tbuckley/cabot-search huggingface dataset:
Intensive vs Conventional Blood Pressure Control After Thrombectomy in Acute Ischemic Stroke
Authors: Sherief Ghozy, Ali Mortezaei, Mohamed Elfil, Mariam Abdelghaffar, Hassan Kobeissi, Mohammad Aladawi, Alzhraa S. Abbas, Sandeep S. Nayak, Ramanathan Kadirvel, Alejandro A. Rabinstein, David F. Kallmes
Journal: JAMA Network Open (2024)

Importance Endovascular thrombectomy (EVT) is standard treatment for acute ischemic stroke (AIS) due to large-vessel occlusion (LVO), but optimal post-EVT blood pressure (BP) control remains debated. Objective To assess the association of different systolic BP targets following EVT with functional outcomes, mortality, and complications in patients with AIS due to LVO. Data Sources Systematic review and meta-analysis of databases (PubMed, Embase, Web of Science, Scopus, and Cochrane Library) to September 8, 2023. Study Selection Inclusion criteria consisted of randomized clinical trials examining post-EVT management of systolic BP in patients with AIS and LVO comparing intensive vs conventional targets. Nonrandomized studies, observational studies, noninterventional trials, meeting abstracts, duplicate studies, studies with overlapping data, and non–English language studies were excluded. Two authors independently applied these criteria through a blinded review, with discrepancies resolved through consensus. The risk of bias in the included studies was assessed using the revised tool for assessing risk of bias in randomized trials. Data Extraction and Synthesis This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. Three authors extracted data regarding study characteristics, baseline patient data, and outcomes of interest. The pooled data were analyzed using a random-effects meta-analysis. Main Outcomes and Measures Rates of functional independence, 90-day mortality, symptomatic intracranial hemorrhage, and hypotensive events. Results A total of 4 randomized clinical trials with 1571 initially enrolled patients were included in the analysis. Lower functional independence rates were observed in the intensive control group (relative risk [RR], 0.81 [95% CI, 0.67-0.98]). No significant differences were found in 90-day mortality (RR, 1.18 [95% CI, 0.92-1.52]), symptomatic intracranial hemorrhage (RR, 1.12 [95% CI, 0.75-1.67]), or hypotensive events (RR, 1.80 [95% CI, 0.37-8.76]). There was minimal heterogeneity among the studies included in the functional independence outcome ( I 2 = 13% and τ 2 = 0.003), which was absent among other outcomes ( I 2 = 0 and τ 2 = 0). Conclusions and Relevance These findings suggest that intensive post-EVT BP reduction does not yield benefits and may carry risks. While awaiting the results of additional ongoing trials, a conservative BP management strategy after endovascular recanalization is favored in daily practice.
Broad Next-Generation Integrated Sequencing of Myelofibrosis Identifies Disease-Specific and Age-Related Genomic Alterations
Authors: Malathi Kandarpa, Dan Robinson, Yi-Mi Wu, Tingting Qin, Kristen Pettit, Qing Li, Gary Luker, Maureen Sartor, Arul Chinnaiyan, Moshe Talpaz
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Myeloproliferative neoplasms (MPN) are characterized by the overproduction of differentiated myeloid cells. Mutations in JAK2, CALR, and MPL are considered drivers of Bcr-Abl−ve MPN, including essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic primary myelofibrosis (prePMF), and overt myelofibrosis (MF). However, how these driver mutations lead to phenotypically distinct and/or overlapping diseases is unclear. Experimental Design: To compare the genetic landscape of MF to ET/PV/PrePMF, we sequenced 1,711 genes for mutations along with whole transcriptome RNA sequencing of 137 patients with MPN. Results: In addition to driver mutations, 234 and 74 genes were found to be mutated in overt MF (N = 106) and ET/PV/PrePMF (N = 31), respectively. Overt MF had more mutations compared with ET/PV/prePMF (5 vs. 4 per subject, P = 0.006). Genes frequently mutated in MF included high-risk genes (ASXL1, SRSF2, EZH2, IDH1/2, and U2AF1) and Ras pathway genes. Mutations in NRAS, KRAS, SRSF2, EZH2, IDH2, and NF1 were exclusive to MF. Advancing age, higher DIPSS, and poor overall survival (OS) correlated with increased variants in MF. Ras mutations were associated with higher leukocytes and platelets and poor OS. The comparison of gene expression showed upregulation of proliferation and inflammatory pathways in MF. Notably, ADGRL4, DNASE1L3, PLEKHGB4, HSPG2, MAMDC2, and DPYSL3 were differentially expressed in hematopoietic stem and differentiated cells. Conclusions: Our results illustrate that evolution of MF from ET/PV/PrePMF likely advances with age, accumulation of mutations, and activation of proliferative pathways. The genes and pathways identified by integrated genomics approach provide insight into disease transformation and progression and potential targets for therapeutic intervention.
Assessment of ownership of smart devices and the acceptability of digital health data sharing
Authors: Md Mobashir Hasan Shandhi, Karnika Singh, Natasha Janson, Perisa Ashar, Geetika Singh, Baiying Lu, D Sunshine Hillygus, Jennifer M Maddocks, Jessilyn P Dunn
Journal: npj Digital Medicine (2024)

Abstract Smart portable devices- smartphones and smartwatches- are rapidly being adopted by the general population, which has brought forward an opportunity to use the large volumes of physiological, behavioral, and activity data continuously being collected by these devices in naturalistic settings to perform research, monitor health, and track disease. While these data can serve to revolutionize health monitoring in research and clinical care, minimal research has been conducted to understand what motivates people to use these devices and their interest and comfort in sharing the data. In this study, we aimed to characterize the ownership and usage of smart devices among patients from an expansive academic health system in the southeastern US and understand their willingness to share data collected by the smart devices. We conducted an electronic survey of participants from an online patient advisory group around smart device ownership, usage, and data sharing. Out of the 3021 members of the online patient advisory group, 1368 (45%) responded to the survey, with 871 female (64%), 826 and 390 White (60%) and Black (29%) participants, respectively, and a slight majority (52%) age 58 and older. Most of the respondents (98%) owned a smartphone and the majority (59%) owned a wearable. In this population, people who identify as female, Hispanic, and Generation Z (age 18–25), and those completing higher education and having full-time employment, were most likely to own a wearable device compared to their demographic counterparts. 50% of smart device owners were willing to share and 32% would consider sharing their smart device data for research purposes. The type of activity data they are willing to share varies by gender, age, education, and employment. Findings from this study can be used to design both equitable and cost-effective digital health studies, leveraging personally-owned smartphones and wearables in representative populations, ultimately enabling the development of equitable digital health technologies.
Single-cell and whole-transcriptome sequencing of lymph node metastasis-related gene signature: A large-scale pan-cancer cohort, machine learning and experimental study
Authors: Jianguo Lai, Yan He, Xiaoqing Cai, Yuchen Cao, You Long, Zepeng Luo, Kaige Deng, Yiran Lin, Rijia Teng, Haoxuan Huang, Chao Zhu, DQ Cai, Ning Liao
Journal: International Journal of Surgery (2024)

Background: Lymph node metastasis (LNM) is an independent prognostic factor in numerous types of cancer. Therefore, a LNM-related gene-based nomogram may precisely predict survival and drug sensitivity, and reveal the mechanism underlying LNM. Materials and Methods: Gene sequencing profiles of pan-cancer data (33 cancer types) were acquired from The Cancer Genome Atlas UCSC Xena database. Patients were classified into primary (N = 10,071) and testing (N = 5,036) cohorts. The lymph node score (LNscore) was established via single-cell RNA sequencing, whole-transcriptome sequencing, machine learning, and Cox regression analyses. A novel prognosis model, formulated by incorporating the LNscore and clinical characteristics, was evaluated using the concordance index, calibration curve, and decision curve analysis. Moreover, patients were assigned into high- and low-risk groups according to the median LNscore. We investigated these two groups for survival prognosis, functional enrichment, immune infiltration, and drug sensitivity. In addition, we silenced and overexpressed insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2). We also analyzed the behavior of breast cancer (BRCA) cells regarding lymphatic metastasis and lymphangiogenesis in vitro. IGF2BP2 stimulated the proliferation of BRCA cells via 5-Ethynyl-2'-deoxyuridine and Cell Counting Kit-8 experiments. Results: A LNM-related set of 12 genes was identified and utilized to determine the LNscore. The concordance-index of both cohorts in the LNscore-based model was >0.7. The immune landscape revealed that the sensitivity to immunotherapy might be better in the high-risk group versus the low-risk group. In addition, we discovered that IGF2BP2 was overexpressed in BRCA tissues and significantly associated with poor survival. Functional analysis indicated that IGF2BP2 promoted BRCA cell migration and proliferation. Additionally, IGF2BP2 accelerated lymphatic metastasis and lymphangiogenesis in vivo. Conclusions: A novel LNscore-based model was established via comprehensive analysis of LNM-related genes. This model can accurately predict patient survival and drug sensitivity, and reveal the mechanism of LNM in the pan-cancer setting.
Noticeable effect of lower baseline amplitude on the predictive accuracy of intraoperative amplitude changes for postoperative vocal cord palsy: a prospective cohort study
Authors: Jiedong Kou, Yishen Zhao, Yujia Han, Fang Li, Rui Du, Gianlorenzo Dionigi, Francesco Frattini, Jingting Li, Nan Liang, Hui Sun
Journal: International Journal of Surgery (2024)

Background: To explore the effect of lower baseline amplitude on its predictive accuracy of postoperative vocal cord paralysis (VCP) in monitored thyroid surgery. Materials and Methods: Clinical and electrophysiological data were collected during thyroid surgeries performed between November and December 2021 at XXX. Univariate/multivariate regression analysis were applied to these data to examine a possible correlation. A receiver operating characteristic (ROC) curve was used to evaluate predictive efficacy. Results: A total of 631 nerves-at-risk (NAR) were identified in 460 patients who were divided into two groups according to postoperative development of VCP. The VCP group included a higher percentage of NAR with V1&lt;1000 (68.2% vs. 40.7%, respectively; P =0.014) and NAR with R1&lt;1400 (77.3% vs. 47.0%, respectively; P =0.005) compared with the non-VCP group. Multivariate regression analysis further identified V1&lt;1000 (odds ratio (OR)=2.688, P =0.038), R1&lt;1400 (OR=3.484, P =0.018) as independent risk factors for postoperative temporary VCP. The ROC curve showed the AUC value of V signal decline for predicting VCP was 0.87. The diagnostic efficiency of R signal decline reached as high as 0.973. A multivariate logistic regression analysis identified independent risk factors for V1&lt;1000 and these included: higher body mass index (BMI) (OR=1.072, P =0.013), hypertension (OR=1.816, P =0.015), smoking (OR=1.814, P =0.031), and male gender (OR=2.016, P =0.027). Conclusion: In our cohort, lower baseline amplitude was an independent risk factor for developing transient postoperative VCP. It also affected the predictive efficacy of intraoperative amplitude changes on VCP. Higher BMI, hypertension, smoking, and male gender may also be closely associated with lower initial amplitude. Thus, maintaining a higher initial amplitude is critical for patient safety during thyroid surgery.
Integrative transcriptomic and genomic analyses unveil the IFI16 variants and expression as MASLD progression markers
Authors: Doyoon Kim, Masaud Shah, Jang Hyun Kim, JungMo Kim, Yang-Hyun Baek, Jin-Sook Jeong, Sang-Young Han, Yong Sun Lee, Gaeul Park, Jin-Han Cho, Young-Hoon Roh, Sung-Wook Lee, Gi-Bok Choi, Jong Hoon Park, Kyung Hyun Yoo, Rho Hyun Seong, Yeon-Su Lee, Hyun Goo Woo
Journal: Hepatology (2024)

Background and Aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) encompasses a broad and continuous spectrum of liver diseases ranging from fatty liver to steatohepatitis. The intricate interactions of genetic, epigenetic, and environmental factors in the development and progression of MASLD remain elusive. Here, we aimed to achieve an integrative understanding of the genomic and transcriptomic alterations throughout the progression of MASLD. Approach and Results: RNA-Seq profiling (n = 146) and whole-exome sequencing (n = 132) of MASLD liver tissue samples identified 3 transcriptomic subtypes (G1-G3) of MASLD, which were characterized by stepwise pathological and molecular progression of the disease. Macrophage-driven inflammatory activities were identified as a key feature for differentiating these subtypes. This subtype-discriminating macrophage interplay was significantly associated with both the expression and genetic variation of the dsDNA sensor IFI16 (rs6940, A&gt;T, T779S), establishing it as a fundamental molecular factor in MASLD progression. The in vitro dsDNA-IFI16 binding experiments and structural modeling revealed that the IFI16 variant exhibited increased stability and stronger dsDNA binding affinity compared to the wild-type. Further downstream investigation suggested that the IFI16 variant exacerbated DNA sensing-mediated inflammatory signals through mitochondrial dysfunction–related signaling of the IFI16-PYCARD-CASP1 pathway. Conclusions: This study unveils a comprehensive understanding of MASLD progression through transcriptomic classification, highlighting the crucial roles of IFI16 variants. Targeting the IFI16-PYCARD-CASP1 pathway may pave the way for the development of novel diagnostics and therapeutics for MASLD.
Epidermal barrier impairment predisposes for excessive growth of the allergy‐associated yeast <i>Malassezia</i> on murine skin
Authors: Fiorella Ruchti, Pascale Zwicky, Burkhard Becher, Sandrine Dubrac, Salomé LeibundGut‐Landmann
Journal: Allergy (2024)

Abstract Background The skin barrier is vital for protection against environmental threats including insults caused by skin‐resident microbes. Dysregulation of this barrier is a hallmark of atopic dermatitis (AD) and ichthyosis, with variable consequences for host immune control of colonizing commensals and opportunistic pathogens. While Malassezia is the most abundant commensal fungus of the skin, little is known about the host control of this fungus in inflammatory skin diseases. Methods In this experimental study, MC903‐treated mice were colonized with Malassezia spp. to assess the host–fungal interactions in atopic dermatitis. Additional murine models of AD and ichthyosis, including tape stripping, K5‐Nrf2 overexpression and flaky tail mice, were employed to confirm and expand the findings. Skin fungal counts were enumerated. High parameter flow cytometry was used to characterize the antifungal response in the AD‐like skin. Structural and functional alterations in the skin barrier were determined by histology and transcriptomics of bulk skin. Finally, differential expression of metabolic genes in Malassezia in atopic and control skin was quantified. Results Malassezia grows excessively in AD‐like skin. Fungal overgrowth could, however, not be explained by the altered immune status of the atopic skin. Instead, we found that by upregulating key metabolic genes in the altered cutaneous niche, Malassezia acquired enhanced fitness to efficiently colonise the impaired skin barrier. Conclusions This study provides evidence that structural and metabolic changes in the dysfunctional epidermal barrier environment provide increased accessibility and an altered lipid profile, to which the lipid‐dependent yeast adapts for enhanced nutrient assimilation. Our findings reveal fundamental insights into the implication of the mycobiota in the pathogenesis of common skin barrier disorders.
Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment
Authors: Xue-Yan He, Yuan Gao, David Ng, Evdokia Michalopoulou, Shanu George, Jose M. Adrover, Lijuan Sun, Jean Albrengues, Juliane Daßler-Plenker, Xiao Han, Ledong Wan, Xiaoli Sky Wu, Longling S. Shui, Yu-Han Huang, Bodu Liu, Chang Su, David L. Spector, Christopher R. Vakoc, Linda Van Aelst, Mikala Egeblad
Journal: Cancer Cell (2024)
One-third of amenorrheic transmasculine people on testosterone ovulate
Authors: Joyce D. Asseler, Julieta S. del Valle, Susana M. Chuva de Sousa Lopes, Marieke O. Verhoeven, Mariette Goddijn, Judith A.F. Huirne, Norah M. van Mello
Journal: Cell Reports Medicine (2024)

Transmasculine people usually reach amenorrhea within 6 months of adequate testosterone treatment. It is often assumed that no ovulation occurs during amenorrhea. However, in this study, we report recent ovulatory activity in amenorrheic transmasculine people on testosterone therapy at gender-affirming oophorectomy. Histological signs of recent ovulatory activity, including the presence of ovulatory follicles, corpus luteum, and corpus albicans, are observed in 17 of 52 individuals (33%). This is not significantly correlated to the duration, testosterone serum levels, or type of testosterone used. These results suggest that amenorrhea does not equal anovulation in transmasculine people on adequate testosterone therapy, emphasizing the importance of contraception for people who engage in sexual activity that can result in pregnancy.
SEPN1-related myopathy depends on the oxidoreductase ERO1A and is druggable with the chemical chaperone TUDCA
Authors: Serena Germani, Andrew Tri Van Ho, Alessandro Cherubini, Ersilia Varone, Alexander Chernorudskiy, Giorgia Maria Renna, Stefano Fumagalli, Marco Gobbi, Jacopo Lucchetti, Marco Bolis, Luca Guarrera, Ilaria Craparotta, Giorgia Rastelli, Giorgia Piccoli, Cosimo de Napoli, Leonardo Nogara, Elena Poggio, Marisa Brini, Angela Cattaneo, Angela Bachi, Thomas Simmen, Tito Calì, Susana Quijano-Roy, Simona Boncompagni, Bert Blaauw, Ana Ferreiro, Ester Zito
Journal: Cell Reports Medicine (2024)

Selenoprotein N (SEPN1) is a protein of the endoplasmic reticulum (ER) whose inherited defects originate SEPN1-related myopathy (SEPN1-RM). Here, we identify an interaction between SEPN1 and the ER-stress-induced oxidoreductase ERO1A. SEPN1 and ERO1A, both enriched in mitochondria-associated membranes (MAMs), are involved in the redox regulation of proteins. ERO1A depletion in SEPN1 knockout cells restores ER redox, re-equilibrates short-range MAMs, and rescues mitochondrial bioenergetics. ERO1A knockout in a mouse background of SEPN1 loss blunts ER stress and improves multiple MAM functions, including Ca2+ levels and bioenergetics, thus reversing diaphragmatic weakness. The treatment of SEPN1 knockout mice with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) mirrors the results of ERO1A loss. Importantly, muscle biopsies from patients with SEPN1-RM exhibit ERO1A overexpression, and TUDCA-treated SEPN1-RM patient-derived primary myoblasts show improvement in bioenergetics. These findings point to ERO1A as a biomarker and a viable target for intervention and to TUDCA as a pharmacological treatment for SEPN1-RM.
Bacterial defense systems exhibit synergistic anti-phage activity
Authors: Yi Wu, Sofya K. Garushyants, Anne van den Hurk, Cristian Aparicio-Maldonado, Simran Krishnakant Kushwaha, Claire M. King, Yaqing Ou, Thomas C. Todeschini, Martha R.J. Clokie, Andrew D. Millard, Yilmaz Emre Gençay, Eugene V. Koonin, Franklin L. Nobrega
Journal: Cell Host & Microbe (2024)

Bacterial defense against phage predation involves diverse defense systems acting individually and concurrently, yet their interactions remain poorly understood. We investigated >100 defense systems in 42,925 bacterial genomes and identified numerous instances of their non-random co-occurrence and negative association. For several pairs of defense systems significantly co-occurring in Escherichia coli strains, we demonstrate synergistic anti-phage activity. Notably, Zorya II synergizes with Druantia III and ietAS defense systems, while tmn exhibits synergy with co-occurring systems Gabija, Septu I, and PrrC. For Gabija, tmn co-opts the sensory switch ATPase domain, enhancing anti-phage activity. Some defense system pairs that are negatively associated in E. coli show synergy and significantly co-occur in other taxa, demonstrating that bacterial immune repertoires are largely shaped by selection for resistance against host-specific phages rather than negative epistasis. Collectively, these findings demonstrate compatibility and synergy between defense systems, allowing bacteria to adopt flexible strategies for phage defense.
Enhanced potency of immunotherapy against B‐cell precursor acute lymphoblastic leukemia by combination of an Fc‐engineered CD19 antibody and CD47 blockade
Authors: Denis M. Schewe, Fotini Vogiatzi, Ira A. Münnich, Tobias Zeller, Roland Windisch, Christian Wichmann, Kristina Müller, Hilal Bhat, Elisa Felix, Dimitrios Mougiakakos, Heiko Bruns, Lennart Lenk, Thomas Valerius, Andreas Humpe, Matthias Peipp, Christian Kellner
Journal: HemaSphere (2024)

Abstract CD19‐directed immunotherapy has become a cornerstone in the therapy of B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL). CD19‐directed cellular and antibody‐based therapeutics have entered therapy of primary and relapsed disease and contributed to improved outcomes in relapsed disease and lower therapy toxicity. However, efficacy remains limited in many cases due to a lack of therapy response, short remission phases, or antigen escape. Here, BCP‐ALL cell lines, patient‐derived xenograft (PDX) samples, human macrophages, and an in vivo transplantation model in NOD.Cg‐Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice were used to examine the therapeutic potency of a CD19 antibody Fc‐engineered for improved effector cell recruitment (CD19‐DE) and antibody‐dependent cellular phagocytosis (ADCP), in combination with a novel modified CD47 antibody (Hu5F9‐IgG2σ). For the in vivo model, only samples refractory to CD19‐DE monotherapy were chosen. Hu5F9‐IgG2σ enhanced ADCP by CD19‐DE in various BCP‐ALL cell line models with varying CD19 surface expression and cytogenetic backgrounds, two of which contained the KMT2A‐AFF1 fusion. Also, the antibody combination was efficient in inducing ADCP by human macrophages in pediatric PDX samples with and adult samples with and without KMT2A ‐rearrangement in vitro. In a randomized phase 2‐like PDX trial using seven KMT2A ‐rearranged BCP‐ALL samples in NSG mice, the CD19/CD47 antibody combination proved highly efficient. Our findings support that the efficacy of Fc‐engineered CD19 antibodies may be substantially enhanced by a combination with CD47 blockade. This suggests that the combination may be a promising therapy option for BCP‐ALL, especially in relapsed patients and/or patients refractory to CD19‐directed therapy.