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"Roy, David M"
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The mutational landscape of adenoid cystic carcinoma
Timothy Chan and colleagues report exome and genome sequencing of 60 adenoid cystic carcinoma (ACC) tumor-normal pairs. They identify multiple pathways recurrently disrupted in ACC and provide evidence that
KDM6A
and
PIK3CA
are functionally relevant candidate ACC driver genes.
Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary gland cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here we determined the ACC mutational landscape and report the exome or whole-genome sequences of 60 ACC tumor-normal pairs. These analyses identified a low exonic somatic mutation rate (0.31 non-silent events per megabase) and wide mutational diversity. Notably, we found mutations in genes encoding chromatin-state regulators, such as
SMARCA2
,
CREBBP
and
KDM6A
, suggesting that there is aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to the DNA damage response and protein kinase A signaling also implicate these processes. We observed
MYB
-
NFIB
translocations and somatic mutations in
MYB
-associated genes, solidifying the role of these aberrations as critical events in ACC. Lastly, we identified recurrent mutations in the FGF-IGF-PI3K pathway (30% of tumors) that might represent new avenues for therapy. Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC.
Journal Article
Roy H. Wagner : a cinematographer's life beyond the shadows
\"Named by Kodak as among the \"100 Top Cinematographers in the World,\" Roy H. Wagner has produced some of the most striking and unique photography on American film and TV screens of the past forty years. Mentored by legendary cinematographers of Hollywood's Golden Age, Wagner has brought both a studio craftsman ethic and maverick artistic sensibility to his work that includes A Nightmare on Elm Street 3: Dream Warriors, Beauty and the Beast, Quantum Leap and House. Together with co-author Wayne Byrne, Wagner takes the reader on a candid journey from his small-town roots in the Midwest to his professional collaborations with industry figures such as John Badham, Richard Franklin, Seymour Friedman, Bill Froehlich, Peter O'Fallon, William Fraker, Diane Keaton, Dennis Maguire, Harry Stradling, Patrick Swayze, Kevin Tenney and many others\"-- Provided by publisher.
BOOK
Driver mutations of cancer epigenomes
Epigenetic alterations are associated with all aspects of cancer, from tumor initiation to cancer progression and metastasis. It is now well understood that both losses and gains of DNA methylation as well as altered chromatin organization contribute significantly to cancerassociated phenotypes. More recently, new sequencing technologies have allowed the identification of driver mutations in epigenetic regulators, providing a mechanistic link between the cancer epigenome and genetic alterations. Oncogenic activating mutations are now known to occur in a number of epigenetic modifiers (i.e. IDH1/ 2, EZH2, DNMT3A), pinpointing epigenetic pathways that are involved in tumorigenesis. Similarly, investigations into the role of inactivating mutations in chromatin modifiers (i.e. KDM6A, CREBBP/ EP300, SMARCB1) implicate many of these genes as tumor suppressors. Intriguingly, a number of neoplasms are defined by a plethora of mutations in epigenetic regulators, including renal, bladder, and adenoid cystic carcinomas. Particularly striking is the discovery of frequent histone H3.3 mutations in pediatric glioma, a particularly aggressive neoplasm that has long remained poorly understood. Cancer epigenetics is a relatively new, promising frontier with much potential for improving cancer outcomes. Already, therapies such as 5-azacytidine and decitabine have proven that targeting epigenetic alterations in cancer can lead to tangible benefits. Understanding how genetic alterations give rise to the cancer epigenome will offer new possibilities for developing better prognostic and therapeutic strategies.
Journal Article
Silvae
\"Statius' Silvae, thirty-two occasional poems, were written probably between 89 and 96 AD. Here the poet congratulates friends, consoles mourners, offers thanks, admires a monument or artistic object, and describes a memorable scene. The verse is light in touch, with a distinct pictorial quality. Statius gives us in these impromptu poems clear images of Domitian's Rome. Statius was raised in the Greek cultural milieu of the Bay of Naples, and his Greek literary education lends a sophisticated veneer to his ornamental verse. The role of the emperor and the imperial circle in determining taste is also readily apparent: the figure of the emperor Domitian permeates these poems.\"-- Publisher description.
Book
Candidate prognostic markers in breast cancer: focus on extracellular proteases and their inhibitors
The extracellular matrix (ECM) is the complex network of proteins that surrounds cells in multicellular organisms. Due to its diverse nature and composition, the ECM has a multifaceted role in both normal tissue homeostasis and pathophysiology. It provides structural support, segregates tissues from one another, and regulates intercellular communication. Furthermore, the ECM sequesters a wide range of growth factors and cytokines that may be released upon specific and well-coordinated cues. Regulation of the ECM is performed by the extracellular proteases, which are tasked with cleaving and remodeling this intricate and diverse protein matrix. Accordingly, extracellular proteases are differentially expressed in various tissue types and in many diseases such as cancer. In fact, metastatic dissemination of tumor cells requires degradation of extracellular matrices by several families of proteases, including metalloproteinases and serine proteases, among others. Extracellular proteases are emerging as strong candidate cancer biomarkers for aiding and predicting patient outcome. Not surprisingly, inhibition of these protumorigenic enzymes in animal models of metastasis has shown impressive therapeutic effects. As such, many of these proteolytic inhibitors are currently in various phases of clinical investigation. In addition to direct approaches, aberrant expression of extracellular proteases in disease states may also facilitate the selective delivery of other therapeutic or imaging agents. Herein, we outline extracellular proteases that are either bona fide or probable prognostic markers in breast cancer. Furthermore, using existing patient data and multiple robust statistical analyses, we highlight several extracellular proteases and associated inhibitors (eg, uPA, ADAMs, MMPs, TIMPs, RECK) that hold the greatest potential as clinical biomarkers. With the recent advances in high-throughput technology and targeted therapies, the incorporation of extracellular protease status in breast cancer patient management may have a profound effect on improving outcomes in this deadly disease.
Journal Article
RECK controls breast cancer metastasis by modulating a convergent, STAT3-dependent neoangiogenic switch
Metastasis is the primary cause of cancer-related death in oncology patients. A comprehensive understanding of the molecular mechanisms that cancer cells usurp to promote metastatic dissemination is critical for the development and implementation of novel diagnostic and treatment strategies. Here we show that the membrane protein RECK (Reversion-inducing cysteine-rich protein with kazal motifs) controls breast cancer metastasis by modulating a novel, non-canonical and convergent signal transducer and activator of transcription factor 3 (STAT3)-dependent angiogenic program. Neoangiogenesis and STAT3 hyperactivation are known to be fundamentally important for metastasis, but the root molecular initiators of these phenotypes are poorly understood. Our study identifies loss of RECK as a critical and previously unknown trigger for these hallmarks of metastasis. Using multiple xenograft mouse models, we comprehensively show that RECK inhibits metastasis, concomitant with a suppression of neoangiogenesis at secondary sites, while leaving primary tumor growth unaffected. Further, with functional genomics and biochemical dissection we demonstrate that RECK controls this angiogenic rheostat through a novel complex with cell surface receptors to regulate STAT3 activation, cytokine signaling, and the induction of both vascular endothelial growth factor and urokinase plasminogen activator. In accordance with these findings, inhibition of STAT3 can rescue this phenotype both
in vitro
and
in vivo
. Taken together, our study uncovers, for the first time, that RECK is a novel regulator of multiple well-established and robust mediators of metastasis; thus, RECK is a keystone protein that may be exploited in a clinical setting to target metastatic disease from multiple angles.
Journal Article
A Standardized Care Pathway Increases Optimal Dialysis Starts
To determine whether an intensive value-based care educational program that includes a standardized end-stage renal disease (ESRD) transition pathway would improve the number of optimal starts within Kidney Contracting Entities (KCEs).
Retrospective cohort study.
We recorded optimal starts, defined as the initiation of dialysis without a central venous catheter, and the initial modality type (hemodialysis vs peritoneal dialysis [PD]) in adult Medicare patients in a Comprehensive Kidney Care Contracting program. The setting was 4 KCEs within a single physician-led nephrology organization. Data were recorded each quarter (Q) during 2022. During Q1-Q2, patients and clinicians received formal instruction on the benefits of optimal starts. Starting in Q3, we implemented a standardized care pathway for patients at high risk for transition to ESRD. The proportion of optimal starts and the proportion of initial PD from Q1-Q2 vs Q3-Q4 were compared using the χ2 test.
A total of 328 study-eligible patients initiated dialysis in 2022, including 166 (50.6%) in Q1-Q2. The proportion of optimal starts increased from 42.8% (71/166) in Q1-Q2 to 58.0% (94/162) in Q3-Q4 (P = .006). The proportion of PD starts increased from 18.7% (31/166) in Q1-Q2 to 28.4% (46/162) in Q3-Q4 (P = .038).
Optimal starts are a key metric of success in value-based care models. We observed a significant increase in optimal starts and in the number of patients starting on PD after implementing a standardized ESRD transition pathway as part of an intensive value-based care educational program.
Journal Article
