tbuckley/cabot-search huggingface dataset:
Epigenetic reprogramming to prevent genetic cardiomyopathy
Authors: Jamie R. Johnston, Daniel F. Selgrade, Elizabeth M. McNally
Journal: Journal of Clinical Investigation (2021)

Mutations in the gene that codes for lamin A/C (LMNA) are a common cause of adult-onset cardiomyopathy and heart failure. In this issue of the JCI, Guénantin and Jebeniani et al. identify impaired cardiomyocyte development and maturation as a prenatal feature in a model of laminopathy. Cardiomyocytes carrying the Lmna point mutation H222P misexpressed genes involved in the epithelial-mesenchymal transition and showed decreased methylation at the fourth lysine of histone H3 (H3K4). Notably, inhibiting lysine-specific demethylase 1 in the LMNA H222P mouse model treated this congenital form of cardiomyopathy and improved survival in utero. These data highlight early epigenomic modifications in lamin A/C-mediated pathology and indicate a unique therapeutic strategy for cardiomyopathy.
Critical Periods in Child Development and the Transition to Adulthood
Authors: Gloria Huei-Jong Graf, Pietro Biroli, Daniel W. Belsky
Journal: JAMA Network Open (2021)

Adverse childhood experiences (ACEs) can affect development in ways that disrupt the formation of human capital and contribute to later-life morbidity and mortality.Theories of development predict that the timing of adversity will affect its outcomes.However, empirical evidence for timing-specific effects remains scant.In this issue of JAMA Network Open, Andersen 1 reports an analysis of population-register data from Denmark that suggests timing-specific associations of household dysfunction ACEs with young people's successful transition to adulthood.Andersen's study 1 linked data from several Danish registers to compose records tracking children born between 1987 and 1995 and their families from the child's birth until they reached age 19 years.The analysis tested how exposure to household dysfunction ACEs during ages 0 to 2, 3 to 5, 6 to 12, and 13 to 17 years were associated with disruptions in children's transition to adulthood.Children's ACE exposure was measured from records of parental unemployment, incarceration, psychiatric diagnoses, and divorce as well as children's placement in foster care.Disruption to the transition to adulthood was measured from records of education, employment, criminal charges, and psychiatric diagnoses.Andersen's analysis 1 compared siblings in the same family who experienced household dysfunction ACEs at different stages of development, eg, when a younger sibling's early-childhood exposure was simultaneously their older sibling's middle-childhood exposure.Using this sibling comparison design, Andersen identified a dose-response association between accumulation of ACEs and increased likelihood of experiencing disruption to the transition to adulthood.Adversity exposures during adolescence (ages 13-17 years) had larger magnitude risk associations compared with adversities that occurred earlier in development.Effect sizes for adolescent exposures were nearly 2-fold those for exposures in middle childhood and more than 3-fold those for exposures earlier in life.The findings of
Cost-Effectiveness of First-Line Versus Second-Line Use of Daratumumab in Older, Transplant-Ineligible Patients With Multiple Myeloma
Authors: Kishan K. Patel, Smith Giri, Terri L. Parker, Noffar Bar, Natalia Neparidze, Scott F. Huntington
Journal: Journal of Clinical Oncology (2021)

PURPOSE The MAIA trial found that addition of daratumumab to lenalidomide and dexamethasone (DRd) significantly prolonged progression-free survival in transplant-ineligible patients with newly diagnosed multiple myeloma, compared with lenalidomide and dexamethasone alone (Rd). However, daratumumab is a costly treatment and is administered indefinitely until disease progression. Therefore, it is unclear whether it is cost-effective to use daratumumab in the first-line setting compared with reserving its use until later lines of therapy. METHODS We created a Markov model to compare healthcare costs and clinical outcomes of transplant-ineligible patients treated with daratumumab in the first-line setting compared with a strategy of reserving daratumumab until the second-line. We estimated transition probabilities from randomized trials using parametric survival modeling. Lifetime direct healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for first-line daratumumab versus second-line daratumumab from a US payer perspective. RESULTS First-line daratumumab was associated with an improvement of 0.52 QALYs and 0.66 discounted life-years compared with second-line daratumumab. While both treatment strategies were associated with considerable lifetime expenditures ($1,434,937 v $1,112,101 in US dollars), an incremental cost of $322,836 for first-line daratumumab led to an ICER of $618,018 per QALY. The cost of daratumumab would need to be decreased by 67% for first-line daratumumab to be cost-effective at a willingness-to-pay threshold of $150,000 per QALY. CONCLUSION Using daratumumab in the first-line setting for transplant-ineligible patients may not be cost-effective under current pricing. Delaying daratumumab until subsequent lines of therapy may be a reasonable strategy to limit healthcare costs without significantly compromising clinical outcomes. Mature overall survival data are necessary to more fully evaluate cost-effectiveness in this setting.
Dismantling Structural Discrimination in Cardiology Fellowship Recruitment
Authors: Joyce Njoroge, Fatima Rodriguez, Michelle A. Albert
Journal: JAMA Network Open (2021)

Jennifer A. Rymer, MD, MBA; Camille G. Frazier-Mills, MD, MHS; Larry R. Jackson II, MD, MHS; Kevin L. Thomas, MD; Pamela S. Douglas, MD; Andrew Wang, MD; Manesh R. Patel, MD; Anna Lisa Crowley, MD
Correspondence to ‘Bacterial citrullinated epitopes generated by<i>Porphyromonas gingivalis</i>infection—a missing link for ACPA production’
Authors: Kevin Sheng-Kai Ma, Cho-Han Chiang, Yi-Wen Chen, Li-Tzu Wang
Journal: Annals of the Rheumatic Diseases (2021)

With great interest, we read the work by Jenning et al , which proposed a mechanism by which Porphyromonas gingivalis (P.g .) is involved in rheumatoid arthritis (RA) progression by citrullinating and producing exogenously citrullinated human and bacterial epitopes.1 This commendable work elucidated the mechanism by which autocitrullinated prokaryotic peptidyl arginine deiminase (PPAD) mediates the inflammatory pathogenesis of RA. In particular, the authors demonstrated a correlation between anti-RA-PPAD and both anticitrullinated peptide/protein antibody (ACPA) levels and interstitial lung disease autoantigen reactivity. The study also provided evidence regarding how PPAD citrullinates the internal arginines of RA autoantigens.1 Moreover, the findings of this study suggested that the failure to clear P.g . induces bacterial citrullinated epitope-specific ACPAs, which might trigger ACPA-mediated autoimmunity.1 P.g . is the main pathogen responsible for periodontitis and has been proposed to be involved in stimulating self-reactive immune responses,2 3 which underlie the association …
Neoadjuvant Chemotherapy in Pancreatic Cancer
Authors: Ankit Jain, Desmond Yip, Sivakumar Gananadha
Journal: JAMA Surgery (2021)

To the Editor We congratulate Perri et al for publishing the comparative analysis of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) vs gemcitabine and nab-paclitaxel chemotherapy for localized pancreatic adenocarcinoma (PDAC).1
Mitigation Policies and COVID-19–Associated Mortality — 37 European Countries, January 23–June 30, 2020
Authors: James A. Fuller, Avi Hakim, Kerton R. Victory, Kashmira Date, Michael Lynch, Benjamin Dahl, Olga Henao
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Response Team * Mitigation policies implemented by government authorities during
Complement C3a receptor–mediated vascular dysfunction: a complex interplay between aging and neurodegeneration
Authors: Kanchan Bhatia, Saif Ahmad, Adam Kindelin, Andrew F. Ducruet
Journal: Journal of Clinical Investigation (2021)

Vascular dysfunction resulting in compromised blood-brain barrier (BBB) integrity is evident in aging and disease. Although the complement C3a/C3a receptor (C3a/C3aR) axis influences normal brain aging and disease progression, the mechanisms governing endothelial C3aR-mediated neurovascular inflammation and BBB permeability remain unexplored. In this issue of the JCI, Propson et al. investigated endothelial C3a/C3aR signaling in normal, aged, and neurodegenerative mouse models. Endothelial C3aR signaling modulated age-dependent increases in VCAM1, initiated peripheral lymphocyte infiltration, and enhanced microglial activity. Increased calcium release downstream of C3aR signaling disrupted the vascular endothelial cadherin (VE-cadherin) junctions, increased BBB permeability, and degraded vascular structure and function. Mice lacking C3aR (C3ar1-/-) and mice treated with a C3aR antagonist showed attenuated age-related microglial reactivity and neurodegeneration. These results confirm that complement-mediated signaling impacts vascular health and BBB function in normal aging and neurodegenerative disease, suggesting that complement inhibitors represent a therapeutic option for cerebral microvascular dysfunction.
Respiratory Effects of Sedentary Ozone Exposure at the 70-ppb National Ambient Air Quality Standard: A Randomized Clinical Trial
Authors: Michelle L. Hernandez, Sally Ivins, Kelly Chason, Allison J. Burbank, Meghan E. Rebuli, Aaron Kobernick, Stephen A. Schworer, Haibo Zhou, Neil E. Alexis, David B. Peden
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

"Respiratory Effects of Sedentary Ozone Exposure at the 70-ppb National Ambient Air Quality Standard: A Randomized Clinical Trial." American Journal of Respiratory and Critical Care Medicine, 203(7), pp. 910–913
춘계학술대회 : 구연 ; 간경변 환자에서 문맥압 항진증의 진단과 약물요법에 따른 평가 방법으로서 간정맥 도플러 초음파 검사의 유용성
Authors: 백순구, 김재우, 원찬식, 변종원, 지명관, 김현수, 권상옥, 김영주, 박중화, 김성현
Journal: Clinical and Molecular Hepatology (2005)

배경/목적: 정상 간정맥 도플러 초음파 파형은 삼위상 파형(triphasic waveform)이나, 간경변증 환자에서는 비정상적으로 이위상(biphasic)이나 단위상(monophasic) 파형을 보인다. 이에 본 연구자들은 간정맥 도플러 파형과 문맥압 항진증간의 상관관계를 알아보고, 문맥압 강하를 일으키는 terlipressin 투여 전 후에 간정맥 도플러 파형의 변화를 비교 분석함으로써, 간정맥 도플러 초음파검사가 문맥압 항진증의 진단과 약물 치료의
Using Prediction Models to Reduce Persistent Racial and Ethnic Disparities in the Draft 2020 USPSTF Lung Cancer Screening Guidelines
Authors: Rebecca Landy, Corey D Young, Martin Skarzynski, Li C Cheung, Christine D Berg, M Patricia Rivera, Hilary A Robbins, Anil K Chaturvedi, Hormuzd A Katki
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract We examined whether draft 2020 United States Preventive Services Task Force (USPSTF) lung cancer screening recommendations “partially ameliorate racial disparities in screening eligibility” compared with the 2013 guidelines, as claimed. Using data from the 2015 National Health Interview Survey, USPSTF-2020 increased eligibility by similar proportions for minorities (97.1%) and Whites (78.3%). Contrary to the intent of USPSTF-2020, the relative disparity (differences in percentages of model-estimated gainable life-years from National Lung Screening Trial–like screening by eligible Whites vs minorities) actually increased from USPSTF-2013 to USPSTF-2020 (African Americans: 48.3%–33.4% = 15.0% to 64.5%–48.5% = 16.0%; Asian Americans: 48.3%–35.6% = 12.7% to 64.5%–45.2% = 19.3%; Hispanic Americans: 48.3%–24.8% = 23.5% to 64.5%–37.0% = 27.5%). However, augmenting USPSTF-2020 with high-benefit individuals selected by the Life-Years From Screening with Computed Tomography (LYFS-CT) model nearly eliminated disparities for African Americans (76.8%–75.5% = 1.2%) and improved screening efficiency for Asian and Hispanic Americans, although disparities were reduced only slightly (Hispanic Americans) or unchanged (Asian Americans). The draft USPSTF-2020 guidelines increased the number of eligible minorities vs USPSTF-2013 but may inadvertently increase racial and ethnic disparities. LYFS-CT could reduce disparities in screening eligibility by identifying ineligible people with high predicted benefit regardless of race and ethnicity.
Clinical characteristics and outcomes of primary versus secondary gastrointestinal mantle cell lymphoma
Authors: Alessia Castellino, Aung M. Tun, Yucai Wang, Thomas M. Habermann, Rebecca L. King, Kay M. Ristow, James R. Cerhan, David J. Inwards, Jonas Paludo, Stephen M. Ansell, Thomas E. Witzig, Grzegorz S. Nowakowski
Journal: Blood Cancer Journal (2021)

Abstract Primary gastrointestinal (GI) mantle cell lymphoma (MCL) is rare and the optimal management is unknown. We reviewed 800 newly diagnosed MCL cases and found 22 primary (2.8%) and 79 (9.9%) secondary GI MCL cases. Age, sex, and performance status were similar between primary and secondary cases. Secondary cases had more elevations in lactate dehydrogenase (28% vs 0%, P = 0.03) and a trend for a higher MCL international prognostic index ( P = 0.07). Observation or local therapy was more common for primary GI MCL (29% vs 8%, P &lt; 0.01), and autologous stem-cell transplant was more common for secondary GI MCL (35% vs 14%, P &lt; 0.05). The median follow-up was 85 months. Primary and secondary GI MCL had similar 5-year progression-free survival (PFS) (30% vs 28%, P = 0.59) and overall survival (OS) (65% vs 66%, P = 0.83). The extent of GI involvement in primary GI MCL affected treatment selection but not outcome, with a 5-year PFS of 43% vs 14% vs 31% ( P = 0.48) and OS of 57% vs 71% vs 69% ( P = 0.54) in cases with single lesion vs multiple lesions in 1 organ vs multiple lesions in ≥2 organs. Less aggressive frontline treatment for primary GI MCL is reasonable. It is unknown whether more aggressive treatment can result in improved outcomes.
Lateral flow tests need low false positives for antibodies and low false negatives for virus
Authors: Keith A Moyse
Journal: BMJ (2021)

The relative importance of the sensitivity and the specificity of lateral flow devices (LFDs) depends on the intended use.

LFDs that are being piloted for the detection of antigens need to have high sensitivity in order to detect the virus in those who should isolate. A false positive, on the other hand, merely risks someone self-isolating unnecessarily.

The reverse is true …
Abstract 15758: Sca-1+ Progenitor Cell Migration Induced by Leptin Enhances Neointima Lesions in Wild-type and db/db Mice
Authors: Yao Xie, Claire Potter, Yanhua Hu, Qingbo Xu
Journal: Circulation (2017)

Introduction: Leptin predominantly secreted by white adipose tissue plays a role in inflammation and vascular disease, to which Sca-1+ vascular progenitor cells within the vessel wall may contribut...
Association of Fresh Embryo Transfers Compared With Cryopreserved-Thawed Embryo Transfers With Live Birth Rate Among Women Undergoing Assisted Reproduction Using Freshly Retrieved Donor Oocytes
Authors: Iris G. Insogna, Andrea Lanes, Malinda S. Lee, Elizabeth S. Ginsburg, Janis H. Fox
Journal: JAMA (2021)

<h3>Importance</h3> In in vitro fertilization cycles using autologous oocytes, data have demonstrated higher live birth rates following cryopreserved-thawed embryo transfers compared with fresh embryo transfers. It remains unknown if this association exists in cycles using freshly retrieved donor oocytes. <h3>Objective</h3> To test the hypothesis that in freshly retrieved donor oocyte cycles, a fresh embryo transfer is more likely to result in a live birth compared with a cryopreserved-thawed embryo transfer. <h3>Design, Setting, and Participants</h3> Retrospective cohort study using national data collected from the Society for Assisted Reproductive Technology for 33 863 recipients undergoing fresh donor oocyte cycles in the US between January 1, 2014 and December 31, 2017. <h3>Exposures</h3> Fresh embryo transfer and cryopreserved-thawed embryo transfer. <h3>Main Outcomes and Measures</h3> The primary outcome was live birth rate; secondary outcomes were clinical pregnancy rate and miscarriage rate. Analyses were adjusted for donor age, day of embryo transfer, use of a gestational carrier, and assisted hatching. <h3>Results</h3> Recipients of fresh and cryopreserved-thawed embryos had comparable median age (42.0 [interquartile range {IQR}, 37.0-44.0] years vs 42.0 [IQR, 36.0-45.0] years), gravidity (1 [IQR, 0-2] vs 1 [IQR, 0-3]), parity (0 [IQR, 0-1] vs 1 [IQR, 0-1]), and body mass index (24.5 [IQR, 21.9-28.7] vs 24.4 [IQR, 21.6-28.7]). Of a total of 33 863 recipients who underwent 51 942 fresh donor oocyte cycles, there were 15 308 (29.5%) fresh embryo transfer cycles and 36 634 (70.5%) cryopreserved-thawed embryo transfer cycles. Blastocysts were transferred in 92.4% of fresh embryo transfer cycles and 96.5% of cryopreserved-thawed embryo transfer cycles, with no significant difference in the mean number of embryos transferred. Live birth rate following fresh embryo transfer vs cryopreserved-thawed embryo transfer was 56.6% vs 44.0% (absolute difference, 12.6% [95% CI, 11.7%-13.5%]; adjusted relative risk [aRR], 1.42 [95% CI, 1.39-1.46]). Clinical pregnancy rates were 66.7% vs 54.2%, respectively (absolute difference, 12.5% [95% CI, 11.6%-13.4%]; aRR, 1.34; [95% CI, 1.31-1.37]). Miscarriage rates were 9.3% vs 9.4%, respectively (absolute difference, 0.2% [95% CI, −0.4% to 0.7%]); aRR, 0.98 [95% CI, 0.91-1.07]). <h3>Conclusions and Relevance</h3> In this retrospective cohort study of women undergoing assisted reproduction using freshly retrieved donor oocytes, the use of fresh embryo transfers compared with cryopreserved-thawed embryo transfers was associated with a higher live birth rate. However, interpretation of the findings is limited by the potential for selection and confounding bias.
Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion
Authors: Nicole E. Scharping, Dayana B. Rivadeneira, Ashley V. Menk, Paolo D. A. Vignali, B. Rhodes Ford, Natalie L. Rittenhouse, Ronal Peralta, Yiyang Wang, Yupeng Wang, Kristin DePeaux, Amanda C. Poholek, Greg M. Delgoffe
Journal: Nature Immunology (2021)
E7386, a Selective Inhibitor of the Interaction between β-Catenin and CBP, Exerts Antitumor Activity in Tumor Models with Activated Canonical Wnt Signaling
Authors: Kazuhiko Yamada, Yusaku Hori, Satoshi Inoue, Yuji Yamamoto, Kentaro Iso, Hiroshi Kamiyama, Atsumi Yamaguchi, Takayuki Kimura, Mai Uesugi, Junichi Ito, Masahiro Matsuki, Kazutaka Nakamoto, Hitoshi Harada, Naoki Yoneda, Atsushi Takemura, Ikuo Kushida, Naomi Wakayama, Kenji Kubara, Yu Kato, Taro Semba, Akira Yokoi, Masayuki Matsukura, Takenao Odagami, Masao Iwata, Akihiko Tsuruoka, Toshimitsu Uenaka, Junji Matsui, Tomohiro Matsushima, Kenichi Nomoto, Hiroyuki Kouji, Takashi Owa, Yasuhiro Funahashi, Yoichi Ozawa
Journal: Cancer Research (2021)

Abstract The Wnt/β-catenin signaling pathway plays crucial roles in embryonic development and the development of multiple types of cancer, and its aberrant activation provides cancer cells with escape mechanisms from immune checkpoint inhibitors. E7386, an orally active selective inhibitor of the interaction between β-catenin and CREB binding protein, which is part of the Wnt/β-catenin signaling pathway, disrupts the Wnt/β-catenin signaling pathway in HEK293 and adenomatous polyposis coli (APC)-mutated human gastric cancer ECC10 cells. It also inhibited tumor growth in an ECC10 xenograft model and suppressed polyp formation in the intestinal tract of ApcMin/+ mice, in which mutation of Apc activates the Wnt/β-catenin signaling pathway. E7386 demonstrated antitumor activity against mouse mammary tumors developed in mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice. Gene expression profiling using RNA sequencing data of MMTV-Wnt1 tumor tissue from mice treated with E7386 showed that E7386 downregulated genes in the hypoxia signaling pathway and immune responses related to the CCL2, and IHC analysis showed that E7386 induced infiltration of CD8+ cells into tumor tissues. Furthermore, E7386 showed synergistic antitumor activity against MMTV-Wnt1 tumor in combination with anti-PD-1 antibody. In conclusion, E7386 demonstrates clear antitumor activity via modulation of the Wnt/β-catenin signaling pathway and alteration of the tumor and immune microenvironments, and its antitumor activity can be enhanced in combination with anti-PD-1 antibody. Significance: These findings demonstrate that the novel anticancer agent, E7386, modulates Wnt/β-catenin signaling, altering the tumor immune microenvironment and exhibiting synergistic antitumor activity in combination with anti-PD-1 antibody.
Siglec15 shapes a non-inflamed tumor microenvironment and predicts the molecular subtype in bladder cancer
Authors: Jiao Hu, Anze Yu, Belaydi Othmane, Dongxu Qiu, Huihuang Li, Chao Li, Peihua Liu, Wenbiao Ren, Minfeng Chen, Guanghui Gong, Xi Guo, Huihui Zhang, Jinbo Chen, Xiongbing Zu
Journal: Theranostics (2021)

Rationale: Siglec15 is an emerging target for normalization cancer immunotherapy. However, pan-cancer anti-Siglec15 treatment is not yet validated and the potential role of Siglec15 in bladder cancer (BLCA) remains elusive. Methods: We comprehensively evaluated the expression pattern and immunological role of Siglec15 using pan-cancer analysis based on RNA sequencing data obtained from The Cancer Genome Atlas. We then systematically correlated Siglec15 with immunological characteristics in the BLCA tumor microenvironment (TME), including immunomodulators, cancer immunity cycles, tumor-infiltrating immune cells (TIICs), immune checkpoints, and T cell inflamed score. We also analyzed the role of Siglec15 in predicting the molecular subtype and the response to several treatment options in BLCA. Our results were validated in several public cohorts as well as our BLCA tumor microarray cohort, the Xiangya cohort. We developed an immune risk score (IRS), validated it, and tested its ability to predict the prognosis and response to cancer immunotherapy. Results: We found that Siglec15 was specifically overexpressed in the TME of various cancers. We hypothesize that Siglec15 designs a non-inflamed TME in BLCA based on the evidence that Siglec15 negatively correlated with immunomodulators, TIICs, cancer immunity cycles, immune checkpoints, and T cell inflamed score. Bladder cancer with high Siglec15 expression was not sensitive to cancer immunotherapy, but exhibited a higher incidence of hyperprogression. High Siglec15 levels indicated a luminal subtype of BLCA characterized by lower immune infiltration, lower response to cancer immunotherapy and neoadjuvant chemotherapy, but higher response to anti-angiogenic therapy and targeted therapies such as blocking Siglec15, β-catenin, PPAR-γ, and FGFR3 pathways. Notably, a combination of anti-Siglec15 and cancer immunotherapy may be a more effective strategy than monotherapy. IRS can accurately predict the prognosis and response to cancer immunotherapy. Conclusions: Anti-Siglec15 immunotherapy might be suitable for BLCA treatment as Siglec15 correlates with a non-inflamed TME in BLCA. Siglec15 could also predict the molecular subtype and the response to several treatment options.
Cabozantinib for neurofibromatosis type 1–related plexiform neurofibromas: a phase 2 trial
Authors: Michael J. Fisher, Chie-Schin Shih, Steven D. Rhodes, Amy E. Armstrong, Pamela L. Wolters, Eva Dombi, Chi Zhang, Steven P. Angus, Gary L. Johnson, Roger J. Packer, Jeffrey C. Allen, Nicole J. Ullrich, Stewart Goldman, David H. Gutmann, Scott R. Plotkin, Tena Rosser, Kent A. Robertson, Brigitte C. Widemann, Abbi E. Smith, Waylan K. Bessler, Yongzheng He, Su-Jung Park, Julie A. Mund, Li Jiang, Khadijeh Bijangi-Vishehsaraei, Coretta Thomas Robinson, Gary R. Cutter, Bruce R. Korf, Chie-Schin Shih, Amy E. Armstrong, Jaishri O. Blakeley, D. Wade Clapp
Journal: Nature Medicine (2021)