tbuckley/cabot-search huggingface dataset:
Hormone blockers: Judges assess whether children should be treated
Authors: Clare Dyer
Journal: BMJ (2020)

The High Court in London is to rule on whether children with gender dysphoria can continue to be given hormone blockers to delay puberty without a judge’s declaration that the treatment is in their best interests.

Three senior judges are expected to give judgment on the issue within weeks, after a two day court hearing.

Keira Bell, 23, who was treated as a teenager, and “Mrs A,” the mother of a 16 year old girl with autism who is on the waiting list for treatment, are challenging NHS guidelines on the use of hormone blockers. They argue that the guidelines are unlawful because …
Inhibition of IL1β by Canakinumab May Be Effective against Diverse Molecular Subtypes of Lung Cancer: An Exploratory Analysis of the CANTOS Trial
Authors: Connie C. Wong, Jason Baum, Angela Silvestro, Michael T. Beste, Bharani Bharani-Dharan, Siyan Xu, Ying A. Wang, Xiaoshan Wang, Margaret F. Prescott, Lynne Krajkovich, Margaret Dugan, Paul M. Ridker, Anne-Marie Martin, Eric C. Svensson
Journal: Cancer Research (2020)

In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), inhibition of the IL1β inflammatory pathway by canakinumab has been shown to significantly reduce lung cancer incidence and mortality. Here we performed molecular characterization of CANTOS patients who developed lung cancer during the study, including circulating tumor DNA (ctDNA) and soluble inflammatory biomarker analysis. Catalogue of Somatic Mutations in Cancer (COSMIC) database ctDNA mutations were detected in 65% (46/71) of the CANTOS patients with lung cancer, with 51% (36/71) having detectable ctDNA at the time point closest to lung cancer diagnosis and 43% (29/67) having detectable ctDNA at trial randomization. Mutations commonly found in lung cancer were observed with no evidence of enrichment in any mutation following canakinumab treatment. Median time to lung cancer diagnosis in patients with (n = 29) versus without (n = 38) detectable COSMIC ctDNA mutations at baseline was 407 days versus 837 days (P = 0.011). For serum inflammatory biomarker analysis, circulating levels of C-reactive protein (CRP), IL6, IL18, IL1 receptor antagonist, TNFα, leptin, adiponectin, fibrinogen, and plasminogen activator inhibitor-1 were determined. Patients with the highest level of baseline CRP or IL6, both downstream of IL1β signaling, trended toward a shorter time to lung cancer diagnosis. Other inflammation markers outside of the IL1β pathway at baseline did not trend with time to lung cancer diagnosis. These results provide further evidence for the importance of IL1β-mediated protumor inflammation in lung cancer and suggest canakinumab's effect may be mediated in part by delaying disease progression of diverse molecular subtypes of lung cancer. SIGNIFICANCE: These findings suggest that targeting the IL1β inflammatory pathway might be critical in reducing tumor-promoting inflammation and lung cancer incidence.
Provision of smartphones in a symptom monitoring program of gynecologic and breast cancer patients during active therapy.
Authors: Michelle Joy Naughton, Jennifer Moon, Hibaq Loyan, Juan Peng, Cecilia DeGraffinreid, Electra D. Paskett
Journal: Journal of Clinical Oncology (2020)

255 Background: With advances in technology, smartphones are being used for multiple research and clinical care functions. However, not all patients have these devices, leading to disparities in participation. We report on a quality improvement program that provided smartphones to patients without these devices. Methods: Gynecologic (n = 120) and breast (n = 193) cancer patients under active treatment were enrolled in a 12-month text-based symptom monitoring program to facilitate communication and optimize patient management. Patients without a smartphone were provided with an iPhone through a partnership with a U.S. wireless company. The company provided smartphone devices at zero cost, and program funds paid for 12 months of phone service. Program staff helped patients set up the iPhones, and provided basic education and ongoing phone support. After 12 months, patients were able to keep their iPhones, but had to secure their own phone plan for calling and texting functions. Results: iPhones were provided to 42 (13.4%) patients across all cancer types. Patients who received iPhones, compared with those who had a smartphone, had incomes below $50,000/year (p = 0.03) and an educational level of &lt; high school (p &lt; 0.0001). Program staff had few difficulties training patients to operate the phones or in patients’ adherence to symptom monitoring after receiving the iPhones. Phone service charges averaged $40 per month or $500 per person for 12 months. Greater than 90% of patients believed the phones enabled them to better communicate with their health care team and family/support networks, and 95% believed the phones had a positive impact on their life. However, only 70% planned on getting a phone service plan at the end of the 12 months, due to cost or believing a smartphone was not a necessity. Conclusions: Providing smartphones to patients enabled them to better communicate with their health care team and families, and participate in remote symptom monitoring during active treatment. Programs such as these are needed to reduce disparities in patient care, and support quality improvement efforts using electronic devices.
Model-Informed Precision Dosing: Background, Requirements, Validation, Implementation, and Forward Trajectory of Individualizing Drug Therapy
Authors: Adam S. Darwich, Thomas M. Polasek, Jeffrey K. Aronson, Kayode Ogungbenro, Daniel F.B. Wright, Brahim Achour, Jean-Luc Reny, Youssef Daali, Birgit Eiermann, Jack Cook, Lawrence Lesko, Andrew J. McLachlan, Amin Rostami-Hodjegan
Journal: The Annual Review of Pharmacology and Toxicology (2020)

Model-informed precision dosing (MIPD) has become synonymous with modern approaches for individualizing drug therapy, in which the characteristics of each patient are considered as opposed to applying a one-size-fits-all alternative. This review provides a brief account of the current knowledge, practices, and opinions on MIPD while defining an achievable vision for MIPD in clinical care based on available evidence. We begin with a historical perspective on variability in dose requirements and then discuss technical aspects of MIPD, including the need for clinical decision support tools, practical validation, and implementation of MIPD in health care. We also discuss novel ways to characterize patient variability beyond the common perceptions of genetic control. Finally, we address current debates on MIPD from the perspectives of the new drug development, health economics, and drug regulations.
Beclin1 haploinsufficiency rescues low ambient temperature-induced cardiac remodeling and contractile dysfunction through inhibition of ferroptosis and mitochondrial injury
Authors: Zhiqiang Yin, Gangbing Ding, Xu Chen, Xing Qin, Haixia Xu, Biru Zeng, Jun Ren, Qijun Zheng, Shuyi Wang
Journal: Metabolism (2020)
Cancer and COVID-19
Authors: Alexandre E Malek, Issam I Raad, Elias Jabbour
Journal: The Lancet (2020)

during the pandemic, the prioritisation in the delivery of cancer therapies is strongly influenced by the magnitude of potential treatment benefits, therapeutic intent, and the access to care. 5 All in all, these changes can definitely affect the outcomes of patients with cancer.In this new landscape, when the cancer community is revising the optimal standards of cancer care, research should focus on identifying the factors that contribute to avoidable mortality and facilitate the implementation of strategies to benefit patients.We declare no competing interests.
Butyrate as a bioactive human milk protective component against food allergy
Authors: Lorella Paparo, Rita Nocerino, Elena Ciaglia, Carmen Di Scala, Carmen De Caro, Roberto Russo, Giovanna Trinchese, Rosita Aitoro, Antonio Amoroso, Cristina Bruno, Margherita Di Costanzo, Annalisa Passariello, Francesco Messina, Annalisa Agangi, Marcello Napolitano, Luana Voto, Giusy Della Gatta, Laura Pisapia, Francesco Montella, Maria Pina Mollica, Antonio Calignano, Annibale Puca, Roberto Berni Canani
Journal: Allergy (2020)

Food allergy (FA) is a growing health problem worldwide. Effective strategies are advocated to limit the disease burden. Human milk (HM) could be considered as a protective factor against FA, but its mechanisms remain unclear. Butyrate is a gut microbiota-derived metabolite able to exert several immunomodulatory functions. We aimed to define the butyrate concentration in HM, and to see whether the butyrate concentration detected in HM is able to modulate the mechanisms of immune tolerance.HM butyrate concentration from 109 healthy women was assessed by GS-MS. The effect of HM butyrate on tolerogenic mechanisms was assessed in in vivo and in vitro models.The median butyrate concentration in mature HM was 0.75 mM. This butyrate concentration was responsible for the maximum modulatory effects observed in all experimental models evaluated in this study. Data from mouse model show that in basal condition, butyrate up-regulated the expression of several biomarkers of gut barrier integrity, and of tolerogenic cytokines. Pretreatment with butyrate significantly reduced allergic response in three animal models of FA, with a stimulation of tolerogenic cytokines, inhibition of Th2 cytokines production and a modulation of oxidative stress. Data from human cell models show that butyrate stimulated human beta defensin-3, mucus components and tight junctions expression in human enterocytes, and IL-10, IFN-γ and FoxP3 expression through epigenetic mechanisms in PBMCs from FA children. Furthermore, it promoted the precursors of M2 macrophages, DCs and regulatory T cells.The study's findings suggest the importance of butyrate as a pivotal HM compound able to protect against FA.
Field Carcinogenesis in Cancer Evolution: What the Cell Is Going On?
Authors: Ansam Sinjab, Guangchun Han, Linghua Wang, Humam Kadara
Journal: Cancer Research (2020)

Abstract Field carcinogenesis describes the prevalence of tumor-related alterations in normal appearing tissues. Here, we summarize recent efforts in profiling molecular field dynamics for resolving early events in cancer evolution. We also highlight gaps in our knowledge of the molecular and cellular heterogeneity of field carcinogenesis and propose directions to tackle these voids using single-cell–based approaches and unique tissue sampling models. By interrogating both the mutagenized epithelium and its microenvironment, we surmise that single-cell–guided studies will help chart the spatiotemporal molecular and cellular “atlas” of field carcinogenesis, will further delineate preneoplastic initiation and progression, and will help identify cancer prevention and early intervention targets.
THU0247 The epidemiology of neck and low back pain in the urban population of antalya, turkey. a preliminary report
Authors: E Gilgil, C Kacar, B Butun, I Tekeoglu, C Yildirim, G Sumbuloglu, V Arikan, S Urhan, U Dundar, MC Oksuz, T Tuncer
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Studies elsewhere suggest a lifetime rate of low back pain of about 50–80% and neck pain of about 12% in women and 9% in men. <h3>Objectives</h3> To identify the lifetime rate of neck pain and prevalence of low back pain in the urban population of Antalya, Turkey. <h3>Methods</h3> This survey study forms a part of larger cross-sectional study still being conducted in the urban area of Antalya (508.840 population according to 1997 national census). So far, 1521 subjects aged 16 or over were interviewed at home visits by 10 trained physicians and 20 accompanying medical students. The subjects were chosen by random cluster sampling from the registries of local offices of the Ministry of Health. Individuals were requested to respond to the questions whether they had at least one episode of neck pain and/or low back pain (both inflammatory and noninflammatory). Additional questions regarding the occurrence of low back pain at present, and in the previous year; loss of work-days in the previous year, the relation of occupation with the symptoms, and whether and how they searched for a solution for the relief of their low back pain were asked to the subjects. <h3>Results</h3> We found a lifetime rate of neck pain of 351(46,4%) of women and 252(33,8%) of men (totally 611(40,3%) individuals) and low back pain of 430(57%) of women and 303(%40,8) of men (totally 739(48,9%) individuals). The point prevalence of low back pain was calculated as 39,9%(324 individuals), of these 210 were women and 110 were men. The point prevalence was 27,3%(n = 21) in men aged over 50 and 34,3%(n = 93) in men aged 50 or under, while it was 57,6%(n = 49) in women aged over 50 and 42,5%(n = 161) in women aged 50 or under. <h3>Conclusion</h3> The lifetime rate of neck and low back pain were both higher in women. The increasing age seems to be associated with the point prevalence of low back pain in women contrary to men. This study is supported by the Akdeniz University Research Fund.
Reducing the wait time to initiate inpatient chemotherapy at Lyndon B. Johnson Hospital.
Authors: Andrew James Wiele, Trung Nguyen, Onyebuchi Ononogbu, Kristyn-Mae Russo, Phat Le, Tejal Amar Patel, Hilary Y. Ma, Alyssa G. Rieber
Journal: Journal of Clinical Oncology (2020)

210 Background: Delays in initiating inpatient (inpt) chemotherapy (chemo) for planned admissions can decrease patient (pt) satisfaction and increase length of stay and healthcare costs. Our center, a community public teaching hospital, lacked clear standard operating procedures for scheduled chemo admissions, resulting in significant delays. We developed a process improvement initiative to reduce the pt wait time from admission to chemo administration (time to chemo [TTC]). Methods: A multidisciplinary team was formed to clarify workflows and identify root causes prolonging wait times for pts admitted to the inpt chemo unit. We implemented two Plan-Do-Study-Act (PDSA) cycles over a 6-month period. First, in early March, we collaborated with pharmacy and nursing to standardize the inpt chemo operating procedures and extend pharmacy’s evening hours for chemo preparation (prep) from 7pm to 9pm. Second, in early June, we implemented a Pre-admission Checklist that was visibly displayed in clinic for fellows to review with faculty, and began discussing pts scheduled for admission during the daily, multidisciplinary huddle that already occurred on the inpt chemo unit. Using the electronic medical record and available time stamps, baseline data was collected from November-December 2019, post-intervention data for PDSA cycle 1 was collected from March-April 2020, and data collection for PDSA cycle 2 is ongoing. Results: Root cause analysis identified late afternoon admissions and PICC line placements as two main sources for TTC delays. Hospital procedures also limited inpt PICC line placement between 8am-4pm and inpt chemo prep between 7am-7pm. Baseline data revealed 77.4% (24/31) of pts were admitted between 3pm-10pm, the median TTC was 20.4 hrs, and 6.5% (2/31) of pts had chemotherapy initiated within 12 hrs of admission (TTC &lt; 12). Additionally, 56.5% (26/46) of pts had PICC lines placed during their admission, but 69.2% (18/26) of the pts with PICC lines were eligible for outpatient port placement according to institutional intravenous (IV) access guidelines. After PDSA cycle 1, median TTC decreased by 10% to 18.4 hrs, and 33.3% (5/15) of pts had TTC &lt; 12. Conclusions: After standardizing inpt chemo procedures and extending chemo prep times, PDSA cycle 1 resulted in a 10% reduction in TTC and a 26.8% increase in the rate of TTC &lt; 12. Although admission times cannot be controlled at this time, the impact of improving pre-admission planning, and specifically addressing IV access, for PDSA cycle 2 is currently being evaluated and will be reported at the time of abstract presentation.
The success of the Rapid Diagnostic Clinic (RDC) detecting new cancers in patients with non-localizing symptoms.
Authors: Jan Sindhar, Sabine Martin, Loay Rahman, Sifan Zheng, Yaseen Mukadam, Sunnyath Ali, Lindsay Steward, Daniel Wheeler, Charlotte L Moss, Geraint Jones, Beth Russell, Mieke Van Hemelrijck, Luigi De Michele, Saoirse Bhattacharjee
Journal: Journal of Clinical Oncology (2020)

303 Background: Rapid Diagnostic Clinics (RDC) are being set up across the UK allow primary care physicians to refer patients with symptoms concerning for cancer that do not fulfil tumour-specific two week wait urgent referral criteria. Guy’s RDC was established to address the high cancer related mortality in our network. There is little data assessing the effectiveness of RDC models is available in a British population. Methods: We evaluated all patients referred to Guy’s RDC pilot scheme between December 2016-June 2019 (n=1,341) to assess the rate and type of cancer diagnosed and clinical outcomes. Results: Of 1341 patients, 96 cancers were diagnoses (7.2%). Most common were lung (16%), haematological (13%) and colorectal (12%). A third were at early stage (I-II) and 40% received radical treatment. Median time to cancer diagnosis 28 days (IQR 15-47) and treatment 56 days (IQR 32-84). 75% of patients were suitable for anti-cancer treatment: surgery (26%), systemic (24%) and radiotherapy (14%). We plan to present updated data on &gt; 2000 patients referred until June 2020. Overall 6% of patients were diagnosed with pre-malignant conditions. Conclusions: RDCs provide a streamlined pathway for complex vague symptoms patients which are challenging for primary care. The 7% rate of cancer diagnosis exceeds many tumour specific urgent pathways which supports the need for rapid tailored diagnostics. The detection of pre-malignant conditions in 6% allows surveillance and intervention to potentially improve long-term outcomes. RDCs are likely to be pivotal in the cancer recovery phase of the COVID-19 pandemic.
Burden and trajectory of multimorbidity in rheumatoid arthritis: a matched cohort study from 2006 to 2015
Authors: Bryant R England, Punyasha Roul, Yangyuna Yang, Harlan Sayles, Fang Yu, Kaleb Michaud, Fenglong Xie, Jeffrey R Curtis, Ted R Mikuls
Journal: Annals of the Rheumatic Diseases (2020)

To compare the onset and trajectory of multimorbidity between individuals with and without rheumatoid arthritis (RA).A matched, retrospective cohort study was completed in a large, US commercial insurance database (MarketScan) from 2006 to 2015. Using validated algorithms, patients with RA (overall and incident) were age-matched and sex-matched to patients without RA. Diagnostic codes for 44 preidentified chronic conditions were selected to determine the presence (≥2 conditions) and burden (count) of multimorbidity. Cross-sectional comparisons were completed using the overall RA cohort and conditional logistic and negative binomial regression models. Trajectories of multimorbidity were assessed within the incident RA subcohort using generalised estimating equations.The overall cohort (n=277 782) and incident subcohort (n=61 124) were female predominant (76.5%, 74.1%) with a mean age of 55.6 years and 54.5 years, respectively. The cross-sectional prevalence (OR 2.29, 95% CI 2.25 to 2.34) and burden (ratio of conditions 1.68, 95% CI 1.66 to 1.70) of multimorbidity were significantly higher in RA than non-RA in the overall cohort. Within the incident RA cohort, patients with RA had more chronic conditions than non-RA (β 1.13, 95% CI 1.10 to 1.17), and the rate of accruing chronic conditions was significantly higher in RA compared with non-RA (RA × follow-up year, β 0.21, 95% CI 0.20 to 0.21, p<0.001). Results were similar when including the pre-RA period and in several sensitivity analyses.Multimorbidity is highly prevalent in RA and progresses more rapidly in patients with RA than in patients without RA during and immediately following RA onset. Therefore, multimorbidity should be aggressively identified and targeted early in the RA disease course.
B7-H3: An Attractive Target for Antibody-based Immunotherapy
Authors: Filippos Kontos, Theodoros Michelakos, Tomohiro Kurokawa, Ananthan Sadagopan, Joseph H. Schwab, Cristina R. Ferrone, Soldano Ferrone
Journal: Clinical Cancer Research (2020)

Abstract The recent impressive clinical responses to antibody-based immunotherapy have prompted the identification of clinically relevant tumor antigens that can serve as targets in solid tumors. Among them, B7-H3, a member of the B7 ligand family, represents an attractive target for antibody-based immunotherapy, it is overexpressed on differentiated malignant cells and cancer-initiating cells, with limited heterogeneity, and high frequency (60% of 25,000 tumor samples) in many different cancer types, but has a limited expression at low level in normal tissues. In nonmalignant tissues, B7-H3 has a predominantly inhibitory role in adaptive immunity, suppressing T-cell activation and proliferation. In malignant tissues, B7-H3 inhibits tumor antigen–specific immune responses, leading to a protumorigenic effect. B7-H3 also has nonimmunologic protumorigenic functions, such as promoting migration and invasion, angiogenesis, chemoresistance, and endothelial-to-mesenchymal transition, as well as affecting tumor cell metabolism. As a result, B7-H3 expression in tumors is associated with poor prognosis. Although experimental B7-H3 silencing reduces cancer cell malignant potential, there has been limited emphasis on the development of B7-H3–blocking antibodies, most likely because the B7-H3 receptor remains unknown. Instead, many antibody-based strategies utilizing distinct effector mechanisms to target B7-H3–expressing cancer cells have been developed. These strategies have demonstrated potent antitumor activity and acceptable safety profiles in preclinical models. Ongoing clinical trials are assessing their safety and efficacy in patients. Identification of the B7-H3 receptor will improve our understanding of its role in tumor immunity, and will suggest rational strategies to develop blocking antibodies, which may enhance the therapeutic efficacy of tumor immunity.
The altered transcriptome of pediatric myelodysplastic syndrome revealed by RNA sequencing
Authors: Lorena Zubovic, Silvano Piazza, Toma Tebaldi, Luca Cozzuto, Giuliana Palazzo, Viktoryia Sidarovich, Veronica De Sanctis, Roberto Bertorelli, Tim Lammens, Mattias Hofmans, Barbara De Moerloose, Julia Ponomarenko, Martina Pigazzi, Riccardo Masetti, Cristina Mecucci, Giuseppe Basso, Paolo Macchi
Journal: Journal of Hematology & Oncology (2020)

Abstract Pediatric myelodysplastic syndrome (PMDS) is a very rare and still poorly characterized disorder. In this work, we identified novel potential targets of PMDS by determining genes with aberrant expression, which can be correlated with PMDS pathogenesis. We identified 291 differentially expressed genes (DEGs) in PMDS patients, comprising genes involved in the regulation of apoptosis and the cell cycle, ribosome biogenesis, inflammation and adaptive immunity. Ten selected DEGs were then validated, confirming the sequencing data. These DEGs will potentially represent new molecular biomarkers and therapeutic targets for PMDS.