PBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth.

p53 acetylation is indispensable for its transcriptional activity and tumor suppressive function. However, the identity of reader protein(s) for p53 acetylation remains elusive. PBRM1, the second most highly mutated tumor suppressor gene in kidney cancer, encodes PBRM1. Here, we identify PBRM1 as a reader for p53 acetylation on lysine 382 (K382Ac) through its bromodomain 4 (BD4). Notably, mutations on key residues of BD4 disrupt recognition of p53 K382Ac. The mutation in BD4 also reduces p53 binding to promoters of target genes such as CDKN1A (p21). Consequently, the PBRM1 BD4 mutant fails to fully support p53 transcriptional activity and is defective as a tumor suppressor. We also find that expressions of PBRM1 and p21 correlate with each other in human kidney cancer samples. Our findings uncover a tumor suppressive mechanism of PBRM1 in kidney cancer and provide a mechanistic insight into the crosstalk between p53 and SWI/SNF complexes

Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer.

Whereas VHL inactivation is a primary event in clear cell renal cell carcinoma (ccRCC), the precise mechanism(s) of how this interacts with the secondary mutations in tumor suppressor genes, including PBRM1, KDM5C/JARID1C, SETD2, and/or BAP1, remains unclear. Gene expression analyses reveal that VHL, PBRM1, or KDM5C share a common regulation of interferon response expression signature. Loss of HIF2α, PBRM1, or KDM5C in VHL-/-cells reduces the expression of interferon stimulated gene factor 3 (ISGF3), a transcription factor that regulates the interferon signature. Moreover, loss of SETD2 or BAP1 also reduces the ISGF3 level. Finally, ISGF3 is strongly tumor-suppressive in a xenograft model as its loss significantly enhances tumor growth. Conversely, reactivation of ISGF3 retards tumor growth by PBRM1-deficient ccRCC cells. Thus after VHL inactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in ccRCC. © 2018, Liao et al

A Literature Review of Renal Surgical Anatomy and Surgical Strategies for Partial Nephrectomy

CONTEXT: A detailed understanding of renal surgical anatomy is necessary to optimize preoperative planning and operative technique and provide a basis for improved outcomes. OBJECTIVE: To evaluate the literature regarding pertinent surgical anatomy of the kidney and related structures, nephrometry scoring systems, and current surgical strategies for partial nephrectomy (PN). EVIDENCE ACQUISITION: A literature review was conducted. EVIDENCE SYNTHESIS: Surgical renal anatomy fundamentally impacts PN surgery. The renal artery divides into anterior and posterior divisions, from which approximately five segmental terminal arteries originate. The renal veins are not terminal. Variations in the vascular and lymphatic channels are common; thus, concurrent lymphadenectomy is not routinely indicated during PN for cT1 renal masses in the setting of clinically negative lymph nodes. Renal-protocol contrast-enhanced computed tomography or magnetic resonance imaging is used for standard imaging. Anatomy-based nephrometry scoring systems allow standardized academic reporting of tumor characteristics and predict PN outcomes (complications, remnant function, possibly histology). Anatomy-based novel surgical approaches may reduce ischemic time during PN; these include early unclamping, segmental clamping, tumor-specific clamping (zero ischemia), and unclamped PN. Cancer cure after PN relies on complete resection, which can be achieved by thin margins. Post-PN renal function is impacted by kidney quality, remnant quantity, and ischemia type and duration. CONCLUSIONS: Surgical renal anatomy underpins imaging, nephrometry scoring systems, and vascular control techniques that reduce global renal ischemia and may impact post-PN function. A contemporary ideal PN excises the tumor with a thin negative margin, delicately secures the tumor bed to maximize vascularized remnant parenchyma, and minimizes global ischemia to the renal remnant with minimal complications. PATIENT SUMMARY: In this report we review renal surgical anatomy. Renal mass imaging allows detailed delineation of the anatomy and vasculature and permits nephrometry scoring, and thus precise, patient-specific surgical planning. Novel off-clamp techniques have been developed that may lead to improved outcomes

“I luoghi di Mercalli”: a travelling exhibition as a tool for scientists to dialogue with the public on volcanoes and earthquakes

On March 19, 1914 Giuseppe Mercalli, a seismologist and volcanologist, well-known around the world for the Intensity scale of earthquakes bearing his name, died tragically. A hundred years after, the Istituto Nazionale di Geofisica e Vulcanologia (INGV) has promoted a variety of activities and cultural events that will take place under the Patronage of the President of the Italian Republic within a year, the so called “Anno Mercalliano” (the Year of Mercalli). The opening ceremony took place in Naples, Italy, on March 19, 2014, in the Convitto Nazionale Vittorio Emanuele II. A scientific conference was held with the participation of experts from INGV and the university of Milano – Bicocca, and presentations of students. On that day the exhibition entitled “I luoghi di Mercalli” (Mercalli's places) was also inaugurated, at the presence of local authorities. The exhibition, organized by INGV, was realized in collaboration with the high school Vittorio Emanuele II, where Mercalli has been teaching for 19 years, and the Università degli Studi Suor Orsola Benincasa, where he was professor of natural sciences. A biographical and geographical description of the places where Mercalli operated introduces the exhibition, which is organized in sections: - Mercalli educator (he taught at high schools in Reggio Calabria and Naples); - Mercalli volcanologist (Mercalli studied Vesuvius volcanic activity for more than twenty years, he was a scientific witness of the Vesuvius 1906 eruption, and of the eruptions occurred at Vulcano (1888-90) and Stromboli (1891) islands. - Mercalli seismologist (Mercalli Intensity scale definition, based on his experience as witness of catastrophic earthquakes, such as Casamicciola in 1883 and Messina in 1908). Another section deals with the Vesuvius Observatory, directed by Mercalli between 1911 and 1914, and the description of the three active volcanoes of the Campania region (Vesuvius, Campi Flegrei and Ischia island), which have been the subject of studies by the well-known scientist. The exhibition is enriched by documents, manuscripts, photos and field notebooks of Mercalli. It is not intended to be only a celebratory exhibition; rather it is designed as a tool for dissemination of scientific culture and to raise awareness about seismic and volcanic hazards. In the exhibition path a continuous thread between the figure of Mercalli as a researcher and the role of an Earth Science researcher today is highlighted, pointing to the development of scientific knowledge in the past century. The goal is to improve the capability of learning from the disasters occurred in the past to implement preventive actions to safely deal with future events. The exhibition is travelling and will be provided on request to institutions and schools.PublishedMilano, Italia1V. Storia e struttura dei sistemi vulcaniciope

Outcomes and predictors of benign histology in patients undergoing robotic partial or radical nephrectomy for renal masses: A multicenter study

Introduction Theaim of this study was to assess preoperative factors associated with benign histology in patients undergoing surgical removal of a renal mass and to analyze outcomes of robotic partial nephrectomy (PN) and radical nephrectomy (RN) for these masses. Material and methods Overall, 2,944 cases (543 benign and 2,401 malignant) who underwent robotic PN and RN between 2003–2018 at 10 institutions worldwide were included. The assessment of the predictors of benign histology was made at the final surgical pathology report. Descriptive statistics, Mann-Whitney U, Pearson’s χ2, and logistic regression analysis were used. Results Patients in the benign group were mostly female (61 vs. 33%; p <0.001), with lower body mass index (BMI) (26.0 vs. 27.1 kg/m2; p <0.001). The benign group presented smaller tumor size (2.8 vs. 3.5 cm; p <0.001), R.E.N.A.L. score (6.0 vs. 7.0; p <0.001). There was a lower rate of hilar (11 vs.18%; p = 0.001), cT≥3 (1 vs. 4.5%; p <0.001) tumors in the benign group. There was a statistically significant higher rate of PN in the benign group (97 vs. 86%; p <0.001) as well as a statistically significant lower 30-day re-admission rate (2 vs. 5%; p = 0.081). Multivariable analysis showed male gender (OR: 0.52; p <0.001), BMI (OR: 0.95; p <0.001), and cT3a (OR: 0.22; p = 0.005) to be inversely associated to benign histology. Conclusions In 18% of cases, a benign histologic type was found. Only 3% of these tumors were treated with RN. Female gender, lower BMI, and higher T staging showed to be independent predictors of benign histology

Активное наблюдение опухолей почки, накапливающих рентгеноконтрастное вещество

Introduction: Prompt surgical excision remains the standard of care for clinically localized enhancing renal tumors, for this reason the natural history of untreated renal cell carcinoma (RCC) has not been established. In order to increase our understanding of the natural history of RCC we reviewed our experience with the active surveillance of enhancing renal tumors.Methods: We reviewed our renal cancer database for enhancing renal masses that were radiographically observed for a period of at least 12 months. Variables examined included patient age, gender, lesion size on presentation, radiographic tumor characteristics, duration of active surveillance, linear tumor growth rate, incidence, type of surgical intervention, and surgical pathology.Results: 109 patients with 124 sporadic enhancing renal tumors were identified undergoing a period of active surveillance of at least 12 months. Mean patient age was 69.8 years (median 73, range 35—87). Mean duration of active surveillance was 33.4 months (median 26, range 12—156). Multifocal disease was present in 9% (10/109) patients on presentation. Tumor size on presentation was a mean of 2.61 cm (median 2.0, range 0.4—12.0). Overall mean tumor growth rate was 0.28 cm/yr (median 0.21, range -1.4—2.47). Observed linear growth rates were independent of patient age, gender, tumor size on presentation, and radiographic characteristics (solid versus cystic), p &gt; 0.05. Of the patients initiating a period of active surveillance 36% (39/109) eventually underwent definitive therapy. Extirpative and ablative therapies were used in 72% (28/39) and 28% (11/39) of the patients undergoing surgical intervention, respectively. Malignant pathology was present in 90% (35/39) of the patients undergoing treatment. Of the malignant tumors evaluated, 68% were clear cell RCC.Conclusions: Our current series reveals that the majority of small enhancing renal tumors show a slow interval growth and they are malignant. The investigation and development of clinical and radiographic predictors of future tumor growth would be of great benefit in order to avoid unnecessary intervention in selected patients.

Preventing Prostate Biopsy Complications: to Augment or to Swab?

Aims for Improvement The aim of this study was to determine the antibiotic prophylaxis associated with the fewest infectious complications following prostate biopsy Determining the safest method allows the Jefferson Department of Urology to modify its biopsy protocol and improve the rate of post-biopsy complication

The Science of Sungrazers, Sunskirters, and Other Near-Sun Comets

This review addresses our current understanding of comets that venture close to the Sun, and are hence exposed to much more extreme conditions than comets that are typically studied from Earth. The extreme solar heating and plasma environments that these objects encounter change many aspects of their behaviour, thus yielding valuable information on both the comets themselves that complements other data we have on primitive solar system bodies, as well as on the near-solar environment which they traverse. We propose clear definitions for these comets: We use the term near-Sun comets to encompass all objects that pass sunward of the perihelion distance of planet Mercury (0.307 AU). Sunskirters are defined as objects that pass within 33 solar radii of the Sun’s centre, equal to half of Mercury’s perihelion distance, and the commonly-used phrase sungrazers to be objects that reach perihelion within 3.45 solar radii, i.e. the fluid Roche limit. Finally, comets with orbits that intersect the solar photosphere are termed sundivers. We summarize past studies of these objects, as well as the instruments and facilities used to study them, including space-based platforms that have led to a recent revolution in the quantity and quality of relevant observations. Relevant comet populations are described, including the Kreutz, Marsden, Kracht, and Meyer groups, near-Sun asteroids, and a brief discussion of their origins. The importance of light curves and the clues they provide on cometary composition are emphasized, together with what information has been gleaned about nucleus parameters, including the sizes and masses of objects and their families, and their tensile strengths. The physical processes occurring at these objects are considered in some detail, including the disruption of nuclei, sublimation, and ionisation, and we consider the mass, momentum, and energy loss of comets in the corona and those that venture to lower altitudes. The different components of comae and tails are described, including dust, neutral and ionised gases, their chemical reactions, and their contributions to the near-Sun environment. Comet-solar wind interactions are discussed, including the use of comets as probes of solar wind and coronal conditions in their vicinities. We address the relevance of work on comets near the Sun to similar objects orbiting other stars, and conclude with a discussion of future directions for the field and the planned ground- and space-based facilities that will allow us to address those science topics

Elevated Expression of Stromal Palladin Predicts Poor Clinical Outcome in Renal Cell Carcinoma

The role that stromal renal cell carcinoma (RCC) plays in support of tumor progression is unclear. Here we sought to determine the predictive value on patient survival of several markers of stromal activation and the feasibility of a fibroblast-derived extracellular matrix (ECM) based three-dimensional (3D) culture stemming from clinical specimens to recapitulate stromal behavior in vitro. The clinical relevance of selected stromal markers was assessed using a well annotated tumor microarray where stromal-marker levels of expression were evaluated and compared to patient outcomes. Also, an in vitro 3D system derived from fibroblasts harvested from patient matched normal kidney, primary RCC and metastatic tumors was employed to evaluate levels and localizations of known stromal markers such as the actin binding proteins palladin, alpha-smooth muscle actin (α-SMA), fibronectin and its spliced form EDA. Results suggested that RCCs exhibiting high levels of stromal palladin correlate with a poor prognosis, as demonstrated by overall survival time. Conversely, cases of RCCs where stroma presents low levels of palladin expression indicate increased survival times and, hence, better outcomes. Fibroblast-derived 3D cultures, which facilitate the categorization of stromal RCCs into discrete progressive stromal stages, also show increased levels of expression and stress fiber localization of α-SMA and palladin, as well as topographical organization of fibronectin and its splice variant EDA. These observations are concordant with expression levels of these markers in vivo. The study proposes that palladin constitutes a useful marker of poor prognosis in non-metastatic RCCs, while in vitro 3D cultures accurately represent the specific patient's tumor-associated stromal compartment. Our observations support the belief that stromal palladin assessments have clinical relevance thus validating the use of these 3D cultures to study both progressive RCC-associated stroma and stroma-dependent mechanisms affecting tumorigenesis. The clinical value of assessing RCC stromal activation merits further study