tbuckley/cabot-search huggingface dataset:
Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies
Authors: Candice R. Gurbatri, Ioana Lia, Rosa Vincent, Courtney Coker, Samuel Castro, Piper M. Treuting, Taylor E. Hinchliffe, Nicholas Arpaia, Tal Danino
Journal: Science Translational Medicine (2020)

An engineered probiotic system locally delivers checkpoint blockade nanobodies to tumors for sustained therapeutic release.
Genetic Ancestry Testing
Authors: Lynn B. Jorde, Michael J. Bamshad
Journal: JAMA (2020)

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BMAL1-Downregulation Aggravates <i>Porphyromonas Gingivalis</i> -Induced Atherosclerosis by Encouraging Oxidative Stress
Authors: Mengru Xie, Qingming Tang, Jiaming Nie, Chao Zhang, Xin Zhou, Shaoling Yu, Jiwei Sun, Xiang Cheng, Nianguo Dong, Yu Hu, Lili Chen
Journal: Circulation Research (2020)

Atherosclerotic cardiovascular diseases are the leading cause of mortality worldwide. Atherosclerotic cardiovascular diseases are considered as chronic inflammation processes. In addition to risk factors associated with the cardiovascular system itself, pathogenic bacteria such as the periodontitis-associated Porphyromonas gingivalis (P gingivalis) are also closely correlated with the development of atherosclerosis, but the underlying mechanisms are still elusive. To elucidate the mechanisms of P gingivalis-accelerated atherosclerosis and explore novel therapeutic strategies of atherosclerotic cardiovascular diseases. Bmal1-/- (brain and muscle Arnt-like protein 1) mice, ApoE-/- mice, Bmal1-/-ApoE-/- mice, conditional endothelial cell Bmal1 knockout mice (Bmal1fl/fl; Tek-Cre mice), and the corresponding jet-legged mouse model were used. Pgingivalis accelerates atherosclerosis progression by triggering arterial oxidative stress and inflammatory responses in ApoE-/- mice, accompanied by the perturbed circadian clock. Circadian clock disruption boosts P gingivalis-induced atherosclerosis progression. The mechanistic dissection shows that P gingivalis infection activates the TLRs-NF-κB signaling axis, which subsequently recruits DNMT-1 to methylate the BMAL1 promoter and thus suppresses BMAL1 transcription. The downregulation of BMAL1 releases CLOCK, which phosphorylates p65 and further enhances NF-κB signaling, elevating oxidative stress and inflammatory response in human aortic endothelial cells. Besides, the mouse model exhibits that joint administration of metronidazole and melatonin serves as an effective strategy for treating atherosclerotic cardiovascular diseases. P gingivalis accelerates atherosclerosis via the NF-κB-BMAL1-NF-κB signaling loop. Melatonin and metronidazole are promising auxiliary medications toward atherosclerotic cardiovascular diseases.
Interferon gamma inhibits CXCL8–CXCR2 axis mediated tumor-associated macrophages tumor trafficking and enhances anti-PD1 efficacy in pancreatic cancer
Authors: Mingjie Zhang, Lifeng Huang, Guoping Ding, Huilian Huang, Guoliang Cao, Xu Sun, Neng Lou, Qiang Wei, Tao Shen, Xiaodong Xu, Liping Cao, Qiang Yan
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Pancreatic cancer (PC) is a common malignancy of the digestive system and is characterized by poor prognosis and early metastasis. Tumor immune escape plays an important role in PC progression. Programmed death 1 (PD1) blockade therapy is a promising treatment for patients with PC, but is yet to achieve significant clinical effects so far. Interferon gamma (IFN-γ) is a soluble dimeric cytokine that is closely associated with tumor immune surveillance and cytotoxicity. IFN-γ suppresses a variety of tumor-derived cytokines in PC, such as CXCL8. In the present study, we investigated the therapeutic efficacy of combined anti-PD1 and IFN-γ treatment in PC. Methods BxPC-3 and Panc-1 human PC cell lines were used to construct a murine PC model. Blood samples (n=44) and surgical resection specimens (n=36) from human patients with PC were also collected. χ 2 test, two-tailed unpaired t-test or Kaplan-Meier survival analysis was used to calculate p values. Results PD1/PD-L1 signaling was overexpressed in PC tumor-bearing mice. Anti-PD1 prevented tumor growth if initiated early after tumor inoculation; however, delayed anti-PD1 treatment showed limited benefit. Murine PC model had a preferential expansion of CXCR2 + CD68 + macrophages, and these cells showed an immunosuppressive nature (M2 polarization). PC tumors overexpressed CXCL8 and tumor-derived CXCL8 deficiency prohibited the trafficking of CXCR2 + CD68 + macrophages. IFN-γ suppressed the expression of tumor-derived CXCL8, and combined with IFN-γ treatment, delayed anti-PD1 treatment showed significant antitumor effects. Thus, we conclude that murine CXCR2 + CD68 + macrophages traffic to PC tumors by tumor-derived CXCL8 and mediate local immunosuppression, which limits the efficacy of PD1 blockade therapy. IFN-γ suppresses tumor-derived CXCL8 and inhibits the tumor trafficking of CXCR2 + CD68 + macrophages by blocking the CXCL8–CXCR2 axis to enhance anti-PD1 efficacy. Human PC also produces high levels of CXCL8. Patients with PC present elevated CXCR2 expression on peripheral and tumor-infiltrating CD68 + macrophages, which are associated with advanced tumor stage and poor prognosis. Conclusion Our findings suggest that IFN-γ is a translatable, therapeutic option to improve the efficacy of PD1 blockade therapy by preventing trafficking of CXCR2 + CD68 + macrophages via blocking the CXCL8–CXCR2 axis.
Abstract 13514: A Novel Machine Learning Algorithm Can Identify Septal Accessory Pathway Location on Pre-Procedural ECG in Children With Wolff-Parkinson-White Syndrome
Authors: Antonio J Escobar, Jin Long, Marco V Perez, Anne M Dubin, Kara Motonaga, Henry Chubb, Anthony Trela, Debra G Hanisch, Scott R Ceresnak
Journal: Circulation (2019)

Background: Recognition of an accessory pathway (AP) in a septal location can significantly impact the decision to proceed with invasive EPS, especially in younger or asymptomatic patients. Current...
Perceived helpfulness of treatment for major depressive disorder: findings from the WHO World Mental Health Surveys
Authors: Harris, Kazdin, chiu, Sampson, Aguilar-Gaxiola, Al-Hamzawi, Alonso, Altwaijri, Andrade, Cardoso, Florescu, Gureje, Hu, Karam, Mneimneh, Navarro-Mateu, Oladeji, Siobhan O'Neill, Scott, Slade, Torres, Vigo, Wojtyniak, Zarkov, Ziv, Kessler
Journal: JAMA Psychiatry (2020)
Declining levels of serum chemokine (C‐X‐C motif) ligand 10 over time are associated with new onset of psoriatic arthritis in patients with psoriasis: a new biomarker?*
Authors: F. Abji, K.‐A. Lee, R.A. Pollock, R. Machhar, R.J. Cook, V. Chandran, D.D. Gladman
Journal: British Journal of Dermatology (2020)

We previously found that serum levels of chemokine (C-X-C motif) ligand 10 (CXCL10) decreased after the onset of psoriatic arthritis (PsA).We measured CXCL10 levels over time in patients with psoriasis who developed PsA to determine whether the drop in CXCL10 was specific to these patients and further assess its association with PsA development.Prospectively followed patients with psoriasis without arthritis [cutaneous psoriasis (PsC)] were assessed yearly by rheumatologists for the presence of PsA. Patients with PsC who developed PsA (converters) were matched to those that did not develop PsA (nonconverters) based on psoriasis duration and the interval between follow-up visits. The duration between baseline and the first visit postconversion in converters was used to assign a pseudoconversion date in nonconverters. Linear mixed-effects models were used to model the expression of CXCL10 over time.CXCL10 significantly declined over time in converters prior to PsA development with a significant difference in the trend over time between converters (n = 29) and nonconverters (n = 52; P < 0·001). CXCL10 continued to decline after PsA onset in a subset of converters. There was a significant difference in the trend of CXCL10 levels between converters (n = 24) and nonconverters (n = 16; P = 0·01) preconversion/pseudoconversion. This difference remained postconversion (P = 0·006) and was not different from the preconversion period (P = 0·75).A large difference in CXCL10 was identified in patients with PsC that are destined to develop PsA over time. This exploratory analysis supports the association of CXCL10 with PsA development in patients with PsC and warrants further study of the predictive ability of this chemokine. What is already known about this topic? Chemokine (C-X-C motif) ligand 10 (CXCL10) is elevated in psoriatic affected tissues and serum and/or plasma. Patients with psoriasis that develop psoriatic arthritis (PsA) have elevated CXCL10 levels at baseline and these levels drop after arthritis onset. What does this study add? By monitoring levels of CXCL10 in serum over multiple visits in patients with psoriasis that develop PsA as well as those that do not develop PsA, an association was identified between CXCL10 and PsA development. What is the translational message? CXCL10 is a strong candidate for use by physicians for the detection of patients with psoriasis that are at risk of developing PsA. Linked Comment: Kirby and Fitzgerald. Br J Dermatol 2020; 183:805-806.
Author Correction: Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution
Authors: Michelle Chan-Seng-Yue, Jaeseung C. Kim, Gavin W. Wilson, Karen Ng, Eugenia Flores Figueroa, Grainne M. O’Kane, Ashton A. Connor, Robert E. Denroche, Robert C. Grant, Jessica McLeod, Julie M. Wilson, Gun Ho Jang, Amy Zhang, Sheng-Ben Liang, Ayelet Borgida, Dianne Chadwick, Sangeetha Kalimuthu, Ilinca Lungu, John M. S. Bartlett, Paul M. Krzyzanowski, Vandana Sandhu, Hervé Tiriac, Fieke E. M. Froeling, Joanna M. Karasinska, James T. Topham, Daniel J. Renouf, David F. Schaeffer, Steven J. M. Jones, Marco A. Marra, Janessa Laskin, Runjan Chetty, Lincoln D. Stein, George Zogopoulos, Benjamin Haibe-Kains, Peter J. Campbell, David A. Tuveson, Jennifer J. Knox, Sandra E. Fischer, Steven Gallinger, Faiyaz Notta
Journal: Nature Genetics (2020)
Targeting CAMKII to reprogram tumor-associated macrophages and inhibit tumor cells for cancer immunotherapy with an injectable hybrid peptide hydrogel
Authors: Xiaomeng Dai, Jingshu Meng, Suke Deng, Lingling Zhang, Chao Wan, Lisen Lu, Jing Huang, Yan Hu, Zhanjie Zhang, Yan Li, Jonathan F. Lovell, Gang Wu, Kunyu Yang, Honglin Jin
Journal: Theranostics (2020)

Simultaneously targeted treatment of tumor cells and their surrounding growth-supporting immune cells is a promising strategy to reshape immunosuppressive tumor microenvironment (TME) and potentiate host innate and adaptive antitumor immune responses.Methods: We designed a series of melittin-(RADA)n hybrid peptide sequences with varying self-assembling motifs of RADA and screened out a melittin-(RADA)6 peptide that has an optimal gel-formation ability and in vitro antitumor activity.Results: The formed melittin-(RADA)6 (MR52) hydrogel scaffold could be loaded with a specific Ca 2+ /calmodulin-dependent protein kinase II (CAMKII) inhibitor, KN93, originally found to have both direct tumoricidal activity and macrophages-reprogramming ability, for potent immunotherapy against melanoma and hepatoma ascites in mice models.Our MR52 hydrogel has an interweaving nanofiber-like structure, possesses direct antitumor and controlled drug release properties, and promotes the enhanced intracellular uptake of loaded cargo.Compared to free KN93, the MR52-KN93 hydrogel (MRK) improved the killing effects and levels of immunogenic cell death (ICD) on tumor cells significantly.Due to the dual role of KN93, the injection of the MRK hydrogel retarded the growth of subcutaneous melanoma tumors dramatically and resulted in a high number of mature dendritic cells of draining lymph nodes, significantly enhancing the portion of cytotoxic T cells and reduced number of M2-like tumor-associated macrophages (TAMs) in tumors.Using a mouse model of malignant ascites (MAs), where traditional therapy was ineffective, we demonstrated that the MRK hydrogel treatment offered a significantly prolonged survival compared to controls.Following treatment with the MRK hydrogel, macrophages had elevated programmed cell death protein ligand-1 (PD-L1) expression, promising follow-up combined anti-PD-1 therapy that confers a cure rate of approximately 30% against MAs in mice models.Conclusion: Thus, the MRK hydrogel may serve as a prospective platform for antitumor applications.
Hookworms Evade Host Immunity by Secreting a Deoxyribonuclease to Degrade Neutrophil Extracellular Traps
Authors: Tiffany Bouchery, Mati Moyat, Javier Sotillo, Solomon Silverstein, Beatrice Volpe, Gillian Coakley, Theodora-Dorita Tsourouktsoglou, Luke Becker, Kathleen Shah, Manuel Kulagin, Romain Guiet, Mali Camberis, Alfonso Schmidt, Arne Seitz, Paul Giacomin, Graham Le Gros, Venizelos Papayannopoulos, Alex Loukas, Nicola L. Harris
Journal: Cell Host & Microbe (2020)

Hookworms cause a major neglected tropical disease, occurring after larvae penetrate the host skin. Neutrophils are phagocytes that kill large pathogens by releasing neutrophil extracellular traps (NETs), but whether they target hookworms during skin infection is unknown. Using a murine hookworm, Nippostrongylus brasiliensis, we observed neutrophils being rapidly recruited and deploying NETs around skin-penetrating larvae. Neutrophils depletion or NET inhibition altered larvae behavior and enhanced the number of adult worms following murine infection. Nevertheless, larvae were able to mitigate the effect of NETs by secreting a deoxyribonuclease (Nb-DNase II) to degrade the DNA backbone. Critically, neutrophils were able to kill larvae in vitro, which was enhanced by neutralizing Nb-DNase II. Homologs of Nb-DNase II are present in other nematodes, including the human hookworm, Necator americanus, which also evaded NETs in vitro. These findings highlight the importance of neutrophils in hookworm infection and a potential conserved mechanism of immune evasion.
Abstract P1-03-10: Establishment and characterization of paired palbociclib-sensitive and resistant luminal A breast PDX models
Authors: Lizette Gamez, Alyssa Moriarty, Tomoyuki Mashimo, Kyriakos Papadopoulos, Drew Rasco, Amita Patnaik, Michael J Wick
Journal: Cancer Research (2020)

Abstract Background: Palbociclib is one of three CDK 4/6 inhibitors approved in combination with an aromatase inhibitor for treatment of hormone receptor-positive breast cancer. Although this combination therapy has been found effective in some patients, resistance often develops. To aid in developing new therapies for CDK4/6-resistant breast cancer and better understand resistance mechanisms, we established a PDX model, designated ST1799, from a patient with luminal A breast cancer which was responsive to palbociclib in vivo and then conditioned the model with chronic drug administration until resistant. The resistant model, designated ST1799/PBR, and the parent were characterized for receptor expression, genomic alterations and in vivo drug sensitivity. Methods: ST1799 was established from an axillary lymph node FNA taken from a 66-year-old woman pretreated with various chemo and hormone therapies. The resulting model was passaged and a cohort challenged with chronic palbociclib treatment to produce drug resistance. The parent ST1799 and resistant ST1799/PBR were subjected to various comparative analyses including receptor expression, NGS and RNAseq and response to various relevant therapies. Results: Both models retained high ER staining (3+) expression and demonstrated comparable histopathology. DNA-based analysis of the parent model confirmed variants concordant with clinical mutation analysis. Comparison of the parent and resistant clone using RNAseq identified several alterations in variants and expression. In vivo palbociclib reported significant (p&amp;lt;0.0001) activity towards ST1799 (T/C=11%) while ST1799/PBR was resistant towards the therapy (T/C=80%). Tamoxifen or fulvestrant treatment of ST1799 resulted in partial tumor regressions while activity in ST1799/PBR was less pronounced. Activity of abemaciclib or ribociclib was greater in ST1799/PBR compared with palbociclib treatment. Conclusion: We have established and characterized paired palbociclib-sensitive and resistant breast PDX models which can be utilized as valuable tools in better understanding CDK4/6i resistance and in developing new therapies for CDK4/6 inhibitor resistant patients. Citation Format: Lizette Gamez, Alyssa Moriarty, Tomoyuki Mashimo, Kyriakos Papadopoulos, Drew Rasco, Amita Patnaik, Michael J Wick. Establishment and characterization of paired palbociclib-sensitive and resistant luminal A breast PDX models [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-03-10.
Alasdair Breckenridge: pharmacologist who expanded research horizons and medicines regulator with vision and passion
Authors: John Illman
Journal: BMJ (2020)

Alasdair Muir Breckenridge was a giant in 20th century medicine—a physician, clinical pharmacologist, visionary, scientific talent spotter, medicines regulator—and a forthright Scot with a softer side. A self-confessed workaholic, he was part of a small elite group who turned clinical pharmacology and therapeutics into an increasingly important specialty.

He established his formidable international reputation at the Royal Postgraduate Medical School, Hammersmith, London, where he and the Australian endocrinologist Tim Wellborn developed the concept of insulin resistance in cardiovascular disease. His work on the anticoagulant warfarin was also seminal, firing his interest in drug metabolism and drug-drug interactions and—critically—expanding the horizons of clinical pharmacology. Identifying new opportunities for the field became a lifelong passion. 

Most medical scientists would dread being kicked out of an intellectual powerhouse like the Hammersmith, especially if they had young families, but not Breckenridge. When his old friend and boss, Colin Dollery, told him it was time to go, he saw …
Coronary artery mechanics induces human saphenous vein remodelling <i>via</i> recruitment of adventitial myofibroblast-like cells mediated by Thrombospondin-1
Authors: Gloria Garoffolo, Matthijs S. Ruiter, Marco Piola, Maura Brioschi, Anita C. Thomas, Marco Agrifoglio, Gianluca Polvani, Lorenzo Coppadoro, Stefano Zoli, Claudio Saccu, Gaia Spinetti, Cristina Banfi, Gianfranco B. Fiore, Paolo Madeddu, Monica Soncini, Maurizio Pesce
Journal: Theranostics (2020)

Rationale: Despite the preferred application of arterial conduits, the greater saphenous vein (SV) remains indispensable for coronary bypass grafting (CABG), especially in multi-vessel coronary artery disease (CAD). The objective of the present work was to address the role of mechanical forces in the activation of maladaptive vein bypass remodeling, a process determining progressive occlusion and recurrence of ischemic heart disease. Methods: We employed a custom bioreactor to mimic the coronary shear and wall mechanics in human SV vascular conduits and reproduce experimentally the biomechanical conditions of coronary grafting and analyzed vein remodeling process by histology, histochemistry and immunofluorescence. We also subjected vein-derived cells to cyclic uniaxial mechanical stimulation in culture, followed by phenotypic and molecular characterization using RNA and proteomic methods. We finally validated our results in vitro and using a model of SV carotid interposition in pigs. Results: Exposure to pulsatile flow determined a remodeling process of the vascular wall involving reduction in media thickness. Smooth muscle cells (SMCs) underwent conversion from contractile to synthetic phenotype. A time-dependent increase in proliferating cells expressing mesenchymal (CD44) and early SMC (SM22α) markers, apparently recruited from the SV adventitia, was observed especially in CABG-stimulated vessels. Mechanically stimulated SMCs underwent transition from contractile to synthetic phenotype. MALDI-TOF-based secretome analysis revealed a consistent release of Thrombospondin-1 (TSP-1), a matricellular protein involved in TGF-β-dependent signaling. TSP-1 had a direct chemotactic effect on SV adventitia resident progenitors (SVPs); this effects was inhibited by blocking TSP-1 receptor CD47. The involvement of TSP-1 in adventitial progenitor cells differentiation and graft intima hyperplasia was finally contextualized in the TGF-β-dependent pathway, and validated in a saphenous vein into carotid interposition pig model. Conclusions: Our results provide the evidence of a matricellular mechanism involved in the human vein arterialization process controlled by alterations in tissue mechanics, and open the way to novel potential strategies to block VGD progression based on targeting cell mechanosensing-related effectors.
Renal TNFα activates the WNK phosphorylation cascade and contributes to salt-sensitive hypertension in chronic kidney disease
Authors: Taisuke Furusho, Eisei Sohara, Shintaro Mandai, Hiroaki Kikuchi, Naohiro Takahashi, Takuya Fujimaru, Hiroko Hashimoto, Yohei Arai, Fumiaki Ando, Moko Zeniya, Takayasu Mori, Koichiro Susa, Kiyoshi Isobe, Naohiro Nomura, Kohei Yamamoto, Tomokazu Okado, Tatemitsu Rai, Shinichi Uchida
Journal: Kidney International (2020)