tbuckley/cabot-search huggingface dataset:
Effect of wheat bran derived prebiotic supplementation on gastrointestinal transit, gut microbiota, and metabolic health: a randomized controlled trial in healthy adults with a slow gut transit
Authors: Mattea Müller, Gerben D. A. Hermes, Canfora Emanuel E., Jens J. Holst, Erwin G. Zoetendal, Hauke Smidt, Freddy Troost, Frank G. Schaap, Steven Olde Damink, Johan W. E. Jocken, Kaatje Lenaerts, Ad A. M. Masclee, Ellen E. Blaak
Journal: Gut Microbes (2020)

Acute intake of the wheat bran extract Arabinoxylan-Oligosaccharide (AXOS) modulates the gut microbiota, improves stool characteristics and postprandial glycemia in healthy humans. Yet, little is known on how long-term AXOS intake influences gastrointestinal (GI) functioning, gut microbiota, and metabolic health. In this randomized, placebo-controlled, double-blind study, we evaluated the effects of AXOS intake on GI function and metabolic health in adults with slow GI transit without constipation. Forty-eight normoglycemic adults were included with whole-gut transit time (WGTT) of >35 h receiving either 15 g/day AXOS or placebo (maltodextrin) for 12-wks. The primary outcome was WGTT, and secondary outcomes included stool parameters, gut permeability, short-chain fatty acids (SCFA), microbiota composition, energy expenditure, substrate oxidation, glucose, insulin, lipids, gut hormones, and adipose tissue (AT) function. WGTT was unchanged, but stool consistency softened after AXOS. 12-wks of AXOS intake significantly changed the microbiota by increasing Bifidobacterium and decreasing microbial alpha-diversity. With a good classification accuracy, overall microbiota composition classified responders with decreased WGTT after AXOS. The incretin hormone Glucagon-like protein 1 was reduced after AXOS compared to placebo. Energy expenditure, plasma metabolites, AT parameters, SCFA, and gut permeability were unchanged. In conclusion, intake of wheat bran extract increases fecal Bifidobacterium and softens stool consistency without major effects on energy metabolism in healthy humans with a slow GI transit. We show that overall gut microbiota classified responders with decreased WGTT after AXOS highlighting that GI transit and change thereof were associated with gut microbiota independent of Bifidobacterium. NCT02491125
Interleukin‐4 Gene Transfection and Spheroid Formation Potentiate Therapeutic Efficacy of Mesenchymal Stem Cells for Osteoarthritis
Authors: Seuk Young Song, Jihye Hong, Seukhyeong Go, Songhyun Lim, Hee Su Sohn, Mikyung Kang, Gun‐Jae Jung, Jeong‐Kee Yoon, Mi Lan Kang, Gun‐il Im, Byung‐Soo Kim
Journal: Advanced Healthcare Materials (2020)

Abstract Osteoarthritis (OA) is a painful intractable disease that significantly affects patients' quality of life. However, current therapies, such as pain killers and joint replacement surgery, do not lead to cartilage protection. Mesenchymal stem cells (MSCs) have been proposed as an alternative strategy for OA therapy because MSCs can secrete chondroprotective and anti‐inflammatory factors. However, interleukin‐4 (IL‐4), a potent anti‐inflammatory cytokine, is barely produced by MSCs, and MSC therapy suffers from rapid MSC death following intra‐articular implantation. MSCs in spheroids survive better than naïve MSCs in vitro and in vivo. IL‐4‐transfected MSCs in spheroids (IL‐4 MSC spheroid) show increased chondroprotective and anti‐inflammatory effects in an OA chondrocyte model in vitro. Following intra‐articular implantation in OA rats, IL‐4 MSC spheroids show better cartilage protection and pain relief than naïve MSCs. Thus, IL‐4 MSC spheroid may potentiate the therapeutic efficacy of MSCs for OA.
Long-term outcomes of Sleeping Beauty–generated CD19-specific CAR T-cell therapy for relapsed-refractory B-cell lymphomas
Authors: S. A. Srour, H. Singh, J. McCarty, E. de Groot, H. Huls, G. Rondon, M. Qazilbash, S. Ciurea, G. Bardelli, J. Buck, A. Alousi, Y. Nieto, K. Rezvani, D. Marin, U. Popat, C. Hosing, E. J. Shpall, W. G. Wierda, H. Kantarjian, R. E. Champlin, L. J. Cooper, P. Kebriaei
Journal: Blood (2020)
A Prognostic Strategy Based on Stage of Cirrhosis and HVPG to Improve Risk Stratification After Variceal Bleeding
Authors: Vincenzo La Mura, Marta Garcia‐Guix, Annalisa Berzigotti, Juan G. Abraldes, Juan Carlos García‐Pagán, Candid Villanueva, Jaime Bosch
Journal: Hepatology (2020)

A hepatic venous pressure gradient (HVPG) decrease of 20% or more (or ≤12 mm Hg) indicates a good prognosis during propranolol/nadolol treatment but requires two HVPG measurements. We aimed to simplify the risk stratification after variceal bleeding using clinical data and HVPG.A total of 193 patients with cirrhosis (62% with ascites and/or hepatic encephalopathy [HE]) who were within 7 days of bleeding had their HVPG measured before and at 1-3 months of treatment with propranolol/nadolol plus endoscopic band ligation. The endpoints were rebleeding and rebleeding/transplantation-free survival for 4 years. Another cohort (n = 231) served as the validation set.During follow-up, 45 patients had variceal bleeding and 61 died. The HVPG responders (n = 71) had lower rebleeding risk (10% vs. 34%, P = 0.001) and better survival than the 122 nonresponders (61% vs. 39%, P = 0.001). Patients with HE (n = 120) had lower survival than patients without HE (40% vs. 63%, P = 0.005). Among the patients with ascites/HE, those with baseline HVPG ≤ 16 mm Hg (n = 16) had a low rebleeding risk (13%). In contrast, among patients with ascites/HE and baseline HVPG > 16 mm Hg, only the HVPG responders (n = 32) had a good prognosis, with lower rebleeding risk and better survival than the nonresponders (n = 72) (respective proportions: 7% vs. 39%, P = 0.018; 56% vs. 30% P = 0.010). These findings allowed us to develop a strategy for risk stratification in which HVPG response was measured only in patients with ascites and/or HE and baseline HVPG > 16 mm Hg. This method reduced the "gray zone" (i.e., high-risk patients who had not died on follow-up) from 46% to 35% and decreased the HVPG measurements required by 42%. The validation cohort confirmed these results.Restricting HVPG measurements to patients with ascites/HE and measuring HVPG response only if the patient's baseline HVPG is over 16 mm Hg improves detection of high-risk patients while markedly reducing the number of HVPG measurements required.
Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: Interim results from the phase 2 KEYNOTE-100 study.
Authors: Ursula A. Matulonis, Ronnie Shapira-Frommer, Alessandro Santin, Alla Sergeevua Lisyanskaya, Sandro Pignata, Ignace Vergote, Francesco Raspagliesi, Gabe S. Sonke, Michael Birrer, Diane M. Provencher, Jalid Sehouli, Nicoletta Colombo, Antonio González-Martín, Ana Oaknin, P. B. Ottevanger, Vilius Rudaitis, Kia Katchar, Zhen Wang, Jane Ruman, Jonathan A. Ledermann
Journal: Journal of Clinical Oncology (2018)

5511 Background: Data from the KEYNOTE-028 study (NCT02054806) suggested that pembrolizumab (pembro) has clinical activity in patients (pts) with PD-L1+ advanced ovarian cancer (AOC). We assessed the antitumor activity and safety of pembro in pts with recurrent AOC in the ongoing, 2-cohort, phase 2 KEYNOTE-100 study (NCT02674061). Methods: Key eligibility criteria included epithelial ovarian, fallopian tube, or primary peritoneal cancer, confirmed recurrence following front-line platinum-based therapy, ECOG PS 0/1, and provision of a tumor sample for biomarker analysis. Cohort A pts received ≤2 prior chemotherapy lines for recurrent AOC and had a platinum-free or treatment-free interval (PFI/TFI) of ≥3 to 12 mo. Cohort B pts received 3-5 prior chemotherapy lines and had a PFI/TFI of ≥3 mo. Pts received pembro 200 mg Q3W IV for 2 yrs or until progression, death, unacceptable toxicity, or consent withdrawal. Tumor imaging was performed every 9 wks for 1 yr and every 12 wks thereafter. Primary study endpoint was ORR per RECIST v1.1 by independent central review for both cohorts and by tumor PD-L1 expression. The effect of PD-L1 expression on ORR was tested with the combined positive score (CPS) assay. Cutpoints were established using the first 100 pts enrolled into Cohort A (training set). Validation was performed among all subsequent pts enrolled. Training set results are presented here. Complete results (n = 378) will be available for presentation. Results: 378 pts were enrolled in KEYNOTE-100. 97/100 training set pts had analyzable results. Mean (±SD) age for this group was 61 (±12) yr, 68% had ECOG PS 0, and 77% had high grade serous disease. ORR was 9% (95% CI, 4, 17). ORR was higher in pts with PD-L1 expression: 14% (8/59) with CPS ≥1 and 25% (5/20) with CPS ≥10. 73% of pts had treatment-related (TR) AEs and 17% had grade 3-5 TR AEs. There was 1 TR death in a pt with Stevens-Johnson syndrome. Conclusions: Pembro monotherapy was associated with antitumor activity in pts with recurrent AOC. ORR increased with PD-L1 expression, better defining a population benefiting from single agent pembro. No new safety signals were identified in this population. Clinical trial information: NCT02674061.
Photoluminescent biodegradable polyorganophosphazene: A promising scaffold material for in vivo application to promote bone regeneration
Authors: Yiqian Huang, Zhaohui Huang, Huanhuan Liu, Xu Zhang, Qing Cai, Xiaoping Yang
Journal: Bioactive Materials (2020)

Tissue engineering scaffolds made of conventional aliphatic polyesters are inherently non-fluorescent, which results in their in vivo degradation hard to be visualized. Photoluminescent biodegradable polyorganophosphazenes (PPOPs) are synthesized by introducing fluorophores onto the polyphosphazene backbone via nucleophilic substitution reaction. In this study, a fluorophore (termed as TPCA), derived from citric acid and 2-aminoethanethiol, was co-substituted with alanine ethyl ester onto the polyphosphazene backbone to obtain a photoluminescent biodegradable POPP (termed as PTA). The scaffolds made of PTA demonstrated non-cytotoxicity and cell affinity, particularly, capacity in promoting osteogenic differentiation of bone marrow mesenchymal stromal cells (BMSCs). In vivo evaluations using the rat calvarial defect model confirmed its strong potential in enhancing osteogenesis, more importantly, the in vivo degradation of the PTA scaffold could be monitored via its fluorescence intensity alongside implantation time.
Efficacy and Safety of Duvelisib Following Disease Progression on Ofatumumab in Patients with Relapsed/Refractory CLL or SLL in the DUO Crossover Extension Study
Authors: Matthew S. Davids, Bryone J. Kuss, Peter Hillmen, Marco Montillo, Carol Moreno, James Essell, Nicole Lamanna, Zsolt Nagy, Constantine S. Tam, Stephan Stilgenbauer, Paolo Ghia, Julio Delgado, Stephanie Lustgarten, David T. Weaver, Hagop Youssoufian, Ulrich Jäger
Journal: Clinical Cancer Research (2020)

In the phase III DUO trial, duvelisib, an oral dual PI3K-δ,γ inhibitor, demonstrated significantly improved efficacy versus ofatumumab [median (m) progression-free survival (PFS), 13.3 vs. 9.9 months (HR, 0.52; P < 0.0001); overall response rate [ORR], 74% vs. 45% (P < 0.0001)], with a manageable safety profile in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report results from patients with progressive disease (PD) after ofatumumab who crossed over to duvelisib in the DUO trial.Patients with radiographically confirmed PD after ofatumumab received duvelisib 25 mg twice daily in 28-day cycles until PD, intolerance, death, or study withdrawal. The primary endpoint was ORR per investigator. Secondary endpoints included duration of response (DOR), PFS, and safety.As of December 14, 2018, 90 ofatumumab-treated patients in the DUO trial prior to crossover had an ORR of 29%, mDOR of 10.4 months, and mPFS of 9.4 months. After crossover, 77% of patients (69/90) achieved a response, with an mDOR of 14.9 months and mPFS of 15.7 months. Patients with del(17p) and/or TP53 mutations had similar outcomes [ORR, 77% (20/26); mPFS, 14.7 months]. Notably, 73% of patients (47/64) with disease previously refractory to ofatumumab achieved a response. The most frequent any-grade/grade 3/4 treatment-emergent adverse events were diarrhea (47%/23%), neutropenia (26%/23%), pyrexia (24%/4%), cutaneous reactions (23%/4%), and thrombocytopenia (10%/6%).Duvelisib demonstrated high response rates with good durability and a manageable safety profile in patients with R/R CLL/SLL who progressed on ofatumumab, including patients with high-risk disease and disease previously refractory to ofatumumab.
Progressive or Relapsed Burkitt Lymphoma or Leukemia in Children and Adolescents after BFM-type First-line Therapy
Authors: Wilhelm Woessmann, Martin Zimmermann, Andrea Meinhardt, Stephanie Mueller, Holger Hauch, Fabian Knörr, Ilske Oschlies, Wolfram Klapper, Felix Niggli, Edita Kabickova, Andishe Attarbaschi, Alfred Reiter, Birgit Burkhardt
Journal: Blood (2020)
Relaxation of Extracellular Matrix Forces Directs Crypt Formation and Architecture in Intestinal Organoids
Authors: Ella A. Hushka, F. Max Yavitt, Tobin E. Brown, Peter J. Dempsey, Kristi S. Anseth
Journal: Advanced Healthcare Materials (2020)

Abstract Intestinal organoid protocols rely on the use of extracellular scaffolds, typically Matrigel, and upon switching from growth to differentiation promoting media, a symmetry breaking event takes place. During this stage, the first bud like structures analogous to crypts protrude from the central body and differentiation ensues. While organoids provide unparalleled architectural and functional complexity, this sophistication is also responsible for the high variability and lack of reproducibility of uniform crypt‐villus structures. If function follows form in organoids, such structural variability carries potential limitations for translational applications (e.g., drug screening). Consequently, there is interest in developing synthetic biomaterials to direct organoid growth and differentiation. It has been hypothesized that synthetic scaffold softening is necessary for crypt development, and these mechanical requirements raise the question, what compressive forces and subsequent relaxation are necessary for organoid maturation? To that end, allyl sulfide hydrogels are employed as a synthetic extracellular matrix mimic, but with photocleavable bonds that temporally regulate the material's bulk modulus. By varying the extent of matrix softening, it is demonstrated that crypt formation, size, and number per colony are functions of matrix softening. An understanding of the mechanical dependence of crypt architecture is necessary to instruct homogenous, reproducible organoids for clinical applications.
Delivery strategies for macromolecular drugs in cancer therapy
Authors: Qin Guo, Chen Jiang
Journal: Acta Pharmaceutica Sinica B (2020)

With the development of biotherapy, biomacromolecular drugs have gained tremendous attention recently, especially in drug development field due to the sophisticated functions in vivo. Over the past few years, a motley variety of drug delivery strategies have been developed for biomacromolecular drugs to overcome the difficulties in the druggability, e.g., the instability and easily restricted by physiologic barriers. The application of novel delivery systems to deliver biomacromolecular drugs can usually prolong the half-life, increase the bioavailability, or improve patient compliance, which greatly improves the efficacy and potentiality for clinical use of biomacromolecular drugs. In this review, recent studies regarding the drug delivery strategies for macromolecular drugs in cancer therapy are summarized, mainly drawing on the development over the last five years.
A06 Tri-complex Inhibitors of the Oncogenic, GTP-Bound Form of KRASG12C Overcome RTK-Mediated Escape Mechanisms and Drive Tumor Regressions in Preclinical Models of NSCLC
Authors: R. Nichols, C. Schulze, A. Bermingham, T. Choy, J. Cregg, G. Kiss, A. Marquez, D. Reyes, M. Saldajeno-Concar, C. Weller, D. Whalen, Y. Yang, Z. Wang, E.S. Koltun, M. Singh, D. Wildes, A.L. Gill, R. Hansen, S. Kelsey, M. Goldsmith, J. Smith
Journal: Journal of Thoracic Oncology (2020)
Abstract 16825: Functional Analysis of Whole Exome Sequencing Candidate Genes for Left Ventricular Hypertrophy Demonstrate Changes in Cardiac Hypertrophic Signaling
Authors: Benjamin Olson, Praful Aggarwal, Marguerite Irvin, Vinodh Srinivasasainagendra, Degui Zhi, Degui Zhi, Charles Gu, Lisa de las Fuentes, Amy Turner, Andrea Matter, Hemant Tiwari, Deborah A Nickerson, Donna K Arnett, Ulrich Broeckel
Journal: Circulation (2018)

As whole exome sequencing (WES) studies identify a large number of potential disease relevant genes and variants, a major challenge will be the subsequent functional analysis and interpretation. We performed WES in 1,382 African American subjects from NHLBI’s HyperGEN cohort to identify novel genes for Left ventricular (LV) hypertrophy. Using criteria that combine significant prior linkage/association signals, expression QTL information, database annotation, and literature search, we prioritized the candidate genes to further scrutinize those with higher functional potentials. As a result, we selected four genes ( FATP6, PDE12, HAX1, TRAPPC11 ) that had not been directly linked to LVH for experimental functional follow up using human iPSC-derived cardiomyocytes (hiPSC-CM). Each gene was knocked-down (KD) using siRNAs in triplicate followed by mRNA sequencing. Differential expression and pathway analyses were performed to evaluate influences of the candidate genes. The KDs of FATP6 and PDE12 , whose variants show significant association with increased LV internal diastolic-dimension, showed regulation changes in cardiac hypertrophy and β-adrenergic signaling pathways (p-value &lt;0.05). In FATP6 KDs we observed 2,696 genes to have significant differential expression (adj. p-value ≤0.05). Furthermore, FATP6 KDs also lead to the upregulation of cholesterol biosynthesis pathways (p-value 1.97E-4) that are important for caveolae formation and signal transduction. Additionally, FATP6 KDs had a moderate increase in FATP1 expression (p-value 0.0024) that has been reported to cause lipotoxicity and increase LV internal diastolic diameter in mice. In PDE12 KDs we observed significant differential expression of 3,276 genes (adj. p-value ≤0.05) and saw significant decreases in Ca2+ channel expression (adj. p-value ≤0.05) that likely lead to decreases in Ca2+ handling. In summary, our study demonstrates the hiPSC-CM based knockdown model as an effective approach to functionally test and characterize candidate genes identified through WES. Further development of the approach using hiPSC derived cells will offer a scalable platform for high-throughput, multi-omics analyses using genome-matched, disease-relevant tissue types.
Tissue Engineering: Full‐Scale Osteochondral Regeneration by Sole Graft of Tissue‐Engineered Hyaline Cartilage without Co‐Engraftment of Subchondral Bone Substitute (Adv. Healthcare Mater. 2/2020)
Authors: Xiaolei Nie, Jian Yang, Yon Jin Chuah, Wenzhen Zhu, Yvonne Peck, Pengfei He, Dong‐An Wang
Journal: Advanced Healthcare Materials (2020)

In article number 1901304, Dong-An Wang and co-workers show how full-scale osteochondral defects, which penetrate articular cartilage and invade into subchondral bones, can be fixed by sole grafting of tissue-engineered hyaline cartilage without co-engraftment of a subchondral bone substitute. The images are respectively MRI and polarized light microscopy of ultra-structural histology by picrosirius stain.
Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR
Authors: Victor M Corman, Olfert Landt, Marco Kaiser, Richard Molenkamp, Adam Meijer, Daniel KW Chu, Tobias Bleicker, Sebastian Brünink, Julia Schneider, Marie Luisa Schmidt, Daphne GJC Mulders, Bart L Haagmans, Bas van der Veer, Sharon van den Brink, Lisa Wijsman, Gabriel Goderski, Jean-Louis Romette, Joanna Ellis, Maria Zambon, Malik Peiris, Herman Goossens, Chantal Reusken, Marion PG Koopmans, Christian Drosten
Journal: Eurosurveillance (2020)

Background The ongoing outbreak of the recently emerged novel coronavirus (2019-nCoV) poses a challenge for public health laboratories as virus isolates are unavailable while there is growing evidence that the outbreak is more widespread than initially thought, and international spread through travellers does already occur. Aim We aimed to develop and deploy robust diagnostic methodology for use in public health laboratory settings without having virus material available. Methods Here we present a validated diagnostic workflow for 2019-nCoV, its design relying on close genetic relatedness of 2019-nCoV with SARS coronavirus, making use of synthetic nucleic acid technology. Results The workflow reliably detects 2019-nCoV, and further discriminates 2019-nCoV from SARS-CoV. Through coordination between academic and public laboratories, we confirmed assay exclusivity based on 297 original clinical specimens containing a full spectrum of human respiratory viruses. Control material is made available through European Virus Archive – Global (EVAg), a European Union infrastructure project. Conclusion The present study demonstrates the enormous response capacity achieved through coordination of academic and public laboratories in national and European research networks.
Prognostic and Predictive Significance of Pharmacogenetic Analysis in Patients with Carcinomas of Unknown Primary (CAUP)
Authors: C. Papadaki, G. Pentheroudakis, A. Cervantes Ruiperez, E. Lagoudaki, D. Petrakis, J. Souglakos, E.R. Braun, V. Georgoulias, D. Mavroudis, N. Pavlidis
Journal: Annals of Oncology (2012)
Role of the Hedgehog Pathway in Mediating Resistance to Anti-Egfr Tyrosine Kinase Inhibitors in Non Small Cell Lung Cancer
Authors: F. Morgillo, C.M. Della Corte, G. Martini, A. Manzo, V. Gambardella, D. Vitagliano, E. Martinelli, T. Troiani, F. Ciardiello
Journal: Annals of Oncology (2012)