tbuckley/cabot-search huggingface dataset:
The preliminary efficacy and safety of KN046 plus concurrent chemoradiation therapy in recurrent and metastatic esophageal squamous cell carcinoma.
Authors: Bing Song Qin, Qi Zhao, Dong Yan Liu, Jiao Xue, Xing Jia Zhu
Journal: Journal of Clinical Oncology (2021)

223 Background: Definitive or palliative chemoradiation therapy has been employed in the management of esophageal squamous cell carcinoma (ESCC). Immune checkpoint inhibitor has improved outcomes in metastatic stage IV pts. Here we report the addition of KN046, a PD-L1/CTLA-4 bispecific antibody, to concurrent chemoradiation (CRT) therapy to determine the safety and efficacy of this approach (ChiCTR2000031544). Methods: Pts with recurrent or metastatic ESCC, not been treated by CRT or other systemic treatment within 6 months, were recruited and received palliative CRT consisting of cisplatin (75 mg/m 2 IV Q3W for 4~6 cycles), paclitaxel (135~175 mg/m 2 IV Q3W for 4-6 cycles) and radiation (SBRT or conventional and dose are determined at the investigator’s discretion according to institutional standard). KN046 at ascending doses of 1, 3 and 5 mg/kg Q3W was added within 7-14 days after the completion of radiation therapy (RT) and concurrently with chemotherapy, followed by KN046 Q2W maintenance. Dose limiting toxicities (DLTs) were assessed for the first treatment cycle of KN046. Anti-tumor activity was assessed according to RECIST 1.1 every 6 weeks within the first year, and every 12 weeks thereafter. Results: As of June 30, 2020, 18 subjects were enrolled and received KN046 treatment (1mg/kg, n = 3; 3mg/kg, n = 11; 5mg/kg, n = 4). The median KN046 exposure was 11.5 weeks. No DLT was reported. 3 (16.7%) subjects experienced Grade 3, KN046 related adverse events (1 Grade 3 pneumonitis and 2 Grade 3 colitis recovered after steroid and antibiotic Tx). For 18 evaluable subjects, the disease control rate and objective response rate were 94.4% and 44.4%, respectively. DOR and PFS were not matured yet as of cutoff date. At 3 mg/kg, objective response was observed in 5 out of 9 subjects (55.6%) with measurable disease and disease control rate was 100%; 7/9 (77.8%) subjects experienced further tumor reduction after initiation of KN046 treatment. It is worth to note that, 2 subjects at 3mg/kg achieved complete response after receiving KN046 treatment. Conclusions: The addition of KN046 to CRT was well tolerated and showed promising efficacy signal in recurrent or metastatic ESCC. This pilot study enables further investigation of a new treatment modality of KN046 with CRT in this detrimental disease with poor prognosis. Clinical trial information: 2000031544.
THU0186 The evaluation of the risk factors for generalised osteoporosis in patients with rheumatoid arthritis
Authors: Ü Bingöl, L Altan, E Dinçsahin, M Yurtkuran
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> In patients with rheumatoid arthritis (RA), the frequency of generalised osteoporosis is increased. The factors related to the disease like duration, functional capacity, medical treatment (corticosteroid, nonsteroidal drugs, methotrexate) and disease activation (C-reactive protein, erythrocyte sedimentation rate) are present among the probable factors which increase the risk of generalised osteoporosis such as the general factors like sex, age and menapausal status. <h3>Objectives</h3> The effects of the general risk factors and the risk factors related to the disease on the formation of osteoporosis were assessed statistically with the ordinal logistic regression test. <h3>Methods</h3> The bone mass of 36 patients with RA (between the ages of 25 – 75 and duration of disease 0,25 – 43 years ? 32 female, 4 male) were evaluated with calcaneal ultrasound. <h3>Results</h3> It was estimated that the risk of osteoporosis is increased 7.44 times in patients using nonsteroidal anti-inflammatory drugs (NSAID) compared with those who received no NSAID treatment. (P = 0.05, Odds Ratio = 7.44, 95% Confidence interval = 1 – 55.46) <h3>Conclusion</h3> This data has shown us the importance of NSAID treatment in increasing the risk of generalised osteoporosis in RA patients. <h3>References</h3> Laan RFJM, van Riel PLCM, van de Pute LBA. Bone mass in patients with rheumatoid arthritis. Ann Rheum Dis. 1992;51:826–32 Gough AKS, Lilley J, Eyre S, Holder RL, Emery P. Generalized bone loss in patients with early rheumatoid arthritis. Lancet 1994;344:23–7 Mellsh RWE, O'Sullivan MM, Garrahan NJ, Compston JE. Iliac crest trabeculer bone mass and structure in patients with non steroid treated rheumatoid arthritis. Ann Rheum Dis 1987;46:830–6 Ewans WD, Ewans C. Long term follow up of spinal trabeculer bone mineral density in women with non-steroid treated rheumatoid arthritis. Ann Rheum Dis. 1994;53:149
Abstract 11643: Atrial Fibrillation Associated Common Risk Variants in SYNE2 Lead to Lower Expression of Nesprin-2A1 and Increased Nuclear Stiffness
Authors: Nana Liu, Jeffrey Hsu, Gautam Mahajan, John Barnard, David Von Vagoner, Mina Chuang, Chandrasekhar Kothapalli, Jonathan D Smith
Journal: Circulation (2019)

Introduction: Atrial fibrillation (AF) genome-wide association studies identified significant associations for rs1152591 and rs1152595, two linked intronic single nucleotide polymorphisms (SNPs) in...
Preclinical Evaluation and Phase Ib Study of Prexasertib, a CHK1 Inhibitor, and Samotolisib (LY3023414), a Dual PI3K/mTOR Inhibitor
Authors: David S. Hong, Kathleen N. Moore, Johanna C. Bendell, Daniel D. Karp, Judy S. Wang, Susanna V. Ulahannan, Suzanne Jones, Wenjuan Wu, Gregory P. Donoho, Yan Ding, Andrew Capen, Xuejing Wang, Aimee Bence Lin, Manish R. Patel
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Prexasertib, a checkpoint kinase 1 inhibitor (CHK1), exhibited modest monotherapy antitumor activity in previous studies. Preclinical data were generated to support the clinical combination of prexasertib + samotolisib, a PI3K/mTOR inhibitor. Patients and Methods: Prexasertib + samotolisib was first evaluated in triple-negative breast cancer (TNBC) cells, MDA-MB-231 orthotopic xenograft tumors, and TNBC patient–derived xenograft (PDX) mouse models. In the phase Ib trial, following dose escalation, the initial expansion arm (E1, solid tumors) explored prexasertib 105 mg/m2 intravenously every 14 days + samotolisib 200 mg orally twice daily. Subsequent expansion arms evaluated samotolisib 150 mg twice daily in patients carrying PIK3CA mutations (E2, solid tumors) or with TNBC (E3). Safety and antitumor activity were assessed. Results: Prexasertib + samotolisib inhibited cell proliferation in TNBC lines and primary tumor growth in the MDA-MB-231 model. Prexasertib + samotolisib exhibited synergistic or additive effects in 30 of 38 PDX single-mouse (“n = 1”) models, and provided rationale for clinical evaluation. In the phase Ib study, 53 patients were enrolled (escalation, n = 13; E1, n = 9; E2, n = 15; and E3, n = 16). No dose-limiting toxicities (DLT) were observed during escalation; however, DLT-equivalent toxicities were observed in E1, leading to samotolisib dose reduction (150 mg twice daily) in E2/E3. Common treatment-related adverse events were leukopenia/neutropenia (94.3%), thrombocytopenia (62.3%), and nausea (52.8%). During escalation, 2 patients achieved partial response for an overall response rate (ORR) of 15.4%, and ORRs were 13.3% for E2 (PIK3CA) and 25% for E3 (TNBC). Conclusions: Prexasertib + samotolisib showed antitumor activity in preclinical models and preliminary efficacy in heavily pretreated patients. The clinical combination was associated with toxicity, suggesting supportive measures may be required. However, these data may inform future trials using other CHK1 and PI3K pathway inhibitors.
Treatment Pathways of Non-Dialysis-Dependent CKD Patients with Anemia: A Report from the DISCOVER CKD Retrospective Cohort
Authors: Eric T. Wittbrodt, Juan J. Carrero, Glen James, Steven Fishbane, Supriya R. Kumar, Roberto Pecoits-Filho, Juan Jose Garcia Sanchez, Carol A. Pollock, James A. Sloand, Katarina Hedman, David C. Wheeler
Journal: Journal of the American Society of Nephrology (2020)
Broad‐Spectrum Antiviral Agents Based on Multivalent Inhibitors of Viral Infectivity
Authors: Alexander N. Zelikin, Francesco Stellacci
Journal: Advanced Healthcare Materials (2021)

Abstract The ongoing pandemic of the coronavirus disease (Covid‐19), caused by the spread of the severe acute respiratory syndrome coronavirus 2 (SARS CoV‐2), highlights the need for broad‐spectrum antiviral drugs. In this Essay, it is argued that such agents already exist and are readily available while highlighting the challenges that remain to translate them into the clinic. Multivalent inhibitors of viral infectivity based on polymers or supramolecular agents and nanoparticles are shown to be broadly acting against diverse pathogens in vitro as well as in vivo. Furthermore, uniquely, such agents can be virucidal. Polymers and nanoparticles are stable, do not require cold chain of transportation and storage, and can be obtained on large scale. Specifically, for the treatment of respiratory viruses and pulmonary diseases, these agents can be administered via inhalation/nebulization, as is currently investigated in clinical trials as a treatment against SARS CoV‐2/Covid‐19. It is believed that with due optimization and clinical validation, multivalent inhibitors of viral infectivity can claim their rightful position as broad‐spectrum antiviral agents.
Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions
Authors: Antonio José Vargas López
Journal: Neuro-Oncology (2020)

Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions." 1 We congratulate the authors since the article summarizes the current status of the treatment of glioblastoma, specially the aspects related to de novo and adjuvant management.Nevertheless, we think that the information concerning the role of surgery in recurrent glioblastoma has been dramatically undervalued and the affirmations about its usefulness may be misunderstood.The article explains, in detail, many of the therapeutic alternatives for the treatment of recurrent glioblastoma as Bevacizumab, Nitrosoureas, Rechallenging Temozolomide, Re-irradiation, or Immunotherapy.In spite of this, the majority of them have not shown any significant improvement in survival or quality of life.We regret that the role of salvage surgery, as opposed to these other tools, has been very briefly discussed in the nonspecific heading "Recurrent glioblastoma."Next, we summarize some of the most relevant aspects related to the role of salvage surgery.][4][5] We agree with the authors that the maximal benefit of salvage surgery is related to complete resection, but this may only be known a posteriori.So, the decision to operate or not to operate a recurrent glioblastoma may not be based on a posteriori measurement, but on the possibility of obtaining a gross total resection (GTR) >95% of the MRI T1-enhanced
Structural characterization of a novel GPVI-nanobody complex reveals a biologically active domain-swapped GPVI dimer
Authors: Alexandre Slater, Ying Di, Joanne C. Clark, Natalie J. Jooss, Eleyna M. Martin, Fawaz Alenazy, Mark R. Thomas, Robert A. S. Ariëns, Andrew B. Herr, Natalie S. Poulter, Jonas Emsley, Steve P. Watson
Journal: Blood (2021)

Glycoprotein VI (GPVI) is the major signaling receptor for collagen on platelets. We have raised 54 nanobodies (Nb), grouped into 33 structural classes based on their complementary determining region 3 loops, against recombinant GPVI-Fc (dimeric GPVI) and have characterized their ability to bind recombinant GPVI, resting and activated platelets, and to inhibit platelet activation by collagen. Nbs from 6 different binding classes showed the strongest binding to recombinant GPVI-Fc, suggesting that there was not a single dominant class. The most potent 3, Nb2, 21, and 35, inhibited collagen-induced platelet aggregation with nanomolar half maximal inhibitory concentration (IC50) values and inhibited platelet aggregation under flow. The binding KD of the most potent Nb, Nb2, against recombinant monomeric and dimeric GPVI was 0.6 and 0.7 nM, respectively. The crystal structure of monomeric GPVI in complex with Nb2 revealed a binding epitope adjacent to the collagen-related peptide (CRP) binding groove within the D1 domain. In addition, a novel conformation of GPVI involving a domain swap between the D2 domains was observed. The domain swap is facilitated by the outward extension of the C-C' loop, which forms the domain swap hinge. The functional significance of this conformation was tested by truncating the hinge region so that the domain swap cannot occur. Nb2 was still able to displace collagen and CRP binding to the mutant, but signaling was abolished in a cell-based NFAT reporter assay. This demonstrates that the C-C' loop region is important for GPVI signaling but not ligand binding and suggests the domain-swapped structure may represent an active GPVI conformation.
A randomized controlled phase III trial of comparing local field with additional prophylactic irradiation in chemoradiotherapy for clinical-T1bN0M0 esophageal cancer:JCOG1904/ARMADILLO study.
Authors: Motoo Nomura, Katsuyuki Sakanaka, Ken Kato, Tomohiro Kadota, Yoshinori Ito, Ryunosuke Machida, Keita Sasaki, Tomoko Kataoka, Yasumasa Nishimura, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2021)

TPS257 Background:Parallel-group controlled trial of esophagectomy versus chemoradiotherapy (JCOG0502) showed chemoradiotherapy (CRT) is considered as a standard treatment option for clinical-T1bN0M0 esophageal squamous cell carcinoma (ESCC) with organ preservation. However, locoregional recurrence after CRT occurs in 20% of patients and requires salvage treatment including salvage surgery, chemo(radio)therapy, and endoscopic resection. Salvage treatments can cause complications and treatment-related death. CRT with elective nodal irradiation (ENI) have been reported to reduce the locoregional recurrence of esophageal cancer. We conduct the clinical trial to evaluate the efficacy of modified CRT with ENI compared with CRT without ENI for the patients with cTbN0M0 ESCC. The primary purpose of this study is to investigate whether modified CRT with ENI reduces the locoregional recurrence that cannot be completely resected by salvage endoscopic resection and preserve esophagus without compromising overall survival. Methods:Eligibility criteria include the followings; thoracic ESCC, adenosquamous, or basaloid cell carcinoma with clinical-T1bN0M0, age 20 or older, performance status 0 or 1, adequate organ function, and patient who do not have a preference to receive a surgical resection as an initial therapy. Patients are randomly assigned to following two arms using the minimization method with a random component to balance institution, tumor length (≤4cm versus &gt; 4cm), and age (≤65 years old versus &gt; 65 years old). Patients in arm A receive CRT consisted of CDDP (70 mg/m 2 /day, days 1 and 29) and 5-FU (700 mg/m 2 /day, days 1-4 and 29-32, civ) with concurrent radiotherapy (60 Gy/30 fr without ENI). Patients in arm B receive CRT consisted of CDDP (75 mg/m 2 /day, days 1 and 29) and 5-FU (1000 mg/m 2 /day, days 1-4 and 29-32, civ) with concurrent radiotherapy (50.4 Gy/ 28 fr with ENI of 41.4 Gy/23 fr). Primary endpoint is major progression-free survival (MPFS), defined as the time from randomization to the date of death or disease progression except achieving curative resection by salvage endoscopic resection. We assumed 5-year MPFS with arm A to be 70% and expected a 10% improvement for arm B. The planned sample size was calculated as a total of 280 patients (140 patients per arm) with a one-sided alpha of 5%, power of 70%, an accrual period of 4 years, and a follow-up period of 5 years. This trial was activated in July 2020. The study was also registered at the Japan Registry of Clinical Trials (jRCT) as study number jRCTs031200067. Clinical trial information: jRCTs031200067.
Outcomes of patients with chronic myelomonocytic leukaemia treated with non-curative therapies: a retrospective cohort study
Authors: Lisa Pleyer, Michael Leisch, Alexandra Kourakli, Eric Padron, Jaroslaw Pawel Maciejewski, Blanca Xicoy Cirici, Jennifer Kaivers, Johanna Ungerstedt, Sonja Heibl, Peristera Patiou, Anthony Michael Hunter, Elvira Mora, Klaus Geissler, Maria Dimou, Maria-José Jimenez Lorenzo, Thomas Melchardt, Alexander Egle, Athina-Nora Viniou, Bhumika Jayantibhai Patel, Montserrat Arnan, Peter Valent, Christoforos Roubakis, Teresa Bernal del Castillo, Athanasios Galanopoulos, Marisa Calabuig Muñoz, Nicolas Bonadies, Antonio Medina de Almeida, Jaroslav Cermak, Andrés Jerez, Maria Julia Montoro, Albert Cortés, Alejandro Avendaño Pita, Bernardo Lopez Andrade, Eva Hellstroem-Lindberg, Ulrich Germing, Mikkael Aaron Sekeres, Alan Francis List, Argiris Symeonidis, Guillermo Francisco Sanz, Julian Larcher-Senn, Richard Greil
Journal: The Lancet Haematology (2021)
Abstract 13883: Pulmonary Vein Stenosis is Associated With Trisomy 21
Authors: Abbas H Zaidi, Jessica M Yamada, Kerry McEnaney, Kathy J Jenkins, Ming Hui Chen
Journal: Circulation (2019)

Introduction: The role of genetics in pulmonary vein stenosis (PVS), a rare and frequently lethal disease in children, is unknown. Trisomy 21 (T21) has only been reported in few patients with PVS f...
Assessing the impact of the 13 valent pneumococcal vaccine on childhood empyema in Australia
Authors: Roxanne Strachan, Nusrat Homaira, Sean Beggs, Mejbah U Bhuiyan, Gwendolyn L Gilbert, Stephen B Lambert, Kristine Macartney, Helen Marshall, Andrew C Martin, Gabrielle B McCallum, Angela McCullagh, Tim McDonald, Peter McIntyre, Shahin Oftadeh, Sarath Ranganathan, Sadasivam Suresh, Claire E Wainwright, Angela Wilson, Melanie Wong, Thomas Snelling, Adam Jaffé
Journal: Thorax (2021)

Background Empyema is a serious complication of pneumonia frequently caused by Streptococcus pneumoniae (SP). We assessed the impact of the 13-valent pneumococcal conjugate vaccine (13vPCV) on childhood pneumonia and empyema after inclusion in the Australian National Immunisation Program. Methods For bacterial pneumonia and empyema hospitalisations, we ascertained incidence rates (IRs) using the National Hospital Morbidity Database International Statistical Classification of Disease discharge codes and relevant population denominators, and calculated incidence rate ratios (IRR) comparing the 13vPCV period (June 2012–May 2017) with the 7vPCV period (June 2007–May 2011). Blood and pleural fluid (PF) cultures and PF PCR of 401 children with empyema from 11 Australian hospitals during the 13vPCV period were compared with our previous study in the 7vPCV period. Findings Across 7vPCV and 13vPCV periods, IRs per million children (95% CIs) were 1605 (1588 to 1621) and 1272 (1259 to 1285) for bacterial pneumonia, and 14.23 (12.67 to 15.79) and 17.89 (16.37 to 19.42) for empyema hospitalisations. IRRs were 0.79 (0.78 to 0.80) for bacterial pneumonia and 1.25 (1.09 to 1.44) for empyema. Of 161 empyema cases with SP serotypes, 147 (91.3%) were vaccine types. ST3 accounted for 76.4% of identified serotypes in the 13vPCV period, more than double than the 7vPCV period (p&lt;0.001); ST19A decreased from 36.4% to 12.4%. No cases of ST1 empyema were identified in the 13vPCV period versus 14.5% in the 7vPCV period. Interpretation 13vPCV resulted in a significant reduction in all-cause hospitalisations for bacterial pneumonia but empyema hospitalisations significantly increased, with emergence of pneumococcal ST3 as the dominant serotype in empyema. Trial registration number Australian and New Zealand Clinical Trial Registry ACTRN 12614000354684.
A critical review of mechanisms of adaptation to trauma: Implications for early interventions for posttraumatic stress disorder
Authors: Richard A. Bryant
Journal: Clinical Psychology Review (2021)

Although many attempts have been made to limit development of posttraumatic stress disorder (PTSD) by early intervention after trauma exposure, these attempts have achieved only modest success. This review critiques the biological and cognitive strategies used for early intervention and outlines the extent to which they have prevented PTSD. The major predictors of PTSD are reviewed, with an emphasis on potential mechanisms that may underpin the transition from acute stress reaction to development of PTSD. This review highlights that there is a wide range of biological and cognitive factors that have been shown to predict PTSD. Despite this, the major attempts at early intervention have focused on strategies that attempt to augment extinction processes or alter appraisals in the acute period. The documented predictors of PTSD indicate that a broader range of potential strategies could be explored to limit PTSD. The evidence that people follow different trajectories of stress response following trauma and there is a wide array of acute predictors of PTSD indicates that a flexible and tailored approach needs to be investigated to evaluate more effective early intervention strategies.
AB0303 PREDICTORS OF SERIOUS INFECTIONS IN PATIENTS WITH RHEUMATOID ARTHRITIS RECEIVING TARGET THERAPY.
Authors: E. Koltsova, G. Lukina, E. Shmidt, K. Lytkina, E. Zhilyaev
Journal: Annals of the Rheumatic Diseases (2020)

Background: The problem of infectious complications in patients receiving bDMARDs deserves special attention. Serious infectious adverse events (SIAE) are a most important issue. To develop measures for their prevention it is necessary to know the predisposing factors. Objectives: to detect predictors of serious infections among patients with rheumatoid arthritis receiving targeted therapy Methods: The study includes patients with rheumatoid arthritis from the Moscow Unified Arthritis Registry (MUAR), receiving treatment with biologics or tofacitinib. Search for predictors was carried out in two steps. At first step we selected patient related predictors (confounders) that significantly correlate with risk of SIAE. At the second step in the Cox risk regression model by forward stepwise selection were identified independent significant predictors of risk. which demonstrated significant correlation with development of serious infections. Then data about the treatment was added to the generated model: used targeted DMARDs, doses of glucocorticoids (GC), doses of methotrexate (MTX). Results: Analysis includes 1052 treatment events in 772 patients. There were 44 serious infections. The mean age was 57,1 ± 12,8 years. The mean observation time – 5.3 years. Independent patient related predictors of SIAE risk were the age RR - 1.12 per year (CI: 1.06-1.19), the age of onset disease RR - 0.94 per year (CI: 0.90-0.98), the year of inclusion in the registry RR - 0.64 per year (CI: 0.49-0.85). The dose of MTX and the doses of GC positively correlate with SIAE risk. RR for MTX is 1.05 per mg (CI: 1.005-1.109), RR for GC - 1.11 per mg (CI: 1.004-1.236). Used targeted DMARD didn’t show any significant correlation with SIAE risk. Conclusion: Higher doses of methotrexate and glucocorticoids are independent significant predictors of serious infections in RA patients receiving targeted DMARDs. Disclosure of Interests: Ekaterina Koltsova: None declared, Galina Lukina Speakers bureau: Novartis, Pfizer, UCB, Abbvie, Biocad, MSD, Roche, Evgeniya Shmidt Speakers bureau: MSD, Novartis, Pfizer, Karine Lytkina Speakers bureau: Novartis, Eli Lilly, Pfizer, UCB, Abbvie, Biocad, MSD, Jonson&amp;Jonson, Evgeniy Zhilyaev Speakers bureau: Novartis, UCB, Pfizer, Biocad, Abbvie, MSD, Roche