tbuckley/cabot-search huggingface dataset:
Underdiagnosis of Hereditary Breast Cancer: Are Genetic Testing Guidelines a Tool or an Obstacle?
Authors: Peter D. Beitsch, Pat W. Whitworth, Kevin Hughes, Rakesh Patel, Barry Rosen, Gia Compagnoni, Paul Baron, Rache Simmons, Linda Ann Smith, Ian Grady, Michael Kinney, Cynara Coomer, Karen Barbosa, Dennis R. Holmes, Eric Brown, Linsey Gold, Patricia Clark, Lee Riley, Samuel Lyons, Antonio Ruiz, Sadia Kahn, Heather MacDonald, Lisa Curcio, Mary Kay Hardwick, Shan Yang, Ed D. Esplin, Robert L. Nussbaum
Journal: Journal of Clinical Oncology (2018)

Purpose An estimated 10% of breast and ovarian cancers result from hereditary causes. Current testing guidelines for germ line susceptibility genes in patients with breast carcinoma were developed to identify carriers of BRCA1/ 2 variants and have evolved in the panel-testing era. We evaluated the capability of the National Comprehensive Cancer Network (NCCN) guidelines to identify patients with breast cancer with pathogenic variants in expanded panel testing. Methods An institutional review board–approved multicenter prospective registry was initiated with 20 community and academic sites experienced in cancer genetic testing and counseling. Eligibility criteria included patients with a previously or newly diagnosed breast cancer who had not undergone either single- or multigene testing. Consecutive patients 18 to 90 years of age were consented and underwent an 80-gene panel test. Health Insurance Portability and Accountability Act–compliant electronic case report forms collected information on patient demographics, diagnoses, phenotypes, and test results. Results More than 1,000 patients were enrolled, and data records for 959 patients were analyzed; 49.95% met NCCN criteria, and 50.05% did not. Overall, 8.65% of patients had a pathogenic/likely pathogenic (P/LP) variant. Of patients who met NCCN guidelines with test results, 9.39% had a P/LP variant. Of patients who did not meet guidelines, 7.9% had a P/LP variant. The difference in positive results between these groups was not statistically significant (Fisher’s exact test P = .4241). Conclusion Our results indicate that nearly half of patients with breast cancer with a P/LP variant with clinically actionable and/or management guidelines in development are missed by current testing guidelines. We recommend that all patients with a diagnosis of breast cancer undergo expanded panel testing.
The COX2 Effector Microsomal PGE2 Synthase 1 is a Regulator of Immunosuppression in Cutaneous Melanoma
Authors: Sun-Hee Kim, Jason Roszik, Sung-Nam Cho, Dai Ogata, Denái R. Milton, Weiyi Peng, David G. Menter, Suhendan Ekmekcioglu, Elizabeth A. Grimm
Journal: Clinical Cancer Research (2018)

Microsomal prostaglandin E2 synthase 1 (mPGES1) was evaluated as an important downstream effector of the COX2 pathway responsible for tumor-mediated immunosuppression in melanoma.The analysis of a stage III melanoma tissue microarray (n = 91) was performed to assess the association between mPGES1, COX2, CD8, and patient survival. Pharmacologic inhibitors and syngeneic mouse models using PTGES-knockout (KO) mouse melanoma cell lines were used to evaluate the mPGES1-mediated immunosuppressive function.We observed correlations in expression and colocalization of COX2 and mPGES1, which are associated with increased expression of immunosuppressive markers in human melanoma. In a syngeneic melanoma mouse model, PTGES KO increased melanoma expression of PD-L1, increased infiltration of CD8a+ T cells, and CD8a+ dendritic cells into tumors and suppressed tumor growth. Durable tumor regression was observed in mice bearing PTGES KO tumors that were given anti-PD-1 therapy. Analysis of a stage III melanoma tissue microarray revealed significant associations between high mPGES1 expression and low CD8+ infiltration, which correlated with a shorter patient survival.Our results are the first to illustrate a potential role for mPGES1 inhibition in melanoma immune evasion and selective targeting in supporting the durability of response to PD-1 checkpoint immunotherapy. More research effort in this drug development space is needed to validate the use of mPGES1 inhibitors as safe treatment options.
Interactions between EGCG and SERMs in a xenograft model of ERα- breast cancer.
Authors: Marissa Scandlyn, Tiffany Somers-Edgar, Emma Stuart, Rhonda Rosengren
Journal: Cancer Research (2008)

1206  Estrogen receptor negative (ERα-) breast cancers represent a highly aggressive subset of cancers for which there is currently no effective treatment. The green tea polyphenol epigallocatechin gallate (EGCG) is known to inhibit the growth of ERα- MDA-MB-231 breast cancer cells when combined with the selective estrogen receptor modulators (SERM) tamoxifen or raloxifene. The current study was designed to assess the efficacy of EGCG-tamoxifen and EGCG-raloxifene combinations in a xenograft model of ERα- breast cancer and to elucidate the underlying mechanism of tumor suppression. Athymic nude female mice were implanted with MDA-MB-231 breast cancer cells into the flank. After 2 weeks, to allow palpable tumors to form, mice were administered tamoxifen (50 or 75 µg/kg/d, po), raloxifene (225, 500 or 850 µg/kg, po), EGCG (25 mg/kg, ip), EGCG and tamoxifen, EGCG and raloxifene or vehicle control (5 ml/kg/d, po) for 10 or 8 weeks (for studies involving tamoxifen and raloxifene, respectively). Tumor volume measurements were conducted weekly using electronic callipers and protein extraction was performed on tumors upon necropsy. Organ weights recorded upon study completion confirmed good animal health and plasma alanine aminotransferase activity was normal, indicating a lack of hepatotoxicity. The combination of EGCG and tamoxifen synergistically inhibited tumor growth with a 66% reduction in tumor volume and a 50% reduction in tumor weight in the EGCG and tamoxifen (75 µg/kg/d) treated mice compared to control mice (p
Comparing the Care of Pediatric Hospitalists With That of General Pediatricians
Authors: William Thomas Basco
Journal: JAMA Network Open (2018)

Mariam Krikorian Atkinson, PhD; Mark A. Schuster, MD, PhD; Jeremy Y. Feng, MD; Temilola Akinola, MBBS, MPH; Kathryn L. Clark, BA; Benjamin D. Sommers, MD, PhD
Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non–Small Cell Lung Cancer
Authors: Valsamo Anagnostou, Patrick M. Forde, James R. White, Noushin Niknafs, Carolyn Hruban, Jarushka Naidoo, Kristen Marrone, I.K. Ashok Sivakumar, Daniel C. Bruhm, Samuel Rosner, Jillian Phallen, Alessandro Leal, Vilmos Adleff, Kellie N. Smith, Tricia R. Cottrell, Lamia Rhymee, Doreen N. Palsgrove, Christine L. Hann, Benjamin Levy, Josephine Feliciano, Christos Georgiades, Franco Verde, Peter Illei, Qing Kay Li, Edward Gabrielson, Malcolm V. Brock, James M. Isbell, Jennifer L. Sauter, Janis Taube, Robert B. Scharpf, Rachel Karchin, Drew M. Pardoll, Jamie E. Chaft, Matthew D. Hellmann, Julie R. Brahmer, Victor E. Velculescu
Journal: Cancer Research (2018)

Abstract Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N = 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57–18.35; P = 0.007 and HR 6.91; 95% CI, 1.37–34.97; P = 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non–small cell lung cancer (N = 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies. Significance: Rapid and sensitive detection of circulating tumor DNA dynamic changes and T-cell expansion can be used to guide immune targeted therapy for patients with lung cancer. See related commentary by Zou and Meyerson, p. 1038
China harvested organs from political prisoners on substantial scale, says tribunal
Authors: Richard Hurley
Journal: BMJ (2018)

Forced harvesting of organs from prisoners of conscience in China has been “substantial,” says an interim judgment of an independent “people’s tribunal” set up to determine whether the country’s transplantation practices breached international criminal law.

The former English judge Geoffrey Nice QC, the tribunal’s chair, said after a three day evidence gathering session, “We, the tribunal members, are all certain, unanimously, beyond reasonable doubt, that in China forced organ harvesting from prisoners of conscience has been practised for a substantial period of time, involving a very substantial number of victims . . . by state organised or approved organisations or individuals.”

The tribunal found that the practices breached the Universal Declaration of Human Rights, including articles 3 (right to life), 6 (recognition as a person before the law), 7 (equality before the law), 9 (not to be subject to arbitrary arrest), 10 (full equality to a fair and public …
Abstract 12470: Carotid Intima-Media Thickness and Risk of Sudden Cardiac Death: The Atherosclerosis Risk In Communities (ARIC) Study
Authors: Takeki Suzuki, Wanmei Wang, Anthony Wilsdon, Kenneth R Butler, Selcuk Adabag, Michael E Griswold, Vijay Nambi, Wayne Rosamond, Nona Sotoodehnia, Thomas H Mosley
Journal: Circulation (2016)

Introduction: Sudden cardiac death (SCD) has been a public health issue worldwide. Carotid intima-media thickness (C-IMT) is a known surrogate marker for atherosclerosis. Whether subclinical atherosclerosis is associated with risk of SCD remains unknown especially in a middle-aged general population. Methods: We investigated the associations of C-IMT with SCD through 2012 among 15,307 blacks and whites participants at the first visit (1987-1989) of the community based-ARIC study. C-IMT (mean and maximum of C-IMT and common carotid artery (CCA)-IMT) was measured at the first visit by ultrasound. Presence of plaque was judged by trained readers and defined as two of the following three criteria: abnormal wall thickness (defined as C-IMT &gt;1.5 mm), abnormal shape (protrusion into the lumen and loss of alignment with adjacent arterial wall boundary), and abnormal wall texture (brighter echoes than adjacent boundaries). Kaplan-Meier curves and Cox proportional hazards models were used to evaluate associations of incident SCD with baseline C-IMT. Results: Over a median of 23.48 years of follow-up, 569 participants had SCD (37 cases per 1,000 person-years). C-IMT was associated with risk of SCD after adjustment for traditional risk factors (Figure and Table). Presence of plaque was associated with risk of SCD (HR 1.55; 95% CI 1.28-1.86, P &lt;0.001). Conclusion: Subclinical atherosclerosis measured by C-IMT was associated with risk of SCD in a middle-aged general population. These results may suggest importance of subclinical atherosclerosis in SCD risk and lead to early therapeutic intervention to prevent SCD.
Potential Benefits of Migraine—What Is It Good For?
Authors: Amy A. Gelfand, Elizabeth Loder
Journal: JAMA Neurology (2018)

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 Neurology 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 Neurology journal
Resistance to Epigenetic-Targeted Therapy Engenders Tumor Cell Vulnerabilities Associated with Enhancer Remodeling
Authors: Amanda Balboni Iniguez, Gabriela Alexe, Emily Jue Wang, Giovanni Roti, Sarvagna Patel, Liying Chen, Samuel Kitara, Amy Conway, Amanda L. Robichaud, Björn Stolte, Pratiti Bandopadhayay, Amy Goodale, Sasha Pantel, Yenarae Lee, Dorian M. Cheff, Matthew D. Hall, Rajarshi Guha, Mindy I. Davis, Marie Menard, Nicole Nasholm, William A. Weiss, Jun Qi, Rameen Beroukhim, Federica Piccioni, Cory Johannessen, Kimberly Stegmaier
Journal: Cancer Cell (2018)
Low Molecular Weight Heparin-Coated and Dendrimer-Based Core-Shell Nanoplatform with Enhanced Immune Activation and Multiple Anti-Metastatic Effects for Melanoma Treatment
Authors: Chunyu Xia, Sheng Yin, Shanshan Xu, Guangyao Ran, Miao Deng, Ling Mei, Xian Tang, Jingdong Rao, Man Li, Zhirong Zhang, Qin He
Journal: Theranostics (2018)

High-efficiency treatment for tumor is not easy to achieve owing to the existence of metastasis, which remains the arch-criminal of most tumor deaths. Conventional chemotherapy exhibits insufficient inhibitory efficiency on tumor metastasis and more powerful strategies to conquer metastatic tumors are urgently needed. In this study, a rational chemoimmunotherapy strategy was adopted to treat highly aggressive melanoma based on a newly developed multifunctional nanoplatform. Firstly, immunoadjuvant cytosine-phosphate-guanine oligonucleotides (CpG ODNs) were used to boost the doxorubicin (DOX)-elicited immune responses, which synergistically suppressed tumor growth and metastasis. And the anti-metastatic low molecular weight heparin (LMWH) was also integrated, thus multiple anti-metastatic effects to against tumor metastasis were achieved. Methods: G4 PAMAM was serving as the main support to conjugate DOX by pH-sensitive hydrazone bond (PPD) and the synthesized conjugates were confirmed by 1H-NMR spectra, IR spectra and HRMS. Immunoadjuvant CpG ODNs were loaded by electrostatic adsorption to formulate PPD/CpG. After the coating of anti-metastatic LMWH, the designed LMWH/PPD/CpG was fabricated and characterized. The platelets-related and platelets-unrelated anti-metastatic mechanisms were investigated on B16F10 the immune activation effects, anti-tumor and anti-metastatic efficacy of LMWH/PPD/CpG were evaluated on a B16F10 melanoma xenograft model. Results: DOX elicited tumor-specific immune responses by ICD, and the immunological effects could be further promoted by CpG ODNs, exhibiting enhanced maturation of dendritic cells (DCs) and increased level of cytolytic T lymphocytes (CTLs) in vivo. Owing to the coating of LMWH, the platelets-induced epithelial-mesenchymal-like transition of tumor cells was hindered and the actin cytoskeletal arrangement of tumor cells was affected, thus the migration ability of tumor cells was further inhibited. This multifunctional nanoplatform showed enhanced treatment efficiency on melanoma primary tumor and pulmonary metastasis. Conclusion: The immune activation and multiple anti-metastatic effects of LMWH/PPD/CpG establish a novel therapeutic strategy for melanoma. This anti-metastatic nanoplatform could be broadly applied for the co-delivery of other nucleic acids and chemotherapeutic drugs to treat highly aggressive tumors.
Implications of Agency in Studies of Self-regulation and Obesity
Authors: Jamie Lim
Journal: JAMA Pediatrics (2018)

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
Abstract 18529: Protease-Activated Receptor-1 Deficiency Reduces Doxorubicin-Induced Cardiotoxicity
Authors: Silvio Antoniak, Nigel Mackman
Journal: Circulation (2013)

Objective: The administration of doxorubicin (Dox), a potent effective anti-cancer anthracycline drug, is limited by its cardiotoxicity and coagulation activation. This study was conducted to investigate whether there is a direct connection between the increased thrombin-mediated signaling via the protease-activated receptor 1 (PAR-1) and the cardiotoxicity after Dox administration. Methods and Results: PAR-1-/- mice and wild-type (WT) littermates were subjected to a single injection of Dox (20mg/kg) or a weekly injection of Dox (5mg/kg) for 5 weeks. Changes in heart size, heart function and cardiotoxicity were measured by echocardiography 5 days or 5 weeks after injection (p.i.). Direct effects of thrombin during Dox stimulation was analyzed on neonatal cardiomyocytes and fibroblasts in vitro. PAR-1-/- mice were protected from Dox-induced cardiac injury and had preserved left ventricular function 5 days p.i. compared to WT littermates (fractional shortening: 53.7±1.8% vs. 43.9±2.0%; P&lt;0.05). The hearts of PAR-1-/- mice had less cardiac expression of 3-Nitrotyrosine, KC and MPO compared to WT mice 5 days p.i.. Furthermore, the hearts of Dox-treated PAR-1-/- mice exhibited increased activation of pro-survival AKT and less acetylation of pro-apoptotic p53 compared to treated WT mice. In addition, PAR-1-/- mice had improved heart function compared WT mice at the 5 weeks’ time point (Dox cumulative dose 25mg/kg). In vitro experiments confirmed the deleterious effects of a thrombin-mediated PAR-1 activation during Dox incubation. Rat cardiomyocytes exhibited increased release of cardiac troponin I which was associated with increased levels of p53 acetylation. Furthermore, Dox-induced p53 accumulation in mouse fibroblast was enhanced by thrombin. Conclusion: These results indicate that PAR-1 activation contributes to Dox-induced cardiotoxicity by enhancing inflammatory response and apoptosis. These findings suggest that PAR-1 antagonist may be useful in preventing Dox-induced heart failure in cancer patients.
Characterization of Allogeneic T Cells Expressing Inducible Caspase-9 Following Adoptive Transfer in Children Receiving an HLA-Haploidentical Hematopoietic Stem Cell Transplant for the Treatment of Myeloid Malignancies
Authors: Joanne Shaw, Xiaoou Zhou, An Lu, Valentina Bertaina, Daria Pagliara, Melissa Aldinger, David M. Spencer, Franco Locatelli, Aaron Foster
Journal: Blood (2018)
TAKling GDF-15 and skeletal muscle atrophy in pulmonary hypertension: are we there yet?
Authors: Yen-Chun Lai, Steeve Provencher, Elena A Goncharova
Journal: Thorax (2018)

Pulmonary arterial hypertension (PAH) is a progressive, life-threatening disease characterised by intense pulmonary vascular remodelling leading to high pulmonary arterial pressure, right ventricular failure and death. Although recent advances in therapies have proven to be effective in alleviating disease symptoms and improving functional capacity and survival, patients with PAH continue to suffer from persistent dyspnoea and significant exercise intolerance, which negatively impact their quality of life. In recent years, it has been increasingly recognised that exercise limitation in PAH is not merely due to right heart dysfunction and respiratory impairment, but is also a consequence of skeletal muscle abnormalities.1–3 Impaired skeletal muscle function, including reduced volitional and nonvolitional muscle strength and endurance2 4 5 decreased contractility,6 reduced capillary density and impaired oxygenation at the microcirculation level,4 7 as well as a shift towards type 2 muscle fibres,1 3 5 have been repeatedly documented in human PAH. Skeletal muscle atrophy has been less frequently reported3 and underlying mechanisms are not well studied.

To date, numerous metabolic and signalling abnormalities associated with muscle dysfunction in PAH have been uncovered. These include a shift from oxidative to glycolytic metabolism, suppression of signalling pathways responsible for a hypertrophic response (eg, Akt and S6K), elevation of negative regulators of muscle homeostasis (eg, myostatin and activin A) and engagement of ubiquitin–proteasome-mediated muscle proteolysis signalling (eg, atrogin-1 and MuRF1).3 8 9 Loss of skeletal muscle microcirculation mediated by microRNA-126 downregulation, as well as sirtuin-3/AMP-activated protein kinase inactivation, and cytokines (ie, tumour necrosis factor-α and interleukin-6)-regulated skeletal muscle insulin resistance and abnormalities of mitochondrial biogenesis have also been documented.4 8 10 The molecular mechanisms of skeletal muscle atrophy in PAH, however, are not well understood, and available human PAH-related data are limited by a small number of studies with only a few …
Photothermal Therapy: ZD2‐Engineered Gold Nanostar@Metal‐Organic Framework Nanoprobes for T<sub>1</sub>‐Weighted Magnetic Resonance Imaging and Photothermal Therapy Specifically Toward Triple‐Negative Breast Cancer (Adv. Healthcare Mater. 24/2018)
Authors: Luyun Zhang, Chuang Liu, Yang Gao, Zihou Li, Jie Xing, Wenzhi Ren, Lili Zhang, Aiguo Li, Guangming Lu, Aiguo Wu, Leyong Zeng
Journal: Advanced Healthcare Materials (2018)

In article number 1801144, Guangming Lu, Aiguo Wu, Leyong Zeng, and co-workers, design ZD2-engineered gold nanostar@MIL-101-NH2(Fe) (AuNS@MOF-ZD2) nanoprobes with well-defined core-shell structures for T1-weighted magnetic resonance imaging and photothermal therapy, specifically toward triple-negative breast cancer (TNBC), but not other subtypes of breast cancers. This study demonstrates AuNS@MOF-ZD2 can be good nanoprobes for visualized theranostics of breast cancers with molecular classification.