tbuckley/cabot-search huggingface dataset:
ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response
Authors: Sankari Nagarajan, Shalini V. Rao, Joseph Sutton, Danya Cheeseman, Shanade Dunn, Evangelia K. Papachristou, Jose-Enrique Gonzalez Prada, Dominique-Laurent Couturier, Sanjeev Kumar, Kamal Kishore, Chandra Sekhar Reddy Chilamakuri, Silvia-Elena Glont, Emily Archer Goode, Cara Brodie, Naomi Guppy, Rachael Natrajan, Alejandra Bruna, Carlos Caldas, Alasdair Russell, Rasmus Siersbæk, Kosuke Yusa, Igor Chernukhin, Jason S. Carroll
Journal: Nature Genetics (2020)
Machine Learning Detection of Cognitive Impairment in Primary Care
Authors: Levy Boaz, Gable Samuel, Tsoy Elena, Haspel Nurit, Wadler Brianna, Wilcox Rand, Hess Courtney, Hogan Jacqueline, Driscoll Daniel, Hashmi Ardeshir
Journal: Alzheimers Disease & Dementia (2017)

Routine cognitive screenings in primary care settings can benefit patient care and preventive medicine in multiple ways; however, their integration to the protocol of physical exams, as a standard of care, may be hampered by systemic considerations related to labor and cost. In an effort to decrease these impediments, the current study evaluated the validity of a screening procedure that had been specifically designed to impose minimal burden on the clinic.
Human Tumor‐Lymphatic Microfluidic Model Reveals Differential Conditioning of Lymphatic Vessels by Breast Cancer Cells
Authors: Jose M. Ayuso, Max M. Gong, Melissa C. Skala, Paul M. Harari, David J. Beebe
Journal: Advanced Healthcare Materials (2020)

Abstract Breast tumor progression is a complex process involving intricate crosstalk between the primary tumor and its microenvironment. In the context of breast tumor‐lymphatic interactions, it is unclear how breast cancer cells alter the gene expression of lymphatic endothelial cells and how these transcriptional changes potentiate lymphatic dysfunction. Thus, there is a need for in vitro lymphatic vessel models to study these interactions. In this work, a tumor‐lymphatic microfluidic model is developed to study the differential conditioning of lymphatic vessels by estrogen receptor‐positive (i.e., MCF7) and triple‐negative (i.e., MDA‐MB‐231) breast cancer cells. The model consists of a lymphatic endothelial vessel cultured adjacently to either MCF7 or MDA‐MB‐231 cells. Quantitative transcriptional analysis reveals expression changes in genes related to vessel growth, permeability, metabolism, hypoxia, and apoptosis in lymphatic endothelial cells cocultured with breast cancer cells. Interestingly, these changes are different in the MCF7‐lymphatic cocultures as compared to the 231‐lymphatic cocultures. Importantly, these changes in gene expression correlate to functional responses, such as endothelial barrier dysfunction. These results collectively demonstrate the utility of this model for studying breast tumor‐lymphatic crosstalk for multiple breast cancer subtypes.
Outcome of patients treated with a single-fraction dose of radiation for lymphomatoid papulosis.
Authors: Michelle Sara Gentile, Tarita O. Thomas, Priya Agrawal, Joan Guitart, Steven T. Rosen, Timothy Kuzel, Bharat Bhushan Mittal
Journal: Journal of Clinical Oncology (2012)

e18523 Background: Lymphomatoid Papulosis (LYP) is a primary cutaneous CD30+ lymphoproliferative disorder and a radiosensitive tumor. Treatment with radiation is typically given in multiple fractions for patients presenting with symptomatic unilesional or multilesional disease. However, a single fraction of radiation is more convenient to the patient. The purpose of this retrospective review was to evaluate the clinical response to a single fraction of radiation for palliation of symptomatic LYP lesions. Methods: The records of 8 (5 female, 3 male) patients with LYP, treated with a single or multi-fractionated palliative radiation therapy between 10/2001 and 9/2011, were reviewed. All patients had received multiple previous treatments such as chemotherapy, PUVA, topical nitrogen mustard, and UVB. A total of 19 sites with disease were given the following single doses: 700 (n=3) and 800 (n=16). In the earlier years, a total of 6 sites with disease were given 250 cGy in 18 fractions for a total dose of 4500 cGy. Radiation therapy was administered with electrons to 20 sites and with photons to 5. A bolus was used in most cases to increase the radiation dosage to the skin. Results: Minimum and median follow-up were 1 and 43 months (range, 1 - 120), respectively. Median age of the patients was 65 (range, 24 - 83). For disease sites receiving a single fraction therapy, a complete response (CR) was seen in 17 of the 19 sites (89.5%), and a partial response (PR) was seen in an additional 2 of the 19 sites (10.5%). Therefore, the overall response rate was 100%. For the disease sites receiving multi-fractionated therapy, a CR was seen in 6 of the 6 sites (100%). Evaluation of patient characteristics and treatment did not reveal any differences between patients achieving a CR or PR. Conclusions: For previously treated, radiation-naıve LYP lesions, palliative radiation therapy with single fractions of 700 - 800 cGy is associated with an excellent CR and is a convenient and cost effective strategy.
OT-82, a novel anticancer drug candidate that targets the strong dependence of hematological malignancies on NAD biosynthesis
Authors: Lioubov Korotchkina, Denis Kazyulkin, Pavel G. Komarov, Alex Polinsky, Ekaterina L. Andrianova, Sangeeta Joshi, Mahima Gupta, Slavoljub Vujcic, Eugene Kononov, Ilia Toshkov, Yuan Tian, Peter Krasnov, Mikhail V. Chernov, Jean Veith, Marina P. Antoch, Shiloh Middlemiss, Klaartje Somers, Richard B. Lock, Murray D. Norris, Michelle J. Henderson, Michelle Haber, Olga B. Chernova, Andrei V. Gudkov
Journal: Leukemia (2020)

Abstract Effective treatment of some types of cancer can be achieved by modulating cell lineage-specific rather than tumor-specific targets. We conducted a systematic search for novel agents selectively toxic to cells of hematopoietic origin. Chemical library screenings followed by hit-to-lead optimization identified OT-82, a small molecule with strong efficacy against hematopoietic malignancies including acute myeloblastic and lymphoblastic adult and pediatric leukemias, erythroleukemia, multiple myeloma, and Burkitt’s lymphoma in vitro and in mouse xenograft models. OT-82 was also more toxic towards patients-derived leukemic cells versus healthy bone marrow-derived hematopoietic precursors. OT-82 was shown to induce cell death by inhibiting nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage pathway of NAD synthesis. In mice, optimization of OT-82 dosing and dietary niacin further expanded the compound’s therapeutic index. In toxicological studies conducted in mice and nonhuman primates, OT-82 showed no cardiac, neurological or retinal toxicities observed with other NAMPT inhibitors and had no effect on mouse aging or longevity. Hematopoietic and lymphoid organs were identified as the primary targets for dose limiting toxicity of OT-82 in both species. These results reveal strong dependence of neoplastic cells of hematopoietic origin on NAMPT and introduce OT-82 as a promising candidate for the treatment of hematological malignancies.
Mitochondrial Complex II in Intestinal Epithelial Cells Is a Critical Metabolic Checkpoint That Regulates Severity of Gastrointestinal Graft-Versus-Host Disease
Authors: Hideaki Fujiwara, Anna V Mathew, Ilya Kovalenko, Pal Anupama, Dan Peltier, Stephanie Kim, Austin Taylor, Katherine Oravecz-Wilson, Yaping Sun, Costas Lyssiotis, Alnawaz Rehemtulla, Subramanian Pennarthur, Pavan Reddy
Journal: Blood (2019)
Human Antigen R (HuR): A Regulator of Heme Oxygenase‐1 Cytoprotection in Mouse and Human Liver Transplant Injury
Authors: Kenneth J. Dery, Kojiro Nakamura, Kentaro Kadono, Hirofumi Hirao, Shoichi Kageyama, Takahiro Ito, Hidenobu Kojima, Fady M. Kaldas, Ronald W. Busuttil, Jerzy W. Kupiec‐Weglinski
Journal: Hepatology (2019)

Ischemia-reperfusion injury (IRI) represents a risk factor in liver transplantation (LT). We have shown that overexpression of heme oxygenase-1 (HO-1) mitigates hepatic IRI in LT recipients. Here, we hypothesized that human antigen R (HuR), the stabilizer of adenylate-uridylate (AU)-rich mRNAs, is required for hepatoprotection in LT.In an experimental arm, HuR/HO-1 protein expression was correlated with hepatic IRI phenotype. In an in vitro inflammation mimic model of hepatic warm IRI, induction of HuR/HO-1 and cytoplasmic localization following cytokine preconditioning were detected in primary hepatocyte cultures, whereas HuR silencing caused negative regulation of HO-1, followed by enhanced cytotoxicity. Using the HuR-inhibitor, we showed that HuR likely regulates HO-1 through its 3' untranslated region and causes neutrophil activation (CD69+/lymphocyte antigen 6 complex locus G [Ly6-G]). HuR silencing in bone marrow-derived macrophages decreased HO-1 expression, leading to the induction of proinflammatory cytokines/chemokines. RNA sequencing of HuR silenced transcripts under in vitro warm IRI revealed regulation of genes thymus cell antigen 1 (THY1), aconitate decarboxylase 1 (ACOD1), and Prostaglandin E Synthase (PTGES). HuR, but not hypoxia-inducible protein alpha, positively regulated HO-1 in warm, but not cold, hypoxia/reoxygenation conditions. HuR modulated HO-1 in primary hepatocytes, neutrophils, and macrophages under reperfusion. Adjunctive inhibition of HuR diminished microtubule-associated proteins 1A/1B light chain 3B (LC3B), a marker for autophagosome, under HO-1 regulation, suggesting a cytoprotective mechanism in hepatic IR. In a clinical arm, hepatic biopsies from 51 patients with LT were analyzed at 2 hours after reperfusion. Graft HuR expression was negatively correlated with macrophage (CD80/CD86) and neutrophil (Cathepsin G) markers. Hepatic IRI increased HuR/HO-1 expression and inflammatory genes. High HuR-expressing liver grafts showed lower serum alanine aminotransferase/serum aspartate aminotransferase levels and improved LT survival.This translational study identifies HuR as a regulator of HO-1-mediated cytoprotection in sterile liver inflammation and a biomarker of ischemic stress resistance in LT.
Imaging the Landmarks of Vascular Recovery
Authors: Jamila Hedhli, MinWoo Kim, Hailey J. Knox, John A. Cole, Than Huynh, Matthew Schuelke, Iwona T. Dobrucki, Leszek Kalinowski, Jefferson Chan, Albert J. Sinusas, Michael F. Insana, Lawrence W. Dobrucki
Journal: Theranostics (2020)

Background: Peripheral arterial disease (PAD) is a major worldwide health concern.Since the late 1990s therapeutic angiogenesis has been investigated as an alternative to traditional PAD treatments.Although positive preclinical results abound in the literature, the outcomes of human clinical trials have been discouraging.Among the challenges the field has faced has been a lack of standardization of the timings and measures used to validate new treatment approaches.Methods: In order to study the spatiotemporal dynamics of both perfusion and neovascularization in mice subjected to surgically-induced hindlimb ischemia (n= 30), we employed three label-free imaging modalities (a novel high-sensitivity ultrasonic Power Doppler methodology, laser speckle contrast, and photoacoustic imaging), as well as a tandem of radio-labeled molecular probes, 99m Tc-NC100692 and 99m Tc-BRU-5921 respectively, designed to detect two key modulators of angiogenic activity, αVβ3 and HIF-1α , via scintigraphic imaging. Results:The multimodal imaging strategy reveals a set of "landmarks"-key physiological and molecular events in the healing process-that can serve as a standardized framework for describing the impact of emerging PAD treatments.These landmarks span the entire process of neovascularization, beginning with the rapid decreases in perfusion and oxygenation associated with ligation surgery, extending through pro-angiogenic changes in gene expression driven by the master regulator HIF-1α , and ultimately leading to complete functional revascularization of the affected tissues.Conclusions: This study represents an important step in the development of multimodal non-invasive imaging strategies for vascular research; the combined results offer more insight than can be gleaned through any of the individual imaging methods alone.Researchers adopting similar imaging strategies and will be better able to describe changes in the onset, duration, and strength of each of the landmarks of vascular recovery, yielding greater biological insight, and enabling more comprehensive cross-study comparisons.Perhaps most important, this study paves the road for more efficient translation of PAD research; emerging experimental treatments can be more effectively assessed and refined at the preclinical stage, ultimately leading to better next-generation therapies.
Investigational new drug enabling angiotensin oral-delivery studies to attenuate pulmonary hypertension
Authors: Henry Daniell, Venkata Mangu, Bakhtiyor Yakubov, Jiyoung Park, Peyman Habibi, Yao Shi, Patricia A. Gonnella, Amanda Fisher, Todd Cook, Lily Zeng, Steven M. Kawut, Tim Lahm
Journal: Biomaterials (2019)

Pulmonary arterial hypertension (PAH) is a deadly and uncurable disease characterized by remodeling of the pulmonary vasculature and increased pulmonary artery pressure. Angiotensin Converting Enzyme 2 (ACE2) and its product, angiotensin-(1-7) [ANG-(1-7)] were expressed in lettuce chloroplasts to facilitate affordable oral drug delivery. Lyophilized lettuce cells were stable up to 28 months at ambient temperature with proper folding, assembly of CTB-ACE2/ANG-(1-7) and functionality. When the antibiotic resistance gene was removed, Ang1-7 expression was stable in subsequent generations in marker-free transplastomic lines. Oral gavage of monocrotaline-induced PAH rats resulted in dose-dependent delivery of ANG-(1-7) and ACE2 in plasma/tissues and PAH development was attenuated with decreases in right ventricular (RV) hypertrophy, RV systolic pressure, total pulmonary resistance and pulmonary artery remodeling. Such attenuation correlated well with alterations in the transcription of Ang-(1-7) receptor MAS and angiotensin II receptor AGTRI as well as IL-1β and TGF-β1. Toxicology studies showed that both male and female rats tolerated ~10-fold ACE2/ANG-(1-7) higher than efficacy dose. Plant cell wall degrading enzymes enhanced plasma levels of orally delivered protein drug bioencapsulated within plant cells. Efficient attenuation of PAH with no toxicity augurs well for clinical advancement of the first oral protein therapy to prevent/treat underlying pathology for this disease.
A magnetism/laser-auxiliary cascaded drug delivery to pulmonary carcinoma
Authors: Jialiang Lin, Qingqing Yin, Binlong Chen, Haoran Zhang, Dong Mei, Jijun Fu, Bing He, Hua Zhang, Wenbing Dai, Xueqing Wang, Yiguang Wang, Qiang Zhang
Journal: Acta Pharmaceutica Sinica B (2020)

Although high-efficiency targeted delivery is investigated for years, the efficiency of tumor targeting seems still a hard core to smash. To overcome this problem, we design a three-step delivery strategy based on streptavidin-biotin interaction with the help of c(RGDfK), magnetic fields and lasers. The ultrasmall superparamagnetic iron oxide nanoparticles (USIONPs) modified with c(RGDfK) and biotin are delivered at step 1, followed by streptavidin and the doxorubicin (Dox) loaded nanosystems conjugated with biotin at steps 2 and 3, respectively. The delivery systems were proved to be efficient on A549 cells. The co-localization of signal for each step revealed the targeting mechanism. The external magnetic field could further amplify the endocytosis of USPIONs based on c(RGDfK), and magnify the uptake distinctions among different test groups. Based on photoacoustic imaging, laser-heating treatment could enhance the permeability of tumor venous blood vessels and change the insufficient blood flow in cancer. Then, it was noticed in vivo that only three-step delivery with laser-heating and magnetic fields realized the highest tumor distribution of nanosystem. Finally, the magnetism/laser-auxiliary cascaded delivery exhibited the best antitumor efficacy. Generally, this study demonstrated the necessity of combining physical, biological and chemical means of targeting.
The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas
Authors: Karmele Valencia, Oihane Erice, Kaja Kostyrko, Simone Hausmann, Elizabeth Guruceaga, Anuradha Tathireddy, Natasha M. Flores, Leanne C. Sayles, Alex G. Lee, Rita Fragoso, Tian-Qiang Sun, Adrian Vallejo, Marta Roman, Rodrigo Entrialgo-Cadierno, Itziar Migueliz, Nerea Razquin, Puri Fortes, Fernando Lecanda, Jun Lu, Mariano Ponz-Sarvise, Chang-Zheng Chen, Pawel K. Mazur, E. Alejandro Sweet-Cordero, Silvestre Vicent
Journal: Journal of Clinical Investigation (2019)

Few therapies are currently available for patients with KRAS-driven cancers, highlighting the need to identify new molecular targets that modulate central downstream effector pathways. Here we found that the microRNA (miRNA) cluster including miR181ab1 is a key modulator of KRAS-driven oncogenesis. Ablation of Mir181ab1 in genetically engineered mouse models of Kras-driven lung and pancreatic cancer was deleterious to tumor initiation and progression. Expression of both resident miRNAs in the Mir181ab1 cluster, miR181a1 and miR181b1, was necessary to rescue the Mir181ab1-loss phenotype, underscoring their nonredundant role. In human cancer cells, depletion of miR181ab1 impaired proliferation and 3D growth, whereas overexpression provided a proliferative advantage. Lastly, we unveiled miR181ab1-regulated genes responsible for this phenotype. These studies identified what we believe to be a previously unknown role for miR181ab1 as a potential therapeutic target in 2 highly aggressive and difficult to treat KRAS-mutated cancers.
Isotretinoin: experts convene to investigate new concerns over suicide risk
Authors: Elisabeth Mahase
Journal: BMJ (2019)

An expert group has been reconvened to review recent safety data relating to the acne drug isotretinoin (marketed as Roaccutane) and evaluate the risk of sexual and psychiatric adverse effects, including suicide.

The Medicines and Healthcare Products Regulatory Agency’s isotretinoin expert working group had looked at the risk of psychiatric adverse reactions suspected to be associated with isotretinoin in 2014, but it has now reformed to look at more recently reported adverse reactions. In 2019 12 deaths were recorded among people to whom isotretinoin had been prescribed, 10 by suicide, MHRA data …
Response to Open Peer Commentaries on “Ethics and Collateral Findings in Pragmatic Clinical Trials”
Authors: Stephanie Morain, Debra Mathews, Juli Murphy Bollinger, Jeremy Sugarman
Journal: The American Journal of Bioethics (2020)

"Response to Open Peer Commentaries on “Ethics and Collateral Findings in Pragmatic Clinical Trials”." The American Journal of Bioethics, 20(1), pp. W9–W11
An endocannabinoid-regulated basolateral amygdala–nucleus accumbens circuit modulates sociability
Authors: Oakleigh M. Folkes, Rita Báldi, Veronika Kondev, David J. Marcus, Nolan D. Hartley, Brandon D. Turner, Jade K. Ayers, Jordan J. Baechle, Maya P. Misra, Megan Altemus, Carrie A. Grueter, Brad A. Grueter, Sachin Patel
Journal: Journal of Clinical Investigation (2019)

Deficits in social interaction (SI) are a core symptom of autism spectrum disorders (ASDs); however, treatments for social deficits are notably lacking. Elucidating brain circuits and neuromodulatory signaling systems that regulate sociability could facilitate a deeper understanding of ASD pathophysiology and reveal novel treatments for ASDs. Here we found that in vivo optogenetic activation of the basolateral amygdala-nucleus accumbens (BLA-NAc) glutamatergic circuit reduced SI and increased social avoidance in mice. Furthermore, we found that 2-arachidonoylglycerol (2-AG) endocannabinoid signaling reduced BLA-NAc glutamatergic activity and that pharmacological 2-AG augmentation via administration of JZL184, a monoacylglycerol lipase inhibitor, blocked SI deficits associated with in vivo BLA-NAc stimulation. Additionally, optogenetic inhibition of the BLA-NAc circuit markedly increased SI in the Shank3B-/- mouse, an ASD model with substantial SI impairment, without affecting SI in WT mice. Finally, we demonstrated that JZL184 delivered systemically or directly to the NAc also normalized SI deficits in Shank3B-/- mice, while ex vivo JZL184 application corrected aberrant NAc excitatory and inhibitory neurotransmission and reduced BLA-NAc-elicited feed-forward inhibition of NAc neurons in Shank3B-/- mice. These data reveal circuit-level and neuromodulatory mechanisms regulating social function relevant to ASDs and suggest 2-AG augmentation could reduce social deficits via modulation of excitatory and inhibitory neurotransmission in the NAc.
Government to spend £40m on streamlining NHS staff logins
Authors: Elisabeth Mahase
Journal: BMJ (2020)

The government has pledged £40m (€47m; $53m) to cut the time it takes staff in certain parts of the NHS in England to sign in to all the required IT programmes to see patients’ details.

The money, which will come from the Department of Health and Social Care’s budget, will be used to standardise logins and provide access in different ways, such as through fingerprints, working with IT suppliers.

The health department told The BMJ that the project will focus on the parts of the NHS where the need to reduce login times is greatest. It said it wanted to hear from the NHS to determine where the priority …
DP1 Activation Reverses Age-Related Hypertension Via NEDD4L-Mediated T-Bet Degradation in T Cells
Authors: Deping Kong, Qiangyou Wan, Juanjuan Li, Shengkai Zuo, Guizhu Liu, Qian Liu, Chenchen Wang, Peiyuan Bai, Sheng-Zhong Duan, Bin Zhou, Fotini Gounari, Ankang Lyu, Michael Lazarus, Richard M. Breyer, Ying Yu
Journal: Circulation (2020)

Blood pressure often rises with aging, but exact mechanisms are still not completely understood. With aging, the level of proinflammatory cytokines increases in T lymphocytes. Prostaglandin D2, a proresolution mediator, suppresses Type 1 T helper (Th1) cytokines through D-prostanoid receptor 1 (DP1). In this study, we aimed to investigate the role of the prostaglandin D2/DP1 axis in T cells on age-related hypertension.To clarify the physiological and pathophysiological roles of DP1 in T cells with aging, peripheral blood samples were collected from young and older male participants, and CD4+ T cells were sorted for gene expression, prostaglandin production, and Western blot assays. Mice blood pressure was quantified by invasive telemetric monitor.The prostaglandin D2/DP1 axis was downregulated in CD4+ T cells from older humans and aged mice. DP1 deletion in CD4+ T cells augmented age-related hypertension in aged male mice by enhancing Th1 cytokine secretion, vascular remodeling, CD4+ T cells infiltration, and superoxide production in vasculature and kidneys. Conversely, forced expression of exogenous DP1 in T cells retarded age-associated hypertension in mice by reducing Th1 cytokine secretion. Tumor necrosis factor α neutralization or interferon γ deletion ameliorated the age-related hypertension in DP1 deletion in CD4+ T cells mice. Mechanistically, DP1 inhibited Th1 activity via the PKA (protein kinase A)/p-Sp1 (phosphorylated specificity protein 1)/neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) pathway-mediated T-box-expressed-in-T-cells (T-bet) ubiquitination. T-bet deletion or forced NEDD4L expression in CD4+ T cells attenuated age-related hypertension in CD4+ T cell-specific DP1-deficient mice. DP1 receptor activation by BW245C prevented age-associated blood pressure elevation and reduced vascular/renal superoxide production in male mice.The prostaglandin D2/DP1 axis suppresses age-related Th1 activation and subsequent hypertensive response in male mice through increase of NEDD4L-mediated T-bet degradation by ubiquitination. Therefore, the T cell DP1 receptor may be an attractive therapeutic target for age-related hypertension.