tbuckley/cabot-search huggingface dataset:
Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor
Authors: Lisa M. Godsel, Quinn R. Roth-Carter, Jennifer L. Koetsier, Lam C. Tsoi, Amber L. Huffine, Joshua A. Broussard, Gillian N. Fitz, Sarah M. Lloyd, Junghun Kweon, Hope E. Burks, Marihan Hegazy, Saki Amagai, Paul W. Harms, Xianying Xing, Joseph Kirma, Jodi L. Johnson, Gloria Urciuoli, Lynn T. Doglio, William R. Swindell, Rajeshwar Awatramani, Eli Sprecher, Xiaomin Bao, Eran Cohen-Barak, Caterina Missero, Johann E. Gudjonsson, Kathleen J. Green
Journal: Journal of Clinical Investigation (2021)

Desmoglein 1 (Dsg1) is a cadherin restricted to stratified tissues of terrestrial vertebrates, which serve as essential physical and immune barriers. Dsg1 loss-of-function mutations in humans result in skin lesions and multiple allergies, and isolated patient keratinocytes exhibit increased proallergic cytokine expression. However, the mechanism by which genetic deficiency of Dsg1 causes chronic inflammation is unknown. To determine the systemic response to Dsg1 loss, we deleted the 3 tandem Dsg1 genes in mice. Whole transcriptome analysis of embryonic Dsg1–/– skin showed a delay in expression of adhesion/differentiation/keratinization genes at E17.5, a subset of which recovered or increased by E18.5. Comparing epidermal transcriptomes from Dsg1-deficient mice and humans revealed a shared IL-17–skewed inflammatory signature. Although the impaired intercellular adhesion observed in Dsg1–/– mice resembles that resulting from anti-Dsg1 pemphigus foliaceus antibodies, pemphigus skin lesions exhibit a weaker IL-17 signature. Consistent with the clinical importance of these findings, treatment of 2 Dsg1-deficient patients with an IL-12/IL-23 antagonist originally developed for psoriasis resulted in improvement of skin lesions. Thus, beyond impairing the physical barrier, loss of Dsg1 function through gene mutation results in a psoriatic-like inflammatory signature before birth, and treatment with a targeted therapy significantly improved skin lesions in patients.
A Phase 1b/2 Study of the CD123-Targeting Antibody-Drug Conjugate IMGN632 As Monotherapy or in Combination with Venetoclax and Azacitidine for Patients with CD123-Positive Acute Myeloid Leukemia
Authors: Naval Daver, Ahmed Aribi, Pau Montesinos, Gail J. Roboz, Eunice S. Wang, Roland B. Walter, Deepa Jeyakumar, Daniel J. DeAngelo, Harry P. Erba, Anjali Advani, Patrick W. Burke, Giovanni Martinelli, Lauris Gastaud, Xavier Thomas, Jessica K. Altman, Lourdes M. Mendez, Adolfo de la Fuente, Elisabetta Todisco, Gianluca Gaidano, Antonio Curti, Nicolas Boissel, Christian Recher, Christoph Schliemann, Callum M Sloss, Jiuzhou Wang, Kara E Malcolm, Patrick A Zweidler-McKay, Kendra Sweet
Journal: Blood (2021)
The environmental impact of inhaled therapy: making informed treatment choices
Authors: Ashley Woodcock, Kai M. Beeh, Hironori Sagara, Simon Aumônier, Emmanuel Addo-Yobo, Javaid Khan, Jørgen Vestbo, Helen Tope
Journal: European Respiratory Journal (2021)

When selecting the best inhaler and drug combination for a patient with respiratory disease, a number of factors should be considered. While efficacy and safety of medical treatments are always a priority, in recent years the environmental impacts of all aspects of life have become an increasingly necessary consideration and inhaled therapies are no exception. The carbon footprint of an item, individual or organisation is one of the most important and quantifiable environmental impacts, assessed by the amount of greenhouse gases (often expressed in terms of carbon dioxide equivalents) generated throughout the life cycle. The two most commonly prescribed and manufactured inhaler types worldwide are pressurised metered-dose inhalers (pMDIs) containing hydrofluorocarbon (HFC) propellants and dry powder inhalers (DPIs). Most of the carbon footprint of current pMDIs is a result of the propellants that they contain (HFC-134a and HFC-227ea, which are potent greenhouse gases). In comparison, the powder in DPIs is dispersed by the patient's own inhalation, meaning DPIs do not contain a propellant and have a lower carbon footprint than most pMDIs currently available. Soft mist inhalers are another propellant-free option: the device contains a spring, which provides the energy to disperse the aqueous medication. In this review, we examine the published data on carbon footprint data for inhalers, providing an analysis of potential implications for treatment decision making and industry initiatives.
Mcm2 Deficiency Leads to Bone Marrow Failure and Lymphoid Malignancies Dependent on Age and Genetic Background
Authors: Toshihiro Matsukawa, Yin Mianmian, Timour Baslan, Yang Jo Chung, Dengchao Cao, Ryan Bertoli, Jack Zhu, Robert L. Walker, Amy Freeland, Erik Knudsen, Paul S. Meltzer, Peter D. Aplan
Journal: Blood (2021)
Low Percentage of Microenvironment Immune Cells in Bone Marrow and Lymph Node Measured By Flow Cytometry Is Associated with Inferior Overall Survival in Diffuse Large B Cell Lymphoma
Authors: Laura Korin, Maria Lucia Fuente, Santiago Cranco, Paola Ochoa, Adriana Vitriu, Evelina Babuin, Anahí Vijnovich Baron, Maria Belen Venegas, Paula Tempra, Andrea Novoa, Norma Elisabeth Tartas, Maria Del Rosario Custidiano, Maria Cecilia Foncuberta, Julio Cesar Sanchez Avalos
Journal: Blood (2021)
Outcomes Based on Plasma Biomarkers for the Phase 3 CELESTIAL Trial of Cabozantinib versus Placebo in Advanced Hepatocellular Carcinoma
Authors: Lorenza Rimassa, Robin Kate Kelley, Tim Meyer, Baek-Yeol Ryoo, Philippe Merle, Joong-Won Park, Jean-Frederic Blanc, Ho Yeong Lim, Albert Tran, Yi-Wah Chan, Paul McAdam, Evelyn Wang, Ann-Lii Cheng, Anthony B. El-Khoueiry, Ghassan K. Abou-Alfa
Journal: Liver Cancer (2021)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Cabozantinib, an inhibitor of MET, AXL, and VEGF receptors, significantly improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). In this exploratory analysis, outcomes were evaluated according to plasma biomarker levels. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Baseline plasma levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, EPO, ANG2, IGF-1, VEGF-C, and c-KIT for 674/707 randomized patients; and Week 4 levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, and EPO for 614 patients. OS and PFS were analyzed by baseline levels as dichotomized or continuous variables and by on-treatment changes at Week 4 as continuous variables; biomarkers were considered potentially prognostic if &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.05 and predictive if &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.05 for the interaction between treatment and the biomarker. Multivariable analyses adjusting for clinical covariates were also performed. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; In the placebo group, high levels of MET, HGF, GAS6, IL-8, and ANG2 and low levels of IGF-1 were associated with shorter OS in univariate and multivariable analyses; these associations were also observed for MET, IL-8, and ANG2 in the cabozantinib group. Hazard ratios for OS and PFS favored cabozantinib over the placebo at low and high baseline levels for all biomarkers. No baseline biomarkers were predictive of a treatment benefit. Cabozantinib promoted pharmacodynamic changes in several biomarkers, including increases in VEGF-A, PlGF, AXL, and GAS6 levels and decreases in VEGFR2 and HGF levels; these changes were not associated with OS or PFS. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Cabozantinib improved OS and PFS versus placebo at high and low baseline concentrations for all biomarkers analyzed. Low baseline levels of MET, HGF, GAS6, IL-8, and ANG2 and high levels of IGF-1 were identified as potential favorable prognostic biomarkers for survival in previously treated advanced HCC. Although cabozantinib promoted pharmacodynamic changes in several biomarkers, these changes were not associated with survival.
Using Policy Tools to Improve Population Health — Combating the U.S. Opioid Crisis
Authors: Colleen L. Barry, Brendan Saloner
Journal: New England Journal of Medicine (2021)

Interview with Dr. Colleen Barry on using public policy to improve population health. (11:41)Download Policy has been critical to achieving major public health advances, including in tobacco control, maternal and child health, and injury prevention. The opioid crisis illustrates five steps essential for using policy to produce substantial gains in population health.
Thank You, Santa!
Authors: Margaret Tempero
Journal: Journal of the National Comprehensive Cancer Network (2021)

It's Margaret here.Gosh, a lot has happened since I wrote you last year.I do hope that you, Mrs. Claus, and the elves have been safe this year, as I imagine COVID-19 found its way even to the North Pole.But I know you!I believe you would follow every CDC recommendation, even if it is tough to stuff that beard into a face mask.I have to say that you really delivered on my list from 2020! Usually I feel kind of neglected, as if you aren't getting my letters.And I admit I had a very aggressive list-ten wishes!(Although I was just joking about the diamond necklace!)First, thank you SO much for delivering the effective vaccines that I requested against COVID-19.These may be the most effective vaccines ever manufactured, and trust me, we are all relieved and grateful!But I wish I had also asked for your help in minimizing vaccine hesitancy.Many people have died because low vaccination rates allowed more aggressive variants to emerge.But I believe things are improving now.You also brought new jobs, encouraged discussions about drug prices, kept the Affordable Care Act from being struck down, and gave us each a mirror to help us see our own biases.That makes 5 of my requests that you delivered on.Unbelievable!Now, I admit that I didn't wake up to all these things on Christmas morning.But I got my first vaccine on Christmas Eve, and I appreciated the promissory notes left in my stocking.I don't want to seem greedy, but since I scored so well last year, I am going to ask for the other things again.Maybe you are feeling generous?
Effects of delayed versus immediate umbilical cord clamping in reducing death or major disability at 2 years corrected age among very preterm infants (APTS): a multicentre, randomised clinical trial
Authors: Kristy P Robledo, William O Tarnow-Mordi, Ingrid Rieger, Preeti Suresh, Andrew Martin, Carbo Yeung, Alpana Ghadge, Helen G Liley, David Osborn, Jonathan Morris, Wendy Hague, Martin Kluckow, Kei Lui, Roger Soll, Melinda Cruz, Anthony Keech, Adrienne Kirby, John Simes, Himanshu Popat, Shelley Reid, Adrienne Gordon, Koert De Waal, Ian M Wright, Anne Wright, Jane Buchan, Michelle Stubbs, John Newnham, Karen Simmer, Cherry Young, Diane Loh, Yen Kok, Andy Gill, Tobias Strunk, Michele Jeffery, Yan Chen, Scott Morris, Sanjay Sinhal, Kathryn Cornthwaite, Sue P Walker, Andrew M Watkins, Clare L Collins, James R Holberton, Elizabeth J Noble, Arvind Sehgal, Emma Yeomans, Kristy Elsayed, Abdel-Latif Mohamed, Margaret Broom, Guan Koh, Annemarie Lawrence, Glen Gardener, Jane Fox, David W Cartwright, Pieter Koorts, Margo A Pritchard, Lisa McKeown, Anne Lainchbury, Antonia W Shand, Joanna Michalowski, John P Smyth, Srinivas Bolisetty, Alan Adno, Gaksoo Lee, Anna L Seidler, Lisa M Askie, Katie M Groom, Deborah A Eaglen, Ella C Baker, Harshad Patel, Natalie Wilkes, Joanna E Gullam, Nicola Austin, Dianne E Leishman, Phil Weston, Nicola White, Nadia A Cooper, Roland Broadbent, Michael Stitely, Pauline Dawson, Walid El-Naggar, Marlene Furlong, Tara Hatfield, Daniele de Luca, Alexandra Benachi, Emmanuelle Letamendia-Richard, Guillaume Escourrou, Valentina Dell'Orto, David Sweet, Muriel Millar, Shilpa Shah, Lumaan Sheikh, Shabina Ariff, Erin A Morris, Leslie Young, Shannon K Evans, Michael Belfort, Kjersti Aagaard, Mohan Pammi, George Mandy, Manisha Gandhi, Jane Davey, Emma Shenton, Jennifer Middleton, Roslyn Black, Annie Cheng, Jamie Murdoch, Claire Jacobs, Lizzie Meyer, Kathryn Medlin, Heather Woods, Kerry-Ann O'Connor, Caitlin Bice, Katherine Scott, Marie Hayes, Debbie Cruickshank, Mekha Sam, Susan Ireland, Corrine Dickinson, Leith Poulsen, Andreja Fucek, Jo Hegarty, Jenny Rogers, Dorothy Sanchez, Veronique Zupan Simunek, Bakhtawar Hanif, Adrienne Pahl, Jerilyn Metayer, Lelia Duley, Neil Marlow, Deborah Schofield, Jennifer Bowen
Journal: The Lancet Child & Adolescent Health (2021)
Radiologic Diagnostics of Lung Lesions by Granulomatosis with Polyangiitis in the Context of the COVID-19 Pandemic
Authors: T. D. Safonova, Zh. V. Sheikh
Journal: Radiology - Practice (2021)

Granulomatosis with polyangiitis (GPA), formerly known as Wegener’s granulomatosis, and lung damage in coronavirus infection have many common clinical and radiological symptoms. In the context of the COVID-19 pandemic the ability of a radiologist to differentiate a viral lung lesion from a granulomatous one is relevant due to the difficulty of recognizing them. In order to develop differential radiation diagnostics, a comparative analysis of the computer tomographic picture of lung lesions in each disease was carried out and the leading X-ray patterns were determined. 61 patients with lung damage were examined, including 30 with HPA, 30 with COVID-19 and 1 patient with a combination of these diseases. A total of 74 native computer tomography examinations of the chest organs were accomplished using a Toshiba Aquilion 64 multi-slice CT scanner. It was found that the most informative radiological sign of HPA are nodes, nodules and masses in the lungs, which were detected in 22 (73.3 %) patients, including 11 (36.7 %) with a necrotic cavitation. Ground-glass opacity is often found in both diseases, but COVID-19 is more characterized by a rounded (56.7 %) or polygonal shape (20.0 %) of pathological areas and their peripheral location (70.0 %) mainly in the posterior parts of the lungs, and triangular areas (42.1 %) with a central location (42.1 %) are more often found in HPA. The rapid dynamics of changes in the lungs on control CT scans is of great diagnostic value, which indicates the viral nature of the disease.
Reply to P. Kaul et al
Authors: Yasuhisa Hasegawa, Kiyoaki Tsukahara, Seiichi Yoshimoto, Kouki Miura, Junkichi Yokoyama, Shigeru Hirano, Hirokazu Uemura, Masashi Sugasawa, Tomokazu Yoshizaki, Akihiro Homma, Kazuaki Chikamatsu, Mikio Suzuki, Akihiro Shiotani, Takashi Matsuzuka, Naoyuki Kohno, Masakazu Miyazaki, Isao Oze, Keitaro Matsuo, Shigeru Kosuda, Yasushi Yatabe
Journal: Journal of Clinical Oncology (2021)
Emerging microfluidics-enabled platforms for osteoarthritis management: from benchtop to bedside
Authors: Zhou Zou, Xiaohe Luo, Zhengkun Chen, Yu Shrike Zhang, Chunyi Wen
Journal: Theranostics (2021)

Osteoarthritis (OA) is a prevalent debilitating age-related joint degenerative disease. It is a leading cause of pain and functional disability in older adults. Unfortunately, there is no cure for OA once the damage is established. Therefore, it promotes an urgent need for early detection and intervention of OA. Theranostics, combining therapy and diagnosis, emerges as a promising approach for OA management. However, OA theranostics is still in its infancy. Three fundamental needs have to be firstly fulfilled:
Management of Stage III Non–Small-Cell Lung Cancer: ASCO Guideline
Authors: Megan E. Daly, Navneet Singh, Nofisat Ismaila, Mara B. Antonoff, Douglas A. Arenberg, Jeffrey Bradley, Elizabeth David, Frank Detterbeck, Martin Früh, Matthew A. Gubens, Amy C. Moore, Sukhmani K. Padda, Jyoti D. Patel, Tanyanika Phillips, Angel Qin, Clifford Robinson, Charles B. Simone
Journal: Journal of Clinical Oncology (2021)

To provide evidence-based recommendations to practicing clinicians on management of patients with stage III non-small-cell lung cancer (NSCLC).An Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary oncology, community oncology, research methodology, and advocacy experts was convened to conduct a literature search, which included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2021. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations.The literature search identified 127 relevant studies to inform the evidence base for this guideline.Evidence-based recommendations were developed to address evaluation and staging workup of patients with suspected stage III NSCLC, surgical management, neoadjuvant and adjuvant approaches, and management of patients with unresectable stage III NSCLC.Additional information is available at www.asco.org/thoracic-cancer-guidelines.
FTO promotes multiple myeloma progression by posttranscriptional activation of HSF1 in an m6A-YTHDF2-dependent manner
Authors: Aoshuang Xu, Jiasi Zhang, Liping Zuo, Han Yan, Lei Chen, Fei Zhao, Fengjuan Fan, Jian Xu, Bo Zhang, Yuyang Zhang, Xuejiao Yin, Qianwen Cheng, Su Gao, Jun Deng, Heng Mei, Zhiping Huang, Chunyan Sun, Yu Hu
Journal: Molecular Therapy (2021)

N6-methyladenosine (m6A), as the most pervasive internal modification of eukaryotic mRNA, plays a crucial role in various cancers, but its role in multiple myeloma (MM) pathogenesis has not yet been investigated. In this study, we revealed significantly decreased m6A methylation in plasma cells (PCs) from MM patients and showed that the abnormal m6A level resulted mainly from upregulation of the demethylase fat mass and obesity-associated protein (FTO). Gain- and loss-of-function studies demonstrated that FTO plays a tumor-promoting and pro-metastatic role in MM. Combined m6A and RNA sequencing (RNA-seq) and subsequent validation and functional studies identified heat shock factor 1 (HSF1) as a functional target of FTO-mediated m6A modification. FTO significantly promotes MM cell proliferation, migration, and invasion by targeting HSF1/HSPs in a YTHDF2-dependent manner. FTO inhibition, especially when combined with bortezomib (BTZ) treatment, synergistically inhibited myeloma bone tumor formation and extramedullary spread in NOD-Prkdcem26Cd52il2rgem26Cd22/Nju (NCG) mice. We demonstrated the functional importance of m6A demethylase FTO in MM progression, especially in promoting extramedullary myeloma (EMM) formation, and proposed the FTO-HSF1/HSP axis as a potential novel therapeutic target in MM. N6-methyladenosine (m6A), as the most pervasive internal modification of eukaryotic mRNA, plays a crucial role in various cancers, but its role in multiple myeloma (MM) pathogenesis has not yet been investigated. In this study, we revealed significantly decreased m6A methylation in plasma cells (PCs) from MM patients and showed that the abnormal m6A level resulted mainly from upregulation of the demethylase fat mass and obesity-associated protein (FTO). Gain- and loss-of-function studies demonstrated that FTO plays a tumor-promoting and pro-metastatic role in MM. Combined m6A and RNA sequencing (RNA-seq) and subsequent validation and functional studies identified heat shock factor 1 (HSF1) as a functional target of FTO-mediated m6A modification. FTO significantly promotes MM cell proliferation, migration, and invasion by targeting HSF1/HSPs in a YTHDF2-dependent manner. FTO inhibition, especially when combined with bortezomib (BTZ) treatment, synergistically inhibited myeloma bone tumor formation and extramedullary spread in NOD-Prkdcem26Cd52il2rgem26Cd22/Nju (NCG) mice. We demonstrated the functional importance of m6A demethylase FTO in MM progression, especially in promoting extramedullary myeloma (EMM) formation, and proposed the FTO-HSF1/HSP axis as a potential novel therapeutic target in MM.
Clinical Outcomes With Metformin and Sulfonylurea Therapies Among Patients With Heart Failure and Diabetes
Authors: Muhammad Shahzeb Khan, Nicole Solomon, Adam D. DeVore, Abhinav Sharma, G. Michael Felker, Adrian F. Hernandez, Paul A. Heidenreich, Roland A. Matsouaka, Jennifer B. Green, Javed Butler, Clyde W. Yancy, Pamela N. Peterson, Gregg C. Fonarow, Stephen J. Greene
Journal: JACC Heart Failure (2021)
A Randomized Phase II Study Comparing Nivolumab with Carboplatin–Pemetrexed for <i>EGFR</i>-Mutated NSCLC with Resistance to EGFR Tyrosine Kinase Inhibitors (WJOG8515L)
Authors: Hidetoshi Hayashi, Shunichi Sugawara, Yasushi Fukuda, Daichi Fujimoto, Satoru Miura, Keiichi Ota, Yuichi Ozawa, Satoshi Hara, Junko Tanizaki, Koichi Azuma, Shota Omori, Motoko Tachihara, Kazumi Nishino, Akihiro Bessho, Yasutaka Chiba, Koji Haratani, Kazuko Sakai, Kazuto Nishio, Nobuyuki Yamamoto, Kazuhiko Nakagawa
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Although the efficacy of programmed cell death–1 (PD-1) blockade is generally poor for non–small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR) gene, EGFR tyrosine kinase inhibitors (TKIs) may improve the tumor immune microenvironment. We performed a randomized study to assess whether nivolumab improves outcome compared with chemotherapy in such patients previously treated with EGFR-TKIs. Patients and Methods: Patients with EGFR-mutated NSCLC who acquired EGFR-TKI resistance not due to a secondary T790M mutation of EGFR were randomized 1:1 to nivolumab (n = 52) or carboplatin–pemetrexed (n = 50). The primary endpoint was progression-free survival (PFS). Results: Median PFS and 1-year PFS probability were 1.7 months and 9.6% for nivolumab versus 5.6 months and 14.0% for carboplatin–pemetrexed [log-rank P &amp;lt; 001; hazard ratio (HR) of 1.92, with a 60% confidence interval (CI) of 1.61–2.29]. Overall survival was 20.7 and 19.9 months [HR, 0.88 (95% CI, 0.53–1.47)], and response rate was 9.6% and 36.0% for nivolumab and carboplatin–pemetrexed, respectively. No subgroup including patients with a high tumor mutation burden showed a substantially longer PFS with nivolumab than with carboplatin-pemetrexed. The T-cell–inflamed gene expression profile score (0.11 vs. −0.17, P = 0.036) and expression of genes related to cytotoxic T lymphocytes or their recruitment were higher in tumors that showed a benefit from nivolumab. Conclusions: Nivolumab did not confer a longer PFS compared with carboplatin-pemetrexed in the study patients. Gene expression profiling identified some cases with a favorable tumor immune microenvironment that was associated with nivolumab efficacy.
To Restrain or Not to Restrain
Authors: Mary K. Finta, Raymond Y. Yeow
Journal: JAMA Internal Medicine (2021)

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Challenges and health-care priorities for reducing the burden of paediatric sepsis in Latin America: a call to action
Authors: Daniela C Souza, Juan Camilo Jaramillo-Bustamante, Miguel Céspedes-Lesczinsky, Edwin Mauricio Cantillano Quintero, Hassel Jimmy Jimenez, Roberto Jabornisky, Jefferson Piva, Niranjan Kissoon
Journal: The Lancet Child & Adolescent Health (2021)