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1دورية أكاديمية
المؤلفون: Clarissa Wormsbaecher, Andrea R. Hindman, Alex Avendano, Marcos Cortes-Medina, Caitlin E. Jones, Andrew Bushman, Lotanna Onua, Claire E. Kovalchin, Alina R. Murphy, Hannah L. Helber, Ali Shapiro, Kyle Voytovitch, Xingyan Kuang, Renan Aguilar-Valenzuela, Jennifer L. Leight, Jonathan W. Song, Craig J. Burd
المصدر: Breast Cancer Research, Vol 22, Iss 1, Pp 1-12 (2020)
مصطلحات موضوعية: Bisphenol A, Bisphenol S, Diethylstilbestrol, Endocrine disruptors, Breast cancer, Collagen, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: Abstract Background In utero endocrine disruption is linked to increased risk of breast cancer later in life. Despite numerous studies establishing this linkage, the long-term molecular changes that predispose mammary cells to carcinogenic transformation are unknown. Herein, we investigated how endocrine disrupting compounds (EDCs) drive changes within the stroma that can contribute to breast cancer susceptibility. Methods We utilized bisphenol A (BPA) as a model of estrogenic endocrine disruption to analyze the long-term consequences in the stroma. Deregulated genes were identified by RNA-seq transcriptional profiling of adult primary fibroblasts, isolated from female mice exposed to in utero BPA. Collagen staining, collagen imaging techniques, and permeability assays were used to characterize changes to the extracellular matrix. Finally, gland stiffness tests were performed on exposed and control mammary glands. Results We identified significant transcriptional deregulation of adult fibroblasts exposed to in utero BPA. Deregulated genes were associated with cancer pathways and specifically extracellular matrix composition. Multiple collagen genes were more highly expressed in the BPA-exposed fibroblasts resulting in increased collagen deposition in the adult mammary gland. This transcriptional reprogramming of BPA-exposed fibroblasts generates a less permeable extracellular matrix and a stiffer mammary gland. These phenotypes were only observed in adult 12-week-old, but not 4-week-old, mice. Additionally, diethylstilbestrol, known to increase breast cancer risk in humans, also increases gland stiffness similar to BPA, while bisphenol S does not. Conclusions As breast stiffness, extracellular matrix density, and collagen deposition have been directly linked to breast cancer risk, these data mechanistically connect EDC exposures to molecular alterations associated with increased disease susceptibility. These alterations develop over time and thus contribute to cancer risk in adulthood.
وصف الملف: electronic resource
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المؤلفون: Caitlin E. Jones, Joe T. Sharick, Steven T. Sizemore, Edna Cukierman, Anne Marie Strohecker, Jennifer L. Leight
المصدر: Cancer Res Commun
مصطلحات موضوعية: Article
الوصف: Extracellular matrix (ECM) alignment contributes to metastasis in a number of cancers and is a known prognostic stromal factor; however, the mechanisms controlling matrix organization remain unclear. Cancer-associated fibroblasts (CAF) play a critical role in this process, particularly via matrix production and modulation of key signaling pathways controlling cell adhesion and contractility. Stroma normalization, as opposed to elimination, is a highly sought strategy, and screening for drugs that effectively alter ECM alignment is a practical way to identify novel CAF-normalizing targets that modulate ECM organization. To meet this need, we developed a novel high-throughput screening platform in which fibroblast-derived matrices were produced in 384-well plates, imaged with automated confocal microscopy, and analyzed using a customized MATLAB script. This platform is a technical advance because it miniaturizes the assay, eliminates costly and time-consuming experimental steps, and streamlines data acquisition and analysis to enable high-throughput screening applications. As a proof of concept, this platform was used to screen a kinase inhibitor library to identify modulators of matrix alignment. A number of novel potential regulators were identified, including several receptor tyrosine kinases [c-MET, tropomyosin receptor kinase 1 (NTRK1), HER2/ERBB2] and the serine/threonine kinases protein kinase A, C, and G. The expression of these regulators was analyzed in publicly available patient datasets to examine the association between stromal gene expression and patient outcomes. Significance: ECM fiber organization and alignment contribute to metastasis in a number of cancers and are a known prognostic stromal factor; however, the mechanisms controlling matrix organization remain unclear. Here, a high-throughput assay was developed to enable discovery-based screening for an in vitro ECM fiber alignment assay. As proof of concept, this platform was used to screen a kinase inhibitor library and identified several novel modulators of matrix alignment.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e19fe1b401d9f4dcf162758322d1d313
https://doi.org/10.1158/2767-9764.crc-22-0157 -
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المؤلفون: Jennifer L. Leight, Anne Marie Strohecker, Edna Cukierman, Steven T. Sizemore, Joe T. Sharick, Caitlin E. Jones
الوصف: Figure S1, S2, S3, Table S1 and S2
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::470a2199c9615c25a9055293c1b0d24a
https://doi.org/10.1158/2767-9764.22546143.v1 -
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المؤلفون: Jennifer L. Leight, Anne Marie Strohecker, Edna Cukierman, Steven T. Sizemore, Joe T. Sharick, Caitlin E. Jones
الوصف: Extracellular matrix (ECM) alignment contributes to metastasis in a number of cancers and is a known prognostic stromal factor; however, the mechanisms controlling matrix organization remain unclear. Cancer-associated fibroblasts (CAF) play a critical role in this process, particularly via matrix production and modulation of key signaling pathways controlling cell adhesion and contractility. Stroma normalization, as opposed to elimination, is a highly sought strategy, and screening for drugs that effectively alter ECM alignment is a practical way to identify novel CAF-normalizing targets that modulate ECM organization. To meet this need, we developed a novel high-throughput screening platform in which fibroblast-derived matrices were produced in 384-well plates, imaged with automated confocal microscopy, and analyzed using a customized MATLAB script. This platform is a technical advance because it miniaturizes the assay, eliminates costly and time-consuming experimental steps, and streamlines data acquisition and analysis to enable high-throughput screening applications. As a proof of concept, this platform was used to screen a kinase inhibitor library to identify modulators of matrix alignment. A number of novel potential regulators were identified, including several receptor tyrosine kinases [c-MET, tropomyosin receptor kinase 1 (NTRK1), HER2/ERBB2] and the serine/threonine kinases protein kinase A, C, and G. The expression of these regulators was analyzed in publicly available patient datasets to examine the association between stromal gene expression and patient outcomes.Significance:ECM fiber organization and alignment contribute to metastasis in a number of cancers and are a known prognostic stromal factor; however, the mechanisms controlling matrix organization remain unclear. Here, a high-throughput assay was developed to enable discovery-based screening for an in vitro ECM fiber alignment assay. As proof of concept, this platform was used to screen a kinase inhibitor library and identified several novel modulators of matrix alignment.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::014d811363b82582fb69b125d15f4a0f
https://doi.org/10.1158/2767-9764.c.6551109 -
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المؤلفون: Christopher J.D. Wallis, Rashid K. Sayyid, Soum D. Lokeshwar, David Tella, Zachary Klaassen, Caitlin E. Jones, Phillip Woodruff, Michael D. Oberle
المصدر: Surgical Endoscopy. 36:2600-2606
مصطلحات موضوعية: medicine.medical_specialty, business.industry, MEDLINE, Ethnic group, Odds ratio, Logistic regression, law.invention, External validity, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, 030220 oncology & carcinogenesis, Family medicine, Cohort, medicine, 030211 gastroenterology & hepatology, Surgery, business
الوصف: Enrolment of racial/ethnic minorities in randomized controlled trials (RCTs) has historically been poor, despite efforts at improving access to RCTs. Under-representation of racial/ethnic minorities limits the external validity and generalizability of trials. Our objective was to determine to what extent are published RCTs of minimally invasive surgical techniques reporting the racial composition of their study cohorts and to describe the racial composition of patients enrolled in these trials, where data were available. EMBASE (OvidSP®), MEDLINE (OvidSP®), and Cochrane (Wiley®) databases were systematically searched from inception to December 22, 2017 to identify all RCTs comparing minimally invasive and classical surgical techniques. The Mann–Kendall trend test was used to evaluate reporting trends over the study period. Predictors of racial reporting were evaluated using logistic regression analyses. Our search strategy yielded 9,321 references of which 496 RCTs met our inclusion/exclusion criteria. Racial information was reported in 20 (4.03%) studies. There was no significant improvement in racial reporting over the study period (p for trend = 0.31). Of the 17 different patient populations accounting for the 20 RCTs, 14 (82.4%) originated from the USA. Multicenter RCTs had significantly increased likelihood of reporting racial composition of the patient cohort (odds ratio 5.10, p = 0.025). White/Caucasian patients accounted for 84.5% of the pooled patient population, with Black/African American, Asian and Latin/Hispanic patients accounting for 7.9%, 1.2%, and 2.1%, respectively. Among RCTs assessing minimally invasive surgical techniques over the past 30 years, data on included patients’ race is poorly reported. In addition to important efforts to improve access to clinical trials for racial and ethnic minorities, efforts aimed at improving reporting and transparency of surgical RCTs are sorely needed.
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المؤلفون: Tania K. Arora, Frank D. Lewis, Ayana Worthey, Chase J. Wehrle, Morgan Walker, Caitlin E. Jones
المصدر: Journal of Surgical Research. 260:95-103
مصطلحات موضوعية: Water-Electrolyte Imbalance, Staffing, Nurses, Tertiary care, Perioperative Care, 03 medical and health sciences, Fluid intake, 0302 clinical medicine, Cronbach's alpha, Patient Load, Humans, Medicine, Qualitative Research, business.industry, Perioperative, Focus Groups, medicine.disease, Focus group, 030220 oncology & carcinogenesis, Fluid Therapy, 030211 gastroenterology & hepatology, Surgery, Clinical Competence, Medical emergency, business, Surgical patients
الوصف: Surgeons depend on fluid intake and output (I/O) measurements for assessment of resuscitation and fluid balance during the perioperative period. Frequently, these measurements are taken by Registered Nurses (RNs) and/or Patient Care Technicians (PCTs). There is variability in the accuracy and consistency of these measurements across nursing units. The goal of this study is to establish what barriers exist in obtaining accurate fluid measurements and potential solutions.A mixed-method, sequential study design was utilized. First, a survey was conducted at a tertiary care institution of 8 nonintensive care nursing units assessing the perceptions of RNs (n = 85) and PCTs (n = 38) regarding fluid intake and output measurements for surgical patients. Four focus groups were then conducted to expand upon the results of the survey. Fourteen participants (10 RNs and 4 PCTs) were interviewed, and transcripts were analyzed by three reviewers. Qualitative data were manually coded by reviewers using a hierarchical methodology.Survey response rate was 40.6%. The strongest barriers in the survey were patient load and staff time limitations. About half (49%) of the respondents acknowledged that fluid measurements were inaccurate half of the time. PCTs spend more time collecting and charting I/Os and have higher patient loads (P 0.001) than RNs. PCTs noted more difficulty with complex patients (P = 0.017) and devices for outputs (P = 0.004). PCT's (94%) handwrite data prior to electronic entry. One-third of nurses reported direct electronic entry (P 0.001). Overall, 71% would prefer to chart in patient's rooms. Most (80%) of respondents received5 h of fluids-related training at the time they were hired. Cronbach's alpha for three focus group reviewers was 0.84 (95% CI 0.693-0.923). Themes included understaffing, lack of training, a high percentage of traveling nurses, and poor communication regarding new orders. Recommended solutions to improve I/Os included in-room kiosks for electronic entry and relief of staffing burdens.Fluid I/O measurement accuracy and efficiency may be improved by increased staffing, educational programs, and computer access, streamlining of order sets, simplicity of EMR data entry, and a standardized process for measuring, recording, and charting I/Os.
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المؤلفون: Chris Gillette, Edward H. Ip, Courtney J. Perry, Stefanie P. Ferreri, Caroline Grey Bell Sisson, Gayle B. Bodner, Samantha D. Rogers, Kirstin Manges, Caitlin E. Jones, Tiffany H. Rose, Kristin Lindaman, Nicole Ludwig, Sonia Crandall
المصدر: Research in socialadministrative pharmacy : RSAP. 19(1)
مصطلحات موضوعية: Physician Assistants, Psychometrics, Surveys and Questionnaires, Pharmaceutical Science, Humans, Reproducibility of Results, Pharmacy, Drug Prescriptions, Aged
الوصف: (1) Present the factor structure of two psychometric instruments for self-efficacy and one for outcome expectations of medication prescribing; (2) evaluate the reliability of the scales, and (3) present preliminary evidence of validity.Physician assistants (PA) and PA students completed a survey evaluating three psychometric instruments: (1) Self-Efficacy in Prescribing (SEP), (2) Self-Efficacy in Prescribing-Geriatric (SEPG), and (3) Outcomes Expectations of Prescribing Errors (OEP). Students also evaluated 3 hypothetical prescriptions, two of which contained a prescribing error. Students were instructed to identify (1) if an error occurred and (2) what type of error. The data were analyzed using parallel analysis with a varimax rotation, Cronbach's α, Pearson and Spearman correlations.One hundred eighty five (n = 185) respondents completed the survey (response rate = 63.8%). The parallel analysis found that the SEP had one 7-item factor with α = 0.94 (M = 5.7 (SD = 1.9) out of 10). The SEPG also had one 7-item factor with α = 0.95 (M = 5.5 (1.9). The OEP had one 6-item factor with α = 0.89 (M = 3.5 (SD = 0.8) out of 5). The SEP and SEPG, were correlated to the OEP each other (both p 0.01). Actively practicing PAs had the highest composite mean SEP and SEPG scores. First-year PA students had the highest mean scores for the OEP. There was a weak association between the mean SEPG score and the number of correctly identified prescriptions (rThe SEP, SEPG, and OEP show preliminary evidence of reliability and structural, construct, and known-group validities using simulated prescriptions. These tools may be able to be used by educators and implementation scientists as one method to show the effectiveness of future interventions to reduce incidence of prescribing errors.
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المؤلفون: Soum D. Lokeshwar, Christopher J.D. Wallis, Zachary Klaassen, Caitlin E. Jones, David Tella, Rashid K. Sayyid
المصدر: Journal of Clinical Epidemiology. 131:163-165
مصطلحات موضوعية: medicine.medical_specialty, Surgical approach, Impact factor, Epidemiology, business.industry, MEDLINE, Regression analysis, Outcome (game theory), Confidence interval, law.invention, 03 medical and health sciences, 0302 clinical medicine, Primary outcome, Randomized controlled trial, law, Internal medicine, Humans, Minimally Invasive Surgical Procedures, Medicine, 030212 general & internal medicine, business, Publication Bias, 030217 neurology & neurosurgery, Randomized Controlled Trials as Topic
الوصف: Objective To determine whether a positive primary outcome in randomized controlled trials of minimally invasive surgical techniques predicted publication in higher impact factor journals. Study Design and Setting A systematic review of EMBASE (OvidSP®), MEDLINE (OvidSP®), and Cochrane (Wiley®) databases from inception to December 22, 2017 was performed to identify all randomized controlled trials comparing minimally invasive and classical surgical techniques. Our primary study outcome was journal “corrected impact factor”, accounting for journal impact factor inflation over more recent publication years. Sensitivity analyses with impact factor operationalized in five additional ways was performed. Univariable and multivariable gamma regression analyses were used to evaluate the association of a positive primary outcome and journal “corrected impact factor”. Results 410 studies were identified. On multivariable gamma regression analysis, a positive primary outcome was not associated with a higher likelihood of publication in a higher impact factor journal (coefficient 1.05, 95% Confidence Interval 0.82-1.35, p= 0.66), with similar negative results consistently demonstrated in all sensitivity analyses performed. Conclusion In a systematic review of randomized controlled trials of minimally invasive surgical approaches over the last 20 years, we failed to find evidence that the minimally invasive surgical literature is subject to a positive outcome bias.
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المؤلفون: Andrew G. Lawson, Clive J. Miranda, Caitlin E. Jones, Mitra D. Poorak
المصدر: The American Surgeon. 87:645-647
مصطلحات موضوعية: Adult, Incidental Findings, medicine.medical_specialty, Hernia, business.industry, General surgery, General Medicine, Appendix, Appendicitis, Text mining, Appendectomy, Humans, Medicine, Female, Laparoscopy, Ovarian Diseases, business, Herniorrhaphy
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المؤلفون: Caitlin E. Jones, Gina M. Sizemore, Youjin Cho, Jennifer L. Leight, Anisha M. Hammer, Edna Cukierman, Lisa D. Yee, Samir N. Ghadiali, Michael C. Ostrowski
المصدر: Neoplasia: An International Journal for Oncology Research, Vol 21, Iss 1, Pp 132-145 (2019)
مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Stromal cell, biology, Chemistry, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Traction force microscopy, lcsh:RC254-282, Cell biology, Extracellular matrix, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Tumor progression, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, medicine, PTEN, Fibroblast, Extracellular matrix organization
الوصف: The organization of the extracellular matrix has a profound impact on cancer development and progression. The matrix becomes aligned throughout tumor progression, providing "highways" for tumor cell invasion. Aligned matrix is associated with breast density and is a negative prognostic factor in several cancers; however, the underlying mechanisms regulating this reorganization remain poorly understood. Deletion of the tumor suppressor Pten in the stroma was previously shown to promote extracellular matrix expansion and tumor progression. However, it was unknown if PTEN also regulated matrix organization. To address this question, a murine model with fibroblast-specific Pten deletion was used to examine how PTEN regulates matrix remodeling. Using second harmonic generation microscopy, Pten deletion was found to promote collagen alignment parallel to the mammary duct in the normal gland and further remodeling perpendicular to the tumor edge in tumor-bearing mice. Increased alignment was observed with Pten deletion in vitro using fibroblast-derived matrices. PTEN loss was associated with fibroblast activation and increased cellular contractility, as determined by traction force microscopy. Inhibition of contractility abrogated the increased matrix alignment observed with PTEN loss. Murine mammary adenocarcinoma cells cultured on aligned matrices derived from Pten-/- fibroblasts migrated faster than on matrices from wild-type fibroblasts. Combined, these data demonstrate that PTEN loss in fibroblasts promotes extracellular matrix deposition and alignment independently from cancer cell presence, and this reorganization regulates cancer cell behavior. Importantly, stromal PTEN negatively correlated with collagen alignment and high mammographic density in human breast tissue, suggesting parallel function for PTEN in patients.
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