tbuckley/cabot-search huggingface dataset:
The global and promoter-centric 3D genome organization temporally resolved during a circadian cycle
Authors: Mayra Furlan-Magaril, Masami Ando-Kuri, Rodrigo G. Arzate-Mejía, Jörg Morf, Jonathan Cairns, Abraham Román-Figueroa, Luis Tenorio-Hernández, A. César Poot-Hernández, Simon Andrews, Csilla Várnai, Boo Virk, Steven W. Wingett, Peter Fraser
Journal: Genome biology (2021)

Abstract Background Circadian gene expression is essential for organisms to adjust their physiology and anticipate daily changes in the environment. The molecular mechanisms controlling circadian gene transcription are still under investigation. In particular, how chromatin conformation at different genomic scales and regulatory elements impact rhythmic gene expression has been poorly characterized. Results Here we measure changes in the spatial chromatin conformation in mouse liver using genome-wide and promoter-capture Hi-C alongside daily oscillations in gene transcription. We find topologically associating domains harboring circadian genes that switch assignments between the transcriptionally active and inactive compartment at different hours of the day, while their boundaries stably maintain their structure over time. To study chromatin contacts of promoters at high resolution over time, we apply promoter capture Hi-C. We find circadian gene promoters displayed a maximal number of chromatin contacts at the time of their peak transcriptional output. Furthermore, circadian genes, as well as contacted and transcribed regulatory elements, reach maximal expression at the same timepoints. Anchor sites of circadian gene promoter loops are enriched in DNA binding sites for liver nuclear receptors and other transcription factors, some exclusively present in either rhythmic or stable contacts. Finally, by comparing the interaction profiles between core clock and output circadian genes, we show that core clock interactomes are more dynamic compared to output circadian genes. Conclusion Our results identify chromatin conformation dynamics at different scales that parallel oscillatory gene expression and characterize the repertoire of regulatory elements that control circadian gene transcription through rhythmic or stable chromatin configurations.
Predictors of falls after starting an exercise program: A secondary analysis in inactive, female cancer survivors participating in the GET FIT trial.
Authors: Deanne Tibbitts, Sydnee Stoyles, Nathan Dieckmann, Fay B. Horak, Shiuh-Wen Luoh, Fuzhong Li, Kerri M. Winters-Stone
Journal: Journal of Clinical Oncology (2021)

12075 Background: Women treated for cancer are more likely to fall than women without a cancer history. Exercise is a fall prevention strategy for older adults that we are testing in the GET FIT trial as a fall prevention approach in women cancer survivors. Increasing physical activity, though, could acutely increase the risk of falls in inactive survivors with known fall risk related to treatment. Knowing who might be at risk prior to beginning an exercise program would inform additional safety precautions during exercise. Methods: We conducted a secondary analysis of baseline data from the GET FIT trial that enrolled inactive, older women who had completed chemotherapy for cancer. Women completed objective (muscle strength, static postural control, range of motion, physical functioning) and self-report (fall history, comorbidities, presence of neuropathy symptoms, pain severity, depressive symptoms, cognitive functioning, perceptions of lower extremity functioning, disability, fear of falling, demographic, and clinical characteristics) measures at baseline. Falls were prospectively collected during the 6 month intervention using monthly self report. Potential predictors of falls were included if univariate tests revealed significant differences between fallers and non-fallers. To identify the strongest predictors of falls, we used an automated model selection and multimodel inference approach to perform an exhaustive model search. Results: Baseline data were available for 415 participants with known faller status at the end of the intervention, of whom 31.3% (n = 130) reported at least one fall. The average age of the sample was 62.1±6.4 years and consisted mostly of non-Hispanic white, married, highly educated, overweight or obese women treated for breast cancer. Fallers (1+ falls) and non-fallers significantly differed on measures of fall history, comorbidities, pain, neuropathy, fear of falling, disability, perceived lower extremity functioning, cognitive functioning, depression, and postural control. The best model of faller status (per BIC) included postural control (p = 0.004), perceived lower extremity functioning (p = 0.072), and fear of falling (p = 0.030). Odds of ≥1 fall during the intervention increased by 1.72 (95% CI: 1.05-2.83) times for a 0.1-point decrease in postural control, 1.11 (1.04-1.19) times for a 0.1-point increase in fear of falling, and 1.02 (1.00-1.03) times for a 1-point decrease in perceived lower extremity functioning. Conclusions: Women cancer survivors with poor balance, poor self-rated functioning, and a fear of falling may need to take additional fall precautions when starting an exercise program. Clinical trial information: NCT01635413.
Radiographical assessment of tumour stroma and treatment outcomes using deep learning: a retrospective, multicohort study
Authors: Yuming Jiang, Xiaokun Liang, Zhen Han, Wei Wang, Sujuan Xi, Tuanjie Li, Chuanli Chen, Qingyu Yuan, Na Li, Jiang Yu, Yaoqin Xie, Yikai Xu, Zhiwei Zhou, George A Poultsides, Guoxin Li, Ruijiang Li
Journal: The Lancet Digital Health (2021)
Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection
Authors: Francisco Caiado, Eric M. Pietras, Markus G. Manz
Journal: The Journal of Experimental Medicine (2021)

Inflammation is an evolutionarily selected defense response to infection or tissue damage that involves activation and consumption of immune cells in order to reestablish and maintain organismal integrity. In this process, hematopoietic stem cells (HSCs) are themselves exposed to inflammatory cues and via proliferation and differentiation, replace mature immune cells in a demand-adapted fashion. Here, we review how major sources of systemic inflammation act on and subsequently shape HSC fate and function. We highlight how lifelong inflammatory exposure contributes to HSC inflamm-aging and selection of premalignant HSC clones. Finally, we explore emerging areas of interest and open questions remaining in the field.
Correspondence on ‘Variants in urate transporters, <i>ADH1B</i>, <i>GCKR</i> and <i>MEPE</i> genes associated with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank’
Authors: Riku Takei, Nicholas A Sumpter, Amanda Phipps-Green, Murray Cadzow, Ruth K Topless, Richard J Reynolds, Tony R Merriman
Journal: Annals of the Rheumatic Diseases (2021)

Gene expression changes are a hallmark of the neuropathology of Huntington9s disease (HD), but the exact molecular mechanisms of this effect remain uncertain. Here, we report that <i>in vitro</i> models of disease comprised of primary striatal neurons expressing N-terminal fragments of mutant huntingtin (via lentiviral gene delivery) faithfully reproduce the gene expression changes seen in human HD. Neither viral infection nor unrelated (enhanced green fluorescent protein) transgene expression had a major effect on resultant RNA profiles. Expression of a wild-type fragment of huntingtin [htt171-18Q] also caused only a small number of RNA changes. The disease-related signal in htt171-82Q versus htt171-18Q comparisons was far greater, resulting in the differential detection of 20% of all mRNA probe sets. Transcriptomic effects of mutated htt171 are time- and polyglutamine-length dependent and occur in parallel with other manifestations of polyglutamine toxicity over 4–8 weeks. Specific RNA changes in htt171-82Q-expressing striatal cells accurately recapitulated those observed in human HD caudate and included decreases in PENK (proenkephalin), RGS4 (regulator of G-protein signaling 4), dopamine D<sub>1</sub> receptor (DRD1), DRD2, CNR1 (cannabinoid CB<sub>1</sub> receptor), and DARPP-32 (dopamine- and cAMP-regulated phosphoprotein-32; also known as PPP1R1B) mRNAs. HD-related transcriptomic changes were also observed in primary neurons expressing a longer fragment of mutant huntingtin (htt853-82Q). The gene expression changes observed in cultured striatal neurons are not secondary to abnormalities of neuronal firing or glutamatergic, dopaminergic, or brain-derived neurotrophic factor signaling, thereby demonstrating that HD-induced dysregulation of the striatal transcriptome might be attributed to intrinsic effects of mutant huntingtin.
Confronting Housing Insecurity—A Key to Getting Kids Back to School
Authors: Jonathan Todres, Lauren Meeler
Journal: JAMA Pediatrics (2021)

Discussions about the impact of COVID-19 on children have primarily centered around disruptions in education.Somestudentsareapproachingayearsincetheyhavebeen in the classroom, and the challenges and inequities of virtual learning are well documented.But as momentum and planning for reopenings have grown, an issue continues to be overlooked: housing and the looming eviction cliff.Housing insecurity undermines children's education, and unless we address it, the return to in-school instruction will not solve the inequities harming so many children.Millions of individuals have lost their jobs and been pushed into poverty since the start of the pandemic, creating and exacerbating housing insecurity.The Eviction Lab at Princeton University, which tracks 5 states and 27 cities in the US, has reported 1 that more than 270 000 evictions have been filed since the pandemic began.As of February 2021, about 5.2 million households with children were behind on rent, and 46% of those said they would likely have to leave their home in the next 2 months, while an additional 4.5 million homeowners with children were behind on mortgage payments. 2n September 4, 2020, the US Centers for Disease Control and Prevention (CDC) issued an eviction moratorium, which prevents landlords from removing tenants who have not paid their rent. 3While this was a much-needed step, in practice it has 2 fundamental weaknesses.It has not prevented some families from losing their homes, and it does not relieve families of their obligations to pay back rent, fees, penalties, or interest, which means renters could face insurmountable debts when the moratorium expires at the end of June.First, many renters are losing their homes despite the moratorium.The moratorium still allows landlords to file the eviction; it just cannot be enforced during the moratorium period.Many renters choose to leave when an eviction is filed, because they either do not know their rights or have concerns that an eviction record may prevent them from securing other housing.If a renter chooses to fight the eviction, they bear the burden of proof on numerous issues, including that they cannot pay the full amount (because of lost income or extraordinary out-of-pocket medical expenses), they have made best efforts to make partial payments, they have no other available housing options, and more.This burden, coupled with a general lack of legal representation, leaves renters at a considerable disadvantage.Landlords have found other loopholes that prevent renters from claiming eligibility under the moratorium at all.Landlords have the option to nonrenew a lease for any reason or evict for other violations of the contract, such as damaging property.Finally, in some jurisdictions, certain judges have been reluctant to enforce the moratorium.
Telemedicine use and satisfaction amongst radiation oncologists during the COVID-19 pandemic: Evaluation of current trends and future opportunities.
Authors: Alok Deshane, Nicholas Damico, Michael Kharouta, Anna Wu, GI-Ming WANG, Mitchell Machtay, Aryavarta M. S. Kumar, Serah Choi, Aashish D. Bhatt
Journal: Journal of Clinical Oncology (2021)

e13503 Background: During the COVID-19 pandemic telemedicine became an attractive alternative to in person appointments. The role of telemedicine in patients who undergo frequent on site treatment, such as radiation therapy, is unclear. The purpose of this study was to examine telemedicine use, physician satisfaction and barriers to continued use in radiation oncology. Methods: An anonymous, electronic survey was distributed to radiation oncologists internationally. Participants described demographic and practice characteristics and a 5 point Likert scale assessed provider satisfaction, ease of use and overall utility of telemedicine. Analyses include descriptive statistics and subgroup comparisons using Chi-square and Fisher’s exact test. Results: 232/5343 (4.3%) completed the survey, 63.8% of whom were male, 52.6% age 50 or younger and 78.0% from the United States (U.S.). Only 14.2% used Telemedicine previously, which increased to 93.1% during COVID-19. Amongst all telemedicine users, usage rates were 77.9% for initial consultations, 97.2% for follow-up visits, and 35.9% for on-treatment visits. 69.8% report that &lt;25% of patients requiring treatment experienced delays due to COVID-19. Most conducted appointments from the workplace, with 40.1% also doing so from home. Satisfaction was high at 73.8%, perceived usefulness was 76.9% and 81.5% hope to continue using telemedicine after the pandemic. However, 82.4% had concerns with the inability to examine patients. Although 82.1 % believed that telemedicine would improve patient access to health care services overall, 63.0% were concerned with patient ability to access required technology. 49.5% had concerns regarding continued billing/reimbursement; less commonly at government centers (18.8%) compared to academic/satellite facilities (52.7%) and free-standing centers/community hospitals (50.7%), p=0.039 for both comparisons. These concerns were also significantly higher amongst US physicians (53.2% vs 34.9%, p=0.048). Conclusions: Widespread adoption of telemedicine by radiation oncologists occurred during COVID-19 with high rates of satisfaction and interest in continued use. Sustained reimbursement for telemedicine services is a significant concern, particularly in the US and outside of government facilities. [Table: see text]
Identifying research priorities to improve the health of incarcerated populations: results of citizens' juries in Australian prisons
Authors: Paul L Simpson, Jill Guthrie, Jocelyn Jones, Tony Butler
Journal: The Lancet Public Health (2021)

Health disparities in incarcerated populations should guide investment in the health care and research of these communities. Although users of health-care services are important in providing input into decisions about research, the voices of people in prison are absent regarding research into their health. In this Health Policy paper, we present priorities for research into the health of people in prison according to people in prison themselves. By use of a deliberative research approach, citizens' juries were conducted in six prisons (three men's and three women's prisons) in Australia. Participants were selected following submissions of expression of interest forms that were distributed within the prisons. Prerecorded information by experts in the health of incarcerated people was shown to participants. Participants deliberated for up to 4 h before agreeing on five research priorities. All citizens' juries endorsed mental health as a number one research priority. Prison health-care services, alcohol and other drug use, education, and infectious diseases were identified as research priorities by most citizens' juries. Focal points within priorities included serious mental illness; grief and trauma; medication management; health-care service access, quality, and resources; drug withdrawal and peer support; prison-based needle and syringe programmes; and health and life skills education. If endeavours in research priority setting are to consider health equity goals, the views of our most health affected citizens need to be included.
Cost evaluation of adjunctive osimertinib use in resected epidermal growth factor receptor-positive non-small cell lung cancer.
Authors: Briana Choi, Neda Alrawashdh, Ali McBride, Ivo Abraham
Journal: Journal of Clinical Oncology (2021)

8525 Background: About 30% of patients with epidermal growth factor receptor positive (EGFR+) non small cell lung cancer (NSCLC) are eligible for surgical resection. Osimertinib, a first line therapy for advanced EGFR+ NSCLC (stages 1B, 2, 3A), has shown clinical efficacy compared to placebo as an adjunctive therapy post resection. We evaluated the cost effectiveness/utility of this regimen. Methods: A two health state Markov model was built (disease free vs. disease recurrence or death). Disease free survival (DFS) curves were digitized and fitted to exponential function. 3 year timeline as patients received osimertinib for 3 years in published data. US payer perspective and 3% discount rate were applied. Drug costs were per Redbook whole acquisition cost and monitoring costs were from published data (US$ 2020). No adverse events &gt; 5% were reported hence none were included. Life years (LY) and quality adjusted life years (QALY) were estimated for each stage. Incremental cost-effectiveness and utility ratios (ICER/ICUR) for LY and QALY gained were estimated in base case (BCA) and probabilistic sensitivity analyses (PSA). Results: Shown in the table are BCA and (PSA) results. Using LY as outcome, for stage 1B, incremental DFSLY of 0.40 (0.39) and incremental cost of $500,782 ($501,034) yielded an ICER/DFSLYG of ̃$1.3 million (M) (̃$1.2 M). For stage 2, incremental DFSLY of 0.79 (0.79) and incremental cost of $503,144 ($503,092) resulted in an ICER/DFSLYG of $636,913 ($638,278). For stage 3A, incremental of DFSLY of 0.18 (0.07) and incremental cost of $322,356 ($293,377) yielded an ICER/DFSLYG of ̃$1.2 M (̃1.2 M). The incremental costs are the same for QALY outcomes. Using QALY as outcome, for stage 1B, incremental of DFSQALY of 0.26 (0.27) yielded an ICUR/DFSQALY of ̃$1.9 M. In stage 2, incremental DFSQALY of 0.53 (0.53) resulted in an ICUR/DFSQALY of $950,616 ($952,654). For stage 1C, incremental DFSQALY of 0.18 (0.07) yielded an ICUR/DFSQALY of ̃$1.8 M (̃$3.7 M). Conclusions: The ICERs and ICURs indicate that cost effectiveness varies markedly across stages of disease. Stage 2 showed the lowest cost to outcome association. In general, the cost burden of adjunctive maintenance therapy with osimertinib in resected EGFR+ NSCLC is substantial relative to the observed clinical benefit. The incremental benefit of osimertinib in stage 2b is more evident than the ones in 1B and 3A.[Table: see text]
Paul’s Addiction
Authors: Brad Borsari
Journal: JAMA (2021)

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Surgical outcomes for early-stage non-small cell lung cancer at facilities with stereotactic body radiation therapy programs.
Authors: Yusef Syed, William A. Stokes, Onkar Khullar, Nikhil Sebastian, Manali Rupji, Liu Yuan, Jeffrey D. Bradley, Kristin Ann Higgins, Walter J Curran, Suresh S. Ramalingam, Manu Sancheti, Felix Fernandez, Drew Moghanaki
Journal: Journal of Clinical Oncology (2021)

8538 Background: Patients undergoing surgery for early-stage non-small cell lung cancer (NSCLC) may be at high-risk for post-operative mortality. Access to stereotactic body radiation therapy (SBRT) offers a less invasive alternative for this population that may facilitate more appropriate patient selection for surgery. Methods: An analysis of all patients with early-stage NSCLC reported to the National Cancer Database between 2004-2015 was performed. Post-operative mortality rates were derived using vital status data. Utilization of SBRT was defined by each facility’s SBRT Experience in years and SBRT-to-Surgery volume ratios, defined by quartiles. Multivariable logistic regression with backward elimination was used to test for independence of associations between exposures of interest and post-operative mortality. Interaction testing was performed to assess the statistical relationship of covariates found to have independent associations. Results: The study cohort consisted of 202,542 patients who underwent surgical resection of clinical stage T1-T2 NSCLC (AJCC 7 th edition). The 90-day post-operative mortality rate declined significantly during the study period from 4.6% to 2.6% (p &lt; 0.001). During this period, the proportion of facilities that utilized SBRT increased from 3.3% to 77.5% (p &lt; 0.001) and the proportion of patients treated with SBRT increased significantly from 0.7% to 15.4% (p &lt; 0.001). Lower 90-day post-operative mortality rates were observed at facilities with greater than six years of SBRT experience (OR 0.84, CI 0.76-0.94, p = 0.003) and SBRT-to-Surgery volume ratios above 17% (OR 0.85, CI 0.79-0.92, p &lt; 0.001). Additional covariates associated with 90-day mortality included higher surgical volume, geographic region, year of diagnosis, age, sex, race, insurance status, facility type, Charlson-Deyo score, clinical T stage, histology, anatomic location, surgery type, and prior malignancy. Interaction testing between these covariates was negative, demonstrating that higher SBRT Experience and SBRT-to-Surgery volume ratios were independently associated with lower 90-day surgical mortality. Conclusions: Patients who underwent surgery for early-stage NSCLC at facilities with higher SBRT Experience and SBRT-to-Surgery volume ratios had lower rates of post-operative mortality. These findings suggest that the availability of SBRT may be a surrogate for a more comprehensive and safer approach to matching patients to surgery or SBRT. The observation of higher post-operative mortality rates at facilities without an SBRT program deserves further study.