To highlight common pitfalls observed in scientific research derived from national cancer registries, predominantly the Survival, Epidemiology, and End Results Program and the National Cancer ...Database.
Literature review and expert opinion.
This state-of-the-art review consolidates the literature with editorial experiences describing how and why statistically flawed studies are usually rejected for publication, highlighting common errors in submitted articles employing national cancer registries.
Pitfalls were identified in 2 major areas-design and data analysis. Design pitfalls included unbalanced cohorts, uncontrolled covariates, and flawed oncologic variables. Analytical pitfalls included incorrect application of univariate analyses, inclusion of inaccurate data, and inclusion of stage IVc disease in curative survival analysis. Additional limitations of database studies were identified, including absence of patient-related outcomes, hypothesis-generating vs practice-changing implications, and inability to differentiate between overall survival and disease-specific survival.
Methodological strategies are suggested to ensure careful analytical design and appropriate interpretation. Although national cancer registries provide a wealth of data, researchers must remain vigilant when designing studies and analyzing these data sets. Inherent design flaws raise considerable problems with interpretation; however, when analyzed judiciously, registries can lead to a better understanding of cancer outcomes.
Cardiometabolic diseases are the leading cause of death worldwide. Despite a known genetic component, our understanding of these diseases remains incomplete. Here, we analyzed the contribution of ...rare variants to 57 diseases and 26 cardiometabolic traits, using data from 200,337 UK Biobank participants with whole-exome sequencing. We identified 57 gene-based associations, with broad replication of novel signals in Geisinger MyCode. There was a striking risk associated with mutations in known Mendelian disease genes, including MYBPC3, LDLR, GCK, PKD1 and TTN. Many genes showed independent convergence of rare and common variant evidence, including an association between GIGYF1 and type 2 diabetes. We identified several large effect associations for height and 18 unique genes associated with blood lipid or glucose levels. Finally, we found that between 1.0% and 2.4% of participants carried rare potentially pathogenic variants for cardiometabolic disorders. These findings may facilitate studies aimed at therapeutics and screening of these common disorders.
Abstract
Gravitational lenses can magnify distant galaxies, allowing us to discover and characterize the stellar populations of intrinsically faint, quiescent galaxies that are otherwise extremely ...difficult to directly observe at high redshift from ground-based telescopes. Here, we present the spectral analysis of two lensed, quiescent galaxies at
z
≳ 1 discovered by the
ASTRO 3D Galaxy Evolution with Lenses
survey:
AGEL
1323 (
M
*
∼ 10
11.1
M
⊙
,
z
= 1.016,
μ
∼ 14.6) and
AGEL
0014 (
M
*
∼ 10
11.5
M
⊙
,
z
= 1.374,
μ
∼ 4.3). We measured the age, Fe/H, and Mg/Fe of the two lensed galaxies using deep, rest-frame-optical spectra (S/N ≳40 Å
−1
) obtained on the Keck I telescope. The ages of
AGEL
1323 and
AGEL
0014 are
5.6
−
0.8
+
0.8
Gyr and
3.1
−
0.3
+
0.8
Gyr, respectively, indicating that most of the stars in the galaxies were formed less than 2 Gyr after the Big Bang. Compared to nearby quiescent galaxies of similar masses, the lensed galaxies have lower Fe/H and Mg/H. Surprisingly, the two galaxies have comparable Mg/Fe to similar-mass galaxies at lower redshifts, despite their old ages. Using a simple analytic chemical evolution model connecting the instantaneously recycled element Mg with the mass-loading factors of outflows averaged over the entire star formation history, we found that the lensed galaxies may have experienced enhanced outflows during their star formation compared to lower-redshift galaxies, which may explain why they quenched early.
Reactive interface patterning promoted by lithographic electrochemistry serves as a facile method for generating submicron structures on conductive substrates. A binary‐potential step applied to a ...metal layer with a resist overlayer allows silicon to be patterned with metal oxides. In this study, the role and influence of the resist overlayer on the uniformity of pattern formation are examined. The ability of the resist to detach from the underlying metal is a critical determinant of pattern geometry. By choosing an appropriate resist, large patterns with submicron precision are generated quickly by the application of the binary‐potential steps. From this information, a lithography‐free approach to generating identical patterns is achieved with simple resists such as that furnished from a lacquer–water emulsion, thus greatly simplifying the patterning of silicon with metal oxide catalysts.
Electrochemical surface‐patterning of silicon is achieved with a step potential to oxidize a metal substrate underneath a lithographic mask. Flexible lithographic masks allow for uniform and large metal oxide patterns with submicron precision. The approach is extended to patterning without the need for a lithographic mask. A lacquer–water emulsion serves as a mask and furnishes well‐defined patterns.
Inturned (INTU), a cilia and planar polarity effector, performs prominent ciliogenic functions during morphogenesis, such as in the skin. INTU is expressed in adult tissues but its role in tissue ...maintenance is unknown. Here, we report that the expression of the INTU gene is aberrantly elevated in human basal cell carcinoma (BCC), coinciding with increased primary cilia formation and activated hedgehog (Hh) signaling. Disrupting Intu in an oncogenic mutant Smo (SmoM2)-driven BCC mouse model prevented the formation of BCC through suppressing primary cilia formation and Hh signaling, suggesting that Intu performs a permissive role during BCC formation. INTU is essential for intraflagellar transport A complex assembly during ciliogenesis. To further determine whether Intu is directly involved in the activation of Hh signaling downstream of ciliogenesis, we examined the Hh signaling pathway in mouse embryonic fibroblasts, which readily responds to the Hh pathway activation. Depleting Intu blocked Smo agonist-induced Hh pathway activation, whereas the expression of Gli2ΔN, a constitutively active Gli2, restored Hh pathway activation in Intu-deficient cells, suggesting that INTU functions upstream of Gli2 activation. In contrast, overexpressing Intu did not promote ciliogenesis or Hh signaling. Taken together, data obtained from this study suggest that INTU is indispensable during BCC tumorigenesis and that its aberrant upregulation is likely a prerequisite for primary cilia formation during Hh-dependent tumorigenesis.
Infectious hematopoietic necrosis (IHN) is a significant viral disease affecting salmonids, whereas Flavobacterium psychrophilum (Fp), the causative agent of bacterial coldwater disease (BCWD), ...remains one of the most significant bacterial pathogens of salmonids. We explored maternal immunity in the context of IHN and BCWD management in rainbow trout (Oncorhynchus mykiss) aquaculture. Two experimental trials were conducted where different groups of female broodstock were immunized prior to spawning with an IHNV DNA vaccine or a live attenuated F. psychrophilum (Fp B.17-ILM) vaccine alone, or in combination. Progeny were challenged with either a low or high dose of IHNV at 13 days post hatch (dph) and 32 dph or challenged with F. psychrophilum at 13 dph. Mortality following a low-dose IHNV challenge at 13 dph was significantly lower in progeny from vaccinated broodstock vs. unvaccinated broodstock, but no significant differences were observed at 32 dph. Mortality due to BCWD was also significantly reduced in 13 dph fry that originated from broodstock immunized with the Fp B.17-ILM vaccine. After vaccination broodstock developed specific or neutralizing antibodies respectively to F. psychrophilum and IHNV; however, antibody titers in eggs and fry were undetectable. In the eggs and fry mRNA transcripts of the complement components C3 and C5 were detected at much higher levels in progeny from vaccinated broodstock and showed a significantly increased and rapid response post-challenge compared with unvaccinated broodstock. After challenges pro-inflammatory cytokine expression was immediately and considerably elevated in the fry from vaccinated broodstock vs. unvaccinated broodstock, whereas adaptive immune genes were elevated to a lesser degree. Results suggest that maternal transfer of innate and adaptive factors at the transcript level occurred because development of lymphomyeloid organs is not complete in such young fry. In addition to documenting maternally derived immunity in teleosts, this study demonstrates that broodstock vaccination can confer some degree of protection to progeny against viral and bacterial pathogens.
•Maternal immunity in the context of IHN/BCWD management in rainbow trout was explored.•After vaccination, broodstock developed antibodies respectively to Fp and IHNV.•Mortality was significantly reduced in 13 dph fry from immunized broodstock.•Maternal transfer of innate and adaptive factors at the transcript level occurred.•Broodstock vaccination confers some degree of protection to progeny against pathogens.
The most sensitive direct method to establish the absolute neutrino mass is observation of the endpoint of the tritium beta-decay spectrum. Cyclotron radiation emission spectroscopy (CRES) is a ...precision spectrographic technique that can probe much of the unexplored neutrino mass range with ( eV ) resolution. A lower bound of m ( e ) 9 ( 0.1 ) meV is set by observations of neutrino oscillations, while the KATRIN experiment-the current-generation tritium beta-decay experiment that is based on magnetic adiabatic collimation with an electrostatic (MAC-E) filter-will achieve a sensitivity of m ( e ) 0.2 eV . The CRES technique aims to avoid the difficulties in scaling up a MAC-E filter-based experiment to achieve a lower mass sensitivity. In this paper we review the current status of the CRES technique and describe Project 8, a phased absolute neutrino mass experiment that has the potential to reach sensitivities down to m ( e ) 40 meV using an atomic tritium source.
Pancreatitis is a disease continuum, starting with acute pancreatitis (AP) and progressing in some cases to recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP). Currently, there are no ...approved therapies or early diagnostic or prognostic biomarkers for pancreatitis. The current study examined whether patient serum immune profiling could identify noninvasive biomarkers and provide mechanistic insight into the disease continuum of pancreatitis.
Using Olink immunoassay, we assessed the protein levels of 92 immune markers in serum samples from participants enrolled in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) study of the Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) consortium. Samples (N = 231) were obtained from individuals without pancreatic disease (n = 56) and from those with chronic abdominal pain (CAP) (n = 24), AP (n = 38), RAP (n = 56), and CP (n = 57).
A total of 33 immune markers differentiated the combined pancreatitis groups from controls. Immune markers related to interleukin (IL) 17 signaling distinguished CP from AP and RAP. Similarly, the serum level of IL17A and C-C motif chemokine ligand 20 differentiated CP from CAP, suggesting the involvement of T helper 17 cells in CP pathogenesis. The receiver operator characteristic curve with 2 immune markers (IL17A and sulfotransferase 1A1) could differentiate CP from CAP (optimistic area under the curve = 0.78). The macrophage classical activation pathway elevated along the continuum of pancreatitis, suggesting an accumulation of proinflammatory signals over disease progression. Several immune markers were associated with smoking, alcohol, and diabetes status.
Immune profiling of serum samples from a large pancreatitis cohort led to identifying distinct immune markers that could serve as potential biomarkers to differentiate the varying pancreatitis disease states. In addition, the finding of IL17 signaling in CP could provide insight into the immune mechanisms underlying disease progression.
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Analysis of serum immune markers in a large cohort of pancreatitis allowed the identification of distinct immune markers that could serve as potential biomarkers providing mechanistic insights into pancreatitis progression.
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other ...carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.
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•Expanded the somatic genetic landscape of papillary thyroid cancer•Identified new cancer genes and new driver events in known cancer genes.•Signaling signatures and differentiation properties characterized across cohort•Developed a molecular classification of papillary thyroid carcinoma
A TCGA analysis of papillary thyroid carcinoma paints a nearly complete picture of its genomic drivers, reveals intriguing differences between the consequences of mutant BRAF and RAS signaling, and enables development of a scoring and classification scheme that may beneficially alter treatment courses.
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