tbuckley/cabot-search huggingface dataset:
A Phase 2a, Double-Blind, Placebo-controlled Randomized Trial of Inhaled TLR9 Agonist AZD1419 in Asthma
Authors: Ioannis Psallidas, Vibeke Backer, Piotr Kuna, Robert Palmér, Sofia Necander, Malin Aurell, Katarina Korsback, Ziad Taib, Mahdi Hashemi, Per Gustafson, Sara Asimus, Stephen Delaney, Katerina Pardali, Fanyi Jiang, Joachim Almquist, Sam Jackson, Robert L. Coffman, David Keeling, Tariq Sethi
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: To examine the potential of TLR9 (Toll-like receptor 9) activation to modulate the type 2 immune response in asthma.Objectives: To evaluate efficacy and safety of AZD1419, an inhaled TLR9 agonist, in a phase 2a, randomized, double-blind trial.Methods: Adult patients with asthma with a history of elevated eosinophils (>250 cells/μl) were randomized 1:1 to receive 13 once-weekly doses of inhaled AZD1419 (1, 4, or 8 mg; n = 40) or placebo (n = 41). Inhaled corticosteroids and long-acting β2-agonist were tapered down and then discontinued. The last four doses of AZD1419 were given without maintenance medication, followed by a 40-week observation period. Primary endpoint was time to loss of asthma control (LOC).Measurements and Main Results: AZD1419 induced a T-helper cell type 1-type IFN response with a sustained reduction in markers of type 2 inflammation. However, there were no statistically significant differences between AZD1419 and placebo for time to LOC, proportion of patients with LOC, changes in Asthma Control Questionnaire-five-item version, exacerbations, reliever use, FEV1, peak expiratory flow, or fractional exhaled nitric oxide (FeNO). LOC was predicted by an early rise in FeNO in 63% of patients. Despite withdrawal of maintenance treatment, 24 patients completed the study without LOC; AZD1419 n = 11, placebo n = 13. Adverse events were balanced across groups, with no deaths or serious adverse events judged as causally related to AZD1419.Conclusions: AZD1419 was safe and well tolerated but did not lead to improved asthma control, despite reducing markers of type 2 inflammation. Results suggest that a novel accelerated step-down approach based on FeNO is possible for patients with well-controlled asthma.
Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery
Authors: Xiaoxiao Yang, Zhixiang Pan, Manjusha R. Choudhury, Zhengnan Yuan, Abiodun Anifowose, Bingchen Yu, Wenyi Wang, Binghe Wang
Journal: Medicinal Research Reviews (2020)

Abstract Smart drugs, such as antibody‐drug conjugates, for targeted therapy rely on the ability to deliver a warhead to the desired location and to achieve activation at the same site. Thus, designing a smart drug often requires proper linker chemistry for tethering the warhead with a vehicle in such a way that either allows the active drug to retain its potency while being tethered or ensures release and thus activation at the desired location. Recent years have seen much progress in the design of new linker activation strategies. Herein, we review the recent development of chemical strategies used to link the warhead with a delivery vehicle for preferential cleavage at the desired sites.
Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression
Authors: Cory R. Weissman, Daniel M. Blumberger, Julia Dimitrova, Alanah Throop, Daphne Voineskos, Jonathan Downar, Benoit H. Mulsant, Tarek K. Rajji, Paul B. Fitzgerald, Zafiris J. Daskalakis
Journal: JAMA Network Open (2020)

<h3>Importance</h3> There is an unmet need for effective treatments for suicidality in mental disorders. Magnetic seizure therapy (MST) has been investigated as an alternative to electroconvulsive therapy, a known effective treatment for suicidality, in the management of treatment-resistant major depressive disorder, with promising findings. Yet, there are very limited data on the association of MST with suicidality directly. It is important to explore the potential of MST as a viable treatment alternative to electroconvulsive therapy for suicidality. <h3>Objective</h3> To determine the association of MST with suicidality in patients with treatment-resistant major depressive disorder. <h3>Design, Setting, and Participants</h3> This nonrandomized controlled trial took place at a single tertiary care psychiatric facility in Canada. It followed an open-label study design with consecutive treatment cohorts. Consecutive groupings of 67 patients with treatment-resistant major depressive disorder and with baseline suicidality present were treated for up to 24 treatments. The study was run from February 2012 through June 2019. Patients were followed up for 6 months at the end of the treatment period. This post hoc secondary analysis of the trial was performed from January to November 2019. <h3>Interventions</h3> MST was delivered at 100% stimulator output over the prefrontal cortex with low (25 Hz), moderate (50 or 60 Hz), or high (100 Hz) frequency, for a maximum of 24 sessions. <h3>Main Outcomes and Measures</h3> Remission from suicidality was measured as an end point score of 0 on the Beck Scale for Suicidal Ideation. A linear mixed model was used to assess the trajectory of Beck Scale for Suicidal Ideation scores. <h3>Results</h3> A total of 67 patients (mean [SD] age, 46.3 [13.6] years; 40 women [60.0%]) received a mean (SD) of 19.5 (5.1) MST treatments. The overall number of patients achieving remission was 32 (47.8%). Sixteen patients (55.2%) receiving low-frequency MST achieved remission, as well as 12 patients (54.5%) in the moderate-frequency group, and 4 patients (25.0%) in the high-frequency group. The linear mixed model revealed an association of time with Beck Scale for Suicidal Ideation scores (<i>F</i><sub>8,293.95</sub> = 5.73;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> These findings suggest that MST may be an effective treatment for suicidality, and sensitivity analysis shows this may be particularly so at low and moderate frequencies. Future studies should directly compare MST with electroconvulsive therapy for treating suicidality and should evaluate MST as a treatment for suicidality across mental disorders. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01596608
CRISPR and transposon in vivo screens for cancer drivers and therapeutic targets
Authors: Imran Noorani, Allan Bradley, Jorge de la Rosa
Journal: Genome biology (2020)

Abstract Human cancers harbor substantial genetic, epigenetic, and transcriptional changes, only some of which drive oncogenesis at certain times during cancer evolution. Identifying the cancer-driver alterations amongst the vast swathes of “passenger” changes still remains a major challenge. Transposon and CRISPR screens in vivo provide complementary methods for achieving this, and each platform has its own advantages. Here, we review recent major technological breakthroughs made with these two approaches and highlight future directions. We discuss how each genetic screening platform can provide unique insight into cancer evolution, including intra-tumoral heterogeneity, metastasis, and immune evasion, presenting transformative opportunities for targeted therapeutic intervention.
The effect of mental fatigue on sport-specific endurance and technical performances (PhD Academy Award)
Authors: Luca Filipas
Journal: British Journal of Sports Medicine (2020)

Acute mental fatigue is defined as a psychobiological state that may arise during or after prolonged cognitive activities.1 While the effects of mental fatigue on cognitive performance have been widely investigated,2 the interest of researchers in investigating a potential impact of mental fatigue on physical performance remains a hot topic. Despite some studies showing that mental fatigue appears to impair sport performance through an increased rating of perceived exertion (RPE) for the same physical effort,3 the scientific comprehension of this topic is still limited. Therefore, the aim of this PhD was to investigate the effects of mental fatigue on sport-specific endurance and technical performances. In addition, the project sought to clarify whether mental fatigue tolerance could be trainable or not.

The PhD project was divided into five different studies that cover different aspects of the connection between mental fatigue and physical performance. In three of them, running, rowing and cycling, endurance performances were evaluated after …
Impact of sarilumab on mechanical ventilation in patients with COVID-19. Response to: ‘Correspondence on: ‘Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation–an open-label cohort study’ by Della-Torre<i>et al</i>’ by Cheng and Zhang
Authors: Emanuel Della-Torre, Giovanni Landoni, Alberto Zangrillo, Lorenzo Dagna
Journal: Annals of the Rheumatic Diseases (2020)

We thank Dr Zhang and colleagues for appreciating our work and for raising relevant comments on the use of non-invasive ventilation (NIV) and mechanical ventilation (MV) in our population of critical patients.1 The authors correctly noticed that the vast majority of patients (52/58, 93%) fulfilled the criteria for acute respiratory distress syndrome (ARDS) but they did not undergo MV or glucocorticoids as per the ‘Surviving Sepsis Campaign Guidelines for Critically Ill Adults with COVID-19’.2 3 Indeed, the standard therapeutic approach adopted in our institution during the pandemic wave that struck Northern Italy varied in light of the practical experience that we rapidly accumulated and of the scientific data that progressively became available.

Between 24 February and 22 May 2020, San Raffaele Hospital (Milan, Italy) admitted more than 1000 patients with COVID-19, and our study was carried out in March, when shortcomings of MV in this specific clinical setting were increasingly being reported.4 5 Mounting evidence on invasively ventilated patients with COVID-19, in fact, was pointing at an extremely high mortality rate, ranging from 86% to 97%, and available guidelines at that time were not recommending early MV in …
Abstract 6618: A database of potential T cell epitopes for cancer immunotherapy
Authors: Chongming Jiang, Cheng-chi Chao, Chao Cheng
Journal: Cancer Research (2020)

Abstract Background: Adoptive immunotherapy with tumor-specific T cells is a promising treatment strategy for patients with malignancy. A key of adoptive T cell immunotherapy is to determine suitable immunogenic tumor antigens for targeting. The main challenges of T cell therapy are the relative lack of comprehensive information about proper antigens immunogenic to T cells, and excessive time-consumption to identify which kinds of peptides can be used for vaccine application and cancer immunotherapy. The objective of our work is to build a systematic database for those prospective tumor peptide antigens (dataset A), the documented promising immunogenic epitopes on cell surface having been experimentally validated (dataset B), and the antigens that have been tested in clinical studies (dataset C). The establishment of this database could overcome the prior inconvenience caused by the lack of collection data sets. Finding: In the dataset A, we predicted a total of 4,999,192 neoantigen from 463 cancer patients across 10 main kinds of cancer types. The dataset B includes 118,564 T cell epitopes that were experimentally proved to exist on various cancer cell surfaces and could be immunogenic. In dataset C, 636 peptides from different stages of 121 clinical trials with 31 cancer types were collected. Finally, a clinical trial by using adoptive immunotherapy with tumor-specific T cells was designed to apply a similar method to identify suitable tumor antigens. Conclusion: An informative database has been systemically built and tested in both theoretical and practical aspects, which enables a convenient and efficient approach for the selection of tumor antigens in vaccine design and cancer immunotherapy. Citation Format: Chongming Jiang, Cheng-chi Chao, Chao Cheng. A database of potential T cell epitopes for cancer immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6618.
CD70 antibody based drugs: two different mechanisms of action for the treatment of multiple cancer types
Authors: Jonathan A. Terrett, Chin Pan, Sanjeev Gangwar, Lisheng Lu, Liang Chen, Chetana Rao, Mary Huber, Peter Sattari, Mary Do, Rory Dai, Colin Chong, Carol Soderberg, Hao Li, Bilal Sufi, Sharon Boyd, Haichun Huang, Jun Zhang, Erika Meaddough, Vincent Guerlavais, Killian Horgan, Nick Sharkov, Pina Cardarelli, David King, Dapeng Yao, Sarah Pogue
Journal: Cancer Research (2006)

1995  CD70 (CD27L) is a ligand for CD27 mediated co-stimulation of B, T and NK cells. Recently it has been shown that CD70 expression is dramatically and specifically upregulated in clear cell renal cell carcinoma ( ccRCC ) at the mRNA and protein levels. There have also been sporadic reports of increased expression of CD70 in certain types of lymphomas and leukemias. Here we describe fully human anti-human CD70 antibodies derived from transgenic mice that express human immunoglobulin genes. Immunohistochemical analyses using one of these antibodies reveals that CD70 expression is highly prevalent in both ccRCC and Non-Hodgkins lymphomas. FACs analysis, as well as IHC, confirm normal tissue expression in activated B and T cells. We have developed two different strategies to specifically target and destroy CD70 expressing cancer cells. The first uses ADCC and the second a small molecule toxin conjugated to the antibody that is specifically released on internalization in CD70 expressing malignant cells. In vitro and in vivo experiments using both of these mechanisms will be presented.
Is short‐term exposure to grass pollen adversely associated with lung function and airway inflammation in the community?
Authors: Nur Sabrina Idrose, Rachel C. A. Tham, Caroline J. Lodge, Adrian J. Lowe, Dinh Bui, Jennifer L. Perret, Don Vicendese, Edward J. Newbigin, Mimi L. K. Tang, Fahad M. Aldakheel, Nilakshi T. Waidyatillake, Jo A. Douglass, Michael J. Abramson, Eugene Haydn Walters, Bircan Erbas, Shyamali C. Dharmage
Journal: Allergy (2020)

The association between grass pollen exposure and early markers of asthma exacerbations such as lung function changes and increase in airway inflammation is limited. We investigated the associations between short-term grass pollen exposure and lung function and airway inflammation in a community-based sample, and whether any such associations were modified by current asthma, current hay fever, pollen sensitization, age, and other environmental factors.Cross-sectional and short-term analyses of data from the Melbourne Atopy Cohort Study (MACS) participants (n = 936). Lung function was assessed using spirometry. Airway inflammation was assessed by fractional exhaled nitric oxide (FeNO) and exhaled breath condensate pH and nitrogen oxides (NOx). Daily pollen counts were collected using a volumetric spore trap. The associations were examined by linear regression.Higher ambient levels of grass pollen 2 days before (lag 2) were associated with lower mid-forced expiratory flow (FEF25%-75% ) and FEV1 /FVC ratio (Coef. [95% CI] = -119 [-226, -11] mL/s and -1.0 [-3.0, -0.03] %, respectively) and also 3 days before (lag 3). Increased levels of grass pollen a day before (lag 1) were associated with increased FeNO (4.35 [-0.1, 8.7] ppb) and also at lag 2. Adverse associations between pollen and multiple outcomes were greater in adults with current asthma, hay fever, and pollen sensitization.Grass pollen exposure was associated with eosinophilic airway inflammation 1-2 days after exposure and airway obstruction 2-3 days after exposure. Adults and individuals with asthma, hay fever, and pollen sensitization may be at higher risk.
Abstract 1716: Relationship between Coronary Artery Distensibility and Tissue Characteristics Evaluated by Three-dimensional Integrated Backscatter Intravascular Ultrasound (3D IB-IVUS)
Authors: Yoshiyuki Ishihara, Masanori Kawasaki, Munenori Okubo, Urara Takeyama, Tomoki Kubota, Shinji Yasuda, Nobuhiro Takasugi, Shinichiro Tanaka, Takahiko Yamaki, Shinsuke Ojio, Genzou Takemura, Kazuhiko Nishigaki, Hisayoshi Fujiwara, Shinya Minatoguchi
Journal: Circulation (2007)

Background: We developed an Integrated Backscatter Intravascular Ultrasound (IB-IVUS) for tissue characterization of coronary plaques. The relationship between the coronary artery distensibility and tissue components has not been investigated. Methods: Fourty-seven plaques with moderate stenosis (30 to 50%) in 36 patients were evaluated by three-dimensional (3D) IB-IVUS at every one millimeter. Plaque distensibility, lumen distensibility, vessel area, lumen area (LA) and plaque area (PA) were measured. Plaque distensibility was defined as follows: [In (systolic BP/diastolic BP)]/[(diastolic PA - systolic PA)/diastolic PA]. Lumen distensibility was defined as follows: [In (systolic BP/diastolic BP)]/[(diastolic LA -systolic LA)/diastolic LA]. % lipid area (lipid area/plaque area) were automatically calculated by IB-IVUS. Results: As the % lipid area increased, the lumen distensibility also increased (r = 0.32, p = 0.040). There was a tendency that the plaque distensibility increased as the % lipid area increased (r = 0.31, p = 0.056). 3D plaque distensibility map showed the difference in the plaque distensibility of each segment well. Conclusion: This is the first clinical demonstration of the relationship between the % lipid area and plaque distensibility of coronary arteries. The plaque area with greater % lipid area were more likely to increase from systolic to diastolic phase. 3D IB-IVUS color-coded mapping is useful for the evaluation of tissue characteristics and dynamics of coronary plaques.
Functional effects of chimeric antigen receptor co-receptor signaling domains in human regulatory T cells
Authors: Nicholas A. J. Dawson, Isaac Rosado-Sánchez, German E. Novakovsky, Vivian C. W. Fung, Qing Huang, Emma McIver, Grace Sun, Jana Gillies, Madeleine Speck, Paul C. Orban, Majid Mojibian, Megan K. Levings
Journal: Science Translational Medicine (2020)

Comparison of 10 co-receptor variant CARs revealed a requirement for CD28wt for optimal suppression by human regulatory T cells.
Case 26-2020: A 60-Year-Old Woman with Altered Mental Status and Weakness on the Left Side
Authors: Aneesh B. Singhal, R. Gilberto Gonzalez, Bart K. Chwalisz, Shibani S. Mukerji
Journal: New England Journal of Medicine (2020)

A Woman with Altered Mental Status and Weakness on the Left Side A 60-year-old woman presented with altered mental status and weakness on the left side during the Covid-19 pandemic. Diffusion-weigh...
Exploring novel systemic biomarker approaches in grass‐pollen sublingual immunotherapy using omics
Authors: Tomas Clive Barker‐Tejeda, Raphaelle Bazire, David Obeso, Leticia Mera‐Berriatua, Domenico Rosace, Sonia Vazquez‐Cortes, Tania Ramos, Maria del Pilar Rico, Tomás Chivato, Coral Barbas, Alma Villaseñor, Maria M. Escribese, Montserrat Fernández‐Rivas, Carlos Blanco, Domingo Barber
Journal: Allergy (2020)

Sublingual allergen-specific immunotherapy (SLIT) intervention improves the control of grass pollen allergy by maintaining allergen tolerance after cessation. Despite its widespread use, little is known about systemic effects and kinetics associated to SLIT, as well as the influence of the patient sensitization phenotype (Mono- or Poly-sensitized). In this quest, omics sciences could help to gain new insights to understand SLIT effects.47 grass-pollen-allergic patients were enrolled in a double-blind, placebo-controlled, multicenter trial using GRAZAX® during 2 years. Immunological assays (sIgE, sIgG4, and ISAC) were carried out to 31 patients who finished the trial. Additionally, serum and PBMCs samples were analyzed by metabolomics and transcriptomics, respectively. Based on their sensitization level, 22 patients were allocated in Mono- or Poly-sensitized groups, excluding patients allergic to epithelia. Individuals were compared based on their treatment (Active/Placebo) and sensitization level (Mono/Poly).Kinetics of serological changes agreed with those previously described. At two years of SLIT, there are scarce systemic changes that could be associated to improvement in systemic inflammation. Poly-sensitized patients presented a higher inflammation at inclusion, while Mono-sensitized patients presented a reduced activity of mast cells and phagocytes as an effect of the treatment.The most relevant systemic change detected after two years of SLIT was the desensitization of effector cells, which was only detected in Mono-sensitized patients. This change may be related to the clinical improvement, as previously reported, and, together with the other results, may explain why clinical effect is lost if SLIT is discontinued at this point.
Discrimination in US Surgical Training Programs
Authors: Andrea Amabile, Panos N. Vardas, Carlo Maria Rosati
Journal: JAMA Surgery (2020)

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Flexible electrical stimulation device with Chitosan-Vaseline® dressing accelerates wound healing in diabetes
Authors: Xiao-Feng Wang, Meng-Lu Li, Qing-Qing Fang, Wan-Yi Zhao, Dong Lou, Yan-Yan Hu, Jun Chen, Xiao-Zhi Wang, Wei-Qiang Tan
Journal: Bioactive Materials (2020)

The healing process of diabetic wounds is typically disordered and prolonged and requires both angiogenesis and epithelialization. Disruptions of the endogenous electric fields (EFs) may lead to disordered cell migration. Electrical stimulation (ES) that mimics endogenous EFs is a promising method in treating diabetic wounds; however, a microenvironment that facilitates cell migration and a convenient means that can be used to apply ES are also required. Chitosan-Vaseline® gauze (CVG) has been identified to facilitate wound healing; it also promotes moisture retention and immune regulation and has antibacterial activity. For this study, we created a wound dressing using CVG together with a flexible ES device and further evaluated its potential as a treatment for diabetic wounds. We found that high voltage monophasic pulsed current (HVMPC) promoted healing of diabetic wounds in vivo. In studies carried out in vitro, we found that HVMPC promoted the proliferation and migration of human umbilical vein endothelial cells (HUVECs) by activating PI3K/Akt and ERK1/2 signaling. Overall, we determined that the flexible ES-chitosan dressing may promoted healing of diabetic wounds by accelerating angiogenesis, enhancing epithelialization, and inhibiting scar formation. These findings provide support for the ongoing development of this multidisciplinary product for the care and treatment of diabetic wounds.