tbuckley/cabot-search huggingface dataset:
Oncogene-specific inhibition in the treatment of advanced pediatric thyroid cancer
Authors: Aime T. Franco, Julio C. Ricarte-Filho, Theodore W. Laetsch, Andrew J. Bauer
Journal: Journal of Clinical Investigation (2021)

Papillary thyroid cancer (PTC) is the most common form of differentiated thyroid cancer in the pediatric population and represents the second most common malignancy in adolescent females. Historically, PTC has been classified on the basis of histology, however, accumulating data indicate that molecular subtyping based on somatic oncogenic alterations along with gene expression profiling can better predict clinical behavior and may provide opportunities to incorporate oncogene-specific inhibitory therapy to improve the response to radioactive iodine (RAI). In this issue of the JCI, Y.A. Lee, H. Lee, and colleagues showed that oncogenic fusions were more commonly associated with invasive disease, increased expression of MAPK signaling pathway genes (ERK score), and decreased expression of the sodium-iodine symporter, which was restored by RET- and NTRK-inhibitory therapy. These findings lend credence to the idea of reclassifying pediatric thyroid cancers using a three-tiered system, rather than the two-tiered adult system, and open avenues for the treatment of progressive, RAI-refractory PTC in patients.
Treatment of Acute Uncomplicated Appendicitis
Authors: David A. Talan, Salomone Di Saverio
Journal: New England Journal of Medicine (2021)

Treatment for acute uncomplicated appendicitis may involve appendectomy or nonoperative care (pain control, antibiotics, and careful follow-up). The advantages and disadvantages of each should be discussed with the patient. Over 5 years, 30 to 40% of patients who received antibiotics will undergo appendectomy, although the range may vary, depending on patient characteristics and practice patterns.
The association of access to systemic therapy and overall survival in metastatic bladder cancer in Russia: An analysis of URRU register.
Authors: Vladislav Petkau, Galina Alekseeva, Ruslan Zukov, Mikhail Mazhbich, Galina Statsenko, Liubov Yu Vladimirova, Olga Novikova, Andrey Semenov, Igor Zaitsev, Ludmila Gurina, Ilya Tsimafeyeu
Journal: Journal of Clinical Oncology (2021)

88 Background: Social, economic and community disadvantages are well-described for metastatic bladder cancer (mBC) in different geographical regions. For the first time in Russian Federation we investigated treatment options and survival disparities for patients with mBC including urothelial cancer in URRU register. Methods: Patients were retrospectively identified at 9 cancer centers in southern, central, and eastern regions of Russia (Astrakhan, Ekaterinburg, Ivanovo, Khabarovsk, Krasnoyarsk, Moscow, Omsk, Rostov-on-Don, Vladivostok). Patients were included in the study if histologically confirmed mBC was diagnosed between January 2017 and January 2018 and they had at least one visit to the cancer center during the follow-up period. Anonymised data were collected by online registry. The outcomes of interest were overall survival (OS), patient characteristics and treatment patterns. Results: 246 adult patients were included in the study for analysis. Mean number of patients in one region per year was 31. All patients had metastatic disease. Median age at diagnosis of mBC was 72 (37-99) years (with 60.6% of patients aged ≥70 years). Patients were predominantly male (75%), histological subtype of BC (urothelial carcinoma, etc.) was determined in 70.32%. 92 (37.4%) patients received systemic therapy for mBC. Despite the approved checkpoint inhibitors for mBC in 2017-2018 in Russia the main treatment option was chemotherapy (n=70; 76%). Multivariate analysis by adjusting demographic and cancer variables showed that non-receipt of systemic therapy was independently associated with higher odds of death (Odds Ratio=3.1, confidence interval (CI)=1.89 to 5.18). Median OS (21 months; 95% CI 17.38-24.62) of patients who received systemic therapy was significantly longer than that of patients who did not received the therapy (3 months; 95% CI 1.79-4.22; p&lt;0.0001). Patients receiving immunotherapy had better survival outcomes comparing to chemotherapy (median OS 34.5 vs. 18 months, p=0.003). Conclusions: In Russia only one third of patients with mBC received systemic therapy for metastatic disease which affected OS. Consistent with other studies these results indicate that patients should have access to novel therapies.
Phenotype Bias Determines How Natural RNA Structures Occupy the Morphospace of All Possible Shapes
Authors: Kamaludin Dingle, Fatme Ghaddar, Petr Šulc, Ard A Louis
Journal: Molecular Biology and Evolution (2021)

Morphospaces-representations of phenotypic characteristics-are often populated unevenly, leaving large parts unoccupied. Such patterns are typically ascribed to contingency, or else to natural selection disfavoring certain parts of the morphospace. The extent to which developmental bias, the tendency of certain phenotypes to preferentially appear as potential variation, also explains these patterns is hotly debated. Here we demonstrate quantitatively that developmental bias is the primary explanation for the occupation of the morphospace of RNA secondary structure (SS) shapes. Upon random mutations, some RNA SS shapes (the frequent ones) are much more likely to appear than others. By using the RNAshapes method to define coarse-grained SS classes, we can directly compare the frequencies that noncoding RNA SS shapes appear in the RNAcentral database to frequencies obtained upon a random sampling of sequences. We show that: 1) only the most frequent structures appear in nature; the vast majority of possible structures in the morphospace have not yet been explored; 2) remarkably small numbers of random sequences are needed to produce all the RNA SS shapes found in nature so far; and 3) perhaps most surprisingly, the natural frequencies are accurately predicted, over several orders of magnitude in variation, by the likelihood that structures appear upon a uniform random sampling of sequences. The ultimate cause of these patterns is not natural selection, but rather a strong phenotype bias in the RNA genotype-phenotype map, a type of developmental bias or "findability constraint," which limits evolutionary dynamics to a hugely reduced subset of structures that are easy to "find."
Identification of resident memory CD8 <sup>+</sup> T cells with functional specificity for SARS-CoV-2 in unexposed oropharyngeal lymphoid tissue
Authors: Julia Niessl, Takuya Sekine, Joshua Lange, Viktoria Konya, Marianne Forkel, Jovana Maric, Anna Rao, Luca Mazzurana, Efthymia Kokkinou, Whitney Weigel, Sian Llewellyn-Lacey, Emma B. Hodcroft, Annika C. Karlsson, Johan Fehrm, Joar Sundman, David A. Price, Jenny Mjösberg, Danielle Friberg, Marcus Buggert
Journal: Science Immunology (2021)

Tissue-resident memory CD8 + T cells in unexposed oropharyngeal lymphoid tissue exhibit specificity for SARS-CoV-2.
A comparative analysis of attribution methods for newly diagnosed cancer patients to hospitals in oncology care.
Authors: Anamika Chaudhuri
Journal: Journal of Clinical Oncology (2021)

60 Background: Attribution is the term that describes how payers and employers determine which provider is responsible for a member’s care, when prospective patient selection is not available. Several claims-based attribution models exist for primary care. The challenges of attribution become salient in oncology because cancer care is often multidisciplinary—involving medical oncologists, surgeons, and radiation oncologists—rendering it difficult to discern which practice should be held accountable. Given the uniqueness of the population the generic primary care attribution model does not fit well. Methods: The objective of this study was to propose and compare methods that attribute patients to hospitals using administrative databases. The models were defined as pre-specified rules that determine the specific patients, types of health care services, and the duration of care for which providers are responsible. Both National Medicare database and Statewide All Payers Claims Database (2014-2015) were used for the purpose to analyze Medicare and commercial population. Two different methods with 6 and 12-months episodes were compared. Method 1 defined episode trigger as first diagnosis of cancer and Method 2 as first treatment of cancer, both with no prior 12 months of cancer diagnosis. Patients were attributed to a hospital based on plurality of claims (including both outpatient and inpatient) with a minimum threshold of 2 claims from the same hospital. Ties were broken with the most recent visit, if not, the highest cost. Success measure was defined as highest attribution rate vs. lowest feasible unassigned rate. Results: A total of 1.7 million patients were included in the Medicare cohort and 98,005 from All Payers Claims database (APCD). Results suggested for a 6 months episode, Method 1 vs. Method 2 attributed 94% vs. 98% to a hospital. For a 12-months episode, Method 1 vs. Method 2 attributed 96% vs. 98% to a hospital. Similar results were evident from APCD. It was evident attribution of patients were higher towards their first diagnosed hospital. Also, longer the duration of care, better the attribution. The outcome of the study was a tool in tableau. Conclusions: Attribution is not a problem to be solved and left alone; it requires ongoing work, enhancements. This study results in a framework for attribution that can be used as a mechanism to link indicators of patient-level health care quality and spending to specific providers for the purpose of profiling and accountability. Better systems will seek to identify specific care for a condition based on the types of doctors a patient is seeing (chemotherapy), and identify who is delivering most of that care vs. who is delivering different types of care (surgery, radiation, primary care).
#JACCCardioOnc
Authors: Sherry-Ann Brown, Eric H. Yang, Nosheen Reza, Avirup Guha, Roohi Ismail-Khan, Naveen Pemmaraju, Michael G. Fradley, Juan Lopez-Mattei
Journal: JACC CardioOncology (2021)

Author(s): Brown, Sherry-Ann; Yang, Eric H; Reza, Nosheen; Guha, Avirup; Ismail-Khan, Roohi; Pemmaraju, Naveen; Fradley, Michael G; Lopez-Mattei, Juan
A bone-targeted engineered exosome platform delivering siRNA to treat osteoporosis
Authors: Yongzhi Cui, Yuanyuan Guo, Li Kong, Jingyu Shi, Ping Liu, Rui Li, Yongtao Geng, Weihang Gao, Zhiping Zhang, Dehao Fu
Journal: Bioactive Materials (2021)

The complex pathogenesis of osteoporosis includes excessive bone resorption, insufficient bone formation and inadequate vascularization, a combination which is difficult to completely address with conventional therapies. Engineered exosomes carrying curative molecules show promise as alternative osteoporosis therapies, but depend on specifically-functionalized vesicles and appropriate engineering strategies. Here, we developed an exosome delivery system based on exosomes secreted by mesenchymal stem cells (MSCs) derived from human induced pluripotent stem cells (iPSCs). The engineered exosomes BT-Exo-siShn3, took advantage of the intrinsic anti-osteoporosis function of these special MSC-derived exosomes and collaborated with the loaded siRNA of the Shn3 gene to enhance the therapeutic effects. Modification of a bone-targeting peptide endowed the BT-Exo-siShn3 an ability to deliver siRNA to osteoblasts specifically. Silencing of the osteoblastic Shn3 gene enhanced osteogenic differentiation, decreased autologous RANKL expression and thereby inhibited osteoclast formation. Furthermore, Shn3 gene silencing increased production of SLIT3 and consequently facilitated vascularization, especially formation of type H vessels. Our study demonstrated that BT-Exo-siShn3 could serve as a promising therapy to kill three birds with one stone and implement comprehensive anti-osteoporosis effects.
Exploring the challenges of accessing medication for patients with cystic fibrosis
Authors: Sophie Herbert, Nicola Jane Rowbotham, Sherie Smith, Patrick Wilson, Zoe C Elliott, Paul A Leighton, Alistair Duff, Alan Robert Smyth
Journal: Thorax (2021)

Reducing treatment burden in cystic fibrosis (CF) is the top research priority for patients and clinicians. Difficulty accessing medication is one aspect of treatment burden. We investigated this with an online survey available globally for patients with CF and healthcare professionals. Almost three quarters of patients with CF in our survey report difficulty getting repeat prescriptions on time, and most community pharmacists experience interrupted supplies of CF-specific medications. These barriers affect emotional and physical health of people with CF. Two-thirds of people with CF would like to get all their CF medication from one place, their CF centre.
Combination treatment with rituximab, low-dose cyclophosphamide and plasma exchange for severe antineutrophil cytoplasmic antibody-associated vasculitis
Authors: Kavita Gulati, Helena Edwards, Maria Prendecki, Thomas D. Cairns, Marie Condon, Jack Galliford, Megan Griffith, Jeremy B. Levy, Frederick W.K. Tam, Anisha Tanna, Charles D. Pusey, Stephen P. McAdoo
Journal: Kidney International (2021)

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis can present with life-threatening lung-kidney syndromes. However, many controlled treatment trials excluded patients with diffuse alveolar hemorrhage or severely impaired glomerular filtration rates, and so the optimum treatment in these cases is unclear. In this retrospective cohort study, we report the outcomes of 64 patients with life-threatening disease treated with a combination regimen of rituximab, low-dose intravenous cyclophosphamide, oral glucocorticoids, and plasma exchange. At entry, the median estimated glomerular filtration rate was 9 mL/min, 47% of patients required dialysis, and 52% had diffuse alveolar hemorrhage. All patients received a minimum of seven plasma exchanges, and the median cumulative doses of rituximab, cyclophosphamide, and glucocorticoid were 2, 3, and 2.6 g, respectively, at six months. A total of 94% of patients had achieved disease remission (version 3 Birmingham Vasculitis Activity Score of 0) at this time point, and 67% of patients who required dialysis recovered independent kidney function. During long-term follow-up (median duration 46 months), overall patient survival was 85%, and 69% of patients remained free from end-stage kidney disease, which compares favorably to a historic cohort with severe disease treated with a conventional induction regimen. Combination treatment was associated with prolonged B cell depletion and low rates of relapse; 87% of patients were in continuous remission at month 36. The serious infection rate during total follow-up was 0.28 infections/patient/year, suggesting that combination treatment is not associated with an enduring risk of infection. Thus, we suggest that combination immunosuppressive therapy may permit glucocorticoid avoidance and provide rapid and prolonged disease control in patients with severe ANCA-associated vasculitis.
Genomic and functional characterization of a mucosal symbiont involved in early-stage colorectal cancer
Authors: Melissa C. Kordahi, Ian B. Stanaway, Marion Avril, Denise Chac, Marie-Pierre Blanc, Benjamin Ross, Christian Diener, Sumita Jain, Paul McCleary, Anika Parker, Vincent Friedman, Jennifer Huang, Wynn Burke, Sean M. Gibbons, Amy D. Willis, Richard P. Darveau, William M. Grady, Cynthia W. Ko, R. William DePaolo
Journal: Cell Host & Microbe (2021)
Lung cancer mortality reduction by LDCT screening: UKLS randomised trial results and international meta-analysis
Authors: John K. Field, Daniel Vulkan, Michael P.A. Davies, David R. Baldwin, Kate E. Brain, Anand Devaraj, Tim Eisen, John Gosney, Beverley A. Green, John A. Holemans, Terry Kavanagh, Keith M. Kerr, Martin Ledson, Kate J. Lifford, Fiona E. McRonald, Arjun Nair, Richard D. Page, Mahesh K.B. Parmar, Doris M. Rassl, Robert C. Rintoul, Nicholas J. Screaton, Nicholas J. Wald, David Weller, David K. Whynes, Paula R. Williamson, Gasham Yadegarfar, Rhian Gabe, Stephen W. Duffy
Journal: The Lancet Regional Health - Europe (2021)

BackgroundThe NLST reported a significant 20% reduction in lung cancer mortality with three annual low-dose CT (LDCT) screens and the Dutch-Belgian NELSON trial indicates a similar reduction. We present the results of the UKLS trial.MethodsFrom October 2011 to February 2013, we randomly allocated 4 055 participants to either a single invitation to screening with LDCT or to no screening (usual care). Eligible participants (aged 50–75) had a risk score (LLPv2) ≥ 4.5% of developing lung cancer over five years. Data were collected on lung cancer cases to 31 December 2019 and deaths to 29 February 2020 through linkage to national registries. The primary outcome was mortality due to lung cancer. We included our results in a random-effects meta-analysis to provide a synthesis of the latest randomised trial evidence.Findings1 987 participants in the intervention and 1 981 in the usual care arms were followed for a median of 7.3 years (IQR 7.1–7.6), 86 cancers were diagnosed in the LDCT arm and 75 in the control arm. 30 lung cancer deaths were reported in the screening arm, 46 in the control arm, (relative rate 0.65 [95% CI 0.41–1.02]; p=0.062). The meta-analysis indicated a significant reduction in lung cancer mortality with a pooled overall relative rate of 0.84 (95% CI 0.76–0.92) from nine eligible trials.InterpretationThe UKLS trial of single LDCT indicates a reduction of lung cancer death of similar magnitude to the NELSON and NLST trials and was included in a meta-analysis of nine randomised trials which provides unequivocal support for lung cancer screening in identified risk groups.FundingNIHR Health Technology Assessment programme; NIHR Policy Research programme; Roy Castle Lung Cancer Foundation.
Assessment of Hearing Screening Combined With Limited and Expanded Genetic Screening for Newborns in Nantong, China
Authors: Qing-Wen Zhu, Mu-Ting Li, Xun Zhuang, Kai Chen, Wan-Qing Xu, Yin-Hua Jiang, Gang Qin
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Early identification and intervention for newborns with hearing loss (HL) may lead to improved physiological and social-emotional outcomes. The current newborn hearing screening is generally beneficial but improvements can be made. <h3>Objective</h3> To assess feasibility and evaluate utility of a modified genetic and hearing screening program for newborn infants. <h3>Design, Setting, and Participants</h3> This population-based cohort study used a 4-stage genetic and hearing screening program at 6 local hospitals in Nantong city, China. Participants were newborn infants born between January 2016 and June 2020 from the Han population. Statistical analysis was performed from April 1 to May 1, 2021. <h3>Exposures</h3> Limited genetic screening for 15 variants in 4 common HL-associated genes and newborn hearing screening (NHS) were offered concurrently to all newborns. Hearing rescreening and/or diagnostic tests were provided for infants with evidence of HL on NHS or genetic variants on screening. Expanded genetic tests for a broader range of genes were targeted to infants with HL with negative results of limited genetic tests. <h3>Main Outcomes and Measures</h3> The detection capability for infants with hearing impairment who passed conventional hearing screening, as well as infants with normal hearing at risk of late-onset HL due to genetic susceptibility. <h3>Results</h3> Among a total of 35 930 infants, 32 512 infants completed the follow-up and were included for analysis. Among the infants included in the analysis, all were from the Han population in China and 52.3% (16 988) were male. The modified genetic and hearing screening program revealed 142 cases of HL and 1299 cases of genetic variation. The limited genetic screening helped identify 31 infants who passed newborn hearing screening, reducing time for diagnosis and intervention; 425 infants with normal hearing with pathogenic<i>SLC26A4</i>variation and 92 infants with<i>MT-RNR1</i>variation were at risk for enlarged vestibular aqueduct and aminoglycoside-induced ototoxicity respectively, indicating early aversive or preventive management. <h3>Conclusions and Relevance</h3> This study found that performing modified genetic and hearing screening in newborns was feasible and provides evidence that the program could identify additional subgroups of infants who need early intervention. These findings suggest an advantage for universal adoption of such a practice.
Radioactive Iodine Treatment in Hyperthyroidism and Cancer Mortality—A Still Controversial Issue
Authors: Bernadette Biondi
Journal: JAMA Network Open (2021)

Sung Ryul Shim, PhD; Cari M. Kitahara, PhD; Eun Shil Cha, PhD; Seong-Jang Kim, MD, PhD; Ye Jin Bang, MPH; Won Jin Lee, MD, PhD
LEFTY-PITX2 signaling pathway is critical for generation of mature and ventricular cardiac organoids in human pluripotent stem cell-derived cardiac mesoderm cells
Authors: Myeong-Hwa Song, Seung-Cheol Choi, Ji-Min Noh, Hyung Joon Joo, Chi-Yeon Park, Jung-Joon Cha, Tae Hoon Ahn, Tae Hee Ko, Jong-Il Choi, Ji Eun Na, Im Joo Rhyu, Yongjun Jang, Yongdoo Park, Jeong-An Gim, Jong-Hoon Kim, Do-Sun Lim
Journal: Biomaterials (2021)