tbuckley/cabot-search huggingface dataset:
140P Preliminary results from PROPEL: A phase I/II study of bempegaldesleukin (BEMPEG: NKTR-214) plus pembrolizumab (PEMBRO) with or without chemotherapy in patients with metastatic NSCLC
Authors: E. Felip, D.R. Spigel, O.J. Juan Vidal, J.T. Beck, C. Aguado de la Rosa, D.H. Johnson, E. Spath-Schwalbe, A. Reinacher-Schick, D. Rodriguez Abreu, M. Altan, N. Reinmuth, M.J. Edelman, M. Reck, Q. Zhao, S. Banerjee, S. Chaudhry, D. Chien, M.A. Tagliaferri, J. Zalevsky, A. Ganti
Journal: Annals of Oncology (2021)
Design of a highly potent GLP-1R and GCGR dual-agonist for recovering hepatic fibrosis
Authors: Nazi Song, Hongjiao Xu, Jiahua Liu, Qian Zhao, Hui Chen, Zhibin Yan, Runling Yang, Zhiteng Luo, Qi Liu, Jianmei Ouyang, Shuohan Wu, Suijia Luo, Shuyin Ye, Runfeng Lin, Xi Sun, Junqiu Xie, Tian Lan, Zhongdao Wu, Rui Wang, Xianxing Jiang
Journal: Acta Pharmaceutica Sinica B (2021)

Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) agonist with higher affinity towards GCGR, could retard the progression of liver fibrosis in various rodent models, with remarkable potency, selectivity, extended half-life and low toxicity. Four types of liver fibrosis animal models which were induced by CCl4, α-naphthyl-isothiocyanate (ANIT), bile duct ligation (BDL) and Schistosoma japonicum were used in our study. We found that TB001 treatment dose-dependently significantly attenuated liver injury and collagen accumulation in these animal models. In addition to decreased levels of extracellular matrix (ECM) accumulation during hepatic injury, activation of hepatic stellate cells was also inhibited via suppression of TGF-β expression as well as downstream Smad signaling pathways particularly in CCl4-and S. japonicum-induced liver fibrosis. Moreover, TB001 attenuated liver fibrosis through blocking downstream activation of pro-inflammatory nuclear factor kappa B/NF-kappa-B inhibitor alpha (NFκB/IKBα) pathways as well as c-Jun N-terminal kinase (JNK)-dependent induction of hepatocyte apoptosis. Furthermore, GLP-1R and/or GCGR knock-down results represented GCGR played an important role in ameliorating CCl4-induced hepatic fibrosis. Therefore, TB001 can be used as a promising therapeutic candidate for the treatment of multiple causes of hepatic fibrosis demonstrated by our extensive pre-clinical evaluation of TB001.
EXTH-38. TARGETING KIF11 TO RADIOSENSITIZE GLIOBLASTOMA
Authors: Abby Zalenski, Miranda Tallman, Luke Kollin, Monica Venere
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is the most lethal primary brain tumor, with a 5 year survival rate of only 5%. The standard of care for GBM is maximal surgical resection of the tumor, followed by irradiation and chemotherapy. Despite treatment, tumors recur in almost 100% of patients. There are subpopulations of cells in GBM that are radioresistant and chemoresistant, and new treatments will need to inclusively target these cells. KIF11 is a mitotic protein that drives bipolar spindle formation and is crucial for successful completion of mitosis. We previously reported that KIF11 is overexpressed in GBM over normal brain tissue, and that inhibiting KIF11 in a patient-derived xenograft (PDX) GBM mouse model increased survival. However, in this model, tumors recurred after treatment was stopped, indicating that treatment may have had a cytostatic effect, rather than cytotoxic. Importantly, it has been reported that cells are most vulnerable to irradiation when they are in mitosis. Because using a KIF11 inhibitor arrests cells in mitosis, we hypothesized that combining irradiation and a KIF11 inhibitor would radiosensitize GBM cells, and lead to greater tumor cell death. In this study, we found that combination therapy increased cell death over vehicle or either treatment used alone in patient-derived GBM cells in vitro. Additionally, we found that inhibiting KIF11 combined with radiotherapy increased survival over vehicle or monotherapy in orthotopic PDX models. Our results demonstrate that combining KIF11 inhibitors with radiotherapy is a promising potential therapy for GBM.
A Lesion Microenvironment‐Responsive Fungicide Nanoplatform for Crop Disease Prevention and Control
Authors: Chao‐Yi Wang, Chengguo Jia, Ming‐Zhe Zhang, Song Yang, Jian‐Chun Qin, Ying‐Wei Yang
Journal: Advanced Healthcare Materials (2021)

Abstract Controlled fungicide delivery in response to the specific microenvironment produced by fungal pathogens is an advisable strategy to improve the efficacy of fungicides. Herein, the authors construct a smart fungicide nanoplatform, using mesoporous silica nanoparticles (MSNs) as nanocarriers loaded with eugenol (EU) and Ag + coordinated polydopamine (Ag + ‐PDA) as a coating to form Ag + ‐PDA@MSNs‐EU NPs for Botrytis cinerea ( B. cinerea ) control. As a botanical fungicide, EU offers an eco‐friendly alternative to synthetic fungicides and can upregulate several defense‐related genes in the tomato plant. The Ag + ‐PDA coating can lock the EU inside the nanocarriers and respond to the oxalic acid produced by B. cinerea to corelease the loaded EU and Ag + . The results demonstrate that Ag + ‐PDA@MSNs‐EU NPs can effectively inhibit the mycelial growth of B. cinerea on detached and potted tomato leaves. The construction of such a smart fungicide nanoplatform provides new guidance to design controlled fungicides release systems, which can respond to the microenvironment associated with plant pathogen to realize fungus control.
Temperature‐Dependent CAT‐Like RGD‐BPNS@SMFN Nanoplatform for PTT‐PDT Self‐Synergetic Tumor Phototherapy
Authors: Luping Song, Bo Chen, Zhiguo Qin, Xin Liu, Zhanhang Guo, Hongchao Lou, Hui Liu, Wei Sun, Chunxian Guo, Changming Li
Journal: Advanced Healthcare Materials (2021)

Abstract Phototherapies such as photothermal therapy (PTT) and photodynamic therapy (PDT) are considered as alternatives for tumor remedies, because of their advantages of precise spatial orientation, minimally invasive, and nonradiative operation. However, most of phototherapeutic agents still suffer from low photothermal conversion efficacy and photodynamic performance, poor biocompatibility, and intratumor accumulation. Herein a biocompatible and target‐deliverable PTT–PDT self‐synergetic nanoplatform of RGD‐BPNS@SMFN based on temperature‐dependent catalase (CAT)‐like behavior for tumor elimination is presented. The homogeneously dispersible nanoplatform is designed and fabricated through anchoring spherical manganese ferrite nanoparticles (SMFN) to black phosphorus nanosheets (BPNS), followed by arginine–glycine–aspartic acid (RGD) peptide modification. The nanoplatform exhibits excellent targeting ability and enhanced photonic response in comparison to plain BPNS and SMFN in vitro and in vivo. It is found that PTT and PDT have a self‐synergetic behavior by means of the dual phototherapy mode interaction. The self‐synergetic mechanism is mainly ascribed to PTT‐promoted inherent CAT‐like activity in the nanoplatform, which remodels the tumor hypoxia microenvironment and further ameliorates the PDT efficiency, providing promising high performance nanoplatform for synergetic dual mode phototherapy, enriching the design for the antitumor nanozyme.
E-Videos Are Going Open Access!
Journal: Endoscopy (2021)

E-Videos Are Going Open Access! 2022 will see an important change to Endoscopy’s E-Video section: with the ever-growing demand for this format and the steady rise of open access as an important publication mode, E-Videos will be published open access in the future. Benefits for authors include retaining full copyright of their publication and experiencing faster impact of their research as others can quickly built on their findings. E-Video papers submitted on or after 1 January 2022 and accepted for publication will be subject to an open access article publication charge (APC) of EUR 375 per E-Video paper. All E-Videos will be published with a Creative Commons CC-BY license. Endoscopy E-Videos qualify for HINARI discounts and waivers, and eligibility is automatically checked during the submission process. A full list of countries participating in HINARI can be found at https://www.who.int/hinari/eligibility/en/
Observations on improving COVID-19 vaccination responses in kidney transplant recipients: heterologous vaccination and immunosuppression modulation
Authors: Christophe Masset, Simon Ville, Claire Garandeau, Florent Le Borgne, Thibaut Letellier, Diego Cantarovich, Aurélie Meurette, Cécile Guillot-Gueguen, Maxime Bentoumi-Loaec, Magali Giral, Jacques Dantal, Gilles Blancho
Journal: Kidney International (2021)
GWAS of stool frequency provides insights into gastrointestinal motility and irritable bowel syndrome
Authors: Ferdinando Bonfiglio, Xingrong Liu, Christopher Smillie, Anita Pandit, Alexander Kurilshikov, Rodrigo Bacigalupe, Tenghao Zheng, Hieu Nim, Koldo Garcia-Etxebarria, Luis Bujanda, Anna Andreasson, Lars Agreus, Susanna Walter, Gonçalo Abecasis, Chris Eijsbouts, Luke Jostins, Miles Parkes, David A. Hughes, Nicholas Timpson, Jeroen Raes, Andre Franke, Nicholas A. Kennedy, Aviv Regev, Alexandra Zhernakova, Magnus Simren, Michael Camilleri, Mauro D’Amato
Journal: Cell Genomics (2021)

Gut dysmotility is associated with constipation, diarrhea, and functional gastrointestinal disorders like irritable bowel syndrome (IBS), although its molecular underpinnings are poorly characterized. We studied stool frequency (defined by the number of bowel movements per day, based on questionnaire data) as a proxy for gut motility in a GWAS meta-analysis including 167,875 individuals from UK Biobank and four smaller population-based cohorts. We identify 14 loci associated with stool frequency (p ≤ 5.0 × 10−8). Gene set and pathway analyses detected enrichment for genes involved in neurotransmitter/neuropeptide signaling and preferentially expressed in enteric motor neurons controlling peristalsis. PheWAS identified pleiotropic associations with dysmotility syndromes and the response to their pharmacological treatment. The genetic architecture of stool frequency correlates with that of IBS, and UK Biobank participants from the top 1% of stool frequency polygenic score distribution were associated with 5× higher risk of IBS with diarrhea. These findings pave the way for the identification of actionable pathological mechanisms in IBS and the dysmotility syndromes.
Abstract 13082: Region-Specific Diffusion-Weighted Imaging Predicts Neurological Outcome in Comatose Post-Cardiac Arrest Patients
Authors: Wang Pong Chan, Troy Gallerani, Caitlyn Keenan, Darya Musatova, Katie Dam, Heping Sheng, Taylor Jamil, Hana Gross, Rebecca Stafford, David Greer
Journal: Circulation (2021)

Introduction &amp; Hypothesis: Diffusion-weighted imaging (DWI), a technique sensitive to acute brain ischemia, may hold utility in predicting neurological outcome in comatose post-cardiac arrest patients. Outcome studies are biased by early withdrawal of life sustaining therapy (WLST), leading to a self-fulfilling prophecy. This creates a need to reassess the use of DWI as a neuroprognostic tool in patients who have not undergone WLST. We hypothesize that DWI abnormalities is a robust predictor of poor neurological outcome in our WLST - controlled cohort. Methods: We leveraged the MOCHA database, a registry of over 300 comatose post-cardiac arrest patients, to retrospectively examine neurological outcomes in a cohort of patients who did not undergo WLST. A good outcome was defined by a cerebral performance category (CPC) score at discharge of 1 - 3, while a poor outcome CPC 4 - 5 (n=43). We first examined the relationship between the number of brain regions with DWI abnormalities and CPC score using a linear regression. We then examined how DWI abnormalities in specific brain regions correlated with CPC score outcome groups using a fisher exact test. DWI abnormalities were qualitatively determined by two vascular neurologists. Results: We found a positive correlation between the number of brain regions with DWI abnormalities and CPC score ( linear regression , R 2 =0.572, p=2.670x10 -9 ). Interestingly, the association between DWI abnormalities and CPC score exhibited brain region-specific variability. DWI abnormalities exhibited the strongest association with poor neurological outcome in the occipital lobe ( fisher exact test , p=7.413x10 -10 ), parietal lobe (p=9.125x10 -9 ), frontal lobe (p=5.385x10 -9 ), temporal lobe (p=3.904x10 -8 ) and basal ganglia (p=2.342x10 -7 ); and the weakest association in the white matter (p=1.000) and brain stem (p=6.612x10 -2 ). Conclusion: Our preliminary results suggest that the region of ischemia is an important factor to consider in predicting neurological outcome. This warrants a larger scale WLST-controlled study examining region-specific DWI abnormalities and neurological outcome - the findings of which would improve our neuroprognostication capabilities in comatose post-cardiac arrest patients.
Pseudoreticulocytosis in a patient with myelodysplastic syndrome
Authors: Noemy De Rossi, Lorenzo Alberio, Grégoire Stalder
Journal: American Journal of Hematology (2021)

A 52-year-old woman diagnosed in 2017 with low-risk myelodysplastic syndrome (MDS) with multilineage dysplasia (R-IPSS score 1.5) is evaluated for persistent reticulocytosis since 4 years, without evidence of bleeding or hemolysis. Her laboratory results indicate the following: red blood count 3.56 × 1012/L (reference range: 3.8–5.2 × 1012/L); hemoglobin 10.1 g/dL (11.7–15.7 g/dL); hematocrit 0.32 L/L (0.35–0.47 L/L); MCV 93 fl (81–99 fl); MCHC 313 g/L (310–360 g/L); red cell distribution width 16.7% (11%–15%); reticulocytes 929 × 109/L (20–120 × 109/L), 26.1% (0.5%–1.5%); platelets 146 × 109/L (150–350 × 109/L); and leukocytes 2.2 × 109/L (4.0–10 × 109/L). Of note, MCV, expected to be increased in case of reticulocytosis is normal. Hemolytic parameters (LDH, bilirubin, haptoglobin) and creatinine are normal. The direct antiglobulin test is negative. Scattergram (Image 1A, white circle) shows small-size reticulocytes with dim fluorescence (low RNA content), corresponding to a population of old reticulocytes. Peripheral blood smear (Image 1B) shows marked anisopoikilocytosis, polychromasia, and anisochromia. Presence of reticulocytes is confirmed on cresyl blue stain (Image 1C, arrows). The phenomenon of increased reticulocytes without hemolysis or bleeding among patients with MDS has been described in few publications.1, 2 It is a consequence of abnormal erythropoiesis with underlying delayed reticulocyte maturation, which may arise because of altered ribonucleic acid metabolism or a deficiency of ribonuclease.3 This process results in an increased number of circulating older reticulocytes with smaller size and low RNA content. Under normal conditions, reticulocytes have a half-life of 24–48 h in the peripheral circulation, before losing their RNA and becoming erythrocytes. Due to delayed maturation, reticulocytes retain their RNA for a longer time, resulting in a prolonged half-life in peripheral blood and thus in “pseudoreticulocytosis.” Open access funding enabled and organized by Projekt DEAL. All authors declare that they have no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Endotyping Asthma: Profiling the Metabolic Dimension?
Authors: Michael J. Wilde, Salman Siddiqui
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

A collective representation of complementary approaches for the comprehensive capture of the respiratory metabolome and metabolic dysregulation caused by immune mediated inflammation.Future adoption of multimodal designs, coupling data from tissue scale, liquid and gas phase analyses from across analytical platforms will provide a more integrated, better annotated understanding of the metabolome, associated metabolic endotypes and it's potential for therapeutic development in respiratory disease.338x190mm (300 x 300 DPI)
Immune biomarkers to predict SARS-CoV-2 vaccine effectiveness in patients with hematological malignancies
Authors: Luis-Esteban Tamariz-Amador, Anna Martina Battaglia, Catarina Maia, Anastasiia Zherniakova, Camila Guerrero, Aintzane Zabaleta, Leire Burgos, Cirino Botta, Maria-Antonia Fortuño, Carlos Grande, Andrea Manubens, Jose-Maria Arguiñano, Clara Gomez, Ernesto Perez-Persona, Iñigo Olazabal, Itziar Oiartzabal, Carlos Panizo, Felipe Prosper, Jesus F. San-Miguel, Paula Rodriguez-Otero, Esperanza Martín-Sánchez, Bruno Paiva
Journal: Blood Cancer Journal (2021)

There is evidence of reduced SARS-CoV-2 vaccine effectiveness in patients with hematological malignancies. We hypothesized that tumor and treatment-related immunosuppression can be depicted in peripheral blood, and that immune profiling prior to vaccination can help predict immunogenicity. We performed a comprehensive immunological characterization of 83 hematological patients before vaccination and measured IgM, IgG, and IgA antibody response to four viral antigens at day +7 after second-dose COVID-19 vaccination using multidimensional and computational flow cytometry. Health care practitioners of similar age were the control group (n = 102). Forty-four out of 59 immune cell types were significantly altered in patients; those with monoclonal gammopathies showed greater immunosuppression than patients with B-cell disorders and Hodgkin lymphoma. Immune dysregulation emerged before treatment, peaked while on-therapy, and did not return to normalcy after stopping treatment. We identified an immunotype that was significantly associated with poor antibody response and uncovered that the frequency of neutrophils, classical monocytes, CD4, and CD8 effector memory CD127low T cells, as well as naive CD21+ and IgM+D+ memory B cells, were independently associated with immunogenicity. Thus, we provide novel immune biomarkers to predict COVID-19 vaccine effectiveness in hematological patients, which are complementary to treatment-related factors and may help tailoring possible vaccine boosters.
Ixazomib-based induction regimens plus ixazomib maintenance in transplant-ineligible, newly diagnosed multiple myeloma: the phase II, multi-arm, randomized UNITO-EMN10 trial
Authors: Roberto Mina, Antonietta Pia Falcone, Sara Bringhen, Anna Marina Liberati, Norbert Pescosta, Maria Teresa Petrucci, Giovannino Ciccone, Andrea Capra, Francesca Patriarca, Delia Rota-Scalabrini, Francesca Bonello, Caterina Musolino, Michele Cea, Renato Zambello, Paola Tacchetti, Angelo Belotti, Claudia Cellini, Laura Paris, Mariella Grasso, Sara Aquino, Lorenzo De Paoli, Giovanni De Sabbata, Stelvio Ballanti, Massimo Offidani, Mario Boccadoro, Federico Monaco, Paolo Corradini, Alessandra Larocca
Journal: Blood Cancer Journal (2021)
Inhaled remdesivir reduces viral burden in a nonhuman primate model of SARS-CoV-2 infection
Authors: Meghan S. Vermillion, Eisuke Murakami, Bin Ma, Jared Pitts, Adrian Tomkinson, Davin Rautiola, Darius Babusis, Hammad Irshad, Dustin Seigel, Cynthia Kim, Xiaofeng Zhao, Congrong Niu, Jesse Yang, Andrew Gigliotti, Nani Kadrichu, John P. Bilello, Scott Ellis, Roy Bannister, Raju Subramanian, Bill Smith, Richard L. Mackman, William A. Lee, Philip J. Kuehl, Jim Hartke, Tomas Cihlar, Danielle P. Porter
Journal: Science Translational Medicine (2021)

Remdesivir (RDV) is a nucleotide analog prodrug with demonstrated clinical benefit in patients with coronavirus disease 2019 (COVID-19). In October 2020, the US FDA approved intravenous (IV) RDV as the first treatment for hospitalized COVID-19 patients. Furthermore, RDV has been approved or authorized for emergency use in more than 50 countries. To make RDV more convenient for non-hospitalized patients earlier in disease, alternative routes of administration are being evaluated. Here, we investigated the pharmacokinetics and efficacy of RDV administered by head dome inhalation in African green monkeys (AGM). Relative to an IV administration of RDV at 10 mg/kg, an approximately 20-fold lower dose administered by inhalation produced comparable concentrations of the pharmacologically active triphosphate in lower respiratory tract tissues. Distribution of the active triphosphate into the upper respiratory tract was also observed following inhaled RDV exposure. Inhalation RDV dosing resulted in lower systemic exposures to RDV and its metabolites as compared with IV RDV dosing. An efficacy study with repeated dosing of inhaled RDV in an AGM model of SARS-CoV-2 infection demonstrated reductions in viral replication in bronchoalveolar lavage fluid and respiratory tract tissues compared with placebo. Efficacy was observed with inhaled RDV administered once daily at a pulmonary deposited dose of 0.35 mg/kg beginning approximately 8 hours post-infection. Moreover, the efficacy of inhaled RDV was similar to that of IV RDV administered once at 10 mg/kg followed by 5 mg/kg daily in the same study. Together, these findings support further clinical development of inhalation RDV.
Lipoprotein (a)-mediated vascular calcification: population-based and in vitro studies
Authors: Jia Peng, Ming-Ming Liu, Hui-Hui Liu, Rui-Xia Xu, Cheng-Gang Zhu, Yuan-Lin Guo, Na-Qiong Wu, Qian Dong, Chuan-Jue Cui, Jian-Jun Li
Journal: Metabolism (2021)

BackgroundLipoprotein (a) [Lp(a)] is a causal risk factor for cardiovascular diseases, while its role in vascular calcification has not been well-established. Here, we investigated an association of Lp(a) with vascular calcification using population-based and in vitro study designs.MethodsA total of 2806 patients who received coronary computed tomography were enrolled to assess the correlation of Lp(a) with the severity of coronary artery calcification (CAC). Human aortic smooth muscle cells (HASMCs) were used to explore mechanisms of Lp(a)-induced vascular calcification.ResultsIn the population study, Lp(a) was independently correlated with the presence and severity of CAC (all p < 0.05). In vitro study showed that cell calcific depositions and alkaline phosphatase (ALP) activity were increased and the expression of pro-calcific proteins, including bone morphogenetic protein-2 (BMP2) and osteopontin (OPN), were up-regulated by Lp(a) stimulation. Interestingly, Lp(a) activated Notch1 signaling, resulting in cell calcification, which was inhibited by the Notch1 signaling inhibitor, DAPT. Lp(a)-induced Notch1 activation up-regulated BMP2-Smad1/5/9 pathway. In contrast, Noggin, an inhibitor of BMP2-Smad1/5/9 pathway, significantly blocked Lp(a)-induced HASMC calcification. Notch1 activation also induced translocation of nuclear factor-κB (NF-κB) accompanied by OPN overexpression and elevated inflammatory cytokines production, while NF-κB silencing alleviated Lp(a)-induced vascular calcification.ConclusionsElevated Lp(a) concentrations are independently associated with the presence and severity of CAC and the impact of Lp(a) on vascular calcification is involved in the activation of Notch1-NF-κB and Notch1-BMP2-Smad1/5/9 pathways, thus implicating Lp(a) as a potential novel therapeutic target for vascular calcification.