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Prior studies have shown a broad half time (T1/2) interval on MAG3 diuresis renography (DR) that is indeterminate for obstruction. We aimed to refine and sub-divide the indeterminate range and associate it with clinically meaningful outcomes: pyeloplasty and pyeloplasty-free survival.We identified patients1.5 years-old at presentation with unilateral, isolated moderate to severe hydronephrosis who underwent DR from 2000 to 2016. A logistic regression model was created using T1/2 to predict surgery. An indeterminate range was defined based on patients with90% probability of pyeloplasty or resolution. This group was sub-divided into three T1/2 intervals: 5-20, 21-40, and 41-60 min. Endpoints were pyeloplasty and pyeloplasty free survival. Indications for surgery were loss of differential renal function (DRF), worsening T1/2, family preference, and/or pain.Among 2025 patients with DR, 704 met criteria (169 were lost to follow up). Of the remaining 535, 218 had pyeloplasties and 317 did not. The Pyeloplasty group had significantly worse DRF, T1/2 at initial DR, and exited the study earlier, at a median age 1.1years vs 2.3 years (p 0.001). For all patients with antenatally detected unilateral UPJ obstruction, the odds of undergoing pyeloplasty at any time increased by 1.8 times (p 0.001 [95% CI: 1.04, 1.08]) per 10 unit increase in T1/2 until T1/2 = 60. However, in patients with intermediate drainage, five year surgery-free survival probability for patients with T1/2 5-20, 21-40, and 41-60 min were 79.7%, 46.7% and 33.3% respectively (χ2 = 41.2, P =0.001).Previous efforts to define indeterminate drainage resulted in ranges for T1/2 that were too broad to be clinically useful. Within our endpoint-defined indeterminate range, our data show that there are significant step offs in 5-year surgery-free survival for patients with T1/2 20 min, 21-40 min, and 41-60 min. Although there is a steady decrease in surgery-free survival among patients with a T1/2 of 21-40 min over the first 5 years of life, half can be managed nonoperatively. These patients likely represent the true intermediate risk group and closer follow up is justified.Initial T1/2 on DR is predictive of future surgery. When drainage is "indeterminate" for obstruction, sub-stratification allows for more accurate prognostication.

Somatic copy number alterations that result in loss of tumor suppressor gene function are important drivers of tumorigenesis. However, few existing therapeutic options to target oncogenic processes evoked by tumor suppressor gene inactivation exist. The discovery of synthetic lethal interactions with genetic drivers of cancer may yield new therapeutic strategies with cancer selective potential. We examined genome-scale CRISPR-SpCas9 and RNA interference screens to uncover new synthetic lethal vulnerabilities associated with the loss of common tumor suppressor genes (TSGs). The ATPases Vacuolar protein sorting 4 homolog A (VPS4A) and B (VPS4B) scored as strong synthetic lethal dependencies, with VPS4A selectively essential in cancers harboring loss of VPS4B adjacent to SMAD4 and VPS4B required in tumors with co-deletion of VPS4A and CDH1 (encoding E-cadherin). VPS4B resides 12.3 Mb away from the SMAD4 TSG on chromosome 18q and is lost in approximately 33% of all cancers, suggesting broad clinical applicability. Moreover, VPS4B is commonly lost in pancreatic cancer due to the frequent loss of SMAD4, highlighting VPS4A represents a promising target for this deadly cancer. VPS4A and VPS4B function as AAA ATPases forming a multimeric protein complex within the endosomal sorting complex required for transport (ESCRT) pathway to regulate membrane remodeling in a range of cellular processes. VPS4A suppression in cells with VPS4B/SMAD4 loss led to accumulation of ESCRT-III filaments, cytokinesis defects, nuclear deformation and micronucleation, which ultimately resulted in G2/M cell cycle arrest and apoptosis. Furthermore, upon VPS4A suppression, we observed potent in vivo tumor regression, which led to extended survival, in mouse subcutaneous xenograft models utilizing a pancreatic or rhabdomyosarcoma cancer cell line harboring VPS4B loss. CRISPR-SpCas9 screening and integrative genomic analysis revealed other ESCRT members, regulators of abscission and interferon signaling as modifiers of VPS4A dependency. Using the most comprehensive available CRISPR-SpCas9 and RNA-interference screening datasets to date, we provide a compendium of synthetic lethal vulnerabilities with TSG loss and credential VPS4A as a new and promising therapeutic target in cancers with VPS4B/SMAD4 deletion. Citation Format: Jasper E. Neggers, Brenton R. Paolella, Adhana Asfaw, Michael V. Rothberg, Thomas A. Skipper, Radha L. Kalekar, Michael J. Krill-Burger, Neekesh V. Dharia, Guillaume Kugener, Adam D. Durbin, Annan Yang, Nancy Dumont, Yvonne Y. Li, Brian M. Wolpin, Federica Piccioni, David E. Root, Jesse S. Boehm, Andrew D. Cherniack, Aviad Tsherniak, Andrew L. Hong, William C. Hahn, Kimberly Stegmaier, Todd R. Golub, Francisca Vazquez, Andrew J. Aguirre. Synthetic lethal interaction between the ESCRT paralog enzymes VPS4A and VPS4B in SMAD4 or CDH1-deleted cancers [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-011.

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood. Despite multimodality therapy and trials of molecularly targeted agents, limited improvements in overall survival have been realized for patients with high-risk disease. Thus, we aimed to determine the landscape of tumor-specific gene dependencies that underlie tumorigenesis in RMS and therefore provide a valuable group of targets for the development of novel therapeutics. Using unbiased genome-scale CRISPR-Cas9 approaches, we identified a set of RMS-specific tumor dependencies involved in tumor cell growth and survival. RMS dependencies were enriched for nucleic acid binding proteins, including transcription factors (TFs). We then used genome-wide chromatin-immunoprecipitation coupled to high-throughput sequencing analysis to demonstrate that a small number of essential TFs—MYCN, MYOD1, TCF12, SOX8, ZEB2, ZNF217, and SIX1—are members of the transcriptional core regulatory circuitry (CRC) that maintains the malignant cell state of RMS. Both c-MYC and MYCN were associated with gene and enhancer copy number increases in cell lines and primary tumors and represented strong dependencies in the RMS cell lines screened. c-MYC and MYCN function to similarly invade and regulate the CRC in respectively dependent cells. To disable the CRC, we tested A485, an inhibitor of the histone acetyltransferase enzymes involved in the establishment of super-enhancer elements that are associated with high level expression of the CRC factors. A485 caused a reversible and rapid loss of CRC factor and c-MYC and/or MYCN expression, and prolonged treatment resulted in cell cycle arrest, differentiation, and apoptosis in vitro and in vivo. This phenotype is rescued by exogenous re-expression of either c-MYC or MYCN in a manner insensitive to A485, indicating a mechanism by which these genes subvert a myogenic CRC to produce an oncogenic fate. This study defines a common set of critical dependency genes in RMS and identifies key genomic events surrounding the c-MYC and MYCN loci that lead to elevated expression and tumorigenesis. Citation Format: Adam D. Durbin, Guillaume Kugener, Mark W. Zimmerman, Chuan Yan, Neekesh V. Dharia, Elizabeth S. Frank, Xiang Chen, Ken N. Ross, Brenton Paolella, Michael Krill-Burger, David E. Root, Jesse S. Boehm, Francisca Vazquez, Andrew L. Hong, Aviad Tsherniak, David M. Langenau, William C. Hahn, Todd R. Golub, Brian J. Abraham, Richard A. Young, A. Thomas Look, Kimberly Stegmaier. Rhabdomyosarcoma requires MYC family genomic events to pathogenically subvert core-regulatory circuitry [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B10.

Summary Stomal prolapse is a known late complication of urinary diversions commonly used in urology. While rare, it can lead to ischemia, necrosis, and obstruction of the stoma, requiring urgent reduction before formal revision can be undertaken. Several measures can be attempted to reduce the prolapse including manual pressure and topical osmotic agents. One method that has not been reported in the urologic literature is the use of hyaluronidase. Herein, we report the first case in the literature of hyaluronidase usage to assist in reduction of an ischemic and obstructed prolapsed incontinent ileovesicostomy after manual compression failed.

Considering that there are few absolute indications for the timing and type of surgical correction of vesicoureteral reflux, we objectively measured parental choice in how the child's vesicoureteral reflux should be managed.We prospectively identified patients 0 to 18 years old with any grade of newly diagnosed vesicoureteral reflux. All races and genders were included, and non-English speakers were excluded from analysis. Parents were shown a video presented by a professional actor that objectively described vesicoureteral reflux and the 3 treatment modalities of antibiotic prophylaxis, open ureteral reimplantation and endoscopic treatment. Then they completed a questionnaire regarding their preference for initial management, and at hypothetical followup points of 18, 36 and 54 months. Consultation followed with the pediatric urologist who was blinded to the questionnaire results.A total of 86 girls and 15 boys (150 refluxing units) were enrolled in the study. Mean patient age was 2.6 years old. Preferences for initial treatment were antibiotic prophylaxis in 36, endoscopic surgery in 26, open surgery in 11, unsure in 26 and no response in 2. Among those initially selecting antibiotic prophylaxis, after 18 months the preference was for endoscopic treatment, but after 36 and 54 months preferences trended toward open surgery. After consultation with the pediatric urologist 68 parents chose antibiotic prophylaxis.Our data show that antibiotic prophylaxis is preferred as the initial therapy for vesicoureteral reflux by 35.6% of parents. However, given persistent vesicoureteral reflux, preferences shifted toward surgery. With time the preference for open surgery increased and the preference for endoscopic surgery decreased.

The reaction of the title compound 1 with the p-R-aniline derivatives (R═H, F, OCH3, NO2, and NH2) led to the formation of the aza-2σ3,4σ3-diphosphetidines 2a– 2e, whereas 2-trimethylsiloxyaniline furnished the azadiphosphetidine 2f. The reaction of the sterically crowded 2,6-dimethylaniline with 1 furnished the disubstituted derivative 3. The tricyclic compound 5 was formed during the reaction of 1,2-phenylenediamine with 1. Heptamethyldisilazane formed the aza-2σ 3 ,4σ 3 -diphosphetidine 6 on reaction with 1. The bulkier tert.-butylamine formed with 1 a mixture of the aza-2,4-diphosphetidine 7a and the disubstituted derivative 7b, which could not be separated. The reaction of 2b and 6 with tetrachloro-o-benzoquinone resulted in the formation of the bis-spirophosphoranes 8 and 9b, respectively. The formation of the monospirophosphorane 9a was observed in the 31P NMR spectrum. The characterization of compounds is based in particular on NMR investigations (1H, 13C, 31P). 2a was characterized by a single-cr...

A methodology is provided for state departments of transportation (DOTs) to conduct vulnerability assessments of their highway assets. This tool allows state DOTs to assess the vulnerability of their physical assets, such as bridges and tunnels; to develop possible countermeasures to deter, detect, and delay the consequences of terrorist threats; to estimate the capital and operating costs of such countermeasures; and to improve security operational planning. The audience for this methodology is broad—from senior officials involved in the initial planning stage of the process, to midlevel managers charged with developing the assessment plans and procedures, to field personnel. The state DOTs must organize and manage a multidisciplinary team whose members have a working knowledge of the department’s mission, its critical assets, and its policies, plans, and procedures. The methodology involves six steps for conducting a vulnerability assessment of highway transportation assets. They provide a straightforward method for examining critical assets and identifying cost-effective countermeasures to guard against terrorism. The criteria used in selecting the preferred approaches include availability, accessibility, transparency, replicability, reasonableness, scalability, robustness, costeffectiveness, and modularity.

The title compound 3 was formed in the reaction of Cl2PCCl2PCl2 (2) with catechol in the presence of triethylamine. The reaction of 3 with tetrachloro-o-benzoquinone (TOB), 4, led to the σ3P/σ5P-species 5, and the σ5P/σ5P-species 6a/6b. 5 was stable only in solution, and its existence and identity are postulated on the basis of its 31P-NMR spectrum. The structure of 6a/6b could not be assigned unambiguously to one isomer. The reaction of 6a/6b with water yielded the phosphorate 10. The structures of 3 and 10 were determined by single crystal X-ray methods. A wide PCP angle (123.2°) was observed in 3. The cation of 10 is a centrosymmetric, protonated DMF dimer with OO 241.3 pm.

The title compound 1 was allowed to react with catechol, 2,3-dihydroxynaphthalene, tetrabromocatechol, resorcinol, saligenin, and 3,5-di-tert-butylcatechol in the presence of triethylamine to form compounds 4a–4d and 4f. Whereas the catechol derivative 4a, the naphthol derivative 4b, and the tetrabromocatechol derivative 4c could be readily obtained, the saligenin derivative 4d and the 3,5-di-tert-butylcatechol derivative 4f were found to be stable only in solution. Contrary to expectation, compound 4e was not formed in the reaction of 1 with resorcinol. The reaction of 1 with 1,2,4,5-tetrahydroxybenzene led to the pentacyclic derivative 4g. Reaction of hydroquinone with 1 led to the formation of the dimeric structure 4h. Crystal structure analyses of 4a and 4b show that the nine-membered rings adopt essentially identical “tub” conformations in which the P and O atoms are coplanar. The P-C-P angles (across the CCl2 bridge) are wide (ca. 119°). © 1997 John Wiley & Sons, Inc.

The unique nature of nuclear imaging allows for detailed functional information lacking in other conventional imaging modalities, such as estimation of global and differential renal function, highly sensitive imaging of the renal cortex to document renal scars, evaluation of urinary drainage to aid in the diagnosis of obstruction, surveillance monitoring of vesicoureteral reflux, and evaluation of testis perfusion in cases of suspected testis torsion with equivocal ultrasound imaging.

The iPod Touch, iPhone and iPad from Apple are among the most popular mobile computing platforms in use today. These devices are of forensic interest because of their high adoption rate and potential for containing digital evidence. The uniformity in their design and underlying operating system (iOS) also allows forensic tools and methods to be shared across product types. This paper analyzes the tools and methods available for conducting forensic examinations of the Apple iPad. These include commercial software products, updated methodologies based on existing jailbreaking processes and the analysis of the device backup contents provided by iTunes. While many of the available commercial tools offer promise, the results of our analysis indicate that most comprehensive examination of the iPad requires jailbreaking to perform forensic duplication and manual analysis of its media content.

Bis[(di-tert-butylphosphanyl)methyl]methylphosphane[1] The synthesis of [(di-tert-butylphosphanyl)methyl]dimethyl-phosphane (3) and of the title compound 5 is described. 5 reacts with sulfur to form the trisulfide 6. Both 3 and 5 behave as bidentate ligands in forming the molybdenum complexes 8 and 10, which are characterized by single crystal X-ray structure determinations. 10 reacts with sulfur to yield the sulfide 11, which decomposes in solution within 6 h.

A synthesis of C-chlorinated analogues of 1,5-diaza-2,4-diphosphorinan-6-ones is described. The P-chlorophosphine 3, a key compound for all reported substitution reactions, reacts in an unusual way with N,N′-dimethyl-N,N′-bis(trimethylsilyl)urea to give the unsymmetrical product 5, the formation of which is accounted for by a silatropy of the intermediate compound 4. Compound 5 is stable in solution but rearranges quantitatively into isomer 6 without solvent at room temperature. Compound 3, its fluoro derivative 9, and the alkoxy derivatives 10a–d exist as cis-and trans-isomers. Some stereochemical aspects, as well as the possibility of 1,2-chlorotropy, are discussed.

The title compound, C11H26P2S2, displays crystallographic mirror symmetry. Key bond lengths (A) are P1—C(methyl­ene) 1.8464 (18), P1—C(butyl) 1.8711 (13), P2—C(methyl­ene) 1.8266 (18), P2—C(methyl) 1.7948 (15), P1=S 1.9631 (8) and P2=S 1.9552 (8), where P1 is the di-tert-butyl­phosphino P atom and P2 is the di­methyl­phosphino P atom. The angle P—C—P [124.31 (10)°] is wide and S=P—C(methyl­ene) [108.91 (6)°] narrow. Steric pressure from the tert-butyl groups may cause some of the molecular dimensions to depart from normal values.

The effect of [Nle8,18,Tyr34]bPTH-(1-34)amide on renal plasma membrane adenylate cyclase, in the presence of 0.1 mM guanylylimidodiphosphate was measured in rat, chicken, frog and trout. All species showed an enrichment of at least 8-fold (relative to homogenate) in the marker enzyme Na+,K+-ATPase. A significant dose-dependent adenylate cyclase stimulation was found in frog, with affinity values similar to those of rat and chicken (ED50=8, 10 and 3 nM, respectively), but not in trout. The frog response was specific since [Nle8,18,Tyr34]bPTH-(3-34)amide strongly inhibited the agonist-stimulated enzyme. These results suggest the existence of a PTH-like substance in anurans acting via cyclic AMP formation in the kidney.