tbuckley/cabot-search huggingface dataset:
Antisense oligonucleotide therapy reduces seizures and extends life span in an SCN2A gain-of-function epilepsy model
Authors: Melody Li, Nikola Jancovski, Paymaan Jafar-Nejad, Lisseth E. Burbano, Ben Rollo, Kay Richards, Lisa Drew, Alicia Sedo, Jacqueline Heighway, Svenja Pachernegg, Armand Soriano, Linghan Jia, Todd Blackburn, Blaine Roberts, Alex Nemiroff, Kelley Dalby, Snezana Maljevic, Christopher A. Reid, Frank Rigo, Steven Petrou
Journal: Journal of Clinical Investigation (2021)

De novo variation in SCN2A can give rise to severe childhood disorders. Biophysical gain of function in SCN2A is seen in some patients with early seizure onset developmental and epileptic encephalopathy (DEE). In these cases, targeted reduction in SCN2A expression could substantially improve clinical outcomes. We tested this theory by central administration of a gapmer antisense oligonucleotide (ASO) targeting Scn2a mRNA in a mouse model of Scn2a early seizure onset DEE (Q/+ mice). Untreated Q/+ mice presented with spontaneous seizures at P1 and did not survive beyond P30. Administration of the ASO to Q/+ mice reduced spontaneous seizures and significantly extended life span. Across a range of behavioral tests, Scn2a ASO-treated Q/+ mice were largely indistinguishable from WT mice, suggesting treatment is well tolerated. A human SCN2A gapmer ASO could likewise impact the lives of patients with SCN2A gain-of-function DEE.
TME-targeting theranostic agent uses NIR tracking for tumor diagnosis and surgical resection and acts as chemotherapeutic showing enhanced efficiency and minimal toxicity
Authors: Zhongyuan Xu, Jianqiang Qian, Chi Meng, Yun Liu, Qian Ding, Hongmei Wu, Peng Li, Fansheng Ran, Gong-Qing Liu, Yunyun Wang, Yong Ling
Journal: Theranostics (2022)

Rationale: Precise diagnosis and effective therapy of the tumor microenvironment (TME) remains a challenge. Fluorescence tracers for monitoring primary tumors are currently reported; however, they face challenges in accurately delineating tumors in real-time during surgery, including interference from the background and insufficient accumulation of imaging reagents at tumor sites. Additionally, although the natural product podophyllotoxin (PPT) had potent and broad anti-tumor activity, the poor tumor target specificity and high toxicity of PPT extremely limited its clinical application. Methods: In the current study, a novel theranostic agent PBB was designed and synthesized by coupling the natural chemotherapeutic drug PPT with a near-infrared (NIR) fluorescence probe hemicyanine (CyOH) via redox-responsive thiolactate linker and introducing biotin to CyOH to enhance the active target ability. The activation mechanism of PBB was characterized by absorption spectra, fluorescence spectra, and HPLC. Subsequently, we investigated its imaging action, anti-tumor activity, and toxicity in vitro and in vivo. Results:In vitro experiments, PBB was verified to possess a ROS/GSH-responsive molecular switch, impelling PBB to release a fluorescent fragment and active drug PPT and selectively lighting up tumor cells but not the normal cells. As such, PBB was demonstrated to selectively inhibit the growth of tumor cells by inducing intracellular accumulation of ROS and MMP depolarization. More importantly, PBB significantly suppressed hepatic tumor growth and minimized the adverse effects caused by PPT, including acute toxicity and impaired liver function. Finally, the NIR fluorescence accumulated in the tumor tissue and stayed continuous for over 24h, and PBB provided precise visualization and highly selective fluorescence diagnosis to guide tumor resection. Conclusions: Therefore, the multilevel targeting theranostic agent provided a novel tool for precise diagnosis, real-time monitoring, and efficient tumor chemotherapy with high safety.
Association of trends in child undernutrition and implementation of the National Rural Health Mission in India: A nationally representative serial cross-sectional study on data from 1992 to 2015
Authors: Apurv Soni, Nisha Fahey, Zulfiqar Bhutta, Wenjun Li, Tiffany Moore Simas, Somashekhar Nimbalkar, Jeroan Allison
Journal: PLoS Medicine (2022)

India launched the National Rural Health Mission (NRHM) in 2005 to strengthen its primary healthcare system in high-focus and northeast-focus states. One of the NRHM objectives was to reduce child undernutrition in India.
Swarm learning for decentralized artificial intelligence in cancer histopathology
Authors: Oliver Lester Saldanha, Philip Quirke, Nicholas P. West, Jacqueline A. James, Maurice B. Loughrey, Heike I. Grabsch, Manuel Salto-Tellez, Elizabeth Alwers, Didem Cifci, Narmin Ghaffari Laleh, Tobias Seibel, Richard Gray, Gordon G. A. Hutchins, Hermann Brenner, Marko van Treeck, Tanwei Yuan, Titus J. Brinker, Jenny Chang-Claude, Firas Khader, Andreas Schuppert, Tom Luedde, Christian Trautwein, Hannah Sophie Muti, Sebastian Foersch, Michael Hoffmeister, Daniel Truhn, Jakob Nikolas Kather
Journal: Nature Medicine (2022)

Abstract Artificial intelligence (AI) can predict the presence of molecular alterations directly from routine histopathology slides. However, training robust AI systems requires large datasets for which data collection faces practical, ethical and legal obstacles. These obstacles could be overcome with swarm learning (SL), in which partners jointly train AI models while avoiding data transfer and monopolistic data governance. Here, we demonstrate the successful use of SL in large, multicentric datasets of gigapixel histopathology images from over 5,000 patients. We show that AI models trained using SL can predict BRAF mutational status and microsatellite instability directly from hematoxylin and eosin (H&amp;E)-stained pathology slides of colorectal cancer. We trained AI models on three patient cohorts from Northern Ireland, Germany and the United States, and validated the prediction performance in two independent datasets from the United Kingdom. Our data show that SL-trained AI models outperform most locally trained models, and perform on par with models that are trained on the merged datasets. In addition, we show that SL-based AI models are data efficient. In the future, SL can be used to train distributed AI models for any histopathology image analysis task, eliminating the need for data transfer.
Erratum for Euro Surveill. 2022;27(2)
Journal: Eurosurveillance (2022)

© This work is licensed under a Creative Commons Attribution 4.0 International License. Closure This is a corrected article applying to the following content: Waning antibody levels after COVID-19 vaccination with mRNA Comirnaty and inactivated CoronaVac vaccines in blood donors, Hong Kong, April 2020 to October 2021
Abstract EP01: One Size Does Not Fit All: Impact Of Using A Regular Cuff For All Blood Pressure Measurements
Authors: Tammy M Brady, Jeanne Charleston, Junichi Ishigami, Gregory P Prokopowicz, Edgar R Miller, Kunihiro Matsushita, Lawrence J Appel
Journal: Circulation (2022)

Background: Blood pressure (BP) guidelines recommend individualized cuff selection based on mid-arm circumference, but many clinics, especially in resource-constrained settings, use a regular adult cuff for all patients. Objective: Determine the effects of using a regular adult BP cuff compared to using a BP cuff that is appropriately sized for an individual’s mid-upper arm circumference. Methods: We conducted a randomized cross-over trial of 165 community-dwelling adults [mean age 55 yrs, 33% male (n=54), 68% Black (n=113)]. Participants had 2 sets of triplicate BP measurements (WelchAllyn ProB 2000) using a regular adult cuff and an appropriate cuff, in random order. Results: 30% (n=50) of the study participants had systolic BP (SBP) ≥130 mmHg, and 42% (n=69) had a BMI ≥ 30kg/m 2 . As shown in the Table , among persons who required a small adult cuff, a regular cuff resulted in significantly lower readings [SBP -3.8 (-6.3 to -1.3) and DBP -1.5 (-3.0 to -0.0) mmHg]. In contrast, among persons who required a large or extra-large adult cuff, a regular cuff was associated with significantly higher readings [SBP 4.8 (2.9 to 6.7) and 19.7 (16.3 to 23.2) mmHg, respectively]. The overestimation of BP due to undercuffing misclassified 39 % of participants with a hypertensive BP (≥130/80 mmHg) while the underestimation of BP due to overcuffing missed 22% of participants with a hypertensive BP. Conclusions: In this trial, using a regular adult cuff in all individuals resulted in striking differences in SBP and DBP. A renewed emphasis on cuff size is warranted, particularly in populations with high prevalence of obesity requiring large or extra large cuff sizes.
Abstract MP47: IFNγ-Mediated Associations Between Chronic Stress Related-Neural Activity And PCSK9: Data From The Washington, D.C. Cardiovascular Health And Needs Assessment
Authors: Lola R Ortiz-Whittingham, Yvonne Baumer, Billy Collins, Valerie Mitchell, Nicole Farmer, Tiffany M Powell-Wiley
Journal: Circulation (2022)

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player in dyslipidemia and is linked to cardiovascular disease risk. To our knowledge, the potential link between psychosocial stressors, PCSK9 levels, and related dyslipidemia has not been evaluated. Hypothesis: IFNγ mediates the association between amygdalar activity (AmygA) and PCSK9. Methods: Participants from the D.C. Cardiovascular Health and Needs Assessment (DC-CHNA), a community-engaged cohort study, were recruited to the NIH Clinical Center and underwent phenotyping, including 18 FDG PET/CT to assess AmygA as a marker of chronic stress-related neural activity. Cytokines, PCSK9, and lipoprotein (a) (Lp(a)) were measured using ELISA-based techniques. Regression modeling identified associations between AmygA and PCSK9 and between PCSK9 and Lp(a) while adjusting for atherosclerotic cardiovascular disease (ASCVD) 10-year risk score and body mass index (BMI). Mediation analysis was used to evaluate IFNγ, TNFα, and IL-6 as potential mediators. Results: The DC-CHNA consisted of 60 African American participants (mean age 61±11 years, 93% female) at risk for ASCVD. AmygA associated with PCSK9 and IFNγ after adjusting for ASCVD and BMI; additionally, IFNγ associated with PCSK9 ( Figure ). Mediation analysis indicated that IFNγ mediated 45.8% of the AmygA and PCSK9 relationship. TNFα and IL-6 did not mediate the relationship. Lastly, PCSK9 associated with Lp(a) independent of ASCVD risk factors (β=0.34, p=0.013). Conclusions: The role of psychosocial stressors in PCSK9 related-dyslipidemia is not well known. Thus, we show that AmygA, a measure of chronic stress, associated with PCSK9 in an IFNγ-mediated fashion. PCSK9 then associated with Lp(a) which is notable as Lp(a) is thought to be largely genetically determined and highly atherogenic. Future research should further this hypothesis-generating study by prospectively investigating the impact of psychosocial stressors on PCSK9 and dyslipidemia in larger, diverse populations.
Abstract 026: Rurality And Incident Heart Failure Risk In The Southern Community Cohort Study
Authors: Sarah Turecamo, Meng Xu, Jungnam Joo, Debra Dixon, Deepak K Gupta, Loren Lipworth, Veronique L Roger
Journal: Circulation (2022)

Background: Rural-urban disparities in cardiovascular mortality are increasing, with higher heart failure (HF) mortality among rural residents. Whether rurality is also associated with an increased risk of HF incidence is not known. Methods: A total of 27,119 Southern Community Cohort Study participants without prevalent HF receiving Centers for Medicare and Medicaid Services (CMS) at cohort enrollment (2002-2009) were included. Rurality at enrollment was classified by Rural-Urban Commuting Area codes based on participant census tract. Incident HF was defined using ICD 9/10 codes (428.x, I50x) via CMS linkage through 2016. The association between rurality and incident HF was tested in Cox models adjusted for age, sex, race, socioeconomic status, cardiovascular risk factors and comorbidities, with addition of a race-sex by rurality interaction term. Results: Overall, 20% (5,556) of participants resided in rural areas. Compared with urban-residing participants, individuals in rural areas were more likely to be older, female, married, less educated, and to have a higher burden of traditional cardiovascular risk factors, but were of similar race and income. Over median 13-years follow-up, 1,865 (33.6%) and 5,677 (26.3%) rural and urban individuals developed HF, respectively; p &lt; 0.001. In adjusted analysis, rurality associated with a 19% greater risk of incident HF (HR 1.19, 95% CI 1.12-1.26). The association between rurality and HF risk varied by race-sex (p-interaction = 0.003), with a marked disparity between Black (HR 1.34, 95% CI 1.19-1.50) and white (HR 0.98, 95% CI 0.82-1.17) men (Figure). Conclusions: In this large biracial Southeastern US population, rural residence associated with a substantial excess risk of HF particularly for women and Black men. These disparities highlight need for further research into underlying determinants and public health interventions.
158P Real-world management of patients with EGFR exon 20-mutant NSCLC in the precision oncology era: First report from the European EXOTIC registry
Authors: G. Mountzios, D. Planchard, G. Metro, A. Prelaj, D. Tsiouda, W. Shalata, M. Riudavets, P. Christopoulos, N. Girard, V.M. Albarran Artahona, M.R. Garcia Campelo, K. Samitas, G.L. Banna, I. Boukovinas, A. Agbarya, A. Koumarianou, E.I. Perdikouri, P. Kosmidis, M. Reck, G. Lo Russo
Journal: Annals of Oncology (2022)
Cytomegalovirus Gastroenteritis in Patients with Acute Graft-Versus-Host Disease
Authors: Yu Akahoshi, Shun-ichi Kimura, Yuma Tada, Toshihiro Matsukawa, Masaharu Tamaki, Noriko Doki, Naoyuki Uchida, Masatsugu Tanaka, Hirohisa Nakamae, Takuro Kuriyama, Ken-ichi Matsuoka, Takashi Ikeda, Takafumi Kimura, Takahiro Fukuda, Yoshinobu Kanda, Yoshiko Atsuta, Makoto Murata, Seitaro Terakura, Hideki Nakasone
Journal: Blood (2021)
Multiomics Analysis of Spatially Distinct Stromal Cells Reveals Tumor-Induced O-Glycosylation of the CDK4–pRB Axis in Fibroblasts at the Invasive Tumor Edge
Authors: Gina Bouchard, Fernando Jose Garcia-Marques, Loukia Georgiou Karacosta, Weiruo Zhang, Abel Bermudez, Nicholas McIlvain Riley, Sushama Varma, Lindsey Catherine Mehl, Jalen Anthony Benson, Joseph B. Shrager, Carolyn Ruth Bertozzi, Sharon J. Pitteri, Amato J. Giaccia, Sylvia Katina Plevritis
Journal: Cancer Research (2021)

Abstract The invasive leading edge represents a potential gateway for tumor metastasis. The role of fibroblasts from the tumor edge in promoting cancer invasion and metastasis has not been comprehensively elucidated. We hypothesize that cross-talk between tumor and stromal cells within the tumor microenvironment results in activation of key biological pathways depending on their position in the tumor (edge vs. core). Here we highlight phenotypic differences between tumor-adjacent-fibroblasts (TAF) from the invasive edge and tumor core fibroblasts from the tumor core, established from human lung adenocarcinomas. A multiomics approach that includes genomics, proteomics, and O-glycoproteomics was used to characterize cross-talk between TAFs and cancer cells. These analyses showed that O-glycosylation, an essential posttranslational modification resulting from sugar metabolism, alters key biological pathways including the cyclin-dependent kinase 4 (CDK4) and phosphorylated retinoblastoma protein axis in the stroma and indirectly modulates proinvasive features of cancer cells. In summary, the O-glycoproteome represents a new consideration for important biological processes involved in tumor–stroma cross-talk and a potential avenue to improve the anticancer efficacy of CDK4 inhibitors. Significance: A multiomics analysis of spatially distinct fibroblasts establishes the importance of the stromal O-glycoproteome in tumor–stroma interactions at the leading edge and provides potential strategies to improve cancer treatment. See related commentary by De Wever, p. 537
Clinical Impact of Detecting Low-Frequency Variants in Cell-Free DNA on Treatment of Castration-Resistant Prostate Cancer
Authors: Kei Mizuno, Takayuki Sumiyoshi, Takatsugu Okegawa, Naoki Terada, Satoshi Ishitoya, Yu Miyazaki, Takahiro Kojima, Hiromichi Katayama, Naohiro Fujimoto, Shingo Hatakeyama, Masaki Shiota, Koji Yoshimura, Yoshiyuki Matsui, Shintaro Narita, Hiroaki Matsumoto, Ryoma Kurahashi, Hidenori Kanno, Katsuhiro Ito, Hiroko Kimura, Yuki Kamiyama, Takuro Sunada, Takayuki Goto, Takashi Kobayashi, Hitoshi Yamada, Norihiko Tsuchiya, Tomomi Kamba, Hideyasu Matsuyama, Tomonori Habuchi, Masatoshi Eto, Chikara Ohyama, Akihiro Ito, Hiroyuki Nishiyama, Hiroshi Okuno, Toshiyuki Kamoto, Akihiro Fujimoto, Osamu Ogawa, Shusuke Akamatsu
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Although cell-free DNA (cfDNA) testing is expected to drive cancer precision medicine, little is known about the significance of detecting low-frequency variants in circulating cell-free tumor DNA (ctDNA) in castration-resistant prostate cancer (CRPC). We aimed to identify genomic profile including low-frequency variants in ctDNA from patients with CRPC and investigate the clinical utility of detecting variants with variant allele frequency (VAF) below 1%. Experimental Design: This prospective, multicenter cohort study enrolled patients with CRPC eligible for treatment with abiraterone or enzalutamide. We performed targeted sequencing of pretreatment cfDNA and paired leukocyte DNA with molecular barcodes, and ctDNA variants with a VAF ≥0.1% were detected using an in-house pipeline. We investigated progression-free survival (PFS) and overall survival (OS) after different ctDNA fraction cutoffs were applied. Results: One hundred patients were analyzed (median follow-up 10.7 months). We detected deleterious ATM, BRCA2, and TP53 variants even in samples with ctDNA fraction below 2%. When the ctDNA fraction cutoff value of 0.4% was applied, significant differences in PFS and OS were found between patients with and without defects in ATM or BRCA2 [HR, 2.52; 95% confidence interval (CI), 1.24–5.11; P = 0.0091] and TP53 (HR, 3.74; 95% CI, 1.60–8.71; P = 0.0014). However, these differences were no longer observed when the ctDNA fraction cutoff value of 2% was applied, and approximately 50% of the samples were classified as ctDNA unquantifiable. Conclusions: Detecting low-frequency ctDNA variants with a VAF &amp;lt;1% is important to identify clinically informative genomic alterations in CRPC.
Targeting the vasculature in cardiometabolic disease
Authors: Nabil E. Boutagy, Abhishek K. Singh, William C. Sessa
Journal: Journal of Clinical Investigation (2022)

Obesity has reached epidemic proportions and is a major contributor to insulin resistance (IR) and type 2 diabetes (T2D). Importantly, IR and T2D substantially increase the risk of cardiovascular (CV) disease. Although there are successful approaches to maintain glycemic control, there continue to be increased CV morbidity and mortality associated with metabolic disease. Therefore, there is an urgent need to understand the cellular and molecular processes that underlie cardiometabolic changes that occur during obesity so that optimal medical therapies can be designed to attenuate or prevent the sequelae of this disease. The vascular endothelium is in constant contact with the circulating milieu; thus, it is not surprising that obesity-driven elevations in lipids, glucose, and proinflammatory mediators induce endothelial dysfunction, vascular inflammation, and vascular remodeling in all segments of the vasculature. As cardiometabolic disease progresses, so do pathological changes in the entire vascular network, which can feed forward to exacerbate disease progression. Recent cellular and molecular data have implicated the vasculature as an initiating and instigating factor in the development of several cardiometabolic diseases. This Review discusses these findings in the context of atherosclerosis, IR and T2D, and heart failure with preserved ejection fraction. In addition, novel strategies to therapeutically target the vasculature to lessen cardiometabolic disease burden are introduced.
Biomarkers of Response and Resistance to Palbociclib Plus Letrozole in Patients With ER+/HER2− Breast Cancer
Authors: Mitch Dowsett, Lucy Kilburn, Mothaffar F. Rimawi, C. Kent Osborne, Katherine Pogue-Geile, Yuan Liu, Samuel A. Jacobs, Melanie Finnigan, Shannon Puhalla, Andrew Dodson, Vera Martins, Maggie Cheang, Sophie Perry, Chris Holcombe, Nick Turner, Claire Swift, Judith M. Bliss, Stephen Johnston
Journal: Clinical Cancer Research (2021)

Abstract Purpose: To determine (i) the relationship between candidate biomarkers of the antiproliferative (Ki67) response to letrozole and palbociclib alone and combined in ER+/HER2− breast cancer; and (ii) the pharmacodynamic effect of the agents on the biomarkers. Experimental Design: 307 postmenopausal women with ER+/HER2− primary breast cancer were randomly assigned to neoadjuvant treatment with letrozole for 14 weeks; letrozole for 2 weeks, then letrozole+palbociclib to 14 weeks; palbociclib for 2 weeks, then letrozole+palbociclib to 14 weeks; or letrozole+palbociclib for 14 weeks. Biopsies were taken at baseline, 2 and 14 weeks and surgery at varying times after stopping palbociclib. Immunohistochemical analyses were conducted for Ki67, c-PARP, ER, PgR, RB1, CCNE1, and CCND1. Results: Higher baselines ER and PgR were significantly associated with a greater chance of complete cell-cycle arrest (CCCA: Ki67 &amp;lt;2.7%) at 14 weeks and higher baseline Ki67, c-PARP, and CCNE1 with a lower chance. The interaction with treatment was significant only for c-PARP. CCND1 levels were decreased c.20% by letrozole at 2 and 14 weeks but showed a tendency to increase with palbociclib. CCNE1 levels fell 82% (median) in tumors showing CCCA but were unchanged in those with no CCCA. Only 2/9 tumors showed CCCA 3–9 days after stopping palbociclib. ESR1 mutations were found in 2/4 tumors for which surgery took place ≥6 months after starting treatment. Conclusions: High CCNE1 levels were confirmed as a biomarker of resistance to letrozole+palbociclib. Ki67 recovery within 3–9 days of discontinuing palbociclib indicates incomplete suppression of proliferation during the “off” week of its schedule.
Front Cover Image, Volume 42, Issue 3
Authors: Shipeng He, Guoqiang Dong, Junfei Cheng, Ying Wu, Chunquan Sheng
Journal: Medicinal Research Reviews (2022)

The cover image is based on the Review Article Strategies for designing proteolysis targeting chimaeras (PROTACs) by Shipeng He et al., https://doi.org/10.1002/med.21877.
Derivation and Differentiation of Human Pluripotent Stem Cells in Microfluidic Devices
Authors: Camilla Luni, Onelia Gagliano, Nicola Elvassore
Journal: Annual Review of Biomedical Engineering (2022)

An integrative approach based on microfluidic design and stem cell biology enables capture of the spatial-temporal environmental evolution underpinning epigenetic remodeling and the morphogenetic process. We examine the body of literature that encompasses microfluidic applications where human induced pluripotent stem cells are derived starting from human somatic cells and where human pluripotent stem cells are differentiated into different cell types. We focus on recent studies where the intrinsic features of microfluidics have been exploited to control the reprogramming and differentiation trajectory at the microscale, including the capability of manipulating the fluid velocity field, mass transport regime, and controllable composition within micro- to nanoliter volumes in space and time. We also discuss studies of emerging microfluidic technologies and applications. Finally, we critically discuss perspectives and challenges in the field and how these could be instrumental for bringing about significant biological advances in the field of stem cell engineering.