tbuckley/cabot-search huggingface dataset:
Mesenchymal stromal cell delivery of oncolytic immunotherapy improves CAR-T cell antitumor activity
Authors: Mary K. McKenna, Alexander Englisch, Benjamin Brenner, Tyler Smith, Valentina Hoyos, Masataka Suzuki, Malcolm K. Brenner
Journal: Molecular Therapy (2021)

(Molecular Therapy 29, 1808–1820; May 5,2021) In the originally published version of this article, a reference to Figure 2 was incorrect in the text, and the Figure 3 legend description was reversed for Figures 3E and 3F. The y-axis in Figure 3E was represented as a percentage rather than a fraction. The data remain unchanged. The figure and legend have now been corrected online. The authors regret this error.Figure 3CAdIL-12_PD-L1 MSCs enhance HER.2 CAR-T cell polyfunctionality (Original)Show full captionUninfected MSCs or CAd IL-12_PD-L1 infected MSCs were co-cultured at a 1:10 ratio to A549 tumor cells for 48 h. NTR or CAR-T cells were then added to the culture or added to tumor only. We isolated T cells 20 h later and selected for CD4 and CD8 populations. We measured single cell cytokine secretion on the Isoplexis platform for 32 different cytokines. (A and D) Umap analysis shows clusters of CD4 (A) and CD8 (D) cells color coded by each condition. We determined polyfunctionality by the number of cytokines secreted from each cell and represented as a fraction in selected population. (B) Polyfunctionality and secreted cytokines for inset #1, uninfected MSC, and NTR CD4 T cells. (C) Polyfunctionality and secreted cytokines for inset #2, CAd MSC, and HER.2 CD4 T cells. (E) Polyfunctionality and secreted cytokines for inset #3, CAd MSC and HER.2 CD8 T cells. (F) Polyfunctionality and secreted cytokines for inset #4, non-MSC, and HER.2 CD8 T cells. (G) Overall secretion frequency of CD4 and CD8 populations. Percent of population secreting is represented by color intensity for each detected cytokine. NTR, n = 2 donors; HER2, n = 3 donors for each MSC condition.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Mesenchymal stromal cell delivery of oncolytic immunotherapy improves CAR-T cell antitumor activityMcKenna et al.Molecular TherapyFebruary 8, 2021In BriefOncolytic adenoviruses (OAds) disrupt the tumor microenvironment. Their activity is enhanced by engineering them to release immunostimulatory factors. Here, McKenna and colleagues use mesenchymal stromal cells to systemically deliver oncolytic and helper adenoviruses to the tumor. The OAds further replicate and augment the anti-tumor activity of CAR-T cells. Full-Text PDF Open Archive
Differential Kinetics of Immune Responses Elicited by Covid-19 Vaccines
Authors: Ai-Ris Y Collier, Jingyou Yu, Katherine McMahan, Jinyan Liu, Abishek Chandrashekar, Jenny S Maron, Caroline Atyeo, David R Martinez, Jessica L Ansel, Ricardo Aguayo, Marjorie Rowe, Catherine Jacob-Dolan, Daniel Sellers, Julia Barrett, Kunza Ahmad, Tochi Anioke, Haley VanWyk, Sarah Gardner, Olivia Powers, Esther A Bondzie, Huahua Wan, Ralph S Baric, Galit Alter, Michele R Hacker, Dan H Barouch
Journal: New England Journal of Medicine (2021)
Who Is MB and What Does She Want?
Authors: Joseph O. Jacobson
Journal: Journal of Clinical Oncology (2021)

Though he stands leaning on his cane on the porch of the hotel in Port William, looking out into the first cool morning of September 1952, he is not there.He is four miles and sixty-four years away, in the time that he had music in him and he was light.-Wendell Berry, The Memory of Old Jack My initial glimpse of MB was a virtual one as I reviewed her chart in preparation for her first visit.She was 87, living in a skilled nursing facility, nearly blind, and mostly deaf.She used a wheelchair, had early dementia, and had recently been diagnosed with neglected lung cancer.This is someone who needs to be quickly channeled toward a symptom-based approach, I judged.Pain medication and a brief course of palliative radiation to help for the short term should suffice.Unwillingly, my mind slid back to the long, exhausting days of my internal medicine residency decades ago.I recalled dreading admissions from nursing homes.These patients were widely perceived as old, infirm, difficult to manage, and worst of all, they inevitably presented disposition problems; the nursing homes almost never accepted them back.They could linger in the hospital for weeks on end awaiting placement.
Abstract 015: Genome-wide Association Study Of Variant-by-thiazide Diuretic Interactions In The UK Biobank Identifies A Novel Locus For Thiazide-LDL-C Interaction
Authors: Carolina G Downie, Heather M Highland, Moa P Lee, Laura M Raffield, Michael Preuss, Eric A Whitsel, Bruce Psaty, Mariaelisa Graff, Christy L Avery
Journal: Circulation (2022)

Introduction: Although thiazide diuretics are common therapies for the treatment of hypertension, evidence suggests that they are also associated with elevated blood lipid concentrations after their initiation. Pharmacogenomics studies could help identify potential biological pathways underlying this phenomenon, but few well-powered studies have been conducted. Methods: In participants of European ancestry from the UK Biobank, we conducted a genome-wide association study (GWAS) to examine whether common variants (minor allele frequency [MAF] &gt;1%) modified the effect of thiazide diuretic use on three lipid measures: low density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) concentrations (mmol/L). TG concentrations were natural log transformed, and LDL-C concentrations were adjusted for statin use. Given the conflicting evidence about the impact of loop diuretics on blood lipid concentrations, unexposed participants were defined as those taking neither thiazides nor loop diuretics. GWAS of UK10K plus 1000-Genomes Phase 3 imputed data were performed using SAIGE, adjusting for age, sex, fasting status, body mass index, study center, and the first 10 ancestral principal components. Results: Approximately 7.1% (n=27,971) of participants (n=395,058; mean age=57 years; 54% female [n=214,334]) used thiazides at study baseline. The thiazide-LDL-C GWAS (n=9,680,686 variants) identified one chromosome 19 locus harboring several genome-wide significant variants that modified the effect of thiazide diuretic use on LDL-C. The lead variant rs2199576 (MAF = 0.18) had an effect estimate (standard error) of 0.159 (0.013) among participants exposed to thiazides, and an effect estimate of 0.083 (0.003) among participants unexposed to any diuretic, yielding a significant variant-by-thiazide interaction effect estimate of 0.076 (0.013) ( p = 1.62 x 10 -9 ). These effect estimates are comparable to previously identified main effects of blood lipids loci. The rs2199576 variant resides near the PVRL2 locus, a cholesterol-responsive gene that is located within 100 kb of TOMM40 and the APO cluster, which have both been associated with blood lipid concentrations and Alzheimer’s disease. Conclusion: Our results may provide insights into pathways that influence the adverse effects of thiazide diuretic use and highlight the large sample sizes needed to detect modest pharmacogenetic effects.
Incidental Finding of Pulmonary Embolism at Workup Before SIRT
Authors: Stine Jentoft Kramer, Nerijus Amanavicius, Peter Frøhlich Staanum, Gerda Elisabeth Villadsen, Anne Kirstine Arveschoug
Journal: Clinical Nuclear Medicine (2021)

Abstract Selective internal radiation therapy (SIRT) is a catheter-guided treatment offered to selected patients with primary and secondary liver malignancies. SIRT is preceded by a workup procedure, where 99m Tc-MAA (macroaggregated albumin) is injected in the tumor supplying artery/arteries followed by MAA scintigraphy. SIRT is frequently offered to patients with hepatocellular carcinoma (HCC), but large HCCs are known to be associated with a high risk of liver-to-lung shunting. We present a HCC patient case where a large lung-shunt enabled diagnosis of pulmonary embolism.
Insulin is expressed by enteroendocrine cells during human fetal development
Authors: Adi Egozi, Dhana Llivichuzhca-Loja, Blake T. McCourt, Keren Bahar Halpern, Lydia Farack, Xiaojing An, Fujing Wang, Kong Chen, Liza Konnikova, Shalev Itzkovitz
Journal: Nature Medicine (2021)
Microbial byproducts determine reproductive fitness of free-living and parasitic nematodes
Authors: Mericien Venzon, Ritika Das, Daniel J. Luciano, Julia Burnett, Hyun Shin Park, Joseph Cooper Devlin, Eric T. Kool, Joel G. Belasco, E. Jane Albert Hubbard, Ken Cadwell
Journal: Cell Host & Microbe (2022)
Glycoproteogenomics characterizes the CD44 splicing code associated with bladder cancer invasion
Authors: Cristiana Gaiteiro, Janine Soares, Marta Relvas-Santos, Andreia Peixoto, Dylan Ferreira, Paula Paulo, Andreia Brandão, Elisabete Fernandes, Rita Azevedo, Carlos Palmeira, Rui Freitas, Andreia Miranda, Hugo Osório, Jesús Prieto, Luís Lima, André M. N. Silva, Lúcio Lara Santos, José Alexandre Ferreira
Journal: Theranostics (2022)

Rationale: Bladder cancer (BC) management demands the introduction of novel molecular targets for precision medicine.Cell surface glycoprotein CD44 has been widely studied as a potential biomarker of BC aggressiveness and cancer stem cells.However, significant alternative splicing and multiple glycosylation generate a myriad of glycoproteoforms with potentially distinct functional roles.The lack of tools for precise molecular characterization has led to conflicting results, delaying clinical applications.Addressing these limitations, we have interrogated the transcriptome and glycoproteome of a large BC patient cohort for splicing signatures.Methods: CD44 gene and its splicing variants were assessed by Real Time-Polymerase Chain Reaction (RT-PCR) and RNAseq in tumor tissues.The co-localization of CD44 and short O-glycans was evaluated by proximity ligation assay (PLA), immunohistochemistry and double-immunofluorescence.An innovative glycoproteogenomics approach, integrating transcriptomics-customized datasets and glycomics for protein annotation from nanoLC-ESI-MS/MS experiments, was developed and implemented to identify CD44 variants and associated glycosignatures.The impact of CD44 silencing on proliferation and invasion of BC cell lines and glycoengineered cells was determined by BrdU ELISA and Matrigel invasion assays, respectively.Antibody phosphoarrays were used to investigate the role of CD44 and its glycoforms in the activation of relevant oncogenic signaling pathways.Results: Transcriptomics analysis revealed remarkable CD44 isoforms heterogeneity in bladder cancer tissues, as well as associations between short CD44 standard splicing isoform (CD44s), invasion and poor prognosis.We further demonstrated that targeting short O-glycoforms such as the Tn and sialyl-Tn antigens was key to overcome the lack of cancer specificity presented by CD44.Glycoproteogenomics Ivyspring International
Abstract P204: Association Of Plasma Proteome With Inflammatory Markers Crp And Glyca And Their Responses To Exercise Training
Authors: Jacob Barber, Guoshuai Cai, Prasun K Dev, Jeremy M Robbins, Prashant Rao, Michael Mi, Sujoy Ghosh, Clary Clish, Daniel H Katz, Robert E Gerszten, Claude Bouchard, Mark A Sarzynski
Journal: Circulation (2022)

Introduction: C-reactive protein (CRP) and GlycA are established biomarkers of inflammation. Regular exercise tends to decrease CRP and GlycA levels. However, the molecules underlying CRP and GlycA and their responses to exercise training are less known. Hypothesis: We hypothesized that distinct protein signatures exist for both baseline levels and exercise responsiveness of CRP and GlycA, however with some overlap of proteins across signatures. Methods: Measures were performed before and after 20 weeks of exercise training in 652 Black and White adults from the HERITAGE Family Study. 4,979 circulating proteins were measured using SomaScan. High-sensitivity CRP was measured using automated assays. GlycA was quantified by NMR spectroscopy (LabCorp). Linear mixed models were used to test: 1) Association of baseline proteins with baseline hsCRP and GlycA and 2) Association of change in protein with changes in hsCRP and GlycA. Models were adjusted for age, sex, race, BMI, with family membership as a random variable, with change models also adjusting for baseline trait value. Significance was determined as FDR&lt;0.05. Results: Baseline levels (r=0.51, p&lt;0.0001) and change (r=0.31, p&lt;0.0001) of hsCRP and GlycA were moderately correlated. hsCRP did not change with training, while GlycA trended towards decreasing (Table 1). Across time points, 388 and 1746 unique proteins were associated with hsCRP and GlycA, respectively, with substantial overlap across traits and time points (Table 1). The CRP protein was the top association in 3 of 4 models (range: 1.4x10 -40 &lt; p &lt; 1.2x10 -08 ), with serum amyloid A-2 and A-1 (SAA2, SAA) among the top 6 hits for 3 of 4 models (Table 1). Conclusions: More unique proteins were associated with GlycA levels at both timepoints, with most hsCRP proteins overlapping with GlycA proteins. Overall, a substantial number of proteins are associated with CRP and GlycA levels regardless of when they are measured, which has potential implications for using proteins as signatures of these inflammatory biomarkers.
Abstract 008: Randomized Trial Of A Healthy Weight Intervention For Youth With Mental Illness: The Champion Trial
Authors: Gail Daumit, Robert Findling, Arlene Dalcin, Gerald Jerome, Lawrence J Appel, Stacy Goldsholl, Tammy Brady, Ekaterina Stepanova, Ann Scheimann, Elizabeth Getzoff, Faith Dickerson, Alison Terry, Tyler Fink, Courtney Cook, Rachel Thornton, Rebecca Ozl-Price, Joseph Gennusa, Carmen Lopez-Arvizu, Jeanne Charleston, Nae-yuh Wang
Journal: Circulation (2022)

Introduction: Overweight and obesity in youth with serious emotional disturbance (SED) is exceedingly common. In 2015 the AHA called attention to mental illnesses in youth as important risk conditions for early CVD and the need for transformational change in management of overweight and obesity in this group. Our objective was to test a 12-month, innovative healthy weight intervention in youth with SED. Hypothesis: The active intervention is more effective than control in decreasing BMI Z-score compared at 12 m. Methods: We conducted a two-arm randomized trial in 2 outpatient pediatric mental health settings in 112 youth, ages 8-18 yrs. The active intervention group was offered 12m of in-person and virtual individual weight management sessions led by health coaches who provided guidance on improving diet and increasing physical activity, and engaged parents. Results: At baseline, mean (SD) age was 13.0 (2.7) yrs with 46% ages 8-12 and 54% 13-18; 55% were male, 46% Black, 39% had household income less than $50K/yr and 31% lived in a single-parent household. Primary diagnoses were ADHD (41%), major depression (23%), and anxiety (23%). Mean BMI Z-score (SD) was 2.0(0.4), BMI 30.4 (6.4) kg/m 2 .Mean(SD) psychotropic medications were 2.1(1.4). At 12m, 111 (99%) had a follow-up weight; 42 were collected after the onset of the COVID pandemic). The intervention group compared to the control group had 0.15 decrease in BMI Z-Score (95% CI 0.26 to 0.04), p&lt;0.007) between baseline and 12 m (Figure) and a 1.43 kg/m 2 decrease in BMI (95% CI 2.43, 0.42, p&lt;0.006). Estimated net effect on BMI Z-score for intervention vs. control was enhanced during the pandemic but not statistically different from net effects pre-pandemic (p=0.06). Conclusions: A weight control intervention designed for children with SED decreased BMI Z-score substantially over 12 months, including during the COVID-19 pandemic. These results provide empirical evidence in support of weight control programs in a population at high risk for early development of CVD risk factors.
Independent Drug Action in Combination Therapy: Implications for Precision Oncology
Authors: Deborah Plana, Adam C. Palmer, Peter K. Sorger
Journal: Cancer Discovery (2022)

Combination therapies are superior to monotherapy for many cancers. This advantage was historically ascribed to the ability of combinations to address tumor heterogeneity, but synergistic interaction is now a common explanation as well as a design criterion for new combinations. We review evidence that independent drug action, described in 1961, explains the efficacy of many practice-changing combination therapies: it provides populations of patients with heterogeneous drug sensitivities multiple chances of benefit from at least one drug. Understanding response heterogeneity could reveal predictive or pharmacodynamic biomarkers for more precise use of existing drugs and realize the benefits of additivity or synergy.Significance:. The model of independent drug action represents an effective means to predict the magnitude of benefit likely to be observed in new clinical trials for combination therapies. The "bet-hedging" strategy implicit in independent action suggests that individual patients often benefit from only a subset—sometimes one—of the drugs in a combination. Personalized, targeted combination therapy, consisting of agents likely to be active in a particular patient, will increase, perhaps substantially, the magnitude of therapeutic benefit. Precision approaches of this type will require a better understanding of variability in drug response and new biomarkers, which will entail preclinical research on diverse panels of cancer models rather than studying drug synergy in unusually sensitive models.
Separate substantive from statistical hypotheses and treat them differently
Authors: Mike Dacey
Journal: Behavioral and Brain Sciences (2022)

Abstract I suggest addressing the problems Yarkoni identifies by separating substantive from statistical hypotheses, and treating them differently. A statistical test of experimental data only bears directly on statistical hypotheses. Evaluation of related substantive hypotheses requires an additional, qualitative inference to the best explanation. Statistical inference cannot do all of the work of theory choice.
A Primary Care–Based Cognitive Behavioral Therapy Intervention for Long-Term Opioid Users With Chronic Pain
Authors: Lynn DeBar, Meghan Mayhew, Lindsay Benes, Allison Bonifay, Richard A. Deyo, Charles R. Elder, Francis J. Keefe, Michael C. Leo, Carmit McMullen, Ashli Owen-Smith, David H. Smith, Connie M. Trinacty, William M. Vollmer
Journal: Annals of Internal Medicine (2021)

Chronic pain is common, disabling, and costly. Few clinical trials have examined cognitive behavioral therapy (CBT) interventions embedded in primary care settings to improve chronic pain among those receiving long-term opioid therapy.To determine the effectiveness of a group-based CBT intervention for chronic pain.Pragmatic, cluster randomized controlled trial. (ClinicalTrials.gov: NCT02113592).Kaiser Permanente health care systems in Georgia, Hawaii, and the Northwest.Adults (aged ≥18 years) with mixed chronic pain conditions receiving long-term opioid therapy.A CBT intervention teaching pain self-management skills in 12 weekly, 90-minute groups delivered by an interdisciplinary team (behaviorist, nurse, physical therapist, and pharmacist) versus usual care.Self-reported pain impact (primary outcome, as measured by the PEGS scale [pain intensity and interference with enjoyment of life, general activity, and sleep]) was assessed quarterly over 12 months. Pain-related disability, satisfaction with care, and opioid and benzodiazepine use based on electronic health care data were secondary outcomes.A total of 850 patients participated, representing 106 clusters of primary care providers (mean age, 60.3 years; 67.4% women); 816 (96.0%) completed follow-up assessments. Intervention patients sustained larger reductions on all self-reported outcomes from baseline to 12-month follow-up; the change in PEGS score was -0.434 point (95% CI, -0.690 to -0.178 point) for pain impact, and the change in pain-related disability was -0.060 point (CI, -0.084 to -0.035 point). At 6 months, intervention patients reported higher satisfaction with primary care (difference, 0.230 point [CI, 0.053 to 0.406 point]) and pain services (difference, 0.336 point [CI, 0.129 to 0.543 point]). Benzodiazepine use decreased more in the intervention group (absolute risk difference, -0.055 [CI, -0.099 to -0.011]), but opioid use did not differ significantly between groups.The inclusion of only patients with insurance in large integrated health care systems limited generalizability, and the clinical effect of change in scores is unclear.Primary care-based CBT, using frontline clinicians, produced modest but sustained reductions in measures of pain and pain-related disability compared with usual care but did not reduce use of opioid medication.National Institutes of Health.
End-of-Life Care for Older Adults with Aggressive Non-Hodgkin Lymphoma
Authors: Netana H. Markovitz, Alisha Yi, Oreofe O. Odejide, Richard Newcomb, Hermioni L. Amonoo, Ashley M. Nelson, Matthew J. Reynolds, Julia Rice, Mitchell W. Lavoie, Ryan D. Nipp, Areej El-Jawahri, Patrick Connor Connor Johnson
Journal: Blood (2021)
Abstract 10230: Sestrin2 Plays an Essential Role in Regulating the Unfolded Protein Response During Cardiac Ischemia/Reperfusion and Preventing Excessive Myocardial Apoptosis
Authors: Xuan Li, Zhen Wang, Jussara do Carmo, Alexandre A Da Silva, Alan Mouton, Ana C Omoto, John E Hall
Journal: Circulation (2021)

Introduction: Cardiac ischemia/reperfusion (I/R) alters cellular redox and calcium homeostasis, causing protein-folding errors in the endoplasmic reticulum (ER) which activates the unfolded protein response (UPR). Although appropriate UPR is an adaptive response of the cell, excessive and prolonged UPR can cause cellular apoptosis and aggravate I/R injury. We showed that Sestrin2 (Sesn2) regulates AMP-activated protein kinase (AMPK) activity and acts as an endogenous inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) to modulate protein synthesis and autophagy in the heart. Hypothesis: We hypothesized that Sesn2 regulates activation of UPR and maintains ER homeostasis as a protective response during myocardial I/R. Methods: Ligation and release of the left anterior descending coronary artery (LAD) was performed in wild-type (WT) C57BL/6J and cardiac specific Sesn2 knock out (KO) mice to induce myocardial I/R injury (45’ ischemia with different time of reperfusion). Results: I/R induced UPR in a time-dependent manner, reaching its peak 6 hours post reperfusion, and returning to normal values after 24 hours of reperfusion in WT mice. Pharmacological inhibition of the UPR by 4-phenylbutyrate (100mg/kg, i.p.) after reperfusion attenuated myocardial infarction size and restored systolic function. Conversely, genetic ablation of cardiac-specific Sesn2 was associated with increased myocardial infarction of 49.4%, and decreased systolic function of 22.9%, compared to WT mice. Molecular analysis showed that cardiac Sesn2 deficiency resulted in greater and prolonged activation of the UPR, and increased myocardial apoptosis compared to WT mice. Furthermore, activation of mTORC1 pathway after I/R was more pronounced and prolonged in cardiac-specific Sesn2 KO hearts, whereas AMPK activity post reperfusion was similar in both groups. Inhibiting mTORC1 with rapamycin (3mg/kg, i.p.) after I/R reduced myocardial apoptosis in a similar fashion in WT and cardiac-specific Sesn2 KO mice. Conclusions: During I/R, regulation of mTORC1 signaling pathway by Sesn2 may be a key factor for maintaining ER homeostasis and reducing I/R-induced apoptosis and cardiac injury.