tbuckley/cabot-search huggingface dataset:
Incidence of severe COVID-19 in a Spanish cohort of 1037 patients with rheumatic diseases treated with biologics and JAK-inhibitors
Authors: Vega Jovani, Irene Calabuig, Maria Luisa Peral-Garrido, Ernesto Tovar-Sugrañes, María-del-Carmen López-González, Pilar Bernabeu, Agustín Martínez, Joaquim Esteve-Vives, Jose-Manuel León-Ramírez, Oscar Moreno-Perez, Vicente Boix, Joan Gil, Esperanza Merino, Paloma Vela, Mariano Andrés
Journal: Annals of the Rheumatic Diseases (2020)

The recent outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19, has brought about a great concern for the management of patients with inflammatory rheumatic diseases. Rheumatologists and patients are worried about the risk of contagion and suffering a more severe disease, derived from immunosuppressive treatment. Also, for the risk of relapse in case of discontinuing medications. To date, most of these questions remain to be answered.

Accordingly, we read with interest the recent paper from D’Silva and coauthors.1 They analysed the outcomes of 52 patients with rheumatic diseases (18 under biologics or targeted synthetic disease-modifying antirheumatic drugs (DMARDs)) hospitalised for COVID-19, identifying an independent increased risk of intubation and similar to mortality. These results are welcome and of relevance, but some issues need to be commented. Controls were matched for age, gender and disease duration, but multivariate models repeated adjustment for age. For outcome assessment in COVID-19, some laboratory markers—lymphopenia, troponins2— should have been considered as covariates for the …
Role of nanoparticle-mediated immunogenic cell death in cancer immunotherapy
Authors: Yajie Sun, Xiangru Feng, Chao Wan, Jonathan F. Lovell, Honglin Jin, Jianxun Ding
Journal: Asian Journal of Pharmaceutical Sciences (2020)

Cancer immunotherapy, which suppresses cancer progression by activating the anti-cancer immunity of patients, shows utility in treating multiple types of cancers. Immunogenic cell death (ICD) induced by most clinical treatment modalities plays a critical role in promoting cancer immunotherapy by releasing tumor-associated antigens and neoantigens and exposing "danger signals" to stimulate immune cells. This comment article presents the different roles of nanoparticles in various treatment modalities of cancers, including chemotherapy, radiotherapy, photodynamic and photothermal therapies, and therapy with radiated tumor cell-released nanoparticles, which often activate anti-cancer immunological effects by inducing ICD of cancer cells, and highlights the challenges and opportunities of ICD-related cancer immunotherapy in the clinic.
Does proteostasis get lost in translation? Implications for protein aggregation across the lifespan
Authors: Stephany Francisco, Margarida Ferreira, Gabriela Moura, Ana Raquel Soares, Manuel A.S. Santos
Journal: Ageing Research Reviews (2020)

Protein aggregation is a phenomenon of major relevance in neurodegenerative and neuromuscular disorders, cataracts, diabetes and many other diseases. Research has unveiled that proteins also aggregate in multiple tissues during healthy aging yet, the biological and biomedical relevance of this apparently asymptomatic phenomenon remains to be understood. It is known that proteome homeostasis (proteostasis) is maintained by a balanced protein synthesis rate, high protein synthesis accuracy, efficient protein folding and continual tagging of damaged proteins for degradation, suggesting that protein aggregation during healthy aging may be associated with alterations in both protein synthesis and the proteostasis network (PN) pathways. In particular, dysregulation of protein synthesis and alterations in translation fidelity are hypothesized to lead to the production of misfolded proteins which could explain the occurrence of age-related protein aggregation. Nevertheless, some data on this topic is controversial and the biological mechanisms that lead to widespread protein aggregation remain to be elucidated. We review the recent literature about the age-related decline of proteostasis, highlighting the need to build an integrated view of protein synthesis rate, fidelity and quality control pathways in order to better understand the proteome alterations that occur during aging and in age-related diseases.
Covid-19: healthcare and politics are inexorably intertwined
Authors: Sati Heer-Stavert
Journal: BMJ (2020)

Abbasi discusses transparency and political interference in scientific advice.1 It is time for our profession to accept that healthcare and politics are inexorably intertwined. This is because every healthcare decision involves resources of one kind or another. The term “independent adviser” has lost all meaning in the current era. Everyone either has an agenda or could easily have one manufactured …
Safety, tolerability, and preliminary pharmacokinetic/pharmacodynamic profile of JMT103 in patients with bone metastases from solid tumors: A multicenter, open-label, dose-escalation, phase I clinical study.
Authors: Jin Li, Huiping Li, Shukui Qin, Ye Guo, Xu Liang, Junli Xue, Wei Peng, Xiaoxiao Ge, Changxing Xie, Xiugao Yang, Tao Li, Jinglin Xu, Li Feng, Zhufeng Wu, Guanxi Xiao, Peng Zhang, Tianyi Zhang, Chenchen Wang, Baoxia Zhang, Zijian Hu
Journal: Journal of Clinical Oncology (2020)

3638 Background: Bone is one of the most common metastatic sites of malignancies. The metastatic tumor cells activate osteoclast activity and promote bone resorption via RANKL/RANK signaling pathway, and lead to osteolytic destruction. JMT103 is an innovative fully human IgG4 monoclonal antibody targeting RANKL. It can block RANKL/RANK signaling pathway, inhibit bone resorption, and protect bones from tumor metastasis. This study aimed to evaluate the safety and tolerability of JMT103 in patients with bone metastasis. Methods: This is a multi-center, open label, dose escalation, phase I clinical trial. The patients (ECOG score: 0-1) with bone metastasis from solid tumor who had not received bisphosphonates within 6 weeks before enrollment and were naïve to denosumab were enrolled. The initial dose was 0.5 mg/kg, sequentially escalated to 1.0, 2.0, and 3.0 mg/kg. JMT103 was injected subcutaneously by accelerated titration in 0.5 and 1.0 mg/kg dose groups, but via traditional "3+3" dose-escalation design in 2.0 and 3.0 mg/kg dose groups. Expansion study was conducted for subjects in 1.0, 2.0, and 3.0 mg/kg dose groups. Specifically, 3 additional doses (q4w) were injected after the end of 12-week single-dose study. The primary endpoints were maximum tolerated dose and safety. The secondary outcome measures included PK profile, preliminary efficacy biomarkers, immunogenicity, and bone mineral density (BMD). Results: From May 2018 to January 2020, 56 patients (13 males, 43 females, mean (SD) age: 55.57 (11.42) years) were enrolled, including bone metastasis from breast cancer (n = 36), gastric cancer (n = 5), lung cancer (n = 4), rectal cancer (n = 3), colorectal cancer (n = 2), or other solid tumors (n = 6). Nineteen patients participated in the dose-escalating study and 37 patients participated in the expansion study. JMT103 showed overall good safety. There were 74 drug-related AEs in all, including grade 3 (DLT hypocalcemia, n = 1; hypophosphatemia, n = 3), grade 2 (n = 15), and grade 1 (n = 55) AEs. The most common drug-related AEs were hypophosphatemia (n = 15), hypocalcemia (n = 12), and hypermagnesemia (n = 6). Median uNTx/Cr decrease from baseline was 76.6% (n = 20). Conclusions: JMT103 shows good safety and tolerability in patients with bone metastasis. Clinical trial information: NCT03550508 .
Focus on “COVID Toes”
Authors: Claudia Hernandez, Anna L. Bruckner
Journal: JAMA Dermatology (2020)

Juncal Roca-Ginés, MD; Ignacio Torres-Navarro, MD; Javier Sánchez-Arráez, MD; Carlos Abril-Pérez, MD; Oihana Sabalza-Baztán, BS-M; Sergio Pardo-Granell, PharmG; Vicent Martínez i Cózar, MD; Rafael Botella-Estrada, MD, PhD; Montserrat Évole-Buselli, MD, PhD
N-glycosylation of monoclonal light chains on routine MASS-FIX testing is a risk factor for MGUS progression
Authors: Angela Dispenzieri, D. R. Larson, S. V. Rajkumar, R. A. Kyle, S. K. Kumar, Taxiarchis Kourelis, Bonnie Arendt, Maria Willrcih, Surendra Dasari, David Murray
Journal: Leukemia (2020)
Integrating Immunotherapy and Targeted Therapy in Cancer Treatment: Mechanistic Insights and Clinical Implications
Authors: Johann S. Bergholz, Qiwei Wang, Sheheryar Kabraji, Jean J. Zhao
Journal: Clinical Cancer Research (2020)

Abstract Small-molecule targeted therapies have demonstrated outstanding potential in the clinic. These drugs are designed to minimize adverse effects by selectively attacking cancer cells while exerting minimal damage to normal cells. Although initial response to targeted therapies may be high, yielding positive response rates and often improving survival for an important percentage of patients, resistance often limits long-term effectiveness. On the other hand, immunotherapy has demonstrated durable results, yet for a limited number of patients. Growing evidence indicates that some targeted agents can modulate different components of the antitumor immune response. These include immune sensitization by inhibiting tumor cell–intrinsic immune evasion programs or enhancing antigenicity, as well as direct effects on immune effector and immunosuppressive cells. The combination of these two approaches, therefore, has the potential to result in synergistic and durable outcomes for patients. In this review, we focus on the latest advances on integrating immunotherapy with small-molecule targeted inhibitors. In particular, we discuss how specific oncogenic events differentially affect immune response, and the implications of these findings on the rational design of effective combinations of immunotherapy and targeted therapies.
JAM-A functions as a female microglial tumor suppressor in glioblastoma
Authors: Soumya M Turaga, Daniel J Silver, Defne Bayik, Evi Paouri, Sen Peng, Adam Lauko, Tyler J Alban, Nozha Borjini, Sarah Stanko, Ulhas P Naik, Ruth A Keri, James R Connor, Jill S Barnholtz-Sloan, Joshua B Rubin, Michael Berens, Dimitrios Davalos, Justin D Lathia
Journal: Neuro-Oncology (2020)

Glioblastoma (GBM) is the most aggressive primary brain tumor and has a dismal prognosis. Previously, we identified that junctional adhesion molecule A (JAM-A), a cell adhesion molecule, is highly elevated in human GBM cancer stem cells and predicts poor patient prognosis. While JAM-A is also highly expressed in other cells in the tumor microenvironment, specifically microglia and macrophages, how JAM-A expression in these cells affects tumor growth has yet to be determined. The goal of this study was to understand the role of microenvironmental JAM-A in mediating GBM growth.
Covid-19 and alcohol: parental drinking influences the next generation
Authors: Aric Sigman
Journal: BMJ (2020)

Finlay and Gilmore rightly draw attention to two vulnerable groups of drinkers in the covid-19 lockdown.1 In addition, and of central importance, is that regardless of whether parents drink more alcohol in covid-19 lockdown, their children are far more likely to see them drink simply because they are all at home. And this is happening at a time when substantial evidence indicates the intergenerational transmission of alcohol habits and alcohol misuse through parental role modelling.

Children’s beliefs regarding positive or negative effects of alcohol …
Use of Anakinra to Prevent Mechanical Ventilation in Severe COVID‐19: A Case Series
Authors: Iris Navarro‐Millán, Sebastian E. Sattui, Amit Lakhanpal, Diane Zisa, Caroline H. Siegel, Mary K. Crow
Journal: Arthritis & Rheumatology (2020)

To report the clinical experience with anakinra in preventing mechanical ventilation in patients with coronavirus disease 2019 (COVID-19), symptoms of cytokine storm syndrome, and acute hypoxemic respiratory failure.To be included in this retrospective case series, patients must have had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), fever, ferritin levels >1,000 ng/ml with 1 additional laboratory marker of hyperinflammation, and acute hypoxemic respiratory failure. Acute hypoxemic respiratory failure was defined as requiring 15 liters of supplemental oxygen via a nonrebreather mask combined with 6-liter nasal cannula or use of ≥95% oxygen by high-flow nasal cannula. We excluded patients in whom there was suspicion of bacterial infection or who were receiving immunosuppressants. Subcutaneous anakinra was initiated at 100 mg every 6 hours and gradually tapered off completely. The primary outcome was the prevention of mechanical ventilation.Of the 14 patients who met the criteria, 11 patients received anakinra for a maximum of 19 days. Seven of the patients who started anakinra treatment ≤36 hours after onset of acute hypoxemic respiratory failure did not require mechanical ventilation, and all were discharged home. Four patients who started anakinra ≥4 days after onset of acute hypoxemic respiratory failure required mechanical ventilation. Of those, 3 patients were extubated (2 discharged home and 1 remained hospitalized), and 1 died. All 3 patients who met the criteria but did not receive anakinra required mechanical ventilation. Two patients were extubated (1 discharged home and 1 remained hospitalized), and 1 remained on mechanical ventilation.Our data suggest that anakinra could be beneficial in treating COVID-19 patients with evidence of cytokine storm syndrome when initiated early after onset of acute hypoxemic respiratory failure. Our patient selection and treatment approach should be considered for investigation in a clinical trial to determine the safety and efficacy of anakinra in treating patients with COVID-19 and symptoms of cytokine storm syndrome.
Practice parameters for the use of actigraphy in the military operational context: the Walter Reed Army Institute of Research Operational Research Kit-Actigraphy (WORK-A)
Authors: Jaime K. Devine, Jake Choynowski, Tina Burke, Kajsa Carlsson, Vincent F. Capaldi, Ashlee B. McKeon, Walter J. Sowden
Journal: Military Medical Research (2020)

Abstract Background The Walter Reed Army Institute of Research (WRAIR) Operational Research Kit-Actigraphy (WORK-A) is a set of unique practice parameters and actigraphy-derived measures for the analysis of operational military sleep patterns. The WORK-A draws on best practices from the literature and comprises 15 additional descriptive variables. Here, we demonstrate the WORK-A with a sample of United States Army Reserve Officers’ Training Corps (ROTC) cadets ( n = 286) during a month-long capstone pre-commissioning training exercise. Methods The sleep of ROTC cadets ( n = 286) was measured by Philips Actiwatch devices during the 31-day training exercise. The preliminary effectiveness of the WORK-A was tested by comparing differences in sleep measures collected by Actiwatches as calculated by Philips Actiware software against WORK-A-determined sleep measures and self-report sleep collected from a subset of ROTC cadets ( n = 140). Results Actiware sleep summary statistics were significantly different from WORK-A measures and self-report sleep (all P ≤ 0.001). Bedtimes and waketimes as determined by WORK-A major sleep intervals showed the best agreement with self-report bedtime (22:21 ± 1:30 vs. 22:13 ± 0:40, P = 0.21) and waketime (04:30 ± 2:17 vs. 04:31 ± 0:47, P = 0.68). Though still significantly different, the discrepancy was smaller between the WORK-A measure of time in bed (TIB) for major sleep intervals (352 ± 29 min) and self-report nightly sleep duration (337 ± 57 min, P = 0.006) than that between the WORK-A major TIB and Actiware TIB (177 ± 42, P ≤ 0.001). Conclusions Default actigraphy methods are not the most accurate methods for characterizing soldier sleep, but reliable methods for characterizing operational sleep patterns is a necessary first step in developing strategies to improve soldier readiness. The WORK-A addresses this knowledge gap by providing practice parameters and a robust variety of measures with which to profile sleep behavior in service members.
Doping bioactive elements into a collagen scaffold based on synchronous self-assembly/mineralization for bone tissue engineering
Authors: Huanhuan Liu, Mingli Lin, Xue Liu, Ye Zhang, Yuyu Luo, Yanyun Pang, Haitao Chen, Dongwang Zhu, Xue Zhong, Shiqing Ma, Yanhong Zhao, Qiang Yang, Xu Zhang
Journal: Bioactive Materials (2020)

Pure collagen is biocompatible but lacks inherent osteoinductive, osteoimmunomodulatory and antibacterial activities. To obtain collagen with these characteristics, we developed a novel methodology of doping bioactive elements into collagen through the synchronous self-assembly/mineralization (SSM) of collagen. In the SSM model, amorphous mineral nanoparticles (AMN) (amorphous SrCO
Kv1.3 modulates neuroinflammation and neurodegeneration in Parkinson’s disease
Authors: Souvarish Sarkar, Hai M. Nguyen, Emir Malovic, Jie Luo, Monica Langley, Bharathi N. Palanisamy, Neeraj Singh, Sireesha Manne, Matthew Neal, Michelle Gabrielle, Ahmed Abdalla, Poojya Anantharam, Dharmin Rokad, Nikhil Panicker, Vikrant Singh, Muhammet Ay, Adhithiya Charli, Dilshan Harischandra, Lee-Way Jin, Huajun Jin, Srikant Rangaraju, Vellareddy Anantharam, Heike Wulff, Anumantha G. Kanthasamy
Journal: Journal of Clinical Investigation (2020)

Characterization of the key cellular targets contributing to sustained microglial activation in neurodegenerative diseases, including Parkinson's disease (PD), and optimal modulation of these targets can provide potential treatments to halt disease progression. Here, we demonstrated that microglial Kv1.3, a voltage-gated potassium channel, was transcriptionally upregulated in response to aggregated α-synuclein (αSynAgg) stimulation in primary microglial cultures and animal models of PD, as well as in postmortem human PD brains. Patch-clamp electrophysiological studies confirmed that the observed Kv1.3 upregulation translated to increased Kv1.3 channel activity. The kinase Fyn, a risk factor for PD, modulated transcriptional upregulation and posttranslational modification of microglial Kv1.3. Multiple state-of-the-art analyses, including Duolink proximity ligation assay imaging, revealed that Fyn directly bound to Kv1.3 and posttranslationally modified its channel activity. Furthermore, we demonstrated the functional relevance of Kv1.3 in augmenting the neuroinflammatory response by using Kv1.3-KO primary microglia and the Kv1.3-specific small-molecule inhibitor PAP-1, thus highlighting the importance of Kv1.3 in neuroinflammation. Administration of PAP-1 significantly inhibited neurodegeneration and neuroinflammation in multiple animal models of PD. Collectively, our results imply that Fyn-dependent regulation of Kv1.3 channels plays an obligatory role in accentuating the neuroinflammatory response in PD and identify Kv1.3 as a potential therapeutic target for PD.
iRECIST:試験試験免疫療法における使用のための応答基準のためのガイドライン【Powered by NICT】
Authors: Seymour Lesley, Bogaerts Jan, Perrone Andrea, Ford Robert, Schwartz Lawrence H, Mandrekar Sumithra, Lin Nancy U, Litiere Saskia, Dancey Janet, Chen Alice, Hodi F Stephen, Therasse Patrick, Hoekstra Otto S, Shankar Lalitha K, Wolchok Jedd D, Ballinger Marcus, Caramella Caroline, de Vries Elisabeth G E
Journal: The Lancet Oncology (2017)
Sequential ctDNA whole-exome sequencing in advanced lung adenocarcinoma with initial durable tumor response on immune checkpoint inhibitor and late progression
Authors: Etienne Giroux Leprieur, Zofia Hélias-Rodzewicz, Paul Takam Kamga, Adrien Costantini, Catherine Julie, Alexandre Corjon, Coraline Dumenil, Jennifer Dumoulin, Violaine Giraud, Sylvie Labrune, Simon Garinet, Thierry Chinet, Jean-François Emile
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Despite prolonged tumor response to immune checkpoint inhibitors (ICIs) for a subset of patients with advanced non-small cell lung cancer (NSCLC), a secondary resistance will occur for a majority of these patients. The understanding of late progression mechanisms with ICIs is important to improve future treatment strategies. Methods We performed whole-exome sequencing (WES) on circulating tumor DNA and compared molecular profiles between the beginning of ICI treatment and tumor progression in patients with advanced NSCLC treated with ICIs and who had initial and prolonged tumor response with secondary progression, after at least 6 months of treatment. Results We identified eight patients who experienced initial and durable tumor response, and secondary tumor progression after 6 months of treatment, with available paired blood samples (diagnosis and progression). All had lung adenocarcinoma, three had programmed-death ligand-1 expression ≥50% in immunohistochemistry and all presented low blood tumor mutational burden (bTMB). Seven patients received nivolumab in second-line or more, and one received pembrolizumab as first-line treatment. WES at progression showed clonal selection with molecular alterations of Wnt pathway-related genes, increase of copy number aberrations in cancer-related genes and loss of tumor-suppressor genes (such as PTEN ) or of genes associated with immune response (such as B2M ). No difference in term of bTMB was observed at progression. Conclusions This is the first study describing putative molecular mechanisms associated with late progression under ICI in lung cancer. Studies on treatment strategies adapted to these mechanisms are needed.
Recurrence of primary spontaneous pneumothorax: Associated factors
Authors: V. Riveiro-Blanco, C. Pou-Álvarez, L. Ferreiro, M.E. Toubes, J. Quiroga-Martínez, J. Suárez-Antelo, J.M. García-Prim, J.E. Rivo-Vázquez, R. Castro-Calvo, F.J. González-Barcala, F. Gude, L. Valdés
Journal: Pulmonology (2020)

Determining the risk of recurrence of primary spontaneous pneumothorax is challenging. The objective of this study was to develop a risk assessment model to predict the probability of recurrence in patients with spontaneous pneumothorax.A retrospective study was performed of all episodes of pneumothorax diagnosed in the last 12 years in a hospital, in patients not initially submitted to surgery. Logistic regression was used to estimate the probability of recurrence. Based on a set of variables, a predictive model was built with its corresponding ROC curve to determine its discrimination power and diagnostic precision.Of the 253 patients included, 128 (50.6%) experienced recurrence (37% within the first year). Recurrence was detected within 110 days in 25% of patients. The median of time to recurrence for the whole population was 1120 days. The presence of blebs/bullae was found to be a risk factor of recurrence (OR: 5.34; 95% CI: 2.81-10.23; p=0.000), whereas chest drainage exerted protective effect (OR: 0.19; 95% CI: 0.08-0.40; p=0.000). The variables included in the regression model constructed were hemoglobin and leukocyte count in blood, treatment received, and presence of blebs/bullae, with a fair discriminative power to predict recurrence [AUC=0.778 (95% CI: 0.721-0.835)].The overall recurrence rate was high and was associated with the presence of blebs/bullae, failure to perform an active intervention (chest drainage) and low levels of hemoglobin and leukocytes in blood. Recurrence rarely occurs later than three years after the first episode. Once validated, this precision model could be useful to guide therapeutic decisions.
Digestive endoscopy during Covid-19 outbreak in Italy: a tertiary referral center experience
Authors: Lorenzo Dioscoridi, Aldo Cristalli, Edoardo Forti, Francesco Pugliese, Marcello Cintolo, Angelo Italia, Giulia Bonato, Giulio Petrocelli, Massimiliano Mutignani
Journal: Endoscopy (2020)

Letter to: Suggestions for infection prevention and control in digestive endoscopy during current 2019-nCoV pneumonia outbreak in Wuhan, Hubei province, ChinaEndoscopy 2020; 52(04): 312-314DOI: 10.1055/a-1128-4313