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"Randall, Michael"
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Molecular aberrations, targeted therapy, and renal cell carcinoma: current state-of-the-art
Renal cell carcinoma (RCC) is among the most prevalent malignancies in the USA. Most RCCs are sporadic, but hereditary syndromes associated with RCC account for 2–3 % of cases and include von Hippel-Lindau, hereditary leiomyomatosis, Birt-Hogg-Dube, tuberous sclerosis, hereditary papillary RCC, and familial renal carcinoma. In the past decade, our understanding of the genetic mutations associated with sporadic forms of RCC has increased considerably, with the most common mutations in clear cell RCC seen in the
VHL
,
PBRM1
,
BAP1
, and
SETD2
genes. Among these,
BAP1
mutations are associated with aggressive disease and decreased survival. Several targeted therapies for advanced RCC have been approved and include sunitinib, sorafenib, pazopanib, axitinib (tyrosine kinase inhibitors (TKIs) with anti-vascular endothelial growth factor (VEGFR) activity), everolimus, and temsirolimus (TKIs that inhibit mTORC1, the downstream part of the PI3K/AKT/mTOR pathway). High-dose interleukin 2 (IL-2) immunotherapy and the combination of bevacizumab plus interferon-α are also approved treatments. At present, there are no predictive genetic markers to direct therapy for RCC, perhaps because the vast majority of trials have been evaluated in unselected patient populations, with advanced metastatic disease. This review will focus on our current understanding of the molecular genetics of RCC, and how this may inform therapeutics.
Journal Article
Stardust International Raceway : motorsports meets the mob in Vegas, 1965-1971
\"Established by a notorious racketeer, the track stood at the confluence of shadowy elements--secret wiretaps, casino skimming, Howard Hughes, and the beginnings of Watergate. The author traces the Stardust's colorful history through the auto racing monthlies, national newspapers and the files of the FBI\"-- Provided by publisher.
Book
Axin phosphorylation in both Wnt-off and Wnt-on states requires the tumor suppressor APC
The aberrant activation of Wnt signal transduction initiates the development of 90% of colorectal cancers, the majority of which arise from inactivation of the tumor suppressor Adenomatous polyposis coli (APC). In the classical model for Wnt signaling, the primary role of APC is to act, together with the concentration-limiting scaffold protein Axin, in a \"destruction complex\" that directs the phosphorylation and consequent proteasomal degradation of the transcriptional activator β-catenin, thereby preventing signaling in the Wnt-off state. Following Wnt stimulation, Axin is recruited to a multiprotein \"signalosome\" required for pathway activation. Whereas it is well-documented that APC is essential in the destruction complex, APC's role in this complex remains elusive. Here, we demonstrate in Drosophila that Axin exists in two distinct phosphorylation states in Wnt-off and Wnt-on conditions, respectively, that underlie its roles in the destruction complex and signalosome. These two Axin phosphorylation states are catalyzed by glycogen synthase kinase 3 (GSK3), and unexpectedly, completely dependent on APC in both unstimulated and Wnt-stimulated conditions. In a major revision of the classical model, we show that APC is essential not only in the destruction complex, but also for the rapid transition in Axin that occurs after Wnt stimulation and Axin's subsequent association with the Wnt co-receptor LRP6/Arrow, one of the earliest steps in pathway activation. We propose that this novel requirement for APC in Axin regulation through phosphorylation both prevents signaling in the Wnt-off state and promotes signaling immediately following Wnt stimulation.
Journal Article
هل للرأسمالية مستقبل ؟
الرأسمالية ليست موقعا محسوما أو منطقة مالية يمكن أن تحكم جماهير ثائرة سيطرتها عليها أو يمكن مواجهتها حتى بمظاهرات تحمل شعارات مثالية. ولا هي مجرد مجموعة من السياسات \"المحكمة \" التي يمكن تبنيها وتصحيحها (كما تدعي افتتاحيات صحف الأعمال). بل على العكس تماماً الرأسمالية هي وهم إيديولوجي قديم للكثير من الليبيراليين والماركسيين تعرف ببساطة على أنها ما يساوي العمالة مقابل الأجر في اقتصاد السوق ؛ لقد كان هذا هو التعريف الأساسي الذي اعتقدت جميع تلك الأطراف بصحته خلال القرن العشرين ونحن اليوم نتعامل مع تبعات نشأة الرأسمالية، كما أن التنسيق الاجتماعي من خلال الأسواق سيستمر بكل تأكيد حتى ولو لم يعد كونه تاريخيا للأسواق وبنيويات السلطة حيث يكون الربح الاقتصادي الخاص بأي وسيلة تشكيلا محددا ممكنة هو الغاية العليا والمقياس الأمثل للنجاح. فإذا اعتمدنا هذا التعريف للرأسمالية يمكن لنا التوصل إلى تنظيم مختلف ومرض بشكل أكبر للمجتمع الإنساني.
Book
Genetic susceptibility to neuroblastoma: current knowledge and future directions
Neuroblastoma, a malignancy of the developing peripheral nervous system that affects infants and young children, is a complex genetic disease. Over the past two decades, significant progress has been made toward understanding the genetic determinants that predispose to this often lethal childhood cancer. Approximately 1–2% of neuroblastomas are inherited in an autosomal dominant fashion and a combination of co-morbidity and linkage studies has led to the identification of germline mutations in PHOX2B and ALK as the major genetic contributors to this familial neuroblastoma subset. The genetic basis of “sporadic” neuroblastoma is being studied through a large genome-wide association study (GWAS). These efforts have led to the discovery of many common susceptibility alleles, each with modest effect size, associated with the development and progression of sporadic neuroblastoma. More recently, next-generation sequencing efforts have expanded the list of potential neuroblastoma-predisposing mutations to include rare germline variants with a predicted larger effect size. The evolving characterization of neuroblastoma’s genetic basis has led to a deeper understanding of the molecular events driving tumorigenesis, more precise risk stratification and prognostics and novel therapeutic strategies. This review details the contemporary understanding of neuroblastoma’s genetic predisposition, including recent advances and discusses ongoing efforts to address gaps in our knowledge regarding this malignancy’s complex genetic underpinnings.
Journal Article
Wnt pathway activation by ADP-ribosylation
Wnt/β-catenin signalling directs fundamental processes during metazoan development and can be aberrantly activated in cancer. Wnt stimulation induces the recruitment of the scaffold protein Axin from an inhibitory destruction complex to a stimulatory signalosome. Here we analyse the early effects of Wnt on Axin and find that the ADP-ribose polymerase Tankyrase (Tnks)—known to target Axin for proteolysis—regulates Axin’s rapid transition following Wnt stimulation. We demonstrate that the pool of ADP-ribosylated Axin, which is degraded under basal conditions, increases immediately following Wnt stimulation in both
Drosophila
and human cells. ADP-ribosylation of Axin enhances its interaction with the Wnt co-receptor LRP6, an essential step in signalosome assembly. We suggest that in addition to controlling Axin levels, Tnks-dependent ADP-ribosylation promotes the reprogramming of Axin following Wnt stimulation; and propose that Tnks inhibition blocks Wnt signalling not only by increasing destruction complex activity, but also by impeding signalosome assembly.
Wnt/β-catenin signalling directs several developmental processes and is aberrantly activated in several cancers. Here the authors implicate Tankyrase—previously shown to target the scaffolding protein Axin for proteolysis—in early Wnt signalling by promoting the interaction between Axin and the Wnt co-receptor LRP6.
Journal Article
The Simons Observatory: Detector Polarization Angle Calibration Using a Sparse Wire Grid with Initial Datasets of the Small-aperture Telescopes
Improved measurements of B-modes in the cosmic microwave background can be obtained through accurate calibration of the orientation of detector antennas as projected onto the sky. Miscalibration of the detector polarization angle leads to a leakage of E-modes into B-modes, which can bias the detection of the latter. To achieve a σ(r) of 0.003, the Simons Observatory small-aperture telescopes are required to calibrate the global polarization angle on the sky with an accuracy ≲0 .° 1. We demonstrate a fully remote-controllable calibration system using a “sparse wire grid,” which injects a rotatable linear polarized signal across the telescope’s focal plane. This calibration system is installed and operational on one of the small-aperture telescopes at its observing site at the Parque Astronómico in the Atacama desert in Chile. We developed a pipeline for the detector polarization angle calibration, and demonstrate it using initial data for 93 and 145 GHz frequency bands. The observed distribution of detector polarization angles is in agreement with the instrument design. Statistical uncertainties for the relatively calibrated polarization angles are 0 .° 02 and 0 .° 03 at 93 and 145 GHz, respectively. Systematic uncertainty was evaluated to be 0 .° 08 at the hardware development and fabrication stage. Their sum in quadrature is less than 0 .° 1.
Journal Article
In Vivo Cannabidiol Treatment Improves Endothelium-Dependent Vasorelaxation in Mesenteric Arteries of Zucker Diabetic Fatty Rats
We have shown that
treatment with cannabidiol (CBD, 2 h) enhances endothelial function in arteries from Zucker diabetic fatty (ZDF) rats, partly due to a cyclooxygenase (COX)-mediated mechanism. The aim of the present study was to determine whether treatment with CBD
would also enhance endothelial function.
Male ZDF rats, or ZDF Lean rats, were treated for 7 days (daily i.p. injection) with either 10mg/kg CBD or vehicle (
= 6 per group). Sections of mesenteric resistance arteries, femoral arteries and thoracic aortae were mounted on a wire myograph, and cumulative concentration-response curves to endothelium-dependent (acetylcholine, ACh, 1 nM-100 μM) or endothelium-independent (sodium nitroprusside, SNP, 1 nM-100 μM) agents were constructed. Multiplex analysis was used to measure serum metabolic and cardiovascular biomarkers.
Vasorelaxation to ACh was significantly enhanced in mesenteric arteries from CBD-treated ZDF rats, but not ZDF Lean rats. The enhanced vasorelaxation in ZDF mesenteric arteries was no longer observed after COX inhibition using indomethacin or nitric oxide (NO) inhibition using L-NAME. Increased levels of serum c-peptide, insulin and intracellular adhesion molecule-1 observed in the ZDF compared to ZDF Lean rats were no longer significant after 7 days CBD treatment.
Short-term
treatment with CBD improves
endothelium-dependent vasorelaxation in mesenteric arteries from ZDF rats due to COX- or NO-mediated mechanisms, and leads to improvements in serum biomarkers.
Journal Article