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A world of information
Facts and figures for the curious reader. Covers more than 30 fascinating \"general knowledge\" topics, including shapes, tides, the solar system, and the periodic table.
Book
Multiple renal cancer susceptibility polymorphisms modulate the HIF pathway
Un-physiological activation of hypoxia inducible factor (HIF) is an early event in most renal cell cancers (RCC) following inactivation of the von Hippel-Lindau tumor suppressor. Despite intense study, how this impinges on cancer development is incompletely understood. To test for the impact of genetic signals on this pathway, we aligned human RCC-susceptibility polymorphisms with genome-wide assays of HIF-binding and observed highly significant overlap. Allele-specific assays of HIF binding, chromatin conformation and gene expression together with eQTL analyses in human tumors were applied to mechanistic analysis of one such overlapping site at chromosome 12p12.1. This defined a novel stage-specific mechanism in which the risk polymorphism, rs12814794, directly creates a new HIF-binding site that mediates HIF-1α isoform specific upregulation of its target BHLHE41. The alignment of multiple sites in the HIF cis-acting apparatus with RCC-susceptibility polymorphisms strongly supports a causal model in which minor variation in this pathway exerts significant effects on RCC development.
Journal Article
Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma
Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC protooncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.
Journal Article
Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer
Clear cell renal cell carcinoma (ccRCC) is characterized by loss of function of the von Hippel–Lindau tumour suppressor (VHL) and unrestrained activation of hypoxia-inducible transcription factors (HIFs). Genetic and epigenetic determinants have an impact on HIF pathways. A recent genome-wide association study on renal cancer susceptibility identified single-nucleotide polymorphisms (SNPs) in an intergenic region located between the oncogenes
MYC
and
PVT1
. Here using assays of chromatin conformation, allele-specific chromatin immunoprecipitation and genome editing, we show that HIF binding to this regulatory element is necessary to
trans
-activate
MYC
and
PVT1
expression specifically in cells of renal tubular origins. Moreover, we demonstrate that the risk-associated polymorphisms increase chromatin accessibility and activity as well as HIF binding to the enhancer. These findings provide further evidence that genetic variation at HIF-binding sites modulates the oncogenic transcriptional output of the VHL–HIF axis and provide a functional explanation for the disease-associated effects of SNPs in ccRCC.
Genome-wide association studies have identified multiple loci associated with the risk of developing renal cancer. Here, the authors show that one of these loci generates open chromatin, which enhances the binding of HIF and HIF-mediated transactivation of
MYC
.
Journal Article
Locked compression plating versus retrograde intramedullary nailing in the treatment of periprosthetic supracondylar knee fractures: a systematic review and meta-analysis
Background
Periprosthetic fractures of the distal femur above a total knee arthroplasty (TKA) have traditionally been managed by locking compression plating (LCP). This technique is technically demanding and is associated with high rates of non-union and revision. More recently, retrograde intramedullary nailing (RIMN) has been proposed as an acceptable alternative. This meta-analysis aims to evaluate clinical outcomes in patients with periprosthetic supracondylar femoral fractures who were treated with LCP and RIMN.
Methods
An up-to-date literature search was carried out using the pre-defined search strategy. All studies that met the inclusion criteria were assessed for methodological quality with the Cochrane’s collaboration tool. Operative time, functional score, time-to-union, non-union rates and revision rates were all considered.
Conclusion
Ten studies with a total of 531 periprosthetic fractures were included. This meta-analysis has suggested that there is no significant difference in any of the outcome measures assessed. Further, more extensive literature is required on the subject to draw more robust conclusions.
Journal Article
A Computational Approach for Identifying Synergistic Drug Combinations
A promising alternative to address the problem of acquired drug resistance is to rely on combination therapies. Identification of the right combinations is often accomplished through trial and error, a labor and resource intensive process whose scale quickly escalates as more drugs can be combined. To address this problem, we present a broad computational approach for predicting synergistic combinations using easily obtainable single drug efficacy, no detailed mechanistic understanding of drug function, and limited drug combination testing. When applied to mutant BRAF melanoma, we found that our approach exhibited significant predictive power. Additionally, we validated previously untested synergy predictions involving anticancer molecules. As additional large combinatorial screens become available, this methodology could prove to be impactful for identification of drug synergy in context of other types of cancers.
Journal Article
Measuring the Effectiveness of Conservation: A Novel Framework to Quantify the Benefits of Sage-Grouse Conservation Policy and Easements in Wyoming
Increasing energy and housing demands are impacting wildlife populations throughout western North America. Greater sage-grouse (Centrocercus urophasianus), a species known for its sensitivity to landscape-scale disturbance, inhabits the same low elevation sage-steppe in which much of this development is occurring. Wyoming has committed to maintain sage-grouse populations through conservation easements and policy changes that conserves high bird abundance \"core\" habitat and encourages development in less sensitive landscapes. In this study, we built new predictive models of oil and gas, wind, and residential development and applied build-out scenarios to simulate future development and measure the efficacy of conservation actions for maintaining sage-grouse populations. Our approach predicts sage-grouse population losses averted through conservation action and quantifies return on investment for different conservation strategies. We estimate that without conservation, sage-grouse populations in Wyoming will decrease under our long-term scenario by 14-29% (95% CI: 4-46%). However, a conservation strategy that includes the \"core area\" policy and $250 million in targeted easements could reduce these losses to 9-15% (95% CI: 3-32%), cutting anticipated losses by roughly half statewide and nearly two-thirds within sage-grouse core breeding areas. Core area policy is the single most important component, and targeted easements are complementary to the overall strategy. There is considerable uncertainty around the magnitude of our estimates; however, the relative benefit of different conservation scenarios remains comparable because potential biases and assumptions are consistently applied regardless of the strategy. There is early evidence based on a 40% reduction in leased hectares inside core areas that Wyoming policy is reducing potential for future fragmentation inside core areas. Our framework using build-out scenarios to anticipate species declines provides estimates that could be used by decision makers to determine if expected population losses warrant ESA listing.
Journal Article
Hunk/Mak-v is a negative regulator of intestinal cell proliferation
Background
Conditional deletion of the tumour suppressor gene
Apc
within the murine intestine results in acute Wnt signalling activation. The associated over-expression of a myriad of Wnt signalling target genes yields phenotypic alterations that encompass many of the hallmarks of neoplasia. Previous transcriptomic analysis aimed at identifying genes that potentially play an important role in this process, inferred the Hormonally upregulated Neu-associated kinase (
HUNK/Mak-v/Bstk1
) gene as a possible candidate. Hunk is a SNF1 (sucrose non fermenting 1)-related serine/threonine kinase with a proposed association with many different tumour types, including colorectal cancer.
Methods
Here we describe the generation of a novel Hunk kinase deficient mouse which has been used to investigate the involvement of Hunk-kinase activity in intestinal homeostasis and tumourigenesis.
Results
We show that in the morphologically normal intestine, Hunk-kinase negatively regulates epithelial cell proliferation. However, the increase in cell proliferation observed in the Hunk kinase deficient intestine is counteracted by increased cell migration, thereby maintaining intestinal homeostasis. Using qRT-PCR, we further demonstrate that
Hunk
is significantly over-expressed in
Apc
deficient / Wnt-signalling activated intestinal tissue. Using the classical intestinal tumourigenesis
Apc
Min
mouse model we show that loss of Hunk-kinase activity significantly reduced tumour initiation rates in the small intestine. However, an accompanying increase in the size of the tumours counteracts the impact this has on overall tumour burden or subsequently survival.
Conclusions
In the intestinal setting we demonstrate that
Hunk
has a role in normal intestinal proliferation and homeostasis and, although it does not alter overall survival rates, activity of this kinase does impact on tumour initiation rates during the early stages in tumourigenesis in the small intestine.
Journal Article
Vaccine effectiveness against COVID-19 breakthrough infections in patients with cancer (UKCCEP): a population-based test-negative case-control study
People with cancer are at increased risk of hospitalisation and death following infection with SARS-CoV-2. Therefore, we aimed to conduct one of the first evaluations of vaccine effectiveness against breakthrough SARS-CoV-2 infections in patients with cancer at a population level.
In this population-based test-negative case-control study of the UK Coronavirus Cancer Evaluation Project (UKCCEP), we extracted data from the UKCCEP registry on all SARS-CoV-2 PCR test results (from the Second Generation Surveillance System), vaccination records (from the National Immunisation Management Service), patient demographics, and cancer records from England, UK, from Dec 8, 2020, to Oct 15, 2021. Adults (aged ≥18 years) with cancer in the UKCCEP registry were identified via Public Health England's Rapid Cancer Registration Dataset between Jan 1, 2018, and April 30, 2021, and comprised the cancer cohort. We constructed a control population cohort from adults with PCR tests in the UKCCEP registry who were not contained within the Rapid Cancer Registration Dataset. The coprimary endpoints were overall vaccine effectiveness against breakthrough infections after the second dose (positive PCR COVID-19 test) and vaccine effectiveness against breakthrough infections at 3–6 months after the second dose in the cancer cohort and control population.
The cancer cohort comprised 377 194 individuals, of whom 42 882 had breakthrough SARS-CoV-2 infections. The control population consisted of 28 010 955 individuals, of whom 5 748 708 had SARS-CoV-2 breakthrough infections. Overall vaccine effectiveness was 69·8% (95% CI 69·8–69·9) in the control population and 65·5% (65·1–65·9) in the cancer cohort. Vaccine effectiveness at 3–6 months was lower in the cancer cohort (47·0%, 46·3–47·6) than in the control population (61·4%, 61·4–61·5).
COVID-19 vaccination is effective for individuals with cancer, conferring varying levels of protection against breakthrough infections. However, vaccine effectiveness is lower in patients with cancer than in the general population. COVID-19 vaccination for patients with cancer should be used in conjunction with non-pharmacological strategies and community-based antiviral treatment programmes to reduce the risk that COVID-19 poses to patients with cancer.
University of Oxford, University of Southampton, University of Birmingham, Department of Health and Social Care, and Blood Cancer UK.
Journal Article
Why “Sudden Appearance” Is Not as It Appears
Recent action taken by the Texas State Board of Education has opened the door to the inclusion of creationist arguments into public school science curriculum in that state and—because of the critical role of Texas in textbook adoptions—perhaps in many other states as well. One of the arguments that have been targeted by creationists is the “sudden appearance” of animal phyla at the base of the Cambrian period (i.e., the Cambrian explosion). While the creationist argument is both misleading and deeply flawed, high school biology teachers are often lacking the relevant paleontological knowledge to refute the argument. This paper attempts to provide teachers with a set of core counterpoints to the creationists’ claims along with a list of online resources that are highly visual in nature and should provide the means to help stimulate genuine student critical thinking about this issue, an alleged goal of the creationist agenda.
Journal Article