tbuckley/cabot-search huggingface dataset:
Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma
Authors: Jason K. Sa, Nakho Chang, Hye Won Lee, Hee Jin Cho, Michele Ceccarelli, Luigi Cerulo, Jinlong Yin, Sung Soo Kim, Francesca P. Caruso, Mijeong Lee, Donggeon Kim, Young Taek Oh, Yeri Lee, Nam-Gu Her, Byeongkwi Min, Hye-Jin Kim, Da Eun Jeong, Hye-Mi Kim, Hyunho Kim, Seok Chung, Hyun Goo Woo, Jeongwu Lee, Doo-Sik Kong, Ho Jun Seol, Jung-Il Lee, Jinho Kim, Woong-Yang Park, Qianghu Wang, Erik P. Sulman, Amy B. Heimberger, Michael Lim, Jong Bae Park, Antonio Iavarone, Roel G. W. Verhaak, Do-Hyun Nam
Journal: Genome biology (2020)

Abstract Background Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages. Results We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCO high TAMs induce a phenotypic shift towards mesenchymal cellular state of glioma stem cells, promoting both invasive and proliferative activities, as well as therapeutic resistance to irradiation. MARCO high TAMs also significantly accelerate tumor engraftment and growth in vivo. Moreover, both MA-TAM master regulators and their target genes are significantly correlated with poor clinical outcomes and are often associated with genomic aberrations in neurofibromin 1 (NF1) and phosphoinositide 3-kinases/mammalian target of rapamycin/Akt pathway (PI3K-mTOR-AKT)-related genes. We further demonstrate the origination of MA-TAMs from peripheral blood, as well as their potential association with tumor-induced polarization states and immunosuppressive environments. Conclusions Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.
Night shift work is associated with an increased risk of asthma
Authors: Robert J Maidstone, James Turner, Celine Vetter, Hassan S Dashti, Richa Saxena, Frank A J L Scheer, Steven A Shea, Simon D Kyle, Deborah A Lawlor, Andrew S I Loudon, John F Blaikley, Martin K Rutter, David W Ray, Hannah Jane Durrington
Journal: Thorax (2020)

Introduction Shift work causes misalignment between internal circadian time and the external light/dark cycle and is associated with metabolic disorders and cancer. Approximately 20% of the working population in industrialised countries work permanent or rotating night shifts, exposing this large population to the risk of circadian misalignment-driven disease. Analysis of the impact of shift work on chronic inflammatory diseases is lacking. We investigated the association between shift work and asthma. Methods We describe the cross-sectional relationship between shift work and prevalent asthma in &gt;280000 UK Biobank participants, making adjustments for major confounding factors (smoking history, ethnicity, socioeconomic status, physical activity, body mass index). We also investigated chronotype. Results Compared with day workers, ‘permanent’ night shift workers had a higher likelihood of moderate-severe asthma (OR 1.23 (95% CI 1.03 to 1.46)). Individuals doing any type of shift work had higher adjusted odds of wheeze/whistling in the chest. Shift workers who never or rarely worked on nights and people working permanent nights had a higher adjusted likelihood of having reduced lung function (FEV 1 &lt;80% predicted). We found an increase in the risk of moderate-severe asthma in individuals with extreme chronotypes (morning, OR 1.55 (95% CI 1.06 to 2.27) or evening, OR 1.31 (95%CI 1.22 to 1.40)). Conclusions The public health implications of these findings are far-reaching due to the high prevalence and co-occurrence of both asthma and shift work. Future longitudinal follow-up studies are needed to determine if modifying shift work schedules to take into account chronotype might present a public health measure to reduce the risk of developing inflammatory diseases such as asthma.
Limited Secondary Transmission of SARS-CoV-2 in Child Care Programs — Rhode Island, June 1–July 31, 2020
Authors: Ruth Link-Gelles, Amanda L. DellaGrotta, Caitlin Molina, Ailis Clyne, Kristine Campagna, Tatiana M. Lanzieri, Marisa A. Hast, Krishna Palipudi, Emilio Dirlikov, Utpala Bandy
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

0 (0) Age, yrs, median (range) †, §, ¶ 5 (0.5-12) 5 (0.5-12) 4 (1-5) 30 (20-63) 32 (20-60) 30 (20-63) Days from specimen collection to report to RIDOH, median (range) 2 (0-8) 2 (0-8) N/A 3 (0-11) 3 (0-11) N/A Abbreviations: COVID-19 = coronavirus disease 2019; N/A = not applicable; RIDOH = Rhode Island Department of Health.* Includes all cases considered index and secondary transmission.Reported cases were classified as confirmed if a person received a positive reverse transcriptionpolymerase chain reaction SARS-CoV-2 test result or probable if a person met clinical and epidemiologic criteria, with no laboratory testing.† Age was missing for three children with probable COVID-19.§ Age was missing for two adults with probable COVID-19.¶ In Rhode Island, children up to age 12 years are permitted to attend child care programs during the summer; use of a mask is not currently required for any child in child care.
Final results of a phase I study of TH-302, a hypoxia-activated cytotoxic prodrug (HAP)
Authors: J. C. Bendell, G. J. Weiss, J. R. Infante, E. G. Chiorean, M. Borad, R. Tibes, S. F. Jones, V. K. Langmuir, S. Kroll, H. A. Burris
Journal: Journal of Clinical Oncology (2009)

2573 Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM). TH-302 is essentially inactive under normoxia but in severe hypoxia and in the presence of certain reductases, it is reduced and Br-IPM is released. Methods: Eligible patients (pts) had ECOG ≤1, advanced or metastatic solid tumors, evaluable by RECIST, and acceptable hematologic, liver and renal function. A modified accelerated titration design was used. TH-302 was administered intravenously over 30–60 minutes on Day 1, 8 and 15 of a 28-day cycle. CT scans were obtained after every 2 cycles. Detailed pharmacokinetic sampling was performed on Days 1 and 15. The primary objectives of this study were to determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD). Results: Twenty-nine pts enrolled at 3 sites at 9 dose levels from 7.5–670 mg/m 2 . Median age: 64y. 20 male/9 female. ECOG 0/1: 16/13. Primary tumor: prostate (8), colorectal (8), lung (5) other (8). Two of 5 pts at 670 mg/m 2 had DLT: Herpes simplex perianal/rectal ulcers and dehydration due to mucositis. Reversible skin and mucosal adverse events (AE) occurred in 12 of 15 (80%) pts at ≥480 mg/m 2 including grade 3 events in 3 pts. The most common TH-302-related AEs were nausea, skin lesions, vomiting and fatigue. Hematologic toxicity was mild and limited: two pts with grade 1 and one pt with grade 2 neutropenia and five pts with grade 1 thrombocytopenia. Five pts had grade 3 and one grade 4 lymphopenia. Four pts have enrolled at an intermediate dose of 575 mg/m 2 with no DLT so this is likely the MTD and is well above the predicted biologic effective dose of 100 mg/m 2 . One pt with SCLC treated at 480 mg/m 2 and one with melanoma treated at 670 mg/m 2 had unconfirmed partial responses; 12 pts had stable disease (6 continuing after 4 or more cycles), 7 had PD, 4 were unevaluable and 4 are too early to assess. Cmax and AUC for TH-302 and Br-IPM increased linearly with no accumulation at Day 15. Conclusions: Weekly TH-302 has remarkably little hematologic toxicity. Skin and mucosal AEs have developed at the higher dose levels. Skin/mucosa are known to have hypoxic regions. TH-302 is the first HAP to demonstrate tumor responses in Phase I. The MTD is likely 575 mg/m 2 . Studies in combination with chemotherapy are ongoing. [Table: see text]
On the necessity for postchemotherapy surgery for residual abdominal masses in metastatic nonseminomatous germ cell tumors (NSGCT) of testis
Authors: S. J. Harland, R. Welch, R. Huddart, S. Stenning, P. Pollock, R. Gabe
Journal: Journal of Clinical Oncology (2009)

5088 Background: Residual abdominal masses after chemotherapy for metastatic NSGCT of testis may contain viable tumor-derived tissue which can be a nidus for relapse of disease, particularly when the tissue is frankly malignant. This justifies routine retroperitoneal lymph node dissection (RPLND) for large masses where malignant tissue is found at an appreciable rate. Yet RPLND is often carried out for smaller, or even absent, residual masses and differentiated teratoma (TD) is commonly found. There is little data on the consequence of leaving these smaller masses in situ, which is the practice in some units in the UK. Methods: 51 patients were identified from the MRC patients entered into the TE20 trial of 3 vs 4 cycles of BEP for good prognosis metastatic NSGCT who fell into the following category: metastatic NSGCT, residual abdominal mass only, unresected post-chemotherapy, response evaluation: CR or PR marker -ve. Collaborators were asked to report on mass size, relapse status, whether an operation was ever performed and the latest CT appearance. Results: 51/51 responses were received. Follow-up from the end of chemotherapy was &gt;3years in all but two cases and the median was 5 years. When later surgery was carried out, for persistence or enlargement of the masses, the specimens contained TD with or without necrosis. One patient suffered a relapse one year after the surgery which took place 4.5 years after chemotherapy. Of the 41 patients who did not undergo surgery, 37 were considered on subsequent CTs to have normal appearances without further treatment. Conclusions: For patients with small residual masses in good prognosis metastatic disease no short or medium term benefit from routine surgery would have been seen. Its role in this situation is therefore questionable. For larger (&gt;14mm) masses the need for routine surgery merits further study. [Table: see text] No significant financial relationships to disclose.
Evaluation of Linear Growth at Higher Altitudes
Authors: Kaleab Baye, Kalle Hirvonen
Journal: JAMA Pediatrics (2020)

<h3>Importance</h3> Irrespective of their genetic makeup, children living in an ideal home environment that supports healthy growth have similar growth potential. However, whether this potential is true for children residing at higher altitudes remains unknown. <h3>Objective</h3> To investigate whether altitude is associated with increased risk of linear growth faltering and evaluate the implications associated with the use of the 2006 World Health Organization growth standards, which have not been validated for populations residing 1500 m above sea level. <h3>Design, Settings, and Participants</h3> Analysis of 133 nationally representative demographic and health cross-sectional surveys administered in 59 low- and middle-income countries using local polynomial and multivariate regression was conducted. A total of 964 299 height records from 96 552 clusters at altitudes ranging from −372 to 5951 m above sea level were included. Demographic and Health Surveys were conducted between 1992 and 2018. <h3>Exposures</h3> Residence at higher altitudes, above and below 1500 m above sea level, and in ideal home environments (eg, access to safe water, sanitation, and health care). <h3>Main Outcomes and Measures</h3> The primary outcome was child linear growth deficits expressed in length-for-age/height-for-age<i>z </i>scores (HAZ). Associations between altitude and height among all children and those residing in ideal home environments were assessed. Child growth trajectories above and below 1500 m above sea level were compared and the altitude-mediated height deficits were estimated using multivariable linear regression. <h3>Results</h3> In 2010, a total of 842 million people in the global population (approximately 12%) lived 1500 m above sea level or higher, with 67% in Asia and Africa. Eleven percent of the sample was children who resided 1500 m above sea level or higher. These children were born at shorter length and remained on a lower growth trajectory than children residing in areas less than 1500 m above sea level. The negative association between altitude and HAZ was approximately linear through most part of the altitude distribution, indicating no clear threshold for an abrupt decrease in HAZ. A 1000-m above sea level increase in altitude was associated with a 0.163-unit (95% CI, −0.205 to −0.120 units) decrease in HAZ after adjusting for common risk factors using multivariable linear regressions. The HAZ distribution of children residing in ideal home environments was similar to the 2006 World Health Organization HAZ distribution, but only up to 500 m above sea level. <h3>Conclusions and Relevance</h3> The findings of this study suggest that residing at a higher altitude may be associated with child growth slowing even for children living in ideal home environments. Interventions addressing altitude-mediated growth restrictions during pregnancy and early childhood should be identified and implemented.
24 Measuring the value of endoscopic retrograde cholangiopancreatography (ERCP) activity: an opportunity to stratify endoscopists based on their value
Authors: V Parihar, C Moran, P Maheshwari, S Kumar, J Keohane, S Sengupta, B Hall, D Cheriyan, A O’Toole, F Murray, S Patchett, G Harewood
Journal: Gut (2017)

Background  The value in healthcare can be defined as patient health outcomes achieved per monetary unit spent.  Aim  To characterise the value of ERCP performance of four gastroenterologists.  Method  Medical records of patients undergoing ERCP between September 2014 and September 2016 in an academic medical centre were reviewed; all procedures were performed by one of four experienced gastroenterologists, all of whom have performed at least 1000 ERCPs. Procedure value was defined as the quality of procedure (Q) divided by the duration of procedure (T) adjusted for complexity level (C), that is, Q/(T/C). In those patients undergoing multiple ERCPs during the study period, only the index procedure was considered for analysis. ERCP quality and complexity were both graded on a 1 to 4 Likert scale based on American Society for Gastrointestinal Endoscopy (ASGE) criteria; time was recorded (in minutes) from intubation to extubation. Although individual components of procedure cost (eg, ERCP accessories, patient sedation, etc.) were not itemised, the procedure duration (ie, the cost of endoscopist’s time) was considered to be a reliable surrogate estimate of overall procedure cost.  Results  In total, index procedures on 465 patients were performed over 24 months; mean of 116 index ERCPs per endoscopist. Mean quality varied from 2.25 to 2.53 while adjusted mean duration (T/C) varied from 22.13 to 28.66 min per procedure. Value measurements varied from 8.1 to 10.7.  Conclusions  There was a 32% variation in the value of endoscopist activity. As healthcare costs are scrutinised more closely, such value measurements are likely to become more relevant.
Spontaneous Regression of Mismatch Repair-Deficient Colon Cancer: A Case Series
Authors: Takuya Yokota, Yutaka Saito, Hiroyuki Takamaru, Shigeki Sekine, Takeshi Nakajima, Masayoshi Yamada, Taku Sakamoto, Hirokazu Taniguchi, Ryoji Kushima, Shunsuke Tsukamoto, Dai Shida, Yukihide Kanemitsu, Takahisa Matsuda
Journal: Clinical Gastroenterology and Hepatology (2020)
Injury to the Endothelial Glycocalyx in Critically Ill Patients with COVID-19
Authors: Klaus Stahl, Phillip Alexander Gronski, Yulia Kiyan, Benjamin Seeliger, Anna Bertram, Thorben Pape, Tobias Welte, Marius M. Hoeper, Hermann Haller, Sascha David
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
Claudin-2 pore causes leak that breaches the dam in intestinal inflammation
Authors: Kim E. Barrett
Journal: Journal of Clinical Investigation (2020)

The tight junction protein claudin-2 is upregulated in inflammatory bowel disease, and yet its deficit worsens infectious and chemical colitis. In this issue of the JCI, Raju and Shashikanth et al. examined the contribution of claudin-2 to immune-mediated colitis. The authors used transgenic mouse models to show that claudin-2 deficiency attenuated colitis progression as well as a leak barrier defect, albeit at the risk of intestinal obstruction. Further, inhibition of claudin-2 by targeting casein kinase 2 (CK2) also ameliorated colitis. The findings reveal unsuspected links between the pore and leak pathways of intestinal permeability and immune responses leading to colitis. They additionally suggest potential targets for therapeutic intervention in inflammatory bowel disease.
Lung ultrasound predicts clinical course and outcomes in COVID-19 patients
Authors: Yael Lichter, Yan Topilsky, Philippe Taieb, Ariel Banai, Aviram Hochstadt, Ilan Merdler, Amir Gal Oz, Jacob Vine, Or Goren, Barak Cohen, Orly Sapir, Yoav Granot, Tomer Mann, Shirley Friedman, Yoel Angel, Nimrod Adi, Michal Laufer-Perl, Merav Ingbir, Yaron Arbel, Idit Matot, Yishay Szekely
Journal: Intensive Care Medicine (2020)
Re: Giorgio Gandaglia, Guillaume Ploussard, Massimo Valerio, et al. The Key Combined Value of Multiparametric Magnetic Resonance Imaging, and Magnetic Resonance Imaging–targeted and Concomitant Systematic Biopsies for the Prediction of Adverse Pathological Features in Prostate Cancer Patients Undergoing Radical Prostatectomy. Eur Urol 2020;77:733–41
Authors: Jonathan Aning, Paul McCoubrie, Jon Oxley
Journal: European Urology (2020)
Hello? This Is Your Cardiologist
Authors: Neha Yadav
Journal: JAMA Cardiology (2020)

Hello? This Is Your CardiologistIn the last few weeks as life has upended across the globe and new normals have begun to shape our days, one of my realities has been telemedicine in a public health system.I work at Cook County Hospital in Chicago, Illinois, and the mission of this hospital has defined who I am as a physician.During my training and early career, it has allowed me to grow while letting my roots remain planted in the soil of public service.March 2020 passed by in a haze of protocols, inpatient service, masks, gowns, and some transitions, but I still had use of my stethoscope, my eyes, and the comfort I can bring to patients as a physician.April brought an abrupt and near total transition to telemedicine.
Sustained‐release delivery of antimicrobial drugs for the treatment of periodontal diseases: Fantasy or already reality?
Authors: Doron Steinberg, Michael Friedman
Journal: Periodontology 2000 (2020)

Abstract Periodontal diseases are prevalent in humans. Conventional means of combating these diseases involve basic oral hygiene, mostly toothbrushing, use of mouthwashes, and flossing. Supplementary means of treatment, either clinical or pharmaceutical, are often necessary. The use of sustained‐release delivery systems, applied locally to the periodontal pocket, seems to be one feasible approach: local sustained‐release delivery of antibacterial agents to treat periodontal diseases is conceivable. The use of local (intrapocket) sustained‐release delivery systems has numerous clinical, pharmacologic, and toxicologic advantages over conventional treatments for periodontal diseases. Sustained‐release technology has been proven to be effective over the last few decades. Films, gels, and fibers are the three main classical intrapocket pharmaceutical delivery systems. Research today is more focused on improving drug delivery, and less on introducing new drugs. New approaches, eg, those making use of nanotechnology, are emerging for local drug‐delivery systems. The local sustained‐release delivery system concept is innovative and a few products are already commercially available.
COVID-19 in Philadelphia-negative myeloproliferative disorders: a GIMEMA survey
Authors: Massimo Breccia, Alfonso Piciocchi, Valerio De Stefano, Guido Finazzi, Alessandra Iurlo, Paola Fazi, Stefano Soddu, Bruno Martino, Francesca Palandri, Sergio Siragusa, Francesco Albano, Francesco Passamonti, Marco Vignetti, Alessandro M. Vannucchi
Journal: Leukemia (2020)
Entospletinib in Combination with Induction Chemotherapy in Previously Untreated Acute Myeloid Leukemia: Response and Predictive Significance of <i>HOXA9</i> and <i>MEIS1</i> Expression
Authors: Alison R. Walker, John C. Byrd, James S. Blachly, Bhavana Bhatnagar, Alice S. Mims, Shelley Orwick, Tara L. Lin, Howland E. Crosswell, Danjie Zhang, Mark D. Minden, Veerendra Munugalavadla, Lauren Long, Jinfeng Liu, Yang Pan, Thomas Oellerich, Hubert Serve, Arati V. Rao, William G. Blum
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Spleen tyrosine kinase (SYK) signaling is a proposed target in acute myeloid leukemia (AML). Sensitivity to SYK inhibition has been linked to HOXA9 and MEIS1 overexpression in preclinical studies. This trial evaluated the safety and efficacy of entospletinib, a selective inhibitor of SYK, in combination with chemotherapy in untreated AML. Patients and Methods: This was an international multicenter phase Ib/II study, entospletinib dose escalation (standard 3+3 design between 200 and 400 mg twice daily) + 7+3 (cytarabine + daunorubicin) in phase Ib and entospletinib dose expansion (400 mg twice daily) + 7+3 in phase II. Results: Fifty-three patients (n = 12, phase Ib and n = 41, phase II) with previously untreated de novo (n = 39) or secondary (n = 14) AML were enrolled (58% male; median age, 60 years) in this study. The composite complete response with entospletinib + 7+3 was 70%. Patients with baseline HOXA9 and MEIS1 expression higher than the median had improved overall survival compared with patients with below median HOXA9 and MEIS1 expression. Common adverse events were cytopenias, febrile neutropenia, and infection. There were no dose-limiting toxicities. Entospletinib-related skin rash and hyperbilirubinemia were also observed. Conclusions: Entospletinib with intensive chemotherapy was well-tolerated in patients with AML. Improved survival was observed in patients with HOXA9/MEIS1 overexpression, contrasting published data demonstrating poor survival in such patients. A randomized study will be necessary to determine whether entospletinib was a mediator this observation.
Drug Delivery: Heparin‐Coated Albumin Nanoparticles for Drug Combination in Targeting Inflamed Intestine (Adv. Healthcare Mater. 16/2020)
Authors: Sufeng Zhang, Won Joon Cho, Amy T. Jin, Lie Yun Kok, Yunhua Shi, David E. Heller, Young‐Ah Lucy Lee, Yixuan Zhou, Xi Xie, Joshua R. Korzenik, Jochen K. Lennerz, Giovanni Traverso
Journal: Advanced Healthcare Materials (2020)

Targeting areas of inflammation stands to transform the capacity to effectively treat inflammatory bowel disease while minimizing systemic side effects. In article number 2000536, Giovanni Traverso and co-workers describe heparin-coated human serum albumin nanoparticles that can encapsulate drug combination, suppress inflammation in macrophages in vitro, and selectively bind to inflamed intestine in vivo in a murine model of acute colitis.