Digital Commons Network^™

Blockade Of Interferon Signaling Decreases Gut Barrier Integrity And Promotes Severe West Nile Virus Disease, Shih-Ching Lin, Fang R Zhao, Hana Janova, Adrian Gervais, Summer Rucknagel, Kristy O Murray, Jean-Laurent Casanova, Michael S Diamond

2020-Current year OA Pubs

The determinants of severe disease caused by West Nile virus (WNV) and why only ~1% of individuals progress to encephalitis remain poorly understood. Here, we use human and mouse enteroids, and a mouse model of pathogenesis, to explore the capacity of WNV to directly infect gastrointestinal (GI) tract cells and contribute to disease severity. At baseline, WNV poorly infects human and mouse enteroid cultures and enterocytes in mice. However, when STAT1 or type I interferon (IFN) responses are absent, GI tract cells become infected, and this is associated with augmented GI tract and blood-brain barrier (BBB) permeability, accumulation of gut-derived …

Non-Uniform Temporal Scaling Of Developmental Processes In The Mammalian Cortex, Annalisa Paolino, Elizabeth H Haines, Evan J Bailey, Dylan A Black, Ching Moey, Fernando García-Moreno, Linda J Richards, Rodrigo Suárez, Laura R Fenlon

2020-Current year OA Pubs

The time that it takes the brain to develop is highly variable across animals. Although staging systems equate major developmental milestones between mammalian species, it remains unclear how distinct processes of cortical development scale within these timeframes. Here, we compare the timing of cortical development in two mammals of similar size but different developmental pace: eutherian mice and marsupial fat-tailed dunnarts. Our results reveal that the temporal relationship between cell birth and laminar specification aligns to equivalent stages between these species, but that migration and axon extension do not scale uniformly according to the developmental stages, and are relatively more …

Molecular Imaging Of Ace2 Expression In Infectious Disease And Cancer, Zhiyao Li, Abbie Hasson, Lasya Daggumati, Hanwen Zhang, Daniel L J Thorek

2020-Current year OA Pubs

Angiotensin-converting enzyme 2 (ACE2) is a cell-surface receptor that plays a critical role in the pathogenesis of SARS-CoV-2 infection. Through the use of ligands engineered for the receptor, ACE2 imaging has emerged as a valuable tool for preclinical and clinical research. These can be used to visualize the expression and distribution of ACE2 in tissues and cells. A variety of techniques including optical, magnetic resonance, and nuclear medicine contrast agents have been developed and employed in the preclinical setting. Positron-emitting radiotracers for highly sensitive and quantitative tomography have also been translated in the context of SARS-CoV-2-infected and control patients. Together …

Management Of Constipation In Hospitalized Patients, Gregory S Sayuk, Qi T Yu, Corey Shy

2020-Current year OA Pubs

Constipation is frequently encountered in hospital settings and can have potentially serious consequences yet is often underrecognized and undertreated. Opioid-induced constipation is a common cause of constipation in hospitalized patients. Opioids induce constipation through agonistic effects on enteric µ-opioid receptors. This review aims to provide insight on the identification and management of constipation in inpatient settings, with a particular focus on opioid-induced constipation. Constipation assessment should be routinely initiated at hospital admission and can be facilitated by thorough symptom assessments; relevant patient history, including recent medication use; physical examination; and patient assessment tools developed to evaluate the impact of constipation. …

Bap1 Promotes Osteoclast Function By Metabolic Reprogramming, Nidhi Rohatgi, Wei Zou, Yongjia Li, Kevin Cho, Patrick L Collins, Eric Tycksen, Gaurav Pandey, Carl J Deselm, Gary J Patti, Anwesha Dey, Steven L Teitelbaum

2020-Current year OA Pubs

Treatment of osteoporosis commonly diminishes osteoclast number which suppresses bone formation thus compromising fracture prevention. Bone formation is not suppressed, however, when bone degradation is reduced by retarding osteoclast functional resorptive capacity, rather than differentiation. We find deletion of deubiquitinase, BRCA1-associated protein 1 (Bap1), in myeloid cells (Bap1

18s Rrna Methyltransferases Dimt1 And Bud23 Drive Intergenerational Hormesis, Noa Liberman, Eric Lieberman Greer, Et Al.

2020-Current year OA Pubs

Heritable non-genetic information can regulate a variety of complex phenotypes. However, what specific non-genetic cues are transmitted from parents to their descendants are poorly understood. Here, we perform metabolic methyl-labeling experiments to track the heritable transmission of methylation from ancestors to their descendants in the nematode Caenorhabditis elegans (C. elegans). We find heritable methylation in DNA, RNA, proteins, and lipids. We find that parental starvation elicits reduced fertility, increased heat stress resistance, and extended longevity in fed, naïve progeny. This intergenerational hormesis is accompanied by a heritable increase in N6'-dimethyl adenosine (m

Development And Evaluation Of A Wearable Peripheral Vascular Compensation Sensor In A Swine Model Of Hemorrhage, Francesca Bonetta-Misteli, Toi Collins, Todd Pavek, Madison Carlgren, Derek Bashe, Antonina Frolova, Leonid Shmuylovich, Christine M O'Brien

2020-Current year OA Pubs

Postpartum hemorrhage (PPH) is the leading and most preventable cause of maternal mortality, particularly in low-resource settings. PPH is currently diagnosed through visual estimation of blood loss or monitoring of vital signs. Visual assessment routinely underestimates blood loss beyond the point of pharmaceutical intervention. Quantitative monitoring of hemorrhage-induced compensatory processes, such as the constriction of peripheral vessels, may provide an early alert for PPH. To this end, we developed a low-cost, wearable optical device that continuously monitors peripheral perfusion via laser speckle flow index (LSFI) to detect hemorrhage-induced peripheral vasoconstriction. The measured LSFI signal produced a linear response in phantom …

Social And Psychological Adversity Are Associated With Distinct Mother And Infant Gut Microbiome Variations, Barbara B Warner, Bruce A Rosa, I Malick Ndao, Phillip I Tarr, J Philip Miller, Sarah K England, Joan L Luby, Cynthia E Rogers, Carla Hall-Moore, Renay E Bryant, Jacqueline D Wang, Laura A Linneman, Tara A Smyser, Christopher D Smyser, Deanna M Barch, John Martin, Makedonka Mitreva, Et Al.

2020-Current year OA Pubs

Health disparities are driven by underlying social disadvantage and psychosocial stressors. However, how social disadvantage and psychosocial stressors lead to adverse health outcomes is unclear, particularly when exposure begins prenatally. Variations in the gut microbiome and circulating proinflammatory cytokines offer potential mechanistic pathways. Here, we interrogate the gut microbiome of mother-child dyads to compare high-versus-low prenatal social disadvantage, psychosocial stressors and maternal circulating cytokine cohorts (prospective case-control study design using gut microbiomes from 121 dyads profiled with 16 S rRNA sequencing and 89 dyads with shotgun metagenomic sequencing). Gut microbiome characteristics significantly predictive of social disadvantage and psychosocial stressors in …

Effects Of Computer-Based Cognitive Training Combined With Physical Training For Older Adults With Cognitive Impairment: A Four-Arm Randomized Controlled Trial, I-Ching Chuang, Hui-Yan Chiau, Wan-Wen Liao, Yih-Ru Wu, Chih-Hung Chang, Ching-Yi Wu

2020-Current year OA Pubs

OBJECTIVE: Combined physical (PHY) and cognitive (COG) training in sequential (SEQ) and simultaneous (SIMUL) sessions may delay the progression of cognitive impairment. To date, no study has directly compared in older adults with cognitive impairment the effects of COG training, PHY training, SEQ motor-cognitive training and SIMUL motor-cognitve training on specific indices of cognitive performance and activities of daily living (ADL). The purpose of this study was to determine whether SEQ and SIMUL motor-cognitive training can improve treatment outcomes compared with PHY or COG training alone. We also aimed to compare the effects of SEQ versus SIMUL motor-cognitive training on …

Disentangling Age, Gender, And Racial/Ethnic Disparities In Multiple Myeloma Burden: A Modeling Study, John H Huber, Mengmeng Ji, Yi-Hsuan Shih, Mei Wang, Graham Colditz, Su-Hsin Chang

2020-Current year OA Pubs

Multiple myeloma (MM) is a hematological malignancy that is consistently preceded by an asymptomatic condition, monoclonal gammopathy of undetermined significance (MGUS). Disparities by age, gender, and race/ethnicity in both MGUS and MM are well-established. However, it remains unclear whether these disparities can be explained by increased incidence of MGUS and/or accelerated progression from MGUS to MM. Here, we fit a mathematical model to nationally representative data from the United States and showed that the difference in MM incidence can be explained by an increased incidence of MGUS among male and non-Hispanic Black populations. We did not find evidence showing differences …

Association Of Antimicrobial Perioperative Prophylaxis With Cefuroxime Plus Metronidazole Or Amoxicillin/Clavulanic Acid And Surgical Site Infections In Colorectal Surgery, Elisavet Stavropoulou, Andrew Atkinson, Marie-Christine Eisenring, Christoph A Fux, Jonas Marschall, Laurence Senn, Nicolas Troillet

2020-Current year OA Pubs

OBJECTIVE: To compare intravenous (IV) amoxicillin/clavulanic acid (A/CA) to IV cefuroxime plus metronidazole (C + M) for preventing surgical site infections (SSI) in colorectal surgery.

BACKGROUND: Given their spectra that include most Enterobacterales and anaerobes, C + M is commonly recommended as prophylaxis of SSI in colorectal surgery. A/CA offers good coverage of Enterobacterales and anaerobes as well, but, in contrast to C + M, it also includes Enterococcus faecalis which is also isolated from patients with SSI and could trigger anastomotic leakage.

METHODS: Data from a Swiss SSI surveillance program were used to compare SSI rates after class II …

Virtual Blebbistatin: A Robust And Rapid Software Approach To Motion Artifact Removal In Optical Mapping Of Cardiomyocytes, Louis G Woodhams, Jingxuan Guo, David Schuftan, John J Boyle, Kenneth M Pryse, Elliot L Elson, Nathaniel Huebsch, Guy M Genin

2020-Current year OA Pubs

Fluorescent reporters of cardiac electrophysiology provide valuable information on heart cell and tissue function. However, motion artifacts caused by cardiac muscle contraction interfere with accurate measurement of fluorescence signals. Although drugs such as blebbistatin can be applied to stop cardiac tissue from contracting by uncoupling calcium-contraction, their usage prevents the study of excitation-contraction coupling and, as we show, impacts cellular structure. We therefore developed a robust method to remove motion computationally from images of contracting cardiac muscle and to map fluorescent reporters of cardiac electrophysiological activity onto images of undeformed tissue. When validated on cardiomyocytes derived from human induced pluripotent …

Deep Learning Integrates Histopathology And Proteogenomics At A Pan-Cancer Level, Joshua M Wang, Yize Li, Li Ding, Et Al.

2020-Current year OA Pubs

We introduce a pioneering approach that integrates pathology imaging with transcriptomics and proteomics to identify predictive histology features associated with critical clinical outcomes in cancer. We utilize 2,755 H&E-stained histopathological slides from 657 patients across 6 cancer types from CPTAC. Our models effectively recapitulate distinctions readily made by human pathologists: tumor vs. normal (AUROC = 0.995) and tissue-of-origin (AUROC = 0.979). We further investigate predictive power on tasks not normally performed from H&E alone, including TP53 prediction and pathologic stage. Importantly, we describe predictive morphologies not previously utilized in a clinical setting. The incorporation of transcriptomics and proteomics identifies pathway-level …

First-In-Human Prospective Trial Of Sonobiopsy In High-Grade Glioma Patients Using Neuronavigation-Guided Focused Ultrasound, Jinyun Yuan, Lu Xu, Chih-Yen Chien, Yaoheng Yang, Yimei Yue, Siaka Fadera, Andrew H Stark, Katherine E Schwetye, Arash Nazeri, Rupen Desai, Umeshkumar Athiraman, Aadel A Chaudhuri, Hong Chen, Eric C Leuthardt

2020-Current year OA Pubs

Sonobiopsy is an emerging technology that combines focused ultrasound (FUS) with microbubbles to enrich circulating brain disease-specific biomarkers for noninvasive molecular diagnosis of brain diseases. Here, we report the first-in-human prospective trial of sonobiopsy in high-grade glioma patients to evaluate its feasibility and safety in enriching plasma circulating tumor biomarkers. A nimble FUS device integrated with a clinical neuronavigation system was used to perform sonobiopsy following an established clinical workflow for neuronavigation. Analysis of blood samples collected before and after FUS sonication showed that sonobiopsy enriched plasma circulating tumor DNA (ctDNA), including a maximum increase of 1.6-fold for the mononucleosome …

A Phase I, Multicenter, Open-Label, First-In-Human Study Of Ds-6157a In Patients With Advanced Gastrointestinal Stromal Tumor, Suzanne George, Peter Oppelt, Et Al.

2020-Current year OA Pubs

PURPOSE: To evaluate DS-6157a, an antibody-drug conjugate targeting G protein-coupled receptor 20 (GPR20), in gastrointestinal stromal tumors (GIST).

PATIENTS AND METHODS: In this phase I multicenter, open-label, multiple-dose study, patients with previously treated advanced GIST received intravenous DS-6157a on Day 1 of 21-day cycles, with a starting dose of 1.6 mg/kg. The primary objective evaluated the safety and tolerability of DS-6157a, while determining dose-limiting toxicity (DLT) and the MTD. Secondary objectives included plasma pharmacokinetics parameters, plasma antidrug antibodies (ADA), and efficacy.

RESULTS: A total of 34 patients enrolled. DS-6157a was well tolerated, with DLTs in 4 patients (11.8%) at doses …

Tangent Functional Connectomes Uncover More Unique Phenotypic Traits, Kausar Abbas, Mintao Liu, Michael Wang, Duy Duong-Tran, Uttara Tipnis, Enrico Amico, Alan D Kaplan, Mario Dzemidzic, David Kareken, Beau M Ances, Jaroslaw Harezlak, Joaquín Goñi

2020-Current year OA Pubs

Functional connectomes (FCs) containing pairwise estimations of functional couplings between pairs of brain regions are commonly represented by correlation matrices. As symmetric positive definite matrices, FCs can be transformed via tangent space projections, resulting into tangent-FCs. Tangent-FCs have led to more accurate models predicting brain conditions or aging. Motivated by the fact that tangent-FCs seem to be better biomarkers than FCs, we hypothesized that tangent-FCs have also a higher fingerprint. We explored the effects of six factors: fMRI condition, scan length, parcellation granularity, reference matrix, main-diagonal regularization, and distance metric. Our results showed that identification rates are systematically higher when …

Adding Pharmacist-Led Home Blood Pressure Telemonitoring To Usual Care For Blood Pressure Control: A Systematic Review And Meta-Analysis, Nischit Baral, Annabelle Santos Volgman, Amith Seri, Vijaya Chelikani, Sakiru Isa, Sri L P Javvadi, Timir K Paul, Joshua D Mitchell

2020-Current year OA Pubs

Health systems have been quickly adopting telemedicine throughout the United States, especially since the onset of the COVID-19 pandemic. However, there are limited data on whether adding pharmacist-led home blood pressure (BP) telemonitoring to office-based usual care improves BP. We searched PubMed/MEDLINE and Embase for randomized controlled trials from January 2000 until April 2022, comparing studies on pharmacist-led home BP telemonitoring with usual care. Six randomized controlled trials, including 1,550 participants, satisfied the inclusion criteria. There were 774 participants in the pharmacist-led telemonitoring group and 776 in the usual care group. The addition of pharmacist-led telemonitoring to usual care was …

Ifn-Λ Derived From Nonsusceptible Enterocytes Acts On Tuft Cells To Limit Persistent Norovirus, Harshad Ingle, Heyde Makimaa, Somya Aggarwal, Hongju Deng, Lynne Foster, Yuhao Li, Elizabeth A Kennedy, Stefan T Peterson, Craig B Wilen, Sanghyun Lee, Mehul S Suthar, Megan T Baldridge

2020-Current year OA Pubs

Norovirus is a leading cause of epidemic viral gastroenteritis, with no currently approved vaccines or antivirals. Murine norovirus (MNoV) is a well-characterized model of norovirus pathogenesis in vivo, and persistent strains exhibit lifelong intestinal infection. Interferon-λ (IFN-λ) is a potent antiviral that rapidly cures MNoV. We previously demonstrated that IFN-λ signaling in intestinal epithelial cells (IECs) controls persistent MNoV, and here demonstrate that IFN-λ acts on tuft cells, the exclusive site of MNoV persistence, to limit infection. While interrogating the source of IFN-λ to regulate MNoV, we confirmed that MDA5-MAVS signaling, required for IFN-λ induction to MNoV in vitro, controls …

Clinical Characteristics And Outcome Correlates Of Chinese Patients With Takotsubo Syndrome: Results From The First Chinese Takotsubo Syndrome Registry, Tou Kun Chong, Kan Liu, Et Al.

2020-Current year OA Pubs

OBJECTIVE: To investigate clinical features and outcomes of Chinese patients with Takotsubo syndrome (TTS).

METHODS: We established the first Chinese Registry of Takotsubo Syndrome (ChiTTS Registry) and analyzed demographic, clinical, therapeutical, and outcome data to characterize clinical and outcome features of Chinese TTS patients.

RESULTS: In 112 enrolled patients in the ChiTTS registry from 02/01/2016 to 12/28/2021, the mean age was 59.4 ± 18.7 years old, and 27.7% were men. A total of 41.1% patients experienced respiratory and circulatory complications during hospitalization, and 17.3% patients developed cardiogenic shock. Physical triggers, dyspnea, tachycardia, and younger age (< 70 years old) predicted in-hospital complications. The MACCE rate during follow up was 13.9% per patient per year and the rate of all-cause death was 12.8% per patient per year. TTS patients with in-hospital complications developed more long-term MACCE (24.6% vs. 6.6% per patient-year, P < 0.001) and higher all-cause mortality (21.9% vs. 6.6% per patient-year, P = 0.001) than those without. The Kaplan-Meier survival analysis showed that more MACCE occurred in TTS patients with tachycardia during 3-year follow-up (HR 4.18; 95% CI 1.80-9.74; log-rank test P < 0.001). Among all medications at discharge, only beta-blocker was associated with reduced long-term MACCE (HR: 0.35; 95% CI: 0.12-0.996; P = 0.049).

CONCLUSION: We investigated clinical …

Mosunetuzumab Monotherapy Is Active And Tolerable In Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma, Nancy L Bartlett, Et Al.

2020-Current year OA Pubs

As part of a phase 1 or 2 study, this single-arm expansion cohort established the efficacy and safety of mosunetuzumab monotherapy in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (received ≥2 previous lines of therapy). Intravenous mosunetuzumab was administered with cycle (C) 1 step-up dosing for cytokine release syndrome (CRS) mitigation: C1 day (D) 1: 1 mg; C1D8 2 mg; C1D15 and C2D1: 60 mg; C3 + D1: 30 mg. Hospitalization was not mandatory. Patients with complete response (CR) completed treatment after C8; those with partial response or stable disease continued treatment for a total of 17 cycles. …

Impact Of Detectable Monoclonal Protein At Diagnosis On Outcomes In Marginal Zone Lymphoma: A Multicenter Cohort Study, Narendranath Epperla, Lauren Shea, Nancy L Bartlett, Et Al.

2020-Current year OA Pubs

Given the paucity of data surrounding the prognostic relevance of monoclonal paraprotein (M-protein) in marginal zone lymphoma (MZL), we sought to evaluate the impact of detecting M-protein at diagnosis on outcomes in patients with MZL in a large retrospective cohort. The study included 547 patients receiving first-line therapy for MZL. M-protein was detectable at diagnosis in 173 (32%) patients. There was no significant difference in the time from diagnosis to initiation of any therapy (systemic and local) between the M-protein and no M-protein groups. Patients with M-protein at diagnosis had significantly inferior progression-free survival (PFS) compared with those without M-protein …

Picobirnaviruses Encode Proteins That Are Functional Bacterial Lysins, Tianyu Gan, David Wang

2020-Current year OA Pubs

Picobirnaviruses (PBVs) are double-stranded RNA viruses frequently detected in human and animal enteric viromes. Associations of PBVs with enteric graft-versus-host disease and type I diabetes during pregnancy have been established. Since their discovery in 1988, PBVs have been generally assumed to be animal-infecting viruses despite the lack of culture system, animal model, or detection in animal cells or tissues. Recent studies have proposed that bacteria or fungi could be the hosts of PBVs based on genomic analysis. Here, we functionally demonstrate that multiple PBVs of different genome organizations encode bacterial lysins that lyse

Procedure For Handling And Storage Of Onchocerca Volvulus Microfilariae Obtained From Skin Snips For Downstream Genetic Work, Shannon M Hedtke, Anusha Kode, Tony O Ukety, Jöel L Mande, Germain M Abhafule, Anuarite A Raciu, Claude B Uvon, Stephen R Jada, An Hotterbeekx, Joseph Nelson Siewe Fodjo, Makedonka Mitreva, Wilson Sebit, Robert Colebunders, Warwick N Grant, Annette C Kuesel

2020-Current year OA Pubs

WHO and endemic countries target elimination of transmission of

Proteogenomic Insights Suggest Druggable Pathways In Endometrial Carcinoma, Yongchao Dou, Rita Jui-Hsien Lu, Yige Wu, Matthew A Wyczalkowski, David Mutch, Li Ding, Et Al.

2020-Current year OA Pubs

We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of β-catenin, which may render …

Integrative Multi-Omic Cancer Profiling Reveals Dna Methylation Patterns Associated With Therapeutic Vulnerability And Cell-Of-Origin, Wen-Wei Liang, Rita Jui-Hsien Lu, Reyka G Jayasinghe, Steven M Foltz, Michael C Wendl, Yizhe Song, Akshay Govindan, Xiang Li, Yize Li, Sunantha Sethuraman, Li Ding, Et Al.

2020-Current year OA Pubs

DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A …

Erg K+ Channels Mediate A Major Component Of Action Potential Repolarization In Lymphatic Muscle, Hae Jin Kim, Min Li, Emma C Erlich, Gwendalyn J Randolph, Michael J Davis

2020-Current year OA Pubs

Smooth muscle cells in the walls of collecting lymphatic vessels fire spontaneous action potentials (APs), which conduct rapidly over the muscle layer to initiate contractions that propel lymph. Several ion channels have been implicated in the currents underlying the AP spike and the preceding diastolic depolarization, but the molecular identities of K

Phase Separation Of Protein Mixtures Is Driven By The Interplay Of Homotypic And Heterotypic Interactions, Mina Farag, Wade M Borcherds, Anne Bremer, Tanja Mittag, Rohit V Pappu

2020-Current year OA Pubs

Prion-like low-complexity domains (PLCDs) are involved in the formation and regulation of distinct biomolecular condensates that form via phase separation coupled to percolation. Intracellular condensates often encompass numerous distinct proteins with PLCDs. Here, we combine simulations and experiments to study mixtures of PLCDs from two RNA-binding proteins, hnRNPA1 and FUS. Using simulations and experiments, we find that 1:1 mixtures of A1-LCD and FUS-LCD undergo phase separation more readily than either of the PLCDs on their own due to complementary electrostatic interactions. Tie line analysis reveals that stoichiometric ratios of different components and their sequence-encoded interactions contribute jointly to the driving …

3d-Cultured Blastoids Model Human Embryogenesis From Pre-Implantation To Early Gastrulation Stages, Rowan M Karvas, Joseph E Zemke, Syed Shahzaib Ali, Eric Upton, Eshan Sane, Laura A Fischer, Chen Dong, Kyoung-Mi Park, Brian Chew, Brittany Meyer, Chao Zhou, Sabine Dietmann, Thorold W Theunissen, Et Al.

2020-Current year OA Pubs

Naive human pluripotent stem cells have the remarkable ability to self-organize into blastocyst-like structures ("blastoids") that model lineage segregation in the pre-implantation embryo. However, the extent to which blastoids can recapitulate the defining features of human post-implantation development remains unexplored. Here, we report that blastoids cultured on thick three-dimensional (3D) extracellular matrices capture hallmarks of early post-implantation development, including epiblast lumenogenesis, rapid expansion and diversification of trophoblast lineages, and robust invasion of extravillous trophoblast cells by day 14. Extended blastoid culture results in the localized activation of primitive streak marker TBXT and the emergence of embryonic germ layers by day …

Atezolizumab For Advanced Alveolar Soft Part Sarcoma, Alice P Chen, Brian A Van Tine, Et Al.

2020-Current year OA Pubs

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported.

METHODS: We conducted an investigator-initiated, multicenter, single-group, phase 2 study of the anti-programmed death ligand 1 (PD-L1) agent atezolizumab in adult and pediatric patients with advanced ASPS. Atezolizumab was administered intravenously at a dose of 1200 mg (in patients ≥18 years of age) or 15 mg per kilogram of body weight with a 1200-mg cap (in patients <18 years of age) once every 21 days. Study end points included objective response, duration of response, and progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as well as pharmacodynamic biomarkers of multistep drug action.

RESULTS: A total of 52 patients were evaluated. An objective response was observed in …

The Atm-E6ap-Mastl Axis Mediates Dna Damage Checkpoint Recovery, Yanqiu Li, Feifei Wang, Xin Li, Ling Wang, Zheng Yang, Zhongsheng You, Aimin Peng

2020-Current year OA Pubs

Checkpoint activation after DNA damage causes a transient cell cycle arrest by suppressing cyclin-dependent kinases (CDKs). However, it remains largely elusive how cell cycle recovery is initiated after DNA damage. In this study, we discovered the upregulated protein level of MASTL kinase hours after DNA damage. MASTL promotes cell cycle progression by preventing PP2A/B55-catalyzed dephosphorylation of CDK substrates. DNA damage-induced MASTL upregulation was caused by decreased protein degradation, and was unique among mitotic kinases. We identified E6AP as the E3 ubiquitin ligase that mediated MASTL degradation. MASTL degradation was inhibited upon DNA damage as a result of the dissociation of …