tbuckley/cabot-search huggingface dataset:
Development of microRNA-21 mimic nanocarriers for the treatment of cutaneous wounds
Authors: Sun Young Wang, Hyosuk Kim, Gijung Kwak, Sung Duk Jo, Daeho Cho, Yoosoo Yang, Ick Chan Kwon, Ji Hoon Jeong, Sun Hwa Kim
Journal: Theranostics (2020)

Rationale: Of the regulatory microRNAs expressed in the wounded skin, microRNA-21 (miR21) plays a pivotal role in wound repair by stimulating re-epithelialization, an essential feature to facilitate healing and reduce scar formation.Despite their crucial roles in wound healing, synthetic exogenous microRNAs have limited applications owing to the lack of an appropriate delivery system.Herein, we designed an miR21 mimic nanocarrier system using facial amphipathic bile acid-conjugated polyethyleneimines (BA-PEI) for the intracellular and transdermal delivery of synthetic miR21 molecules to accelerate wound repair.Methods: To design miR21 mimic nanocarriers, BA-conjugated PEIs prepared from three different types of BA at molar feed ratios of 1 and 3 were synthesized.The intracellular uptake efficiency of synthetic miR21 mimics was studied using confocal laser scanning microscopy and flow cytometry analysis.The optimized miR21/BA nanocarrier system was used to evaluate the wound healing effects induced by miR21 mimics in human HaCaT keratinocytes in vitro and a murine excisional acute wound model in vivo.Results: The cell uptake efficiency of miR21 complexed with BA-conjugated PEI was dramatically higher than that of miR21 complexed with PEI alone.Deoxycholic acid (DA)-modified PEI at a molar feed ratio of 3:1 (DA3-PEI) showed the highest transfection efficiency for miR21 without any increase in toxicity.After effective transdermal and intracellular delivery of miR21/DA3 nanocarriers, miR21 mimics promoted cell migration and proliferation through the post-transcriptional regulation of programmed cell death protein 4 (PDCD4) and matrix metalloproteinases.Thus, miR21 mimic nanocarriers improved both the rate and quality of wound healing, as evident from enhanced collagen synthesis and accelerated wound re-epithelialization. Conclusion: Our miRNA nanocarrier systems developed using DA3-PEI conjugates may be potentially useful for the delivery of synthetic exogenous miRNAs in various fields.
Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework
Authors: Sarah E. Brnich, Ahmad N. Abou Tayoun, Fergus J. Couch, Garry R. Cutting, Marc S. Greenblatt, Christopher D. Heinen, Dona M. Kanavy, Xi Luo, Shannon M. McNulty, Lea M. Starita, Sean V. Tavtigian, Matt W. Wright, Steven M. Harrison, Leslie G. Biesecker, Jonathan S. Berg
Journal: Genome Medicine (2019)

Abstract Background The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) clinical variant interpretation guidelines established criteria for different types of evidence. This includes the strong evidence codes PS3 and BS3 for “well-established” functional assays demonstrating a variant has abnormal or normal gene/protein function, respectively. However, they did not provide detailed guidance on how functional evidence should be evaluated, and differences in the application of the PS3/BS3 codes are a contributor to variant interpretation discordance between laboratories. This recommendation seeks to provide a more structured approach to the assessment of functional assays for variant interpretation and guidance on the use of various levels of strength based on assay validation. Methods The Clinical Genome Resource (ClinGen) Sequence Variant Interpretation (SVI) Working Group used curated functional evidence from ClinGen Variant Curation Expert Panel-developed rule specifications and expert opinions to refine the PS3/BS3 criteria over multiple in-person and virtual meetings. We estimated the odds of pathogenicity for assays using various numbers of variant controls to determine the minimum controls required to reach moderate level evidence. Feedback from the ClinGen Steering Committee and outside experts were incorporated into the recommendations at multiple stages of development. Results The SVI Working Group developed recommendations for evaluators regarding the assessment of the clinical validity of functional data and a four-step provisional framework to determine the appropriate strength of evidence that can be applied in clinical variant interpretation. These steps are as follows: (1) define the disease mechanism, (2) evaluate the applicability of general classes of assays used in the field, (3) evaluate the validity of specific instances of assays, and (4) apply evidence to individual variant interpretation. We found that a minimum of 11 total pathogenic and benign variant controls are required to reach moderate-level evidence in the absence of rigorous statistical analysis. Conclusions The recommendations and approach to functional evidence evaluation described here should help clarify the clinical variant interpretation process for functional assays. Further, we hope that these recommendations will help develop productive partnerships with basic scientists who have developed functional assays that are useful for interrogating the function of a variety of genes.
PI3K/AKT inhibition reverses R-CHOP resistance by destabilizing SOX2 in diffuse large B cell lymphoma
Authors: Jianfeng Chen, Xiaowen Ge, Wei Zhang, Peipei Ding, Yiqun Du, Qi Wang, Ling Li, Lan Fang, Yujing Sun, Pingzhao Zhang, Yuzhen Zhou, Long Zhang, Xinyue Lv, Luying Li, Xin Zhang, Qunling Zhang, Kai Xue, Hongyu Gu, Qunying Lei, Jiemin Wong, Weiguo Hu
Journal: Theranostics (2020)

Up to one-third of diffuse large B cell lymphoma (DLBCL) patients eventually develop resistance to R-CHOP regimen, while the remaining therapeutic options are limited. Thus, understanding the underlying mechanisms and developing therapeutic approaches are urgently needed. Methods: We generated two germinal center B cell-like (GCB) and activated B cell-like (ABC) subtype R-CHO resistant DLBCL cell lines, of which the tumor-initiating capacity was evaluated by serial-transplantation and stemness-associated features including CD34 and CD133 expression, side population and ALDH1 activity were detected by flow cytometry or immunoblotting. Expression profiles of these resistant cells were characterized by RNA sequencing. The susceptibility of resistant cells to different treatments was evaluated by in vitro CytoTox-glo assay and in tumor-bearing mice. The expression levels of SOX2, phos-AKT, CDK6 and FGFR1/2 were detected in 12 R-CHOP-resistant DLBCL clinical specimens by IHC. Results: The stem-like CSC proportion significantly increased in both resistant DLBCL subtypes. SOX2 expression level remarkably elevated in both resistant cell lines due to its phosphorylation by activated PI3K/AKT signaling, thus preventing ubiquitin-mediated degradation. Further, multiple factors, including BCR, integrins, chemokines and FGFR1/2 signaling, regulated PI3K/AKT activation. CDK6 in GCB subtype and FGFR1/2 in ABC subtype were SOX2 targets, whose inhibition potently re-sensitized resistant cells to R-CHOP treatment. More importantly, addition of PI3K inhibitor to R-CHOP completely suppressed the tumor growth of R-CHO-resistant DLBCL cells, most likely by converting CSCs to chemo-sensitive differentiated cells. Conclusions: The PI3K/AKT/SOX2 axis plays a critical role in R-CHOP resistance development and the pro-differentiation therapy against CSCs proposed in this study warrants further study in clinical trials for the treatment of resistant DLBCL.
Abstract PD2-03: CDK4/6 inhibitor-resistant ER+ breast cancer cell lines are hypersensitive to TTK inhibition
Authors: Isabel Soria Bretones, Kelsie L Thu, Jennifer Silvester, Reza Kiarash, Graham C Fletcher, Jennifer Cruickshank, Mark R Bray, Tak W Mak, David W Cescon
Journal: Cancer Research (2020)

Abstract Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i), in combination with hormonal therapies, have become standard of care for the treatment of estrogen receptor-positive (ER+)/HER2-negative metastatic breast cancer. Despite demonstrating significant improvements in progression-free survival, acquired resistance to these inhibitors invariably develops. Recent analyses of clinical samples have identified emergent genomic alterations conferring acquired resistance to CDK4/6i, and begin to define the biology of this new clinical entity. Discovery of vulnerabilities of CDK4/6i-resistant tumours is imperative to improve the survival of this group of patients. We modeled CDK4/6i resistance in ER+ breast cancer cell lines using two complementary approaches: (1) spontaneous development of resistance upon continuous exposure to the palbociclib for 6-9 months, and (2) genetic engineering of RB1 loss of function. In both cases, palbociclib resistance was confirmed by colony formation and cell proliferation assays. To identify potential therapeutic strategies for CDK4/6i-resistant cells, we tested the in vitro activity of novel cell cycle inhibitors using sulforhodamine B (SRB) cytotoxicity assays. CFI-402257, a selective TTK inhibitor now in Phase I testing, induced significantly increased cytotoxicity in different CDK4/6i-resistant models compared to parental cell lines, including but not exclusively those with RB1 loss. CFI-402257 treatment caused defects in cell cycle progression and increased DNA damage and genomic instability in CDK4/6i-resistant cells, while these effects were mild in parental, CDK4/6i-sensitive cell lines. In some cases, these phenotypes were accompanied by an increase in apoptotic signaling. Analysis of the molecular determinants of these effects are being evaluated (additional results will be presented). In xenografts derived from MCF7 cells, CFI-402257 treatment completely abrogated the growth of RB1-KO tumours and had a much less pronounced effect on wild-type tumours. In summary, our results nominate the TTK inhibitor CFI-402257 as a promising therapeutic strategy for breast cancer patients who progress after CDK4/6 inhibition. A clinical trial testing this strategy is being launched. Citation Format: Isabel Soria Bretones, Kelsie L Thu, Jennifer Silvester, Reza Kiarash, Graham C Fletcher, Jennifer Cruickshank, Mark R Bray, Tak W Mak, David W Cescon. CDK4/6 inhibitor-resistant ER+ breast cancer cell lines are hypersensitive to TTK inhibition [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD2-03.
Response to: ‘Total adenosine deaminase highly correlated with adenosine deaminase 2 activity in serum’ by Gao <i>et al</i>
Authors: Pui Y Lee, Zhengping Huang, Michael S Hershfield, Peter A Nigrovic
Journal: Annals of the Rheumatic Diseases (2020)

Figure 1 Evaluation of ADA1, ADA2 and tADA in healthy subjects.(A) Correlation between plasma ADA2 activity and tADA activity in 294 healthy individuals (174 children under age 18 years and 120 adults).(B) Comparison of ADA1, ADA2 and tADA in 294 healthy individuals.Median and IQR are displayed in scatter dot plots.(C) Comparison of plasma ADA1 levels and (D) fraction of ADA1 in tADA (ADA1/ tADAx100%) in children and adults.Median and IQR are displayed in scatter dot plots.(E) Correlation between plasma ADA1 activity and ADA2 activity in children (blue; n=174) and adults (red; n=120).(F) ADA1 activity in the supernatant of healthy donor PBMC stimulated with cytokines or Toll-like receptor ligands for 5 days.Dots represent results from three to five healthy donors per condition.(G) Impact of haemolysis on plasma ADA1, ADA2 and tADA levels.Bars represent mean and error bars present SD of duplicate samples.ADA, adenosine deaminase; IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; PAM, Pam3CSK4; PBMC, peripheral blood mononuclear cells; tADA, total adenosine deaminase; TNF, tumour necrosis factor.
Spatiotemporal regulation of type I interferon expression determines the antiviral polarization of CD4+ T cells
Authors: Marco De Giovanni, Valeria Cutillo, Amir Giladi, Eleonora Sala, Carmela G. Maganuco, Chiara Medaglia, Pietro Di Lucia, Elisa Bono, Claudia Cristofani, Eleonora Consolo, Leonardo Giustini, Alessandra Fiore, Sarah Eickhoff, Wolfgang Kastenmüller, Ido Amit, Mirela Kuka, Matteo Iannacone
Journal: Nature Immunology (2020)
Evaluation of long-term efficacy, safety, and reasons for discontinuation of dupilumab for moderate to severe atopic dermatitis in clinical practice: A retrospective cohort study
Authors: Christine E. Jo, Jorge R. Georgakopoulos, Matthew Ladda, Arvin Ighani, Asfandyar Mufti, Aaron M. Drucker, Vincent Piguet, Jensen Yeung
Journal: Journal of the American Academy of Dermatology (2020)
The Value of All-Cause Mortality as a Metric for Assessing Breast Cancer Screening
Authors: Martin J Yaffe, James G Mainprize
Journal: JNCI Journal of the National Cancer Institute (2020)

Although screening mammography has been demonstrated to contribute to reducing mortality due to breast cancer, some have suggested that reduced all-cause mortality should constitute the burden of proof for effectiveness. Using a microsimulation model of the development, detection, and treatment of breast cancer, it is straightforward to demonstrate that this is an unrealistic expectation for trials of practical size and period of observation, even where the reduction of breast cancer mortality is substantial. Estimates of all-cause mortality will depend not only on the efficacy of the screening intervention but also on the alignment between the age distribution of the effect of screening on reduction of deaths and that of the other major causes of death. The size of a randomized trial required to demonstrate a reduction in all-cause mortality will, therefore, depend on the length and timing of the observation period and will typically be at least 10 times larger than the size of a trial powered to test for a reduction in deaths due to breast cancer. For breast cancer, which represents a small fraction of overall deaths, all-cause mortality is neither a practical nor informative metric for assessing the effectiveness of screening.
Underexplored Heterogeneity and Publication Bias for the Electronic Cigarette and Marijuana Use Association
Authors: Guan Wang, Yang Wang, Wenquan Niu
Journal: JAMA Pediatrics (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Tumor-derived soluble CD155 inhibits DNAM-1–mediated antitumor activity of natural killer cells
Authors: Genki Okumura, Akiko Iguchi-Manaka, Rikito Murata, Yumi Yamashita-Kanemaru, Akira Shibuya, Kazuko Shibuya
Journal: The Journal of Experimental Medicine (2020)

CD155 is a ligand for DNAM-1, TIGIT, and CD96 and is involved in tumor immune responses. Unlike mouse cells, human cells express both membranous CD155 and soluble CD155 (sCD155) encoded by splicing isoforms of CD155. However, the role of sCD155 in tumor immunity remains unclear. Here, we show that, after intravenous injection with sCD155-producing B16/BL6 melanoma, the numbers of tumor colonies in wild-type (WT), TIGIT knock-out (KO), or CD96 KO mice, but not DNAM-1 KO mice, were greater than after injection with parental B16/BL6 melanoma. NK cell depletion canceled the difference in the numbers of tumor colonies in WT mice. In vitro assays showed that sCD155 interfered with DNAM-1–mediated NK cell degranulation. In addition, DNAM-1 had greater affinity than TIGIT and CD96 for sCD155, suggesting that sCD155 bound preferentially to DNAM-1. Together, these results demonstrate that sCD155 inhibits DNAM-1–mediated cytotoxic activity of NK cells, thus promoting the lung colonization of B16/BL6 melanoma.
Making the most of a palliative care experience
Authors: Laura Jayne Beeley, Sarah Winfield, Deborah Adams
Journal: BMJ (2020)

At some point in their training, most medical students will encounter palliative care during their placements. In the UK nearly half of all deaths happen in hospital and therefore end of life care is a core skill for junior doctors.1 This article outlines the importance and relevance of palliative care and offers advice on how to use a palliative care placement to optimise the future management of patients who are nearing the end of life.

Palliative care is more than caring for patients at the end of life. It is an approach to terminal illness that focuses on holistic, individualised care and symptom control, rather than cure or prolonging life.2 Palliative care teams support patients with incurable chronic diseases or life limiting illnesses. Adult palliative care teams can attend to patients from age 16 upwards. Although many of the patients will have cancer, the teams also support those with incurable, progressive conditions, such as heart failure, chronic respiratory disease (chronic obstructive pulmonary disease, fibrosis), progressive neurological disease (motor neurone disease, dementia), and end stage renal and liver failure.

You might be exposed to palliative care during many of your medical school placements, particularly general practice and medical specialties such as respiratory or geriatric medicine. Although doctors and nurses often provide palliative care without being specialists in the discipline, you might spend time with dedicated palliative care specialists in a variety of settings.

You could be placed in a hospice, an establishment dedicated to supporting patients receiving palliative care and their families and friends.3 Services offered by hospices are variable; some have only outpatient …
Skipping Nonsense to Maintain Function: The Paradigm of <i>BRCA2</i> Exon 12
Authors: Laëtitia Meulemans, Romy L.S. Mesman, Sandrine M. Caputo, Sophie Krieger, Marine Guillaud-Bataille, Virginie Caux-Moncoutier, Mélanie Léone, Nadia Boutry-Kryza, Johanna Sokolowska, Françoise Révillion, Capucine Delnatte, Hélène Tubeuf, Omar Soukarieh, Françoise Bonnet-Dorion, Virginie Guibert, Myriam Bronner, Violaine Bourdon, Sarab Lizard, Paul Vilquin, Maud Privat, Aurélie Drouet, Charlotte Grout, Fabienne M.G.R. Calléja, Lisa Golmard, Harry Vrieling, Dominique Stoppa-Lyonnet, Claude Houdayer, Thierry Frebourg, Maaike P.G. Vreeswijk, Alexandra Martins, Pascaline Gaildrat
Journal: Cancer Research (2020)

Germline nonsense and canonical splice site variants identified in disease-causing genes are generally considered as loss-of-function (LoF) alleles and classified as pathogenic. However, a fraction of such variants could maintain function through their impact on RNA splicing. To test this hypothesis, we used the alternatively spliced BRCA2 exon 12 (E12) as a model system because its in-frame skipping leads to a potentially functional protein. All E12 variants corresponding to putative LoF variants or predicted to alter splicing (n = 40) were selected from human variation databases and characterized for their impact on splicing in minigene assays and, when available, in patient lymphoblastoid cell lines. Moreover, a selection of variants was analyzed in a mouse embryonic stem cell-based functional assay. Using these complementary approaches, we demonstrate that a subset of variants, including nonsense variants, induced in-frame E12 skipping through the modification of splice sites or regulatory elements and, consequently, led to an internally deleted but partially functional protein. These data provide evidence, for the first time in a cancer-predisposition gene, that certain presumed null variants can retain function due to their impact on splicing. Further studies are required to estimate cancer risk associated with these hypomorphic variants. More generally, our findings highlight the need to exercise caution in the interpretation of putative LoF variants susceptible to induce in-frame splicing modifications. SIGNIFICANCE: This study presents evidence that certain presumed loss-of-function variants in a cancer predisposition gene can retain function due to their direct impact on RNA splicing.
Abstract P4-17-07: Demographics and survival in male breast cancer: An updated analysis of SEER database
Authors: John Khoury, Nwabundo Anusim, David Macari, Ishmael Jaiyesimi
Journal: Cancer Research (2020)

Abstract Background: Male breast cancer is rare accounting for less than 0.5% of all cancer diagnoses in men. Previous epidemiological studies reported conflicting results regarding the prognosis of male breast cancer in comparison to female breast cancer. As treatment for breast cancer has improved significantly, we conducted this study to evaluate male breast cancer characteristics and mortality. Methods: All patients diagnosed with breast cancer between 2010 and 2015 from the population-based cancer registries of the Surveillance Epidemiology and End Results program (SEER) were analyzed. Descriptive statistics, Kaplan-Meier analysis and COX regression model were used to examine the data. Results: A total of 380,116 cases of breast cancer were found including 2,978 cases of male breast cancer. The age-adjusted incidence rate for male breast cancer during the study period was 1.2 per 100,000 individuals per year which is slightly higher than the rate during the 10 years period preceding our study date (1.1 per 100,000 per year). Out of all male breast cancer patients, 80.7% of them were white, 14.6% black and 4.7% from other races. The median age of diagnosis was 68. 34% of male breast cancer patients were diagnosed with stage I, 41.6% with stage II, 16.2% with stage III and 8.2% with stage IV. 97% of male breast cancer cases were ER/PR positive and 11.9% were HER2 positive. 5-year survival rate for male breast cancer patients was 90% for stage I, 86% for stage II, 78% for stage III and 28% for stage IV. Cox proportional-hazards model revealed a slight increase in mortality associated with male breast cancer in comparison to female breast cancer (adjusted hazard ratio, 1.15; 95% confidence interval, 1.06 to 1.24; P&amp;lt;0.01). Conclusions: Male breast cancer represents less than 1% of breast cancer cases. Its age-adjusted incidence rate has slightly increased. It is mostly diagnosed as early stage with positive hormone receptors status. After controlling for other risk factors, male breast cancer patients have a worse survival outcome than female patients. Citation Format: John Khoury, Nwabundo Anusim, David Macari, Ishmael Jaiyesimi. Demographics and survival in male breast cancer: An updated analysis of SEER database [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-17-07.