Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.

BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

The origins of urinary stone disease: upstream mineral formations initiate downstream Randall's plaque.

OBJECTIVES: To describe a new hypothesis for the initial events leading to urinary stones. A biomechanical perspective on Randall's plaque formation through form and function relationships is applied to functional units within the kidney, we have termed the 'medullo-papillary complex' - a dynamic relationship between intratubular and interstitial mineral aggregates. METHODS: A complete MEDLINE search was performed to examine the existing literature on the anatomical and physiological relationships in the renal medulla and papilla. Sectioned human renal medulla with papilla from radical nephrectomy specimens were imaged using a high resolution micro X-ray computed tomography. The location, distribution, and density of mineral aggregates within the medullo-papillary complex were identified. RESULTS: Mineral aggregates were seen proximally in all specimens within the outer medulla of the medullary complex and were intratubular. Distal interstitial mineralisation at the papillary tip corresponding to Randall's plaque was not seen until a threshold of proximal mineralisation was observed. Mineral density measurements suggest varied chemical compositions between the proximal intratubular (330 mg/cm3 ) and distal interstitial (270 mg/cm3 ) deposits. A review of the literature revealed distinct anatomical compartments and gradients across the medullo-papillary complex that supports the empirical observations that proximal mineralisation triggers distal Randall's plaque formation. CONCLUSION: The early stone event is initiated by intratubular mineralisation of the renal medullary tissue leading to the interstitial mineralisation that is observed as Randall's plaque. We base this novel hypothesis on a multiscale biomechanics perspective involving form and function relationships, and empirical observations. Additional studies are needed to validate this hypothesis.

Using an abdominal phantom to teach urology residentes ultrasound-guided percutaneous needle placement.

INTRODUCTION: To assess the effect of a hands-on ultrasound training session to teach urologic trainees ultrasound-guided percutaneous needle placement. MATERIALS AND METHODS: University of California, San Francisco (UCSF) urology residentes completed a time trial, placing a needle into a phantom model target under ultrasound guidance. Participants were randomized into three educational exposure groups: Group 1's time trial occurred prior to any teaching intervention, group 2's after experiencing a hands-on training module, and group 3's after exposure to both the training module and one-on-one attending feedback. Needle placement speed and accuracy as well as trainees' perceived confidence in utilizing ultrasound were measured. RESULTS: The study cohort consisted of 15 resident trainees. Seven were randomized to group 1, three to group 2, and five to group 3. All residents reported minimal prior ultrasound experience. Their confidence in using ultrasound improved significantly after completing the training module with the most significant improvement seen among junior residents. Time to needle placement was fastest after receiving attending feedback (46.6sec in group 3 vs. 82.7sec in groups 1 and 2, p<0.01). Accuracy also improved with attending feedback, though the number of repositioning attempts did not differ significantly between groups. CONCLUSIONS: A hands-on training module and use of an abdominal phantom trainer increased resident confidence and skill in their use of ultrasound to guide percutaneous needle positioning. Attending feedback is critical for improving accuracy in needle guidance toward a target. Ultrasound-guided needle positioning is a teachable skill and can be applicable to multiple urologic procedures.

Laparoscopic Nephrectomy with Autotransplantation: Safety, Efficacy and Long-Term Durability.

PURPOSE: Laparoscopic nephrectomy with autotransplantation is a viable option when renal preservation is required or ureteral reconstruction is impossible. In this study we report on our long-term experience with laparoscopic nephrectomy with autotransplantation. MATERIALS AND METHODS: A retrospective review of data from all patients who underwent laparoscopic nephrectomy with autotransplantation since 2000 revealed data for 52 of 59 patients after study exclusions. Indications for laparoscopic nephrectomy with autotransplantation included ureteral stricture disease (41), renal malignancy (7), ptotic kidney (1), chronic flank pain (1), renal artery aneurysm (1) and renovascular hypertension (1). Followup included ultrasonography, nuclear renography and computerized tomography. Complications analyzed were Clavien-Dindo grade III or higher. RESULTS: A total of 52 patients (30 women, 57.6%) underwent laparoscopic nephrectomy with autotransplantation at a median age of 48 years (range 12 to 76). At a median followup of 73.5 months 47 patients (90.3%) had long-term function of the autotransplanted renal unit including 3 of 4 (75%) solitary kidneys. There were 5 patients (9.7%) who experienced renal unit failure at a median of 15 months. Of these patients 3 required nephrectomy of autotransplant unit secondary to renal vein thrombosis (1 day), pseudoaneurysm (15 months) and chronic pain (48 months). Overall 4 patients had early complications and 8 had late complications. In the tumor group 4 patients had disease progression and all are alive. CONCLUSIONS: Laparoscopic nephrectomy with autotransplantation is an excellent long-term surgical option (greater than 90% success rate with longer than 6-year median followup) for complex ureteral and renal conditions that necessitate preservation of renal parenchyma. However, tumor progression is possible after ex vivo tumor excision. Therefore, careful patient selection and followup are mandatory. This report supports the safety, efficacy and durability of laparoscopic nephrectomy with autotransplantation in experienced hands.

Impact of synchronous metastasis distribution on cancer specific survival in renal cell carcinoma after radical nephrectomy with tumor thrombectomy.

PURPOSE: Metastatic renal cell carcinoma can be clinically diverse in terms of the pattern of metastatic disease and response to treatment. We studied the impact of metastasis and location on cancer specific survival. MATERIALS AND METHODS: The records of 2,017 patients with renal cell cancer and tumor thrombus who underwent radical nephrectomy and tumor thrombectomy from 1971 to 2012 at 22 centers in the United States and Europe were analyzed. Number and location of synchronous metastases were compared with respect to patient cancer specific survival. Multivariable Cox regression models were used to quantify the impact of covariates. RESULTS: Lymph node metastasis (155) or distant metastasis (725) was present in 880 (44%) patients. Of the patients with distant disease 385 (53%) had an isolated metastasis. The 5-year cancer specific survival was 51.3% (95% CI 48.6-53.9) for the entire group. On univariable analysis patients with isolated lymph node metastasis had a significantly worse cancer specific survival than those with a solitary distant metastasis. The location of distant metastasis did not have any significant effect on cancer specific survival. On multivariable analysis the presence of lymph node metastasis, isolated distant metastasis and multiple distant metastases were independently associated with cancer specific survival. Moreover higher tumor thrombus level, papillary histology and the use of postoperative systemic therapy were independently associated with worse cancer specific survival. CONCLUSIONS: In our multi-institutional series of patients with renal cell cancer who underwent radical nephrectomy and tumor thrombectomy, almost half of the patients had synchronous lymph node or distant organ metastasis. Survival was superior in patients with solitary distant metastasis compared to isolated lymph node disease.

Targeted microbubbles: a novel application for the treatment of kidney stones.

Kidney stone disease is endemic. Extracorporeal shockwave lithotripsy was the first major technological breakthrough where focused shockwaves were used to fragment stones in the kidney or ureter. The shockwaves induced the formation of cavitation bubbles, whose collapse released energy at the stone, and the energy fragmented the kidney stones into pieces small enough to be passed spontaneously. Can the concept of microbubbles be used without the bulky machine? The logical progression was to manufacture these powerful microbubbles ex vivo and inject these bubbles directly into the collecting system. An external source can be used to induce cavitation once the microbubbles are at their target; the key is targeting these microbubbles to specifically bind to kidney stones. Two important observations have been established: (i) bisphosphonates attach to hydroxyapatite crystals with high affinity; and (ii) there is substantial hydroxyapatite in most kidney stones. The microbubbles can be equipped with bisphosphonate tags to specifically target kidney stones. These bubbles will preferentially bind to the stone and not surrounding tissue, reducing collateral damage. Ultrasound or another suitable form of energy is then applied causing the microbubbles to induce cavitation and fragment the stones. This can be used as an adjunct to ureteroscopy or percutaneous lithotripsy to aid in fragmentation. Randall's plaques, which also contain hydroxyapatite crystals, can also be targeted to pre-emptively destroy these stone precursors. Additionally, targeted microbubbles can aid in kidney stone diagnostics by virtue of being used as an adjunct to traditional imaging methods, especially useful in high-risk patient populations. This novel application of targeted microbubble technology not only represents the next frontier in minimally invasive stone surgery, but a platform technology for other areas of medicine.

Dynamic contrast-enhanced MR renography for renal function evaluation in ureteropelvic junction obstruction: feasibility study.

OBJECTIVE: The purpose of this study was to evaluate split renal function, estimate single-kidney renal function, and identify cause of obstruction in patients with ureteropelvic junction (UPJ) obstruction by using contrast-enhanced dynamic MR renography (MRR). MATERIALS AND METHODS: Seventeen patients with UPJ obstruction underwent MRR and diuresis nuclear renography. Nuclear renography assessment of split renal function and mechanical versus functional obstruction served as the reference standard. The Baumann-Rudin model for determining glomerular filtration rate (GFR) was applied to generate single-kidney renal function (SK-GFRMRR) from MRR cortical and medullary enhancement curves. MRR split renal function of the right kidney (SK-GFRMRR of the right kidney normalized to the sum of SK-GFRMRR of both kidneys) was compared with nuclear renography. The MRR estimate of total GFR (eGFRMRR) was compared with that derived from Modification of Diet in Renal Disease (MDRD) formula (eGFRMDRD). Renal pelvic rate of signal intensity change (PUR) was compared between functionally and mechanically obstructed kidneys. RESULTS: There was excellent correlation between MRR and nuclear renography measure of split renal function ratio (r = 0.87, p < 0.01), with mean difference of less than 10%. There was moderate correlation (r = 0.60, p = 0.01) between eGFRMRR and eGFRMDRD. eGFRMRR underestimated eGFRMDRD, with mean difference of 13.3 mL/min/1.73 m(2). PUR in mechanically obstructed units was significantly lower (0.39 ± 0.26 vs 2.0 ± 1.38 min(-1); p < 0.01) compared with functionally obstructed units. PUR discriminated mechanical from functional obstruction with accuracy of 89%. CONCLUSION: In patients with UPJ obstruction, MRR can measure split renal function, estimate eGFRMDRD with moderate correlation, and accurately discriminate mechanical from functional obstruction, thus potentially providing a "one-stop shop" examination.

Lessons learned from the International Renal Cell Carcinoma-Venous Thrombus Consortium (IRCC-VTC).

Renal cell carcinoma (RCC) extension into the renal vein or the inferior vena cava occurs in 4%-10% of all kidney cancer cases. This entity shows a wide range of different clinical and surgical scenarios, making natural history and oncological outcomes variable and poorly characterized. Infrequency and variability make it necessary to share the experience from different institutions to properly analyze surgical outcomes in this setting. The International Renal Cell Carcinoma-Venous Tumor Thrombus Consortium was created to answer the questions generated by competing results from different retrospective studies in RCC with venous extension on current controversial topics. The aim of this article is to summarize the experience gained from the analysis of the world's largest cohort of patients in this unique setting to date.

Simplified approach to estimating renal function based on computerized tomography.

INTRODUCTION: To determine whether a simplified approach to estimate renal function based on preoperative computerized tomography (CT) imaging correlates with nuclear renography (NR) following surgical treatment of ureteropelvic junction obstruction (UPJO). MATERIALS AND METHODS: We reviewed the charts of 47 patients who underwent robotic assisted laparoscopic pyeloplasty (RALP) for UPJO who had performed preoperative and postoperative NR and preoperative CT imaging. Twenty patients satisfied our inclusion criteria. We calculated differential renal function by measuring parenchymal thickness at the upper pole, midpole and lower pole regions of the kidney on the preoperative CT. Distances were measured from the edge of the collecting system to the capsule at the midpoint of the kidney in the coronal plane. After parenchymal thickness measurements were calculated bilaterally, a differential parenchymal thickness was obtained, and the ratio of parenchymal area was compared to the observed function on NR. Measurements were taken by three blinded observers and compared to preop and postop differential renal function as measured by NR to assess if preoperative CT renal parenchymal thickness correlates well with differential function of the affected and contralateral kidneys. RESULTS: Estimated renal function was predicted with excellent accuracy and minimal interobserver variability. Pearson correlation coefficients for Observers 1, 2 and 3 were 0.89, 0.88 and 0.91, respectively when compared to the postoperative differential function on NR. The interclass correlation coefficient between the three observers was 0.957, which indicates an almost perfect correlation and reproducibility of the formula. CONCLUSIONS: Estimating differential renal function based on renal parenchymal thickness on preoperative CT imaging correlates very well with observed postoperative differential renal function on NR following RALP.

A draft of the genome and four transcriptomes of a medicinal and pesticidal angiosperm Azadirachta indica.

BACKGROUND: The Azadirachta indica (neem) tree is a source of a wide number of natural products, including the potent biopesticide azadirachtin. In spite of its widespread applications in agriculture and medicine, the molecular aspects of the biosynthesis of neem terpenoids remain largely unexplored. The current report describes the draft genome and four transcriptomes of A. indica and attempts to contextualise the sequence information in terms of its molecular phylogeny, transcript expression and terpenoid biosynthesis pathways. A. indica is the first member of the family Meliaceae to be sequenced using next generation sequencing approach. RESULTS: The genome and transcriptomes of A. indica were sequenced using multiple sequencing platforms and libraries. The A. indica genome is AT-rich, bears few repetitive DNA elements and comprises about 20,000 genes. The molecular phylogenetic analyses grouped A. indica together with Citrus sinensis from the Rutaceae family validating its conventional taxonomic classification. Comparative transcript expression analysis showed either exclusive or enhanced expression of known genes involved in neem terpenoid biosynthesis pathways compared to other sequenced angiosperms. Genome and transcriptome analyses in A. indica led to the identification of repeat elements, nucleotide composition and expression profiles of genes in various organs. CONCLUSIONS: This study on A. indica genome and transcriptomes will provide a model for characterization of metabolic pathways involved in synthesis of bioactive compounds, comparative evolutionary studies among various Meliaceae family members and help annotate their genomes. A better understanding of molecular pathways involved in the azadirachtin synthesis in A. indica will pave ways for bulk production of environment friendly biopesticides.

Unique infective complication after routine vasectomy: a case report.

INTRODUCTION: We present a case of a 51-year-old gentleman who, after undergoing routine vasectomy, presented with an infected wound 7 days after the procedure--one day after receiving oral sex from his wife. AIM: We hope to present a unique case of an infected wound after oral sex. Group A Streptococcus (GAS) was cultured from the patient's wound and the asymptomatic wife's pharyngeal mucosa. MAIN OUTCOME MEASURES: To educate and expose a rare but potentially devastating postvasectomy complication that, without prompt and aggressive treatment, can lead to significant morbidity. METHODS: The patient was promptly treated and after hydration, broad spectrum antibiotics, and supportive care, patient showed excellent recovery. The wife was also treated with oral antibiotics. RESULTS: Infective complicated are relatively uncommon after routine vasectomy. When present, the vast majority of the infections are treated with a simple course of oral antibiotics. There is strong evidence that establishes oral contact as a vector for transmission of virulent pathogens. Some have linked orogenital transmission of GAS since the 1970s. CONCLUSION: To our knowledge, this is the first reported case of oropharyngeal transmission of GAS that led to rapidly progressive infection of the scrotum following vasectomy. Care should be taken to minimize exposure during postoperative healing.

Human and great ape red blood cells differ in plasmalogen levels and composition.

BACKGROUND: Plasmalogens are ether phospholipids required for normal mammalian developmental, physiological, and cognitive functions. They have been proposed to act as membrane antioxidants and reservoirs of polyunsaturated fatty acids as well as influence intracellular signaling and membrane dynamics. Plasmalogens are particularly enriched in cells and tissues of the human nervous, immune, and cardiovascular systems. Humans with severely reduced plasmalogen levels have reduced life spans, abnormal neurological development, skeletal dysplasia, impaired respiration, and cataracts. Plasmalogen deficiency is also found in the brain tissue of individuals with Alzheimer disease. RESULTS: In a human and great ape cohort, we measured the red blood cell (RBC) levels of the most abundant types of plasmalogens. Total RBC plasmalogen levels were lower in humans than bonobos, chimpanzees, and gorillas, but higher than orangutans. There were especially pronounced cross-species differences in the levels of plasmalogens with a C16:0 moiety at the sn-1 position. Humans on Western or vegan diets had comparable total RBC plasmalogen levels, but the latter group showed moderately higher levels of plasmalogens with a C18:1 moiety at the sn-1 position. We did not find robust sex-specific differences in human or chimpanzee RBC plasmalogen levels or composition. Furthermore, human and great ape skin fibroblasts showed only modest differences in peroxisomal plasmalogen biosynthetic activity. Human and chimpanzee microarray data indicated that genes involved in plasmalogen biosynthesis show cross-species differential expression in multiple tissues. CONCLUSION: We propose that the observed differences in human and great ape RBC plasmalogens are primarily caused by their rates of biosynthesis and/or turnover. Gene expression data raise the possibility that other human and great ape cells and tissues differ in plasmalogen levels. Based on the phenotypes of humans and rodents with plasmalogen disorders, we propose that cross-species differences in tissue plasmalogen levels could influence organ functions and processes ranging from cognition to reproduction to aging.

New findings in localized and advanced prostate cancer: AUA 2011 review.

The 2011 American Urological Association (AUA) annual meeting took place in Washington, DC, USA, on May 14-19. It is the largest gathering of urologists in the world, providing unparalleled access to groundbreaking research, new guidelines and the latest advances in urologic medicine. The opportunity to exchange knowledge among urologists on a worldwide level was provided by participation of more than 80 countries in this scientific meeting. As one of the most important subjects, there were more than 500 presented studies in prostate cancer. In this review we will highlight some of the findings and the clinical significance of a few of these abstracts concerning prostate cancer staging and markers.

Identification of differences in human and great ape phytanic acid metabolism that could influence gene expression profiles and physiological functions.

BACKGROUND: It has been proposed that anatomical differences in human and great ape guts arose in response to species-specific diets and energy demands. To investigate functional genomic consequences of these differences, we compared their physiological levels of phytanic acid, a branched chain fatty acid that can be derived from the microbial degradation of chlorophyll in ruminant guts. Humans who accumulate large stores of phytanic acid commonly develop cerebellar ataxia, peripheral polyneuropathy, and retinitis pigmentosa in addition to other medical conditions. Furthermore, phytanic acid is an activator of the PPAR-alpha transcription factor that influences the expression of genes relevant to lipid metabolism. RESULTS: Despite their trace dietary phytanic acid intake, all great ape species had elevated red blood cell (RBC) phytanic acid levels relative to humans on diverse diets. Unlike humans, chimpanzees showed sexual dimorphism in RBC phytanic acid levels, which were higher in males relative to females. Cultured skin fibroblasts from all species had a robust capacity to degrade phytanic acid. We provide indirect evidence that great apes, in contrast to humans, derive significant amounts of phytanic acid from the hindgut fermentation of plant materials. This would represent a novel reduction of metabolic activity in humans relative to the great apes. CONCLUSION: We identified differences in the physiological levels of phytanic acid in humans and great apes and propose this is causally related to their gut anatomies and microbiomes. Phytanic acid levels could contribute to cross-species and sex-specific differences in human and great ape transcriptomes, especially those related to lipid metabolism. Based on the medical conditions caused by phytanic acid accumulation, we suggest that differences in phytanic acid metabolism could influence the functions of human and great ape nervous, cardiovascular, and skeletal systems.

Feasibility of a Telemedicine-Administered, Pharmacist-Staffed, Protocol-Driven, Multicenter Program for Kidney Stone Prevention in a Large Integrated Health Care System: Results of a Pilot Program.

INTRODUCTION: Despite guidelines for prevention of recurrent renal calculi, routine dietary modification and metabolic evaluation are often not performed. OBJECTIVE: To determine feasibility of a multicenter, pharmacist-staffed program to enroll patients at high risk of recurrent kidney stones and provide dietary instruction, metabolic evaluation, and medical therapy via telemedicine. METHODS: A total of 536 consecutive adult patients were referred from 3 Northern California Kaiser Permanente facilities. We determined the proportion of patients who enrolled, received dietary counseling, and completed metabolic evaluation at 12 months. The program was staffed by a clinical pharmacist and supervised by urologists following a protocol based on the American Urological Association guidelines. Patients were contacted entirely via telemedicine. Cystine or struvite kidney stones, renal tubular acidosis, and primary hyperoxaluria were exclusion criteria. RESULTS: Of the 536 patients, 500 agreed to enrollment. Among patients enrolled for 3 months, 99% self-reported compliance with at least 3 of 5 aspects of dietary advice. A complete metabolic evaluation including 24-hour urine collection was performed in 80% of patients by 12 months. A significant improvement in all urinary parameters occurred in 52 patients with calcium stones who repeated 24-hour urine testing. The 12-month dropout rate was 12.4%. CONCLUSION: A telemedicine-administered, pharmacist-staffed, protocol-driven program can provide dietary advice and obtain compliance with metabolic testing for patients at high risk of recurrent kidney stones. Rates of metabolic testing and dropout compare favorably with previously reported rates. This report represents, to our knowledge, the first telemedicine-administered, pharmacist-staffed, kidney stone prevention program published in the literature.

mtDNA depletion confers specific gene expression profiles in human cells grown in culture and in xenograft.

BACKGROUND: Interactions between the gene products encoded by the mitochondrial and nuclear genomes play critical roles in eukaryotic cellular function. However, the effects mitochondrial DNA (mtDNA) levels have on the nuclear transcriptome have not been defined under physiological conditions. In order to address this issue, we characterized the gene expression profiles of A549 lung cancer cells and their mtDNA-depleted rho0 counterparts grown in culture and as tumor xenografts in immune-deficient mice. RESULTS: Cultured A549 rho0 cells were respiration-deficient and showed enhanced levels of transcripts relevant to metal homeostasis, initiation of the epithelial-mesenchymal transition, and glucuronidation pathways. Several well-established HIF-regulated transcripts showed increased or decreased abundance relative to the parental cell line. Furthermore, growth in culture versus xenograft has a significantly greater influence on expression profiles, including transcripts involved in mitochondrial structure and both aerobic and anaerobic energy metabolism. However, both in vitro and in vivo, mtDNA levels explained the majority of the variance observed in the expression of transcripts in glucuronidation, tRNA synthetase, and immune surveillance related pathways. mtDNA levels in A549 xenografts also affected the expression of genes, such as AMACR and PHYH, involved in peroxisomal lipid metabolic pathways. CONCLUSION: We have identified mtDNA-dependent gene expression profiles that are shared in cultured cells and in xenografts. These profiles indicate that mtDNA-depleted cells could provide informative model systems for the testing the efficacy of select classes of therapeutics, such as anti-angiogenesis agents. Furthermore, mtDNA-depleted cells grown culture and in xenografts provide a powerful means to investigate possible relationships between mitochondrial activity and gene expression profiles in normal and pathological cells.

Identifying factors associated with need for flexible ureteroscope repair: a Western Endourology STone (WEST) research consortium prospective cohort study.

Maintenance of flexible ureteroscopes can involve high costs and administrative burden. Instrument fragility necessitates eventual repair, rendering scopes inaccessible during refurbishment. We conducted a multi-institutional prospective cohort study to identify perioperative factors influencing flexible ureteroscope durability. Patients undergoing flexible ureteroscopy (URS) at six United States endourology centers were enrolled between August 2014 and June 2015. Surgeon self-reported concern and satisfaction with scope performance as well as upward and downward angles of deflection for each scope tip were measured before and after each procedure. The need for scope repair was determined by the operating surgeon at the time of the procedure and recorded. 424 URS cases using 74 flexible ureteroscopes were identified. Scope repair was required in 28 cases (6.6%) involving 26 scopes (35.1%). Upon univariate analysis, shorter patient height, absence of guidewire use, presence of a ureteral access sheath (UAS), longer procedure time, larger stone size, lithotrite type, surgeon training level, and self-reported concern were associated with scope repair. Upon multivariate analysis, UAS use (OR = 2.53, p = 0.005) and degree loss of scope upward flexion during a case (OR = 1.02, p = 0.03) increased the odds of a scope needing repair while the use of safety guidewire decreased the odds of a scope repair (OR = 0.50, p = 0.045). Lithotrite use and surgeon concern were associated with degree loss of scope upward flexion. The use of a UAS, absence of a safety guidewire, and the loss of upward ureteroscope flexion should be considered when evaluating means of optimizing reusable ureteroscope durability.

Minihelix-loop RNAs: minimal structures for aminoacylation catalysts.

We report here an in vitro selected ribozyme, KL17, which is active in charging amino acids on its own 5'-OH group. The ribozyme consists of two catalytic domains, one of which (consisting of P5/P6/L6) recognizes amino acid substrates based on the steric environment of the side chain, whereas the other recognizes an aminoacylated oligonucleotide. The secondary structure of this ambidextrous ribozyme arranges into a pseudoknot, where L6 docks onto the 3'-terminal single-stranded region. The formation of this pseudoknot structure brings the P6 region, in which the essential catalytic core is most likely embedded, into the proximity of the 5'-OH group. Our studies show that the P6-L6 domain can be separated from the main body of KL17 and the derived P6-L6 minihelix-loop RNA can act as a trans-aminoacylation catalyst. In this report, we also compare this ribozyme with an analogous aminoacylation system previously characterized in our laboratory and illuminate the similarities and differences between these catalytic systems.

Significance of Pathologic T3a Upstaging in Clinical T1 Renal Masses Undergoing Nephrectomy.

BACKGROUND: The objectives of the present study were to report the incidence of pathologic T3a upstaging in a contemporary cohort of patients with clinical stage T1 (cT1) renal tumors treated with partial or radical nephrectomy; investigate the clinical outcomes; and identify the predictors associated with pathologic upstaging. MATERIALS AND METHODS: From a single-institution, institutional review board-approved renal tumor database of 945 patients, we identified 610 patients who had undergone surgery for a cT1 renal mass. Data for 494 patients were available for analysis. Of these, 66 lesions had been pathologically upstaged to T3a after surgery and 428 had not. The oncologic follow-up data and clinical and pathologic features were recorded, and multivariable logistic regression analysis was performed to identify the risk factors for pT3a upstaging, controlling for age, gender, body mass index, and nephrectomy type. RESULTS: The cT1 tumors of 66 patients (13.3%) were upstaged to pT3a after surgery. Of these 66 patients, 44 (66.7%) had undergone partial and 22 (33.3%) radical nephrectomy. The median follow-up period was 50 months. No patient with upstaging developed recurrence, and all were disease free at their last follow-up visit. On multivariable analysis, tumor size > 4 cm (odds ratio [OR], 3.766; 95% confidence interval [CI], 1.417-10.011; P < .008), clear cell histologic features (OR, 4.461; 95% CI, 1.498-13.461; P < .007), and positive surgical margins (hazard ratio, 5.118; 95% CI, 2.088-12.547; P < .0001) were associated with upstaging. CONCLUSION: Of the cT1 lesions in 66 patients, 13% were pathologically upstaged after surgery. The patients with larger tumors, clear cell histologic features, and positive surgical margins were at the greatest risk of upstaging. However, after an intermediate follow-up period, pathologic upstaging did not appear to result in worsened oncologic outcomes.

The elementome of calcium-based urinary stones and its role in urolithiasis.

Urolithiasis affects around 10% of the US population with an increasing rate of prevalence, recurrence and penetrance. The causes for the formation of most urinary calculi remain poorly understood, but obtaining the chemical composition of these stones might help identify key aspects of this process and new targets for treatment. The majority of urinary stones are composed of calcium that is complexed in a crystalline matrix with organic and inorganic components. Surprisingly, mitigation of urolithiasis risk by altering calcium homeostasis has not been very effective. Thus, studies to identify other therapeutic stone-specific targets, using proteomics, metabolomics and microscopy techniques, have been conducted, revealing a high level of complexity. The data suggest that numerous metals other than calcium and many nonmetals are present within calculi at measurable levels and several have distinct distribution patterns. Manipulation of the levels of some of these elemental components of calcium-based stones has resulted in clinically beneficial changes in stone chemistry and rate of stone formation. The elementome--the full spectrum of elemental content--of calcium-based urinary calculi is emerging as a new concept in stone research that continues to provide important insights for improved understanding and prevention of urinary stone disease.