Citations

The CRISPR-Cas9 system has enabled researchers to precisely modify/edit the sequence of a genome. A typical editing experiment consists of two steps: (1) editing cultured cells; (2) cell cloning and selection of clones with and without intended edit, presumed to be isogenic. The application of CRISPR-Cas9 system may result in off-target edits, whereas cloning will reveal culture-acquired mutations. We analyzed the extent of the former and the latter by whole genome sequencing in three experiments involving separate genomic loci and conducted by three independent laboratories. In all experiments we hardly found any off-target edits, whereas detecting hundreds to thousands of single nucleotide mutations unique to each clone after relatively short culture of 10–20 passages. Notably, clones also differed in copy number alterations (CNAs) that were several kb to several mb in size and represented the largest source of genomic divergence among clones. We suggest that screening of clones for mutations and CNAs acquired in culture is a necessary step to allow correct interpretation of DNA editing experiments. Furthermore, since culture associated mutations are inevitable, we propose that experiments involving derivation of clonal lines should compare a mix of multiple unedited lines and a mix of multiple edited lines.

Purpose To determine the most frequently cited articles relating to ice hockey since 2000 and conduct a bibliometric analysis of these publications. Methods The Clarivate Web of Knowledge database was used to gather data and generate a list of publications relating to “ice hockey” on June 20, 2022. Articles were filtered by the total number of citations accrued and were included or excluded on the basis of relevance to ice hockey; no date of publication, language, or journal restrictions. After the 50 most highly cited articles were identified, articles published before the year 2000 were excluded to avoid bias. The information analyzed from each article included author name (first and last), publication year, country of origin, institutional affiliation (of the first and last author), journal name, research design, main research topic, competition level, and the level of evidence. Results Ultimately, 46 studies were included in this analysis. The total number of citations was 8,267 times with an average of 179.7 citations per article. The most cited article was cited 926 times. The articles came from 5 different countries, with the United States and Canada comprising 27 and 13 articles, respectively. All articles were published in English. The American Journal of Sports Medicine published the greatest number of articles. The most studied topic was concussion/traumatic brain injury (n = 26). Professional hockey was the most studied level of competition (n = 15), while college followed (n = 13). Three institutions, University of Calgary, Dartmouth School of Medicine, and University of North Carolina at Chapel Hill were responsible for 32.6% of the top articles (n = 15). Conclusions The majority of the most cited articles relating to ice hockey are cohort studies, review articles, and epidemiological studies originating from the United States or Canada. The majority of publications included in the analysis focused on concussion and traumatic brain injury prevalence, identification, diagnosis, outcomes, and prevention, as well as the most studied level of competition was professional, but the greatest number of participants arose from the youth and high school level. Level of Evidence Level IV, cross‐sectional study

Abstract Background: Colorectal cancer (CRC) incidence has increased in those 50 years or younger compared to older individuals in recent decades. While the intra-tumoral microbiome is a potent facilitator of tumorigenesis, the role of the microbiome in early onset (eo)CRC is unclear. Identification of the intra-tumoral microbiome may enhance prediction of adverse outcomes to improve survival of CRC overall age groups and eoCRC. Methods: We performed targeted sequencing of tumor and matched normal DNA samples from 3695 colorectal cancer cases within the Genetics and Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry (CCFR). Tumor DNA was extracted from formalin fixed paraffin embedded (FFPE) or fresh frozen tissue. Normal tissue DNA was extracted from blood or normal surrounding colorectal tissue. We designed probes for the bacterial pathogens enterotoxigenic Bacteroides fragilis (ETBF), polyketide synthase positive E. coli (pks+ EC), and Fusobacterium nucleatum (Fn). We used logistic regression to assess tumor-associated bacteria and clinical parameters, tumor molecular characteristics, and tumor stage adjusted for age, sex, and study and a Cox promotional hazard to assess association with CRC-specific survival, overall and in eoCRC, adjusted for age at diagnosis, sex, mutational burden, and microsatellite instability (MSI) and stratified baseline hazards by study. Survival data were available for 2357 and 308 patients, overall and in eoCRC, respectively. Results: The prevalence of different bacteria in tumors differed slightly overall vs. in eoCRC tumors: ETBF (5.2%, 6.3%), pks+ EC (12.9%, 14.8%), and Fn (10.4%, 8.2%). Overall, men had a lower probability of tumors with Fn (odds ratio (OR)=0.8, 95% confidence interval (CI)=0.64-0.99, p=0.04) but higher odds of tumors with pks+ EC (OR=1.38, CI=1.14-1.68, p=0.001), compared to women. The odds of prevalent Fn were higher for proximal vs distal tumors (OR=1.76, CI=1.38-2.26, p<0.001), but there was no association between tumor site and pks+ EC or ETBF. MSI-high tumors were more likely to carry Fn (OR=2.79, CI=2.08-3.75, p<0.001) and less likely to carry pks+ EC (OR=0.63, CI=0.44-0.88, p=0.008) when compared to patients with MSS tumors. In patients with non-hypermutated tumors, we observed that pks+ EC positive tumors were associated with better CRC-specific survival (HR=0.73, CI=0.57-0.93, p=0.01), whereas ETBF positive tumors (HR=1.99, CI=1,18-3.36,p=0.009) and Fn positive tumors (HR=1.33, CI=1.04-1.72, p=0.03) were associated with poorer survival. In eo-CRC patients, Fn positive status was associated with poorer survival (HR=2.4, CI= 1.056 - 5.492, p=0.026). Conclusions: We showed that the intra-tumoral microbiome differs in distribution across patient populations and patient survival over all age groups and, specifically, in eoCRC. Citation Format: Meredith A. Hullar, Keith R. Curtis, Tabitha Harrison, Yi Lin, Robert Steinfelder, Sonja I. Berndt, Daniel D. Buchanan, Andrew T. Chan, David A. Drew, Jane Figueiredo, Amy J. French, Tabitha A. Harrison, Mark A. Jenkins, Johannes Melaku, Victor Moreno, Tomotaka Ugai, Shuji Ogino, Conghui Qu, Chenxu Qu, Steven Thibodeau, Syed Zaidi, Amanda I. Phipps, Ulrike Peters, on behalf of GECCO and CCFR investigators. Evaluation of intra-tumoral pks+ E. coli, enterotoxigenic B. fragilis and Fusobacterium nucleatum, overall and in early onset disease, in colorectal cancer cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3039.

Abstract Background The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci. Methods We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci. Results We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci. Conclusions Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.

Background: African-American (AA) adults have a higher prevalence of cardiovascular (CV) risk factors, leading to higher CV disease mortality than White adults. Prior findings of our mobile health (mHealth) lifestyle intervention (FAITH! App) demonstrated efficacy in promoting ideal cardiovascular health (CVH) in AAs. Hypothesis: We hypothesized that the intervention group with preexisting CV risk factors would have a greater increase in LS7 scores than the control group with the same risk factors following use of the FAITH! App. Methods: A cluster randomized controlled trial was conducted among AAs from 16 churches in Minnesota. The intervention included culturally relevant, LS7-focused education modules, diet/physical activity self-monitoring and a group sharing board. A subgroup of participants with ≥1 diagnosis of overweight/obesity, hyperlipidemia, hypertension (HTN) or diabetes was examined. The primary outcome was change in LS7 score—a measure of CVH ranging from poor to ideal (range 0-14 points)—at 6 months post-intervention. Results: Forty-nine participants (75.5% female) were included in the intervention (n=20; mean age [SD]: 58.8 [9.5]) or control (n=29, mean age [SD]: 52.5 [10.7]) groups (Table 1). There was no significant difference in the CV risk factor prevalence between the two groups. There was a greater increase in LS7 score in the intervention vs. control group across all CV risk factors, with significant differences among those with overweight/obesity (1.77, p<.0001) and with 2+ or 3+ CV risk factors (1.00, p=.03; 1.09, p=.04). Compared to the control group, the increase in the percentage of participants with ideal LS7 scores in the intervention group was higher among those with overweight/obesity, HTN, diabetes and 3+ CV risk factors. Conclusions: Our culturally tailored mHealth lifestyle intervention was associated with notable increases in LS7 scores among AAs with preexisting CV risk factors, suggesting its efficacy in improving CVH among this population.

Abstract Mammographic breast density (MBD) has been shown to be a strong, independent risk factor for breast cancer (BC) irrespective of race/ethnicity. Given the risk association of MBD and its potential to mask tumors on a mammogram, state and federal laws have mandated that women receive information regarding their personal MBD in their mammography reports. However, concerns have been raised regarding the impact of MBD notification on patient anxiety, especially written information for women who experience health disparities such as racial/ethnic minorities, lower health literacy, limited English proficiency and lower socioeconomic status. We performed a randomized controlled clinical trial to examine the impact of three different written and interpersonal approaches to MBD notification on patient anxiety, BC worry, and self-perceived BC risk, among Latinas receiving routine mammography screening at a federally qualified medical center (FQHC). We hypothesized that interpersonal education would reduce anxiety and worry, relative to the written notifications alone. The study was performed at the Baseline Clinic of Mountain Park Health Center, a FQHC in Phoenix, AZ. Women between ages 40 and 74 years presenting for screening mammogram were eligible. After providing signed informed consent, participants were randomized equally to usual care (UC- mailed notification letter); enhanced care (notification letter and MBD educational brochure designed for this study): interpersonal care (notification letter, brochure, promotora education via telephone). A stratified block randomization procedure was used with age &gt; 50 years (yes vs no), ethnicity (Hispanic vs non-Hispanic), and language preference (Spanish vs. English) as strata. Study participants completed surveys at the time of enrollment/pre-intervention (T0), at two weeks to six months after intervention was delivered (T1), and about one year after randomization (T2). Anxiety state was measured using the state anxiety subscale of the State-Trait Anxiety Inventory scale (STAI-S) (range from 20-80). BC worry was probed using the question: “How frequently do you worry about getting breast cancer someday”. The self-perceived lifetime risk of BC was rated between 0% (no chance of BC) to 100% (definitely will get BC). The proportion of participants with an increase or persistence of higher level for each outcome between time points was compared between the three study groups. The study was approved by the Mayo Clinic Institutional Review Board. 1332 Latina women were enrolled and randomized between October 2016 and October 2019. All completed the baseline (T0) survey, 928 completed T1, 632 completed T2, and 516 completed both T1 and T2 surveys. At study entry, majority of the participants were young (64.1% between age 40-49 years), had no family history of breast cancer (81.0%), had less than high school education (68.8%), and were married or partnered (67.8%). At T0, the mean (SD) anxiety STAI score was 32.5 (11.1); 51.8% with moderate or severe anxiety (score &gt; 30). With regard to BC worry, 41.3% reported worrying “sometimes”, “often”, or “almost all the time”. Further, 25.4% reported a self-perceived lifetime risk of developing BC of &gt;10% while only 6.6% had a Gail model estimated lifetime risk score of &gt;10%. There was no significant difference in changes in anxiety, BC worry or self-perceived risk from T0 to either T1 or T2 surveys between the intervention groups. In summary, this study found high levels of baseline anxiety and BC worry (despite the majority being 40-49 years old and having no family history of BC) which persisted regardless of how notification and education were delivered. Future work is needed to improve the understanding of factors that could lower anxiety and BC worry and improve risk perception in this population. Citation Format: Karthik Ghosh, Sarah Jenkins, Jennifer Ridgeway, Jessica D. Austin, Bijan Borah, Bhavika K. Patel, Deborah Rhodes, Aaron Norman, Edna P. Ramos, Matt Jewett, Crystal Gonzalez, Valentina Hernandez, Davinder Singh, Vera Suman, Celine Vachon. Breast Density Notification: Impact on anxiety, breast cancer worry, and self-perceived risk among Latinas at a federally qualified medical center. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-38.

Abstract Background Mendelian randomization (MR) studies are susceptible to metadata errors (e.g. incorrect specification of the effect allele column) and other analytical issues that can introduce substantial bias into analyses. We developed a quality control (QC) pipeline for the Fatty Acids in Cancer Mendelian Randomization Collaboration (FAMRC) that can be used to identify and correct for such errors. Methods We collated summary association statistics from fatty acid and cancer genome-wide association studies (GWAS) and subjected the collated data to a comprehensive QC pipeline. We identified metadata errors through comparison of study-specific statistics to external reference data sets (the National Human Genome Research Institute-European Bioinformatics Institute GWAS catalogue and 1000 genome super populations) and other analytical issues through comparison of reported to expected genetic effect sizes. Comparisons were based on three sets of genetic variants: (i) GWAS hits for fatty acids, (ii) GWAS hits for cancer and (iii) a 1000 genomes reference set. Results We collated summary data from 6 fatty acid and 54 cancer GWAS. Metadata errors and analytical issues with the potential to introduce substantial bias were identified in seven studies (11.6%). After resolving metadata errors and analytical issues, we created a data set of 219 842 genetic associations with 90 cancer types, generated in analyses of 566 665 cancer cases and 1 622 374 controls. Conclusions In this large MR collaboration, 11.6% of included studies were affected by a substantial metadata error or analytical issue. By increasing the integrity of collated summary data prior to their analysis, our protocol can be used to increase the reliability of downstream MR analyses. Our pipeline is available to other researchers via the CheckSumStats package (https://github.com/MRCIEU/CheckSumStats).