Evaluating the definition and distribution of spring ephemeral wildflowers in eastern North America.

PREMISE: The herbaceous layer accounts for the majority of plant biodiversity in eastern North American forests, encompassing substantial variation in life history strategy and function. One group of early-season herbaceous understory species, colloquially referred to as spring ephemeral wildflowers, are ecologically and culturally important, but little is known about the prevalence and biogeographic patterns of the spring ephemeral strategy. METHODS: We used observations collected by the Global Biodiversity Information Facility (GBIF) to quantify the ephemerality of 559 understory forb species across eastern North America and classify them according to a continuous ephemerality index (ranging from 0 = never ephemeral to 1 = always ephemeral). We then used this information to model where ephemeral forbs were most common across the landscape with the goal of identifying geographic and environmental drivers important to their distributions and ranges. RESULTS: Only 3.4% of all understory wildflower species were spring ephemerals in all parts of their range, and 18.4% (103 species) were ephemeral in at least part of their range. Spring ephemerals peaked in absolute species richness and relative proportion at mid latitudes. CONCLUSIONS: Spring ephemeral phenology is an important shade-avoidance strategy for a large segment of the total understory species in temperate deciduous forests. In North America, the strategy is relatively most important for forest understories at mid latitudes. The definitions of spring ephemerality we provide here serve as an important ecological context for conservation priorities and to evaluate responses of this biodiverse group to future environmental change.

Improved phenological escape can help temperate tree seedlings maintain demographic performance under climate change conditions.

Phenological escape, a strategy that deciduous understory plants use to access direct light in spring by leafing out before the canopy closes, plays an important role in shaping the recruitment of temperate tree seedlings. Previous studies have investigated how climate change will alter these dynamics for herbaceous species, but there is a knowledge gap related to how woody species such as tree seedlings will be affected. Here, we modeled temperate tree seedling leaf-out phenology and canopy close phenology in response to environmental drivers and used climate change projections to forecast changes to the duration of spring phenological escape. We then used these predictions to estimate changes in annual carbon assimilation while accounting for reduced carbon assimilation rates associated with hotter and drier summers. Lastly, we applied these estimates to previously published models of seedling growth and survival to investigate the net effect on seedling demographic performance. Our models predict that temperate tree seedlings will experience improved phenological escape and, therefore, increased spring carbon assimilation under climate change conditions. However, increased summer respiration costs will offset the gains in spring under extreme climate change leading to a net loss in annual carbon assimilation and demographic performance. Furthermore, we found that annual carbon assimilation predictions depend strongly on the species of nearby canopy tree that seedlings were planted near, with all seedlings projected to assimilate less carbon (and therefore experience worse demographic performance) when planted near Quercus rubra canopy trees as opposed to Acer saccharum canopy trees. We conclude that changes to spring phenological escape will have important effects on how tree seedling recruitment is affected by climate change, with the magnitude of these effects dependent upon climate change severity and biological interactions with neighboring adults. Thus, future studies of temperate forest recruitment should account for phenological escape dynamics in their models.

Safety and early effectiveness of robot-assisted partial nephrectomy for large angiomyolipomas.

OBJECTIVE: To evaluate a multicentre series of robot-assisted partial nephrectomy (RAPN) performed for the treatment of large angiomyolipomas (AMLs). PATIENTS AND METHODS: Between 2005 and 2016, 40 patients with large or symptomatic AMLs underwent RAPN at five academic centres in the USA. Patient demographics, AML characteristics, operative and postoperative clinical outcomes were recorded and analysed. Surgical outcomes were compared between patients who underwent selective arterial embolisation (SAE) before RAPN and patients who did not undergo pre-RAPN SAE. RESULTS: The median (interquartile range [IQR]) tumour diameter was 7.2 (5-8.5) cm, and the median (IQR) nephrometry score was 9 (7-10). Six patients (15%) had a history of tuberous sclerosis and 11 (28%) had previously undergone SAE. The median (IQR) operative time and warm ischaemia time was 207 (180-231) and 22.5 (16-28) min, respectively. A non-clamping technique was used in eight (20%) patients. The median (IQR) estimated blood loss was 200 (100-245) mL, and four patients (10%) received blood transfusion postoperatively. One intraoperative complication occurred (2.5%), and seven postoperative complications occurred in six patients (15%). During a median (IQR) follow-up of 8 (1-15) months, none of the patients developed AML-related symptoms. The median estimated glomerular filtration rate preservation rate was 95%. There were no differences in operative or perioperative outcomes between patients who underwent SAE before RAPN and those who did not. CONCLUSIONS: Robot-assisted partial nephrectomy appears to be a safe primary or secondary (post-SAE) treatment for large AMLs, with a favourable perioperative morbidity profile and excellent functional preservation. Longer follow-up is required to fully evaluate therapeutic efficacy.

Nanotechnology combined therapy: tyrosine kinase-bound gold nanorod and laser thermal ablation produce a synergistic higher treatment response of renal cell carcinoma in a murine model.

OBJECTIVE: To investigate tyrosine kinase inhibitors (TKI) and gold nanorods (AuNRs) paired with photothermal ablation in a human metastatic clear cell renal cell carcinoma (RCC) mouse model. Nanoparticles have been successful as a platform for targeted drug delivery in the treatment of urological cancers. Likewise, the use of nanoparticles in photothermal tumour ablation, although early in its development, has provided promising results. Our previous in vitro studies of nanoparticles loaded with both TKI and AuNRs and activated with photothermal ablation have shown significant synergistic cell kill greater than each individual arm alone. This study is a translation of our initial findings to an in vivo model. MATERIALS AND METHODS: Immunologically naïve nude mice (athymic nude-Foxn1nu ) were injected subcutaneously bilaterally in both flanks (n = 36) with 2.5 × 106 cells of a human metastatic renal cell carcinoma cell line (RCC 786-O). Subcutaneous xenograft tumours developed into 1-cm palpable nodules. AuNRs encapsulated in human serum albumin protein (HSA) nanoparticles were synthesised with or without a TKI and injected directly into the tumour nodule. Irradiation was administered with an 808-nm light-emitting diode laser for 6 min. Mice were humanely killed 14 days after irradiation; tumours were excised, formalin fixed, paraffin embedded, and evaluated for size and the percentage of necrosis by a genitourinary pathologist. The untreated contralateral flank tumours were used as controls. RESULTS: In mice that did not receive irradiation, TKI alone yielded 4.2% tumour necrosis on the injected side and administration of HSA-AuNR-TKI alone yielded 11.1% necrosis. In the laser-ablation models, laser ablation alone yielded 62% necrosis and when paired with HSA-AuNR there was 63.4% necrosis. The combination of laser irradiation and HSA-AuNR-TKI had cell kill rate of 100%. CONCLUSIONS: In the absence of laser irradiation, TKI treatment alone or when delivered via nanoparticles produced moderate necrosis. Irradiation with and without gold particles alone also improves tumour necrosis. However, when irradiation is paired with gold particles and drug-loaded nanoparticles, the combined therapy showed the most significant and synergistic complete tumour necrosis of 100% (P < 0.05). This study illustrates the potential of combination nanotechnology as a new approach in the treatment of urological cancers.

The contrasting effects of short-term climate change on the early recruitment of tree species.

Predictions of plant responses to climate change are frequently based on organisms' presence in warmer locations, which are then assumed to reflect future performance in cooler areas. However, as plant life stages may be affected differently by environmental changes, there is little empirical evidence that this approach provides reliable estimates of short-term responses to global warming. Under this premise, we analyzed 8 years of early recruitment data, seed production and seedling establishment and survival, collected for two tree species at two latitudes. We quantified recruitment to a wide range of environmental conditions, temperature, soil moisture and light, and simulated recruitment under two forecasted climatic scenarios. Annual demographic transitions were affected by the particular conditions taking place during their onset, but the effects of similar environmental shifts differed among the recruitment stages; seed production was higher in warmer years, while seedling establishment and survival peaked during cold years. Within a species, these effects also varied between latitudes; increasing temperatures at the southern location will have stronger detrimental effects on recruitment than similar changes at the northern locations. Our simulations illustrate that warmer temperatures may increase seed production, but they will have a negative effect on establishment and survival. When the three early recruitment processes were simultaneously considered, simulations showed little change in recruitment dynamics at the northern site and a slight decrease at the southern site. It is only when we considered these three stages that we were able to assess likely changes in early recruitment under the predicted conditions.

Three-dimensional printing of surgical anatomy.

PURPOSE OF REVIEW: Over the past decade, three-dimensional printing for the medical field has been expanding rapidly throughout all of medicine. This manuscript reviews the current and potential applications for three-dimensional printing, including education, presurgical planning, surgical simulation, bioprinting, and printed surgical equipment. RECENT FINDINGS: Three-dimensional printing has proved most relevant in the fields of craniofacial, plastic, orthopedics, and especially, urologic surgery. This review focuses on several examples of how three-dimensional printing can be utilized, with emphasis on renal models for renal cell carcinoma, ureteral stents, and staghorn calculus. From an education standpoint, both patients and residents can benefit from the use of three-dimensional printed models, and even skilled surgeons report better understanding of complex procedures by using printed models. SUMMARY: Three-dimensional printing in the field of medicine is growing quickly, and will soon be incorporated into the way residents are taught and patients are educated. For surgical simulation in a variety of disease processes, this will be particularly useful for urologic surgery.

In Vitro/In Vivo Toxicity Evaluation and Quantification of Iron Oxide Nanoparticles.

Increasing biomedical applications of iron oxide nanoparticles (IONPs) in academic and commercial settings have alarmed the scientific community about the safety and assessment of toxicity profiles of IONPs. The great amount of diversity found in the cytotoxic measurements of IONPs points toward the necessity of careful characterization and quantification of IONPs. The present document discusses the major developments related to in vitro and in vivo toxicity assessment of IONPs and its relationship with the physicochemical parameters of IONPs. Major discussion is included on the current spectrophotometric and imaging based techniques used for quantifying, and studying the clearance and biodistribution of IONPs. Several invasive and non-invasive quantification techniques along with the pitfalls are discussed in detail. Finally, critical guidelines are provided to optimize the design of IONPs to minimize the toxicity.

Nanotechnology applications in urology: a review.

The objectives of this review are to discuss the current literature and summarise some of the promising areas with which nanotechnology may improve urological care. A Medline literature search was performed to elucidate all relevant studies of nanotechnology with specific attention to its application in urology. Urological applications of nanotechnology include its use in medical imaging, gene therapy, drug delivery, and photothermal ablation of tumours. In vitro and animal studies have shown initial encouraging results. Further study of nanotechnology for urological applications is warranted to bridge the gap between preclinical studies and translation into clinical practice, but nanomedicine has shown significant potential to improve urological patient care.

AR loss in prostate cancer stroma mediated by NF-κB and p38-MAPK signaling disrupts stromal morphogen production.

Androgen Receptor (AR) activity in prostate stroma is required to maintain prostate homeostasis. This is mediated through androgen-dependent induction and secretion of morphogenic factors that drive epithelial cell differentiation. However, stromal AR expression is lost in aggressive prostate cancer. The mechanisms leading to stromal AR loss and morphogen production are unknown. We identified TGFß1 and TNFα as tumor-secreted factors capable of suppressing AR mRNA and protein expression in prostate stromal fibroblasts. Pharmacological and RNAi approaches identified NF-κB as the major signaling pathway involved in suppressing AR expression by TNFα. In addition, p38α- and p38δ-MAPK were identified as suppressors of AR expression independent of TNFα. Two regions of the AR promoter were responsible for AR suppression through TNFα. FGF10 and Wnt16 were identified as androgen-induced morphogens, whose expression was lost upon TNFα treatment and enhanced upon p38-MAPK inhibition. Wnt16, through non-canonical Jnk signaling, was required for prostate basal epithelial cell survival. These findings indicate that stromal AR loss is mediated by secreted factors within the TME. We identified TNFα/TGFß as two possible factors, with TNFα mediating its effects through NF-κB or p38-MAPK to suppress AR mRNA transcription. This leads to loss of androgen-regulated stromal morphogens necessary to maintain normal epithelial homeostasis.

Neighborhood social vulnerability and disparities in time to kidney cancer surgical treatment and survival in Arizona.

BACKGROUND: Hispanics and American Indians (AI) have high kidney cancer incidence and mortality rates in Arizona. This study assessed: (1) whether racial and ethnic minority patients and patients from neighborhoods with high social vulnerability index (SVI) experience a longer time to surgery after clinical diagnosis, and (2) whether time to surgery, race and ethnicity, and SVI are associated with upstaging to pT3/pT4, disease-free survival (DFS), and overall survival (OS). METHODS: Arizona Cancer Registry (2009-2018) kidney and renal pelvis cases (n = 4592) were analyzed using logistic regression models to assess longer time to surgery and upstaging. Cox-regression hazard models were used to test DFS and OS. RESULTS: Hispanic and AI patients with T1 tumors had a longer time to surgery than non-Hispanic White patients (median time of 56, 55, and 45 days, respectively). Living in neighborhoods with high (≥75) overall SVI increased odds of a longer time to surgery for cT1a (OR 1.54, 95% CI: 1.02-2.31) and cT2 (OR 2.32, 95% CI: 1.13-4.73). Race and ethnicity were not associated with time to surgery. Among cT1a patients, a longer time to surgery increased odds of upstaging to pT3/pT4 (OR 1.95, 95% CI: 0.99-3.84). A longer time to surgery was associated with PFS (HR 1.52, 95% CI: 1.17-1.99) and OS (HR 1.63, 95% CI: 1.26-2.11). Among patients with cT2 tumor, living in high SVI neighborhoods was associated with worse OS (HR 1.66, 95% CI: 1.07-2.57). CONCLUSIONS: High social vulnerability was associated with increased time to surgery and poor survival after surgery.

Differential effects of obesity on perioperative outcomes in renal cell carcinoma patients based on race and ethnicity and neighborhood-level socioeconomic status.

Background: Obesity is a well-established risk factor of renal cell carcinoma (RCC), however the impact of obesity on surgical outcomes for racial and ethnic minority patients with RCC is unclear. This study investigated whether a higher body mass index (BMI) or obesity (BMI ≥30 kg/m2) was associated with worse perioperative outcomes and if there were heterogeneous effects based on race, ethnicity, and neighborhood-level socioeconomic factor. Methods: In this single-center cross-sectional study, medical records of patients who underwent partial or radical nephrectomy between 2010 and 2022 were retrospectively reviewed. Logistic regression analysis was performed to assess associations of BMI and perioperative outcomes [ischemia time, estimated blood loss (EBL), and length of hospital stay]. Results: A total of 432 patients, including 49.8% non-Hispanic White (NHW), 35.0% Hispanic, and 6.9% American Indian (AI) patients, were included. Median [interquartile range (IQR)] BMI was 30.2 (26.3-35.2) kg/m2, and Hispanic (31.5) and AI (32.5) patients had higher median BMI than NHW (29.1) patients (P=0.006). Median ischemia time, EBL, and length of hospital stay were 18.5 (IQR, 15.0-22.4) minutes, 150 (IQR, 75.0-300.0) mL, and 3 (IQR, 2-5) days. BMI ≥35 kg/m2 was associated with a longer ischemia time [>18.5 minutes; odds ratio (OR), 5.17; 95% confidence interval (CI): 1.81-14.76; P=0.002], and the association was stronger in NHW than Hispanic patients (BMI continuous OR, 1.13; 95% CI: 1.04-1.22; P=0.004 in NHW and OR, 1.07; 95% CI: 0.98-1.17; P=0.12 in Hispanics). Class I and II/III obese patients had over two-fold increased odds of a larger EBL (>150 mL) than patients with normal weight (OR, 2.17; 95% CI: 1.03-4.59; P=0.04 for class I and OR, 2.24; 95% CI: 1.04-4.84; P=0.04 for class II/III obese patients). This association was stronger in patients from neighborhoods with high social deprivation index (SDI) and in NHW patients (BMI ≥30 vs. <30 kg/m2, OR, 3.53; 95% CI: 1.57-7.97; P=0.002 in high SDI neighborhoods and OR, 2.38; 95% CI: 1.10-5.14; P=0.03 in NHW). BMI was not associated with a longer hospital stay. Conclusions: In this study, obesity increased likelihood of worse perioperative outcomes, and the associations varied based on race and ethnicity and neighborhood-level socioeconomic factors.

20(S)-protopanaxadiol-aglycone downregulation of the full-length and splice variants of androgen receptor.

As a public health problem, prostate cancer engenders huge economic and life-quality burden. Developing effective chemopreventive regimens to alleviate the burden remains a major challenge. Androgen signaling is vital to the development and progression of prostate cancer. Targeting androgen signaling via blocking the production of the potent ligand dihydrotestosterone has been shown to decrease prostate cancer incidence. However, the potential of increasing the incidence of high-grade prostate cancers has been a concern. Mechanisms of disease progression after the intervention may include increased expression of androgen receptor (AR) in prostate tissue and expression of the constitutively active AR splice variants (AR-Vs) lacking the ligand-binding domain. Thus, novel agents targeting the receptor, preferentially both the full-length and AR-Vs, are urgently needed. In the present study, we show that ginsenoside 20(S)-protopanaxadiol-aglycone (PPD) effectively downregulates the expression and activity of both the full-length AR and AR-Vs. The effects of PPD on AR and AR-Vs are manifested by an immediate drop in proteins followed by a reduction in transcripts, attributed to PPD induction of proteasome-mediated degradation and inhibition of the transcription of the AR gene. We further show that although PPD inhibits the growth as well as AR expression and activity in LNCaP xenograft tumors, the morphology and AR expression in normal prostates are not affected. This study is the first to show that PPD suppresses androgen signaling through downregulating both the full-length AR and AR-Vs, and provides strong rationale for further developing PPD as a promising agent for the prevention and/or treatment of prostate cancer.

Robotic partial nephrectomy: current technique and outcomes.

Over the past decade, management of the T1 renal mass has focused on nephron-sparing surgery. Robotic partial nephrectomy has played an increasing role in the technique of preserving renal function by decreasing warm ischemia time, as well as optimizing outcomes of hemorrhage and fistula. Robot-assisted partial nephrectomy is designed to provide a minimally-invasive nephron-sparing surgical option utilizing reconstructive capability, decreasing intracorporeal suturing time, technical feasibility and safety. Ultimately, its benefits are resulting in its dissemination across institutions. Articulated instrumentation and three-dimensional vision facilitate resection, collecting system reconstruction and renorrhaphy, leading to decreased warm ischemia time while preserving oncological outcomes. The aim of the present review was to present our surgical sequence and technique, as well as review the current status of robot-assisted partial nephrectomy.

Retrograde renal cooling to minimize ischemia.

OBJECTIVE: During partial nephrectomy, renal hypothermia has been shown to decrease ischemia induced renal damage which occurs from renal hilar clamping. In this study we investigate the infusion rate required to safely cool the entire renal unit in a porcine model using retrograde irrigation of iced saline via dual-lumen ureteral catheter. MATERIALS AND METHODS: Renal cortical, renal medullary, bowel and rectal temperatures during retrograde cooling in a laparoscopic porcine model were monitored in six renal units. Iced normal saline was infused at 300 cc/hour, 600 cc/hour, 1000 cc/hour and gravity (800 cc/hour) for 600 seconds with and without hilar clamping. RESULTS: Retrograde cooling with hilar clamping provided rapid medullary renal cooling and significant hypothermia of the medulla and cortex at infusion rates ≥ 600 cc/hour. With hilar clamping, cortical temperatures decreased at -0.90 C/min. reaching a threshold temperature of 26.90 C, and medullary temperatures decreased at -0.90 C/min. reaching a temperature of 26.10 C over 600 seconds on average for combined data at infusion rates = 600 cc/hour. The lowest renal temperatures were achieved with gravity infusion. Without renal hilum clamping, retrograde cooling was minimal at all infusion rates. CONCLUSIONS: Significant renal cooling by gravity infusion of iced cold saline via a duel lumen catheter with a clamped renal hilum was achieved in a porcine model. Continuous retrograde irrigation with iced saline via a two way ureteral catheter may be an effective method to induce renal hypothermia in patients undergoing robotic assisted and/or laparoscopic partial nephrectomy.

Gemcitabine as first-line therapy for high-grade non-muscle invasive bladder cancer: results from a tertiary center in the contemporary BCG-shortage era.

Background: To evaluate the safety profile and efficacy of intravesical gemcitabine as first-line adjuvant therapy for non-muscle invasive bladder cancer (NMIBC) in the setting of ongoing Bacillus Calmette-Guérin (BCG) shortage. Methods: We performed an institutional, retrospective review of patients treated with intravesical gemcitabine induction and maintenance therapy from March 2019 to October 2021. Patients with intermediate or high-risk NMIBC who were BCG-naïve or experienced a high-grade (HG) recurrence after 12 months since the last dose of BCG were included in the analysis. The primary endpoint was complete response (CR) rate at the 3-month visit. Secondary endpoints were recurrence-free survival (RFS) and assessment of adverse events. Results: A total of 33 patients were included. All had HG disease and 28 (84.8%) were BCG-naive. The median follow-up was 21.4 months (range, 4.1-39.4). Tumor stages were cTa in 39.4%, cT1 in 54.5%, and cTis in 6.1% of patients. Most patients (90.9%) were in the AUA high-risk category. The 3-month CR was 84.8%. Among patients who achieved CR with adequate follow-up, 86.9% (20/23) remained disease-free at 6 months. The 6-month and 12-month RFS were 87.2% and 76.5%, respectively. The estimated median RFS was not reached. Approximately 78.8% of patients were able to complete full induction. Common adverse events (incidence ≥10%) included dysuria and fatigue/myalgia. Conclusions: Intravesical gemcitabine for intermediate and high-risk NMIBC in areas where BCG supply is limited was safe and feasible at short-term follow-up. Larger prospective studies are needed to better ascertain the oncologic efficacy of gemcitabine.

The Invasion of Galinsoga quadriradiata into High Elevations Is Shaped by Variation in AMF Communities.

Mountain ranges have been previously suggested to act as natural barriers to plant invasion due to extreme environmental conditions. However, how arbuscular mycorrhizal fungi (AMF) affect invasion into these systems has been less explored. Here, we investigated how changes in AMF communities affect the performance of Galinsoga quadriradiata in mountain ranges. We performed a greenhouse experiment to study the impact of inoculations of AMF from different elevations on the performance and reproduction of invaders and how competition with native plants changes the effects of invader-AMF interactions. We found strong evidence for a nuanced role of AMF associations in the invasion trajectory of G. quadriradiata, with facilitative effects at low elevations and inhibitory effects at high elevations. Galinsoga quadriradiata performed best when grown with inoculum collected from the same elevation but performed worst when grown with inoculum collected from beyond its currently invaded range, suggesting that AMF communities can help deter invasion at high elevations. Finally, the invasive plants grown alone experienced negative effects from AMF, while those grown in competition experienced positive effects, regardless of the AMF source. This suggests that G. quadriradiata lowers its partnerships with AMF in stressful environments unless native plants are present, in which case it overpowers native plants to obtain AMF support during invasion. Finally, our results indicate that invader-AMF interactions can inhibit invasive range expansion at high elevations, and biotic interactions, in addition to harsh environmental conditions, make high-elevation mountain ranges natural barriers against continued invasion.

Clear cell renal cell carcinoma molecular variations in non-Hispanic White and Hispanic patients.

BACKGROUND: The United States is becoming increasingly diverse, but few molecular studies have assessed the progression of clear cell renal cell carcinoma (ccRCC) in diverse patient populations. This study examined ccRCC molecular variations in non-Hispanic White (NHW) and Hispanic patients and their effect on the association of gene expression with high-grade (Grade 3 or 4) ccRCC and overall mortality. METHODS: A total of 156 patients were included in VHL sequencing and/or TempO-Seq analysis. DESeq2 was used to identify the genes associated with high-grade ccRCC. Logistic regression analysis was performed to assess whether race and ethnicity was associated with high/moderate impact VHL somatic mutations and the ccA/ccB subtype. Cox regression analysis was performed to assess association of molecular subtype and gene expression with overall mortality. RESULTS: NHWs had moderate or high impact mutations in the VHL gene at a higher frequency than Hispanics (40.2% vs. 27.4%), while Hispanics had a higher frequency of the ccA subtype than NHWs (61.9% vs. 45.8%). ccA was more common in patients with BMI≥35 (65.2%) than in those with BMI < 25 (45.0%). There were 11 differentially expressed genes between high- and low-grade tumors. The Haptoglobin (HP) gene was most significantly overexpressed in high- compared to low-grade ccRCC in all samples (p-adj = 1.7 × 10-12 ). When stratified by subtype, the 11 genes were significantly differentially expressed in the ccB subtype, but none of them were significant after adjusting for multiple testing in ccA. Finally, patients with the ccB subtype had a significantly increased risk of overall mortality (HR 4.87; p = 0.01) compared to patients with ccA, and patients with high HP expression and ccB, had a significantly increased risk of mortality compared to those with low HP expression and ccA (HR 6.45, p = 0.04). CONCLUSION: This study reports ccRCC molecular variations in Hispanic patients who were previously underrepresented.

Targeting NEDDylation is a Novel Strategy to Attenuate Cisplatin-induced Nephrotoxicity.

Although cisplatin remains a backbone of standard-of-care chemotherapy regimens for a variety of malignancies, its use is often associated with severe dose-limiting toxicities (DLT). Notably, 30%-40% of patients treated with cisplatin-based regimens are forced to discontinue treatment after experiencing nephrotoxicity as a DLT. New approaches that simultaneously prevent renal toxicity while improving therapeutic response have the potential to make a major clinical impact for patients with multiple forms of cancer. Here, we report that pevonedistat (MLN4924), a first-in-class NEDDylation inhibitor, alleviates nephrotoxicity and synergistically enhances the efficacy of cisplatin in head and neck squamous cell carcinoma (HNSCC) models. We demonstrate that pevonedistat protects normal kidney cells from injury while enhancing the anticancer activity of cisplatin through a thioredoxin-interacting protein (TXNIP)-mediated mechanism. Cotreatment with pevonedistat and cisplatin yielded dramatic HNSCC tumor regression and long-term animal survival in 100% of treated mice. Importantly, the combination decreased nephrotoxicity induced by cisplatin monotherapy as evidenced by the blockade of kidney injury molecule-1 (KIM-1) and TXNIP expression, a reduction in collapsed glomeruli and necrotic cast formation, and inhibition of cisplatin-mediated animal weight loss. Inhibition of NEDDylation represents a novel strategy to prevent cisplatin-induced nephrotoxicity while simultaneously enhancing its anticancer activity through a redox-mediated mechanism. Significance: Cisplatin therapy is associated with significant nephrotoxicity, which limits its clinical use. Here we demonstrate that NEDDylation inhibition with pevonedistat is a novel approach to selectively prevent cisplatin-induced oxidative damage to the kidneys while simultaneously enhancing its anticancer efficacy. Clinical evaluation of the combination of pevonedistat and cisplatin is warranted.

Factors that impact the outcome of minimally invasive pyeloplasty: results of the Multi-institutional Laparoscopic and Robotic Pyeloplasty Collaborative Group.

PURPOSE: We compared laparoscopic and robotic pyeloplasty to identify factors associated with procedural efficacy. MATERIALS AND METHODS: We conducted a retrospective multicenter trial incorporating 865 cases from 15 centers. We collected perioperative data including anatomical and procedural factors. Failure was defined subjectively as pain that was unchanged or worse per medical records after surgery. Radiographic failure was defined as unchanged or worsening drainage on renal scans or worsening hydronephrosis on computerized tomography. Bivariate analyses were performed on all outcomes and multivariate analysis was used to assess factors associated with decreased freedom from secondary procedures. RESULTS: Of the cases 759 (274 laparoscopic pyeloplasties with a mean followup of 15 months and 465 robotic pyeloplasties with a mean followup of 11 months, p <0.001) had sufficient data. Laparoscopic pyeloplasty, previous endopyelotomy and intraoperative crossing vessels were associated with decreased freedom from secondary procedures on bivariate analysis, with a 2-year freedom from secondary procedures of 87% for laparoscopic pyeloplasty vs 95% for robotic pyeloplasty, 81% vs 93% for patients with vs without previous endopyelotomy and 88% vs 95% for patients with vs without intraoperative crossing vessels, respectively. However, on multivariate analysis only previous endopyelotomy (HR 4.35) and intraoperative crossing vessels (HR 2.73) significantly impacted freedom from secondary procedures. CONCLUSIONS: Laparoscopic and robotic pyeloplasty are highly effective in treating ureteropelvic junction obstruction. There was no difference in their abilities to render the patient free from secondary procedures on multivariate analysis. Previous endopyelotomy and intraoperative crossing vessels reduced freedom from secondary procedures.