tbuckley/cabot-search huggingface dataset:
EGFR over expression as a result of receptor stabilization in breast cancer cells with an amphiregulin/EGFR autocrine loop
Authors: Nicole Willmarth, Stephen Ethier
Journal: Cancer Research (2007)

3773  The epidermal growth factor receptor (EGFR) is involved in several cellular processes such as cell proliferation, differentiation, and survival. Regulated degradation of EGFR is critical to maintain normal cellular EGFR levels. EGFR can either be degraded via proteolytic pathways, or it can be recycled to the membrane and become activated again. We have shown that the inflammatory breast cancer cell line SUM149 over expresses EGFR protein without gene amplification, and an AR/EGFR autocrine loop is required for SUM149 cell proliferation. The effects of the EGF family ligand amphiregulin (AR) on EGFR degradation or recycling have not yet been examined. Therefore, we sought to investigate whether AR stabilizes EGFR by decreasing EGFR degradation in SUM149 cells and therefore might contribute to over expression of the receptor. Primarily, we observed that SUM149 cells and immortalized human mammary epithelial MCF10A cells that over express AR (MCF10A AR) or are cultured in the presence of exogenous AR, express higher levels of EGFR protein compared with MCF10A cells growing in EGF. Since the ubiquitin ligase Cbl is known to bind to phosphorylated tyrosine 1045 of the EGFR, we examined phosphorylation of this site in our cell lines. We found that phosphorylation of EGFR tyrosine 1045 is present in MCF10A cells growing in EGF but is completely absent in the SUM149 breast cancer cells and in MCF10A cells cultured in the presence of AR. This result suggests that Cbl is not able to bind to the EGFR and target it for degradation when AR is the activating ligand. We also observed that spiking EGF deprived MCF10A cells with saturating concentrations of EGF dramatically increased ubiquitination of EGFR. However, EGFR was only slightly ubiqutinated after spiking the cells with saturating concentrations of AR. To examine EGFR localization in EGF versus AR-stimulated cells, we visualized EGFR localization using immunofluorescence and confocal microscopy. We observed that in the presence of EGF, EGFR is mostly localized in endosomes. By contrast, in SUM149 cells and MCF10A cells growing in the presence of AR, EGFR is very abundant on the membrane and at cell-cell junctions. Thus, based on our results, we propose that an amphiregulin autocrine loop alters EGFR dynamics in a way that stabilizes EGFR and decreases EGFR degradation resulting in increased steady-state levels of EGFR protein, and accumulation of EGFR at the cell surface. This connection between an AR autocrine loop and EGFR over expression could explain why both factors have been shown to be predictors of aggressive breast cancer.
Testicular Cancer: Biology to Bedside
Authors: Jennifer King, Nabil Adra, Lawrence H. Einhorn
Journal: Cancer Research (2021)

Abstract Testicular cancer is the first solid tumor with a remarkably high cure rate. This success was only made possible through collaborative efforts of basic and clinical research. Most patients with distant metastases can be cured. However, the majority of these patients are diagnosed at a young age, leaving many decades for the development of treatment-related complications. This has magnified the importance of research into survivorship issues after exposure to platinum-based chemotherapy. This research, along with research into newer biomarkers that will aid in the diagnosis and surveillance of patients and survivors of testicular cancer, will continue to advance the field and provide new opportunities for these patients. There also remains the need for further therapeutic options for patients who unfortunately do not respond to standard treatment regimens and ultimately die from this disease, including a cohort of patients with late relapses and platinum-refractory disease. Here we discuss the advancements in management that led to a highly curable malignancy, while highlighting difficult situations still left to solve as well as emerging research into novel biomarkers.
Modeling Hepatitis C Elimination Among People Who Inject Drugs in New Hampshire
Authors: Andrew Blake, James E. Smith
Journal: JAMA Network Open (2021)

The success of direct-acting antiviral therapies for chronic hepatitis C virus (HCV) infection led the World Health Organization to set elimination targets by 2030. For the United States to achieve these benchmarks, public health responses must target high-risk populations, such as people who inject drugs (PWID), a group with high rates of HCV incidence and low rates of treatment uptake.To evaluate potential improvements in the HCV care cascade among PWID, focusing on improved testing, treatment uptake, and access to harm reduction.This decision analytic model used a differential equation-based dynamic transmission model based on data from New Hampshire, an illustrative state with a large number of PWID and limited HCV treatment infrastructure. Surveillance data through 2020 was used for model parameterization, and the final analysis was conducted in May 2021.Model forecasts of chronic HCV cases and advanced-stage HCV outcomes from 2022 to 2045.A total of 6 scenarios were tested: (1) the base case, (2) improved harm reduction, (3) improved testing, (4) improved treatment, (5) improved testing and treatment, and (6) improved testing, treatment, and harm reduction. All scenarios with improved testing, treatment uptake, and/or access to harm reduction were associated with decreases in forecasted HCV prevalence and HCV-associated mortality compared with the base case. Improving harm reduction, testing, and treatment individually were forecast to reduce prevalence of HCV in 2045 from 69.7% in the base case to 62.8%, 45.7%, and 35.5%, respectively. Combining treatment and testing improvements was associated with a 2045 prevalence of 0.3%; adding harm reduction improvements was associated with further reductions in prevalence forecasts (to 0.2%), with fewer total treatments (10 960 vs 13 219 from 2022-2045).In this modeling study, no single intervention was projected to achieve World Health Organization HCV elimination targets. Scenarios with improvements in both testing and treatment were associated with a prevalence of less than 3% by 2030 and achieved elimination targets. Adding improvements in harm reduction was associated with faster reductions in prevalence and fewer treatments.
Stable suppression of mutant KRAS in C26 murine colon carcinoma cells by RNA interference leads to complete loss of metastatic potential and to increased tumor immunity.
Authors: Niels Smakman, Inne Borel Rinkes, Rinke Bos, Rienk Offringa, Onno Kranenburg
Journal: Cancer Research (2005)

338  Introduction. Mutational activation of the KRAS proto-oncogene is an initiating event during the development of 45% of human colorectal carcinomas (CRC). The aim of this study was to assess whether endogenous mutant KRAS is essential during the late metastatic stages of tumor growth when cells have acquired multiple additional genetic changes. Experimental procedures. RAS status of C26 murine CRC cells was assessed by RAS activity assays, RT-PCR and cDNA sequencing. The mutant KRAS mRNA was targeted by RNA interference using a lentivirus-based expression system. Knockdown of mutant KRAS was tested by Western blotting. Cell morphology, cell proliferation and cell cycle distribution were all tested with standard assays. Liver metastases were induced by intrasplenic injection of tumor cells in BALB/c mice. The formation of liver metastases was analyzed by bioluminescence imaging. Subcutaneous tumor growth was analyzed by caliper measurements. CD8+ CTL were depleted by intraperitoneal injections of a monoclonal anti-CD8-antibody. MHC-I expression was assessed by FACS analysis. Results. C26 cells harbor constitutively active KRAS due to an activating mutation in codon 12. We isolated stable cell lines in which the mutant KRAS allele was stably suppressed by RNA interference (C26-KRKD). C26-KRKD cells showed reversion of morphological transformation, exhibited a reduced proliferation rate, showed restored contact inhibition and an increased percentage of cells in G1. While mice challenged with control cells developed massive liver metastases within 12 days, the potential to form liver metastasis was completely abrogated in KRAS-suppressed cells. C26-KRKD cells did grow out as benign subcutaneous tumors in 40% of the mice but this was not associated with morbidity. 30% of subcutaneous tumors regressed spontaneously, and this was dependent on CD8+ CTLs. These mice showed lasting anti-tumor-immunity against parental C26 tumor cell challenges. When C26-KRKD cells were injected in an athymic background, subcutaneous tumors were formed in 100% of the mice and none of these tumors regressed. C26-KRKD cells showed enhanced expression of MHC class I molecules at the cell surface. Conclusion. Sequence specific suppression of mutant KRAS by RNA interference in a highly aggressive and metastatic CRC cell line leads to reversion of malignant characteristics in vitro and to complete abrogation of the metastatic potential in vivo. KRAS knockdown facilitates the development of an effective CTL-mediated anti-tumor immune response.
Air pollution and COVID-19: clearing the air and charting a post-pandemic course: a joint workshop report of ERS, ISEE, HEI and WHO
Authors: Zorana J. Andersen, Barbara Hoffmann, Lidia Morawska, Martin Adams, Eeva Furman, Arzu Yorgancioglu, Dan Greenbaum, Maria Neira, Bert Brunekreef, Francesco Forastiere, Mary B. Rice, François Wakenhut, Erika Coleen, Hanna Boogaard, Ulrike Gehring, Erik Melén, Brian Ward, Sara De Matteis
Journal: European Respiratory Journal (2021)

<b>The potential role of air pollution in the worsening of health impacts of COVID-19, and the influence of the pandemic on air pollution levels in Europe is explored. This editorial outlines the major lessons learned to chart a healthy post-pandemic course.</b>https://bit.ly/3hmbaya
Neutrophilic Eccrine Hidradenitis
Authors: Colleen J. Beatty, Erica R. Ghareeb
Journal: New England Journal of Medicine (2021)

A 42-year-old woman was admitted to the hospital to receive induction chemotherapy for acute monocytic leukemia. On hospital day 10, edematous, erythematous plaques developed on her cheeks, forehead, and neck. A biopsy was performed, and a diagnosis of neutrophilic eccrine hidradenitis was made.
Corrigendum to “Raman spectroscopy for the detection of organ distribution and clearance of PEGylated reduced graphene oxide and biological consequences” [Biomaterials 131 (2017) 121–130]
Authors: Santhakumar Syama, Willi Paul, Arumugam Sabareeswaran, Parayanthala Valappil Mohanan
Journal: Biomaterials (2021)
Low‐dose thymoglobulin for prevention of chronic graft‐versus‐host disease in transplantation from an <scp>HLA</scp> ‐matched sibling donor
Authors: Byung‐Sik Cho, Gi‐June Min, Sung‐Soo Park, Seok Yoon Yoon, Silvia Park, Young‐Woo Jeon, Seung‐Hwan Shin, Seung‐Ah Yahng, Jae‐Ho Yoon, Sung‐Eun Lee, Ki‐Seong Eom, Yoo‐Jin Kim, Chang‐Ki Min, Seok‐Goo Cho, Dong‐Wook Kim, Jong Wook Lee, Hee‐Je Kim, Seok Lee
Journal: American Journal of Hematology (2021)

Despite the proven efficacy of anti-T-cell or antithymocyte globulin (ATG) for chronic graft-versus-host disease (GVHD) prevention in transplantation from an unrelated donor, dosing protocols and the effects of ATG on relapse and infection remain controversial. In the setting of transplantation from an HLA-matched sibling (MSD-T), few randomized studies have been conducted. We conducted a prospective, single-center, open-label, randomized study of low-dose thymoglobulin (2.5 mg/kg) for chronic GVHD prevention. A total of 120 patients with acute leukemia were randomly assigned in a 1:1 ratio. After a median follow-up of 27 months, the cumulative incidence of chronic GVHD in the ATG and non-ATG groups was 25.0% and 65.4% (p < 0.001), respectively. The ATG group had an increased relapse rate compared with the non-ATG-group (20.0% vs. 9.3%; p = 0.055), with risks that differed according to cytogenetic subgroup (high-risk, 29.6% vs. 9.3%, p = 0.042; non-high-risk, 12.2% vs. 9.2%, p = 0.596). Chronic GVHD-free and relapse-free survival (cGRFS) was higher in the ATG group (46.7% vs. 19.4%; p = 0.070), and the difference was significant in a cytogenetic non-high-risk subgroup (45.5% vs. 0%; p = 0.038). No differences were observed in other survival outcomes. Improved physical components in quality-of-life scores were observed in the ATG group at 12 months after transplantation. A higher rate of Epstein-Barr virus reactivation was observed in the ATG group (21.8% vs. 5.1%; p = 0.013), whereas no between-group differences for other complications. In conclusion, the low-dose thymoglobulin effectively prevented chronic GVHD in MSD-T, resulting in improvement in quality-of-life and cGRFS, whereas the necessity of caution for high-risk acute leukemia.
A British Medical Association Lecture ON THE PATHOLOGY OF GASTRIC ULCER: Delivered to the Derby Division, May 18th, 1923
Authors: M. J. Stewart
Journal: BMJ (1923)

1~~~~~~~~~~~~~~~~~~~~~~~~~~MEDICAL JOURtNAL, Application of Experimental Results.If the thesis as to danger ratio is established, when we wish to apply our animal experiments in the clinic it seems clear that we must know approximately what is the ratio for a given drug with the higher mammals.Further, an anaes- thetic with a low danger ratio is much safer for trial than one with a high, the risk of incautiously approaching the letlhal dose being less. 3Butyn.35Experimentally butyn appears, in the hands of four independent workers, to be of toxicity equal to cocaine or rather more toxic.Many of the experiments were done with strong solutions, and there seems some evidence that with weak solutions the toxicity of butyn is less reduced than that of cocaine-that is, its relative toxicity is greater.It is said to have special advantages in eye work.39In the nose it seems an effective aniaesthetic, but more irritant than cocaine."4By courtesy of the proprietors I have received niotes of five deaths following its clinical applications: two for septal resection-5 per cent.solution on tampon; two for tonsil operation*-1/4 per cent.solution injected-no evidence of overdose; one case of definite overdose.Obviously considerable caution is required in using it.Note on Atoxodyne.The claim of this anaesthetic to be without toxicity was found to have no foundation: the toxicity is low.It appears useless on mucous surfaces. Summary.1.The toxicity of various local anaesthetics was com- pared experimentally by determining the minimal lethal doses.2. The effect of dilution was found to be a lowering of toxicity.3. Addition of adrenaline definitely lowered toxicity.4. It appears that the dose of ailaesthetic which will pro- duce alarming symptoms is with different drugs a different fraction of the M.L.D., cocaine having a small fraction, for example, butyn a larger.5. Caution is required in using butyn.RFFERENCES.
Using Electronic Medical Record Data and Block Group Level Estimates of Poverty to Investigate the Association between Socioeconomic Status and Bloodstream Infection Among Pediatric Patients with Acute Leukemia
Authors: Lanair Amaad Lett, Kelly D Getz, Evanette Burrows, Tyler Galvelis, Joseph P. Horowitz, Lena E. Winestone, Alix E. Seif, Brian T Fisher, Richard Aplenc
Journal: Blood (2017)
P-215 Outcomes following surgery for resectable pancreatic neuroendocrine tumors: A Brazilian single institutional experience
Authors: D. Arra, J. Menezes, G. Henklain, E. Fachin, H. de Castro Ribeiro, W. Costa, A. Godoy, S. Torres, I. Farias, N. Marques, A. Diniz, F. Fernandez Coimbra
Journal: Annals of Oncology (2021)
Global Prevalence of Depressive and Anxiety Symptoms in Children and Adolescents During COVID-19
Authors: Nicole Racine, Brae Anne McArthur, Jessica E. Cooke, Rachel Eirich, Jenney Zhu, Sheri Madigan
Journal: JAMA Pediatrics (2021)

Emerging research suggests that the global prevalence of child and adolescent mental illness has increased considerably during COVID-19. However, substantial variability in prevalence rates have been reported across the literature.
Bone mineral density surveillance for childhood, adolescent, and young adult cancer survivors: evidence-based recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group
Authors: Jenneke E van Atteveld, Renée L Mulder, Marry M van den Heuvel-Eibrink, Melissa M Hudson, Leontien C M Kremer, Roderick Skinner, W Hamish Wallace, Louis S Constine, Claire E Higham, Sue C Kaste, Riitta Niinimäki, Sogol Mostoufi-Moab, Nathalie Alos, Danilo Fintini, Kimberly J Templeton, Leanne M Ward, Eva Frey, Roberto Franceschi, Vesna Pavasovic, Seth E Karol, Nadia L Amin, Lynda M Vrooman, Arja Harila-Saari, Charlotte Demoor-Goldschmidt, Robert D Murray, Edit Bardi, Maarten H Lequin, Maria Felicia Faienza, Olga Zaikova, Claire Berger, Stefano Mora, Kirsten K Ness, Sebastian J C M M Neggers, Saskia M F Pluijm, Jill H Simmons, Natascia Di Iorgi
Journal: The Lancet Diabetes & Endocrinology (2021)
Simple models to include influenza vaccination history when evaluating the effect of influenza vaccination
Authors: Iván Martínez-Baz, Ana Navascués, Itziar Casado, Aitziber Aguinaga, Carmen Ezpeleta, Jesús Castilla
Journal: Eurosurveillance (2021)

Background Most reports of influenza vaccine effectiveness consider current-season vaccination only. Aim We evaluated a method to estimate the effect of influenza vaccinations (EIV) considering vaccination history. Methods We used a test-negative design with well-documented vaccination history to evaluate the average EIV over eight influenza seasons (2011/12–2018/19; n = 10,356). Modifying effect was considered as difference in effects of vaccination in current and previous seasons and current-season vaccination only. We also explored differences between current-season estimates excluding from the reference category people vaccinated in any of the five previous seasons and estimates without this exclusion or only for one or three previous seasons. Results The EIV was 50%, 45% and 38% in people vaccinated in the current season who had previously received none, one to two and three to five doses, respectively, and it was 30% and 43% for one to two and three to five prior doses only. Vaccination in at least three previous seasons reduced the effect of current-season vaccination by 12 percentage points overall, 31 among outpatients, 22 in 9–65 year-olds, and 23 against influenza B. Including people vaccinated in previous seasons only in the unvaccinated category underestimated EIV by 9 percentage points on average (31% vs 40%). Estimates considering vaccination of three or five previous seasons were similar. Conclusions Vaccine effectiveness studies should consider influenza vaccination in previous seasons, as it can retain effect and is often an effect modifier. Vaccination status in three categories (current season, previous seasons only, unvaccinated) reflects the whole EIV.
Hypoxia Promotes Breast Cancer Cell Growth by Activating a Glycogen Metabolic Program
Authors: Ke Tang, Liyan Zhu, Jie Chen, Dianheng Wang, Liping Zeng, Chen Chen, Liang Tang, Li Zhou, Keke Wei, Yabo Zhou, Jiadi Lv, Yuying Liu, Huafeng Zhang, Jingwei Ma, Bo Huang
Journal: Cancer Research (2021)

Abstract Hypoxia is known to be commonly present in breast tumor microenvironments. Stem-like cells that repopulate breast tumors, termed tumor-repopulating cells (TRC), thrive under hypoxic conditions, but the underlying mechanism remains unclear. Here, we show that hypoxia promotes the growth of breast TRCs through metabolic reprogramming. Hypoxia mobilized transcription factors HIF1α and FoxO1 and induced epigenetic reprogramming to upregulate cytosolic phosphoenolpyruvate carboxykinase (PCK1), a key enzyme that initiates gluconeogenesis. PCK1 subsequently triggered retrograde carbon flow from gluconeogenesis to glycogenesis, glycogenolysis, and the pentose phosphate pathway. The resultant NADPH facilitated reduced glutathione production, leading to a moderate increase of reactive oxygen species that stimulated hypoxic breast TRC growth. Notably, this metabolic mechanism was absent in differentiated breast tumor cells. Targeting PCK1 synergized with paclitaxel to reduce the growth of triple-negative breast cancer (TNBC). These findings uncover an altered glycogen metabolic program in breast cancer, providing potential metabolic strategies to target hypoxic breast TRCs and TNBC. Significance: Hypoxic breast cancer cells trigger self-growth through PCK1-mediated glycogen metabolism reprogramming that leads to NADPH production to maintain a moderate ROS level.
A comprehensive analysis of the efficacy and safety of COVID-19 vaccines
Authors: Changjing Cai, Yinghui Peng, Edward Shen, Qiaoqiao Huang, Yihong Chen, Ping Liu, Cao Guo, Ziyang Feng, Le Gao, Xiangyang Zhang, Yan Gao, Yihan Liu, Ying Han, Shan Zeng, Hong Shen
Journal: Molecular Therapy (2021)

The numbers of cases and deaths from coronavirus disease 2019 (COVID-19) are continuously increasing. Many people are concerned about the efficacy and safety of the COVID-19 vaccines. We performed a comprehensive analysis of the published trials of COVID-19 vaccines and the real-world data from the Vaccine Adverse Event Reporting System. Globally, our research found that the efficacy of all vaccines exceeded 70%, and RNA-based vaccines had the highest efficacy of 94.29%; moreover, Black or African American people, young people, and males may experience greater vaccine efficacy. The spectrum of vaccine-related adverse drug reactions (ADRs) is extremely broad, and the most frequent ADRs are pain, fatigue, and headache. Most ADRs are tolerable and are mainly grade 1 or 2 in severity. Some severe ADRs have been identified (thromboembolic events, 21-75 cases per million doses; myocarditis/pericarditis, 2-3 cases per million doses). In summary, vaccines are a powerful tool that can be used to control the COVID-19 pandemic, with high efficacy and tolerable ADRs. In addition, the spectrum of ADRs associated with the vaccines is broad, and most of the reactions appear within a week, although some may be delayed. Therefore, ADRs after vaccination need to be identified and addressed in a timely manner.
A comprehensive RNA editome reveals that edited <i>Azin1</i> partners with DDX1 to enable hematopoietic stem cell differentiation
Authors: Fengjiao Wang, Jiahuan He, Siqi Liu, Ai Gao, Liu Yang, Guohuan Sun, Wanqiu Ding, Chuan-Yun Li, Fanglin Gou, Manman He, Fang Wang, Xiaoshuang Wang, Xiangnan Zhao, Ping Zhu, Sha Hao, Yanni Ma, Hui Cheng, Jia Yu, Tao Cheng
Journal: Blood (2021)
De-intensification in older people with type 2 diabetes: why, when and for whom?
Authors: Samuel Seidu, Mansha Seewoodharry, Kamlesh Khunti
Journal: The Lancet Healthy Longevity (2021)

As a result of the dwindling physiological reserves in ageing, medication pharmacokinetics, pharmacodynamics, efficacy, and side-effects differ substantially among people in older age groups compared with those in younger age groups. This decline in physiological capacity worsens gradually until the end of life. Most guidelines on type 2 diabetes treatment are based on clinical trials done in carefully selected younger patients, and therefore implementation of practices based on these findings in older populations might not yield the desired effectiveness.