(1): 261-267, 2021 03.
Article in English | MEDLINE | ID: mdl-32873919

ABSTRACT

BACKGROUND: Upfront chemotherapy prolongs overall survival for men with metastatic, hormone-sensitive prostate cancer (mHSPC) based on data from clinical trials. We sought to assess the association between upfront chemotherapy and overall survival in men with mHSPC in a real-world cohort. METHODS: We performed a retrospective cohort study of men with de novo, treatment-naïve metastatic prostate cancer from a large, national cancer database in the United States (2014-2015). Men in the upfront chemotherapy group received chemotherapy within 4 months of diagnosis (n = 1033, 28%) versus no chemotherapy or chemotherapy later than 12 months after diagnosis (controls; n = 2704, 72%). Overall survival was assessed using Kaplan-Meier estimates and compared using multivariable Cox regression analysis. RESULTS: After a median follow-up of 23 months, median overall survival was 35.7 months in the upfront chemotherapy group and 32.5 months for controls (log-rank p < 0.001). After adjusting for patient and clinical variables, upfront chemotherapy was associated with longer overall survival (hazard ratio 0.78, 95% confidence interval 0.68-0.89, p < 0.001). In exploratory analyses, the association between upfront chemotherapy and overall survival did not differ by age groups, race, or number of comorbidities (all interaction p > 0.2). CONCLUSIONS: In this real-world cohort, upfront chemotherapy for mHSPC was associated with longer overall survival. These data support the continued use of chemotherapy for men with mHSPC regardless of race or age if they are fit for chemotherapy and underscore the importance of evaluating cancer therapeutics outside of clinical trials to demonstrate treatment efficacy in populations that may be underrepresented in clinical trials.


Subject(s)
Antineoplastic Agents/therapeutic use , Prostatic Neoplasms/mortality , Aged , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Metastasis , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/secondary , Retrospective Studies , Survival Rate/trends , Time Factors
10.
Urol Pract ; 8(1): 143-148, 2021 Jan.
Article in English | MEDLINE | ID: mdl-37145444

ABSTRACT

INTRODUCTION: In response to studies showing high rates of program initiated post-interview contact and the use of discriminatory personal questions on topics such as age, intent for children, and religion or political preferences during interviews the Society of Academic Urologists and the American Urological Association published revised guidelines for the 2020 Urology Match. This study assessed the impact of these changes on the applicant experience and prevalence of restricted questions. METHODS: A total of 361 applicants to a single urology residency program were sent an anonymous 20-question survey about post-interview program contact and restricted interview questions. The 20-question survey used branching logic with followup questions based on initial responses. RESULTS: A total of 100 survey responses were received. Of respondents 2% reported unsolicited program initiated post-interview contact and no Match commitments were reported. Among respondents 36% felt they were asked an inappropriate question during an interview, female applicants more commonly than males (50% vs 25%, p=0.01). When asked about specific restricted topics, 98% of respondents reported encountering at least 1. Of the restricted topics asked women more frequently encountered questions about their intent for children (27.3% vs 10.7%, p=0.032) and other programs to which they applied (100% vs 91%, p=0.04). CONCLUSIONS: Following changes to the guidelines for the 2020 Urology Match unsolicited program initiated post-interview contact rates were lower than reported in previous studies. However, applicants continue to encounter restricted topics, and females disproportionately so, demonstrating that continued work must be done to decrease discrimination and bias throughout the interview process.

11.
Bladder Cancer ; 7(1): 53-60, 2021.
Article in English | MEDLINE | ID: mdl-38993211

ABSTRACT

BACKGROUND: Although bladder cancer is much more common in men than in women, female patients with bladder cancer present with more locally advanced tumors and have worse disease-specific outcomes than male patients, even after controlling for biological differences. There is a paucity of research regarding the optimal approach to caring for female patients with bladder cancer in ways that maximize patient satisfaction, preferences, and values. OBJECTIVE: We sought to explore patient-defined priorities and areas in need of improvement for female patients with bladder cancer from the patient perspective. METHODS: We conducted focus group sessions and semi-structured interviews of women treated for bladder cancer to identify patient priorities and concerns until reaching topic saturation. Transcripts were analyzed thematically. RESULTS: Eight patients with muscle-invasive bladder cancer and six patients with non-muscle-invasive bladder cancer participated in two focus groups and seven interviews total. Three themes emerged as significantly affecting the care experience: physical impacts, mental health and emotional wellbeing, and the patient-provider interaction. Each theme included patient-defined specific recommendations on approaches to optimizing the care experience for women with bladder cancer. CONCLUSIONS: Although most participants were satisfied with the quality of care they received, they identified several opportunities for improvement. These concerns centered around enhancing support for patients' physical and mental needs and strengthening the patient-provider interaction. Efforts to address these needs and reduce gender disparate outcomes via quality improvement initiatives are ongoing.

12.
Cancer ; 126(14): 3229-3236, 2020 07 15.
Article in English | MEDLINE | ID: mdl-32343403

ABSTRACT

BACKGROUND: The objective of this study was to determine the effect of Medicaid expansion under the Patient Protection and Affordable Care Act (January 1, 2014) on the epidemiology of high-risk prostate-specific antigen (PSA) levels (≥20 ng/mL) at the time of prostate cancer (PCa) diagnosis. The authors hypothesized that better access to care would result in a reduction of high-risk features at diagnosis. METHODS: A retrospective cohort study was performed of 122,324 men aged <65 years who were diagnosed with PCa within the National Cancer Database. Difference-in-difference (DID) analyses adjusting for sociodemographic variables using linear regression compared PSA levels at diagnosis before expansion (2012-2013) and after expansion (2015-2016) between men residing in states that did or did not expand Medicaid. RESULTS: From 2012 to 2016, the proportion of men with PSA levels ≥20 ng/mL increased (from 18.9% to 19.8%) in nonexpansion states and decreased (from 19.9% to 18.2%) in expansion states. Compared with men in nonexpansion states, men in expansion states experienced a decline in PSA ≥20 ng/mL (DID, -2.33%; 95% CI, -3.21% to -1.44%; P < .001). Accordingly, the proportion of men presenting with high-risk disease decreased in expansion states relative to nonexpansion states (DID, -1.25%; 95% CI, -2.26% to 0.25%; P = .015). A similar statistically significant decrease in PSA levels ≥20 ng/mL was noted among black men (DID, -3.11%; 95% CI, -5.25% to 0.96%; P = .005). CONCLUSIONS: In Medicaid expansion states, there was an associated decrease in the proportion of young men presenting with PSA ≥20 ng/mL at the time of PCa diagnosis. These results suggest that Medicaid expansion improved access to PCa screening. Longer term data should assess oncologic outcomes.


Subject(s)
Early Detection of Cancer/methods , Mass Screening/methods , Medicaid/economics , Prostate-Specific Antigen/blood , Prostatic Neoplasms/blood , Prostatic Neoplasms/diagnosis , Registries , Databases, Factual , Health Services Accessibility , Humans , Insurance Coverage , Male , Medically Uninsured , Middle Aged , Patient Protection and Affordable Care Act , Prostatic Neoplasms/epidemiology , Retrospective Studies , Risk , United States/epidemiology
13.
Clin Genitourin Cancer ; 18(4): e386-e390, 2020 08.
Article in English | MEDLINE | ID: mdl-32280026

ABSTRACT

INTRODUCTION: The absence of health insurance coverage has been associated with worse outcomes for patients with metastatic renal cell carcinoma (mRCC). Medicaid expansion in the United States was an important provision of the Affordable Care Act, which increased the number of low-income individuals eligible for Medicaid starting in January 2014 in several states. The effect of Medicaid expansion on access to healthcare for patients with mRCC is unknown. MATERIALS AND METHODS: We performed a retrospective cohort study of 6844 patients aged < 65 years with mRCC at diagnosis within the National Cancer Database. We compared the time to treatment and the rates of no insurance before (2012-2013) and after (2015-2016) expansion between patients living in states that had and had not expanded Medicaid using difference-in-difference (DID) analyses. DIDs were calculated using linear regression analysis with adjustment for sociodemographic covariates. RESULTS: The rate of no insurance did not change in the expansion states compared with the nonexpansion states (DID, -0.55%; 95% confidence interval, -3.32% to 2.21%; P = .7). The percentage of patients receiving treatment within 60 days of diagnosis had increased in the expansion states from 43% to 49% and in the nonexpansion states from 42% to 46% after expansion. No change was found in treatment within 60 days of diagnosis among all patients (DID, 2.81%; 95% confidence interval, -2.61% to 8.22%; P = .3). CONCLUSIONS: Medicaid expansion was not associated with improved healthcare access for patients with mRCC as reflected by timely treatment. Future work should assess the association between Medicaid expansion and oncologic outcomes.


Subject(s)
Carcinoma, Renal Cell/therapy , Insurance, Health/economics , Kidney Neoplasms/therapy , Medicaid/economics , Time-to-Treatment , Carcinoma, Renal Cell/economics , Carcinoma, Renal Cell/pathology , Combined Modality Therapy , Female , Follow-Up Studies , Health Services Accessibility , Humans , Kidney Neoplasms/economics , Kidney Neoplasms/pathology , Male , Middle Aged , Patient Protection and Affordable Care Act , Prognosis , Retrospective Studies , United States
14.
Med Clin North Am ; 102(2): 313-324, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29406060

ABSTRACT

Female voiding dysfunction and incontinence are common in the general population and symptoms have been shown to have a significant negative impact on health-related quality of life. This article highlights the epidemiology, evaluation, diagnosis, pharmacologic therapies, and surgical treatment for overactive bladder, stress urinary incontinence, and urogenital fistulas.


Subject(s)
Urinary Bladder, Overactive , Urinary Incontinence , Vaginal Fistula , Female , Humans , Urinary Bladder, Overactive/complications , Urinary Bladder, Overactive/therapy , Urinary Incontinence/etiology , Urinary Incontinence/physiopathology , Urinary Incontinence/therapy , Vaginal Fistula/complications , Vaginal Fistula/surgery
15.
J Spinal Cord Med ; 41(1): 55-62, 2018 01.
Article in English | MEDLINE | ID: mdl-27551923

ABSTRACT

OBJECTIVE: Diagnosis of obesity using traditional body mass index (BMI) using length may not be a reliable indicator of body composition in spina bifida (SB). We examine traditional and surrogate measures of adiposity in adults with SB, correlated with activity, metabolic disease, attitudes towards exercise and quality of life. DESIGN: Adult subjects with SB underwent obesity classification using BMI by length and arm span, abdominal girth and percent trunk fat (TF) on dual energy X-ray absorptiometry (DXA). Quality of life measures, activity level and metabolic laboratory values were also reviewed. RESULTS: Among eighteen subjects (6 male, 12 female), median age was 26.5 (range 19-37) years, with level of lesion 16.7% ≤L2, 61.1% L3-4, and 22.2% ≥L5, respectively. Median weight was 71.8 (IQR 62.4, 85.8) kg, similar between sexes (P = 0.66). With median length of 152.0 (IQR 141.8, 163.3) cm, median conventional BMI was 29.4 m/kg2, with 7 (43.8%) subjects with BMI >30. Median BMI by arm span was 30.2 m/kg2, abdominal girth of 105.5 cm, and TF 45.7%. More subjects were classified as obese using alternate measures, with 9 (56.3%) by arm span, 14 (82.4%) by abdominal girth and 15 (83.3%) by TF (P = 0.008). Reclassification of obesity from conventional BMI was significant when using TF (P = 0.03). No difference in quality of life measures, activity level and metabolic abnormalities was demonstrated between obese and non-obese subjects. CONCLUSIONS: Conventional determination of obesity using BMI by length is an insensitive marker in adults with SB. Adults with SB are more often classified as obese using TF by DXA.


Subject(s)
Anthropometry/methods , Obesity/diagnosis , Spinal Dysraphism/pathology , Adiposity , Adult , Body Mass Index , Female , Humans , Male , Obesity/etiology , Spinal Dysraphism/complications
16.
Biochemistry ; 57(16): 2349-2358, 2018 04 24.
Article in English | MEDLINE | ID: mdl-28539047

ABSTRACT

The cytosolic iron-sulfur cluster assembly (CIA) system assembles iron-sulfur (FeS) cluster cofactors and inserts them into >20 apoprotein targets residing in the cytosol and nucleus. Three CIA proteins, called Cia1, Cia2, and Met18 in yeast, form the targeting complex responsible for apo-target recognition. There is little information about the structure of this complex or its mechanism of CIA substrate recognition. Herein, we exploit affinity co-purification and size exclusion chromatography to determine the subunit connectivity and stoichiometry of the CIA targeting complex. We conclude that Cia2 is the organizing center of the targeting complex, which contains one Met18, two Cia1, and four Cia2 polypeptides. To probe target recognition specificity, we utilize the CIA substrates Leu1 and Rad3 as well as the Escherichia coli FeS-binding transcription factor FNR (fumerate nitrate reductase). We demonstrate that both of the yeast CIA substrates are recognized, whereas the bacterial protein is not. Thus, while the targeting complex exhibits flexible target recognition in vitro, it cannot promiscuously recognize any FeS protein. Additionally, we demonstrate that the full CIA targeting complex is required to stably bind Leu1 in vitro, whereas the Met18-Cia2 subcomplex is sufficient to recognize Rad3. Together, these results allow us to propose a unifying model for the architecture of this highly conserved complex and demonstrate what component or subcomplexes are vital for target identification.


Subject(s)
Cell Nucleus/chemistry , Cytosol/chemistry , Iron-Sulfur Proteins/chemistry , Protein Interaction Maps/genetics , Cell Cycle Proteins/chemistry , Cell Cycle Proteins/genetics , Cell Nucleus/genetics , DNA Helicases/chemistry , DNA Helicases/genetics , Hydro-Lyases/chemistry , Hydro-Lyases/genetics , Iron-Sulfur Proteins/genetics , Protein Binding , Saccharomyces cerevisiae/chemistry , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/chemistry , Saccharomyces cerevisiae Proteins/genetics , Transcription Factors/chemistry , Transcription Factors/genetics
17.
Oral Oncol ; 75: 127-132, 2017 12.
Article in English | MEDLINE | ID: mdl-29224809

ABSTRACT

OBJECTIVES: To determine the rate of unplanned readmission after transoral robotic surgery (TORS), and to determine which patient or surgical factors increase the likelihood of readmission. MATERIALS AND METHODS: Retrospective chart review of all patients who underwent TORS for squamous cell carcinoma at our institution from March 2010 through July 2016. Primary outcome was unplanned readmission to the hospital within 30 days of discharge. Univariable and multivariable logistic regression were performed to identify risk factors for unplanned readmission. RESULTS: 297 patients met eligibility criteria. 23 patients (7.7%) had unplanned readmissions within 30 days. Most common reasons for readmission were oropharyngeal bleed (n = 13) and pain/dehydration (n = 10). Average time to unplanned readmission was 6.52 days (range 0-25 days). Discharge on clopidogrel was the only variable independently associated with an increased risk of 30-day unplanned readmission on multivariable analysis with an OR = 6.85 (95% CI 1.59-26.36). Unplanned return to the operating room during initial hospitalization (OR = 7.55, 95% CI 1.26-38.50) and discharge on clopidogrel (OR = 10.45, 95% CI 1.06-82.69) were associated with increased risk of postoperative bleeding. Bilateral neck dissection (OR = 5.17, 95% CI 1.15-23.08) was associated with significantly increased odds of unplanned readmission secondary to pain and dehydration. CONCLUSION: Unplanned readmission following TORS occurs in a small but significant number of patients. Oropharyngeal bleeding and dehydration were the most common reasons for unplanned readmission following TORS.


Subject(s)
Carcinoma, Squamous Cell/surgery , Mouth Neoplasms/surgery , Mouth/surgery , Patient Readmission , Postoperative Complications , Robotic Surgical Procedures/methods , Carcinoma, Squamous Cell/pathology , Clopidogrel , Dehydration/etiology , Dehydration/therapy , Female , Humans , Male , Middle Aged , Mouth Neoplasms/pathology , Oral Hemorrhage/drug therapy , Oral Hemorrhage/etiology , Pain, Postoperative/etiology , Pain, Postoperative/therapy , Platelet Aggregation Inhibitors/therapeutic use , Retrospective Studies , Risk Factors , Robotic Surgical Procedures/adverse effects , Ticlopidine/analogs & derivatives , Ticlopidine/therapeutic use
18.
Metallomics ; 9(11): 1645-1654, 2017 11 15.
Article in English | MEDLINE | ID: mdl-29057997

ABSTRACT

The cytosolic iron-sulfur cluster assembly (CIA) system biosynthesizes iron-sulfur (FeS) cluster cofactors for cytosolic and nuclear proteins. The yeast Cia2 protein is the central component of the targeting complex which identifies apo-protein targets in the final step of the pathway. Herein, we determine that Cia2 contains five conserved motifs distributed between an intrinsically disordered N-terminal domain and a C-terminal domain of unknown function 59 (DUF59). The disordered domain is dispensible for binding the other subunits of the targeting complex, Met18 and Cia1, and the apo-target Rad3 in vitro. While in vivo assays reveal that the C-terminal domain is sufficient to support viability, several phenotypic assays indicate that deletion of the N-terminal domain negatively impacts CIA function. We additionally establish that Glu208, located within a conserved motif found only in eukaryotic DUF59 proteins, is important for the Cia1-Cia2 interaction in vitro. In vivo, E208A-Cia2 results in a diminished activity of the cytosolic iron sulfur cluster protein, Leu1 but only modest effects on hydroxyurea or methylmethane sulfonate sensitivity. Finally, we demonstrate that neither of the two highly conserved motifs of the DUF59 domain are vital for any of Cia2's interactions in vitro yet mutation of the DPE motif in the DUF59 domain results in a nonfunctional allele in vivo. Our observation that four of the five highly conserved motifs of Cia2 are dispensable for targeting complex formation and apo-target binding suggests that Cia2 is not simply a protein-protein interaction mediator but it likely possesses an additional, currently cryptic, function during the final cluster insertion step of CIA.


Subject(s)
Iron-Sulfur Proteins/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/metabolism , Amino Acid Sequence , Binding Sites/genetics , Cytosol/metabolism , Iron-Sulfur Proteins/chemistry , Iron-Sulfur Proteins/genetics , Mutation , Protein Binding , Protein Domains , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/chemistry , Saccharomyces cerevisiae Proteins/genetics
19.
Neurourol Urodyn ; 36(2): 344-348, 2017 02.
Article in English | MEDLINE | ID: mdl-26547063

ABSTRACT

AIMS: To examine surgeon characteristics in certifying urologists performing prolapse surgeries. Anterior compartment prolapse is often associated with apical prolapse, with high rates of recurrence when anterior repair is performed without apical resuspension. METHODS: Six-month case log data of certifying urologists between 2003 and 2013 was obtained from the American Board of Urology (ABU). Cases with a CPT code for common prolapse repairs in females ≥18 years were analyzed. RESULTS: Among 2,588 urologists logging at least one prolapse surgery and a total of 30,983 surgeries, 320 (1.0% of all cases) uterosacral ligament suspension, 3,673 (11.9%) sacrospinous ligament suspension, and 2,618 (8.4%) abdominal sacrocolpopexy were identified. The remaining 14,585 cases were logged as anterior repair. 54.7% of anterior repairs did not include apical suspension. The proportion of anterior repairs without apical suspension has decreased from 77.7% in 2004 to 41.4% in 2012 (P < 0.001). Female subspecialists before 2011 performed anterior repair without apical suspension in 58.5%, versus 70.3% by all others. Since 2011 there has been a decrease in number of anterior repairs without apical suspension, notably in those applying for Female Pelvic Medicine and Reconstructive Surgery (FPMRS) certification (17.1% vs. 30.7% by all other urologists, P < 0.001); nonacademically affiliated urologists are 2.1 times more likely to report anterior repair without apical suspension than academically affiliated colleagues (P < 0.001). CONCLUSIONS: The proportion of prolapse repairs reported as anterior repairs without apical suspension is decreasing, although it remains a substantial portion. Recent log year, FPMRS, and academic affiliation were associated with prolapse repairs addressing apical support. Neurourol. Urodynam. 36:344-348, 2017. © 2015 Wiley Periodicals, Inc.


Subject(s)
Pelvic Organ Prolapse/surgery , Plastic Surgery Procedures/methods , Practice Patterns, Physicians' , Urologic Surgical Procedures/methods , Female , Humans , United States , Urology
20.
Urology ; 97: 273-276, 2016 11.
Article in English | MEDLINE | ID: mdl-27349528

ABSTRACT

OBJECTIVE: To report the distribution of pelvic organ prolapse (POP) stages in adult spina bifida (SB) patients. The severity of POP in the SB population has not been previously reported. MATERIALS AND METHODS: Retrospective review of SB patients ≥18 years with a documented POP quantification examination between 2006 and 2014 were included. Patient demographics, gestation, parity, POP quantification examinations and prolapse symptoms were obtained. RESULTS: Thirty-three SB patients were identified with a mean age of 33.2 years. Five patients (15.2%) had stage 0 prolapse, 12 (36.4%) had stage 1, 12 (36.4%) had stage 2, 3 (9.1%) had stage 3, and 1 (3.0%) had stage 4. Of the 16 patients with advanced POP (stage 2 prolapse or greater), only 6 patients (37.5%) reported symptoms related to POP. All 6 symptomatic patients endorsed sensation of a vaginal bulge. Two of the 6 patients also reported dyspareunia. Additionally, 1 patient with advanced POP presented with vaginal bulge, noted by a caregiver, and cervical bleeding, but was otherwise asymptomatic. Twenty-four patients (72.7%) were nulliparous, and 12 of the 24 nulliparous patients (50%) demonstrated prolapse. CONCLUSION: Despite young age and frequent nulliparity, patients with SB are more likely to have POP than the general population. Additionally, the majority of SB patients with prolapse are asymptomatic. Assessment of pelvic organ prolapse should be included in the evaluation of adult SB females due to the low rate of symptoms even in the setting of advanced stage prolapse and potential impact on both urinary and bowel function.


Subject(s)
Pelvic Organ Prolapse/complications , Severity of Illness Index , Spinal Dysraphism/complications , Adolescent , Adult , Aged , Asymptomatic Diseases , Dyspareunia/etiology , Female , Humans , Middle Aged , Parity , Pelvic Organ Prolapse/therapy , Retrospective Studies , Symptom Assessment , Uterine Hemorrhage/etiology , Young Adult
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