tbuckley/cabot-search huggingface dataset:
Abstract P3-06-12: Autophagy-mediated survival mechanism to c-Src inhibitor therapy in triple negative breast cancer
Authors: Kwanghwa Jung, Junhyoung Park, Tirupataiah Sirupangi, Dongya Jia, Nishant Gandhi, Shivanand Pudakalakatti, Jessica Elswood, Weston Porter, Nagireddy Putluri, Xiang H.-F Zhang, Xi Chen, Pratip K. Bhattacharya, Chad J. Creighton, Michael T. Lewis, Jeffrey M. Rosen, Lee-Jun C. Wong, Gokul M. Das, C. Kent Osborne, Mothaffar F Rimawi, Benny Abraham Kaipparettu
Journal: Cancer Research (2020)

Abstract c-Src (Src) is a proto-oncogene involved in signaling that culminates in the control of multiple biological functions. Src is also one of the most frequently upregulated pathways in triple negative breast cancer (TNBC). Dysregulation of Src has been detected in TNBC and is strongly associated with tumor metastasis and poor prognosis. However, even after promising preclinical studies, Src inhibitors did not show major clinical advantage in unselected TNBC populations. We have previously published that metastatic TNBC has high energy-dependency to mitochondrial fatty acid beta-oxidation (FAO) and FAO activates Src by inducing autophosphorylation at Y419. However, our recent analysis suggests that as observed with the Src inhibitors, TNBC tumors treated with FAO inhibitors also develop drug-resistance and exhibit continuous tumor growth. Evaluation of their drug resistance mechanism revealed that while short-term inhibition of FAO or Src induces autophagic and apoptotic cell deaths, long-term inhibition results in autophagy-mediated drug resistance and survival. Further analyses suggest that FAO/Src inhibitors promote interferon regulatory factor 1 (IRF1) expression and activate mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway via the induction of cellular reactive oxygen species (ROS) in TNBC. Activated MEK/ERK then suppresses IRF1 expression and induces survival pathways for drug resistance and tumor survival. Validation of in vitro findings using in vivo TNBC models confirmed that combination of FAO/Src inhibitors with MEK/ERK inhibitor or ROS scavenger provide significant benefit to overcome the therapeutic resistance of TNBC. These findings open-up new therapeutic opportunities to manage TNBC patients with currently non-targetable metastatic tumors. Citation Format: Kwanghwa Jung, Junhyoung Park, Tirupataiah Sirupangi, Dongya Jia, Nishant Gandhi, Shivanand Pudakalakatti, Jessica Elswood, Weston Porter, Nagireddy Putluri, Xiang H.-F Zhang, Xi Chen, Pratip K. Bhattacharya, Chad J. Creighton, Michael T. Lewis, Jeffrey M. Rosen, Lee-Jun C. Wong, Gokul M. Das, C. Kent Osborne, Mothaffar F Rimawi, Benny Abraham Kaipparettu. Autophagy-mediated survival mechanism to c-Src inhibitor therapy in triple negative breast cancer [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 P3-06-12.
Abstract P5-06-24: Validation of the Johns Hopkins oncotype DX recurrence score estimator
Authors: Kristen Millado, Louis Fogg, Ritu Ghai, Melody Cobleigh
Journal: Cancer Research (2020)

Abstract Objective Oncotype DX (ODX) is a 21-gene assay used to predict the benefit of adjuvant chemotherapy in hormone receptor-positive, HER2-negative, lymph node-negative breast cancer. However, the test is expensive and the incremental contribution of this assay to routinely available clinicopathological information and how to integrate that information to best inform clinical decision making is unknown. Several models have been developed to predict whether there are cases in which a clinician or patient could opt to forgo ODX because the outcome of the test might be predicted with a high degree of accuracy using routinely available measures. One such model was developed and validated at Johns Hopkins University. Here we used their recurrence score estimator to learn whether we could safely adopt the calculator for use at our institution to improve resource utilization. Methods An IRB-approved prospective database was created in 2010 for patients seen by a single medical oncologist at Rush University Medical Center and for whom oncotype DX was performed. From this database, patients were identified with HR+, HER2-negative, node-negative breast cancer and for whom age at diagnosis, tumor size, grade and Ki-67 were known. These data were entered into the Johns Hopkins breast cancer recurrence score estimator (http://www.breastrecurrenceestimator.onc.jhmi.edu). This model categorizes patients with a recurrence score (RS) of less than or equal to 25 as low risk and those with a score of greater than 25 as high risk. Results There were 189 patients. The mean age, tumor size, ER%, PR% and Ki-67% were 58 years old, 1.5 cm, 88%, 44% and 15% respectively. 14% had a RS greater than 25. The estimator assigned 65 patients to low risk, 59 of whom had a low RS and 6 with a high RS. The estimator assigned 4 patients to high risk, all of whom had a high RS. Conclusions The Johns Hopkins recurrence score estimator assigned 69 patients to low or high risk with 91.3% accuracy. Future analysis of a larger sample size is needed to optimize the accuracy of this estimator nationally. It may also be beneficial to separately analyze patients aged 50 or younger with an ODX score between 16 and 25 who had chemotherapy benefit in the TAILORx study in order to improve the utility of this risk estimator. Citation Format: Kristen Millado, Louis Fogg, Ritu Ghai, Melody Cobleigh. Validation of the Johns Hopkins oncotype DX recurrence score estimator [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 P5-06-24.
The role of angiotensin-converting enzyme 2 in coronaviruses/influenza viruses and cardiovascular disease
Authors: Li Chen, Guang Hao
Journal: Cardiovascular Research (2020)

Angiotensin-converting enzyme 2 (ACE2) has emerged as a key regulator of the renin-angiotensin system in cardiovascular (CV) disease and plays a pivotal role in infections by coronaviruses and influenza viruses. The present review is primarily focused on the findings to indicate the role of ACE2 in the relationship of coronaviruses and influenza viruses to CV disease. It is postulated that the risk of coronavirus or influenza virus infection is high, at least partly due to high ACE2 expression in populations with a high CV risk. Coronavirus and influenza virus vaccine usage in high CV risk populations could be a potential strategy to prevent both CV disease and coronavirus/influenza virus infections.
Circulating Tumor DNA Analysis to Assess Risk of Progression after Long-term Response to PD-(L)1 Blockade in NSCLC
Authors: Matthew D. Hellmann, Barzin Y. Nabet, Hira Rizvi, Aadel A. Chaudhuri, Daniel K. Wells, Mark P.S. Dunphy, Jacob J. Chabon, Chih Long Liu, Angela B. Hui, Kathryn C. Arbour, Jia Luo, Isabel R. Preeshagul, Everett J. Moding, Diego Almanza, Rene F. Bonilla, Jennifer L. Sauter, Hyejin Choi, Megan Tenet, Mohsen Abu-Akeel, Andrew J. Plodkowski, Rocio Perez Johnston, Christopher H. Yoo, Ryan B. Ko, Henning Stehr, Linda Gojenola, Heather A. Wakelee, Sukhmani K. Padda, Joel W. Neal, Jamie E. Chaft, Mark G. Kris, Charles M. Rudin, Taha Merghoub, Bob T. Li, Ash A. Alizadeh, Maximilian Diehn
Journal: Clinical Cancer Research (2020)

Treatment with PD-(L)1 blockade can produce remarkably durable responses in patients with non-small cell lung cancer (NSCLC). However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression.In patients with advanced NSCLC achieving long-term benefit from PD-(L)1 blockade (progression-free survival ≥ 12 months), plasma was collected at a surveillance timepoint late during/after treatment to interrogate ctDNA by Cancer Personalized Profiling by Deep Sequencing. Tumor tissue was available for 24 patients and was profiled by whole-exome sequencing (n = 18) or by targeted sequencing (n = 6).Thirty-one patients with NSCLC with long-term benefit to PD-(L)1 blockade were identified, and ctDNA was analyzed in surveillance blood samples collected at a median of 26.7 months after initiation of therapy. Nine patients also had baseline plasma samples available, and all had detectable ctDNA prior to therapy initiation. At the surveillance timepoint, 27 patients had undetectable ctDNA and 25 (93%) have remained progression-free; in contrast, all 4 patients with detectable ctDNA eventually progressed [Fisher P < 0.0001; positive predictive value = 1, 95% confidence interval (CI), 0.51-1; negative predictive value = 0.93 (95% CI, 0.80-0.99)].ctDNA analysis can noninvasively identify minimal residual disease in patients with long-term responses to PD-(L)1 blockade and predict the risk of eventual progression. If validated, ctDNA surveillance may facilitate personalization of the duration of immune checkpoint blockade and enable early intervention in patients at high risk for progression.
Abstract P3-08-42: Disease-free survival prognostic signature in triple-negative breast cancer based on high-throughput proteomics data
Authors: Pilar Zamora Auñon, Silvia García Adrián, Lucia Trilla-Fuertes, Angelo Gámez-Pozo, Guillermo Prado-Vázquez, Andrea Zapater-Moros, Mariana Díaz- Almirón, Rocío López Vacas, Cristina Chiva, Cristina Chiva, Eduard Sabidó, Enrique Espinosa Arranz, Juan Ángel Fresno Vara
Journal: Cancer Research (2020)

Abstract Introduction Triple negative breast cancer (TNBC) accounts for 15-20% of the breast cancer and is characterized by an aggressive phenotype and worst prognosis. TNBC does not benefit from any targeted therapy, so further characterization would be needed to define subgroups with potential therapeutic value. Material and methods 125 TNBC paraffin samples were analyzed using high-throughput proteomics based on SWATH-MS. Survival analyses and a prognostic predictor were done using BRB Array Tools. Proteins related with disease-free survival were established and, then, a prognostic signature was built based on their p-values. Results and discussion Using SWATH-MS, 1,206 proteins were identified in a cohort of 125 TNBC tumors. Of these 1,206 proteins, 29 proteins were related with disease-free survival. In addition, a prognostic signature based on the expression of two proteins, RMB3 and NIPSNAP1, was defined. The predictor split our population into a low-risk and a high-risk group (p=0.0002, HR= 6.519). Multivariate analysis showed that the prognostic signature based on the expression of these two proteins supplied significant information to the clinical parameters. Conclusion SWATH-MS proteomics demonstrates its utility in the analysis of TNBC paraffin samples. Moreover, this proteomics data allows us to build a prognostic signature based on the expression of two proteins (RBM3 and NIPSNAP1). This prognostic signature could be used in the future to identify a population with a high-risk of relapse that may be directed to a clinical trial. Citation Format: Pilar Zamora Auñon, Silvia García Adrián, Lucia Trilla-Fuertes, Angelo Gámez-Pozo, Guillermo Prado-Vázquez, Andrea Zapater-Moros, Mariana Díaz- Almirón, Rocío López Vacas, Cristina Chiva, Cristina Chiva, Eduard Sabidó, Enrique Espinosa Arranz, Juan Ángel Fresno Vara. Disease-free survival prognostic signature in triple-negative breast cancer based on high-throughput proteomics data [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 P3-08-42.
Allele-specific genome targeting in the development of precision medicine
Authors: Junjiao Wu, Beisha Tang, Yu Tang
Journal: Theranostics (2020)

The CRISPR-based genome editing holds immense potential to fix disease-causing mutations, however, must also handle substantial natural genetic variations between individuals. Previous studies have shown that mismatches between the single guide RNA (sgRNA) and genomic DNA may negatively impact sgRNA efficiencies and lead to imprecise specificity prediction. Hence, the genetic variations bring about a great challenge for designing platinum sgRNAs in large human populations. However, they also provide a promising entry for designing allele-specific sgRNAs for the treatment of each individual. The CRISPR system is rather specific, with the potential ability to discriminate between similar alleles, even based on a single nucleotide difference. Genetic variants contribute to the discrimination capabilities, once they generate a novel protospacer adjacent motif (PAM) site or locate in the seed region near an available PAM. Therefore, it can be leveraged to establish allele-specific targeting in numerous dominant human disorders, by selectively ablating the deleterious alleles. So far, allele-specific CRISPR has been increasingly implemented not only in treating dominantly inherited diseases, but also in research areas such as genome imprinting, haploinsufficiency, spatiotemporal loci imaging and immunocompatible manipulations. In this review, we will describe the working principles of allele-specific genome manipulations by virtue of expanding engineering tools of CRISPR. And then we will review new advances in the versatile applications of allele-specific CRISPR targeting in treating human genetic diseases, as well as in a series of other interesting research areas. Lastly, we will discuss their potential therapeutic utilities and considerations in the era of precision medicine.
Abstract P3-01-27: Ectonucleotidase ATP hydrolysis facilitates breast cancer bone metastasis
Authors: Daniel B Shropshire, Jaime Benavides, Jean X Jiang
Journal: Cancer Research (2020)

Abstract Bone is the most common site for breast cancer metastasis. Osteocytes are the most abundant bone cell and can signal nearby cells by releasing ATP through connexin 43 hemichannels. We previously found that this signaling pathway hindered breast cancer growth in bone. In this study, we investigated the role of purinergic signaling on breast cancer bone metastasis in patient samples. Surprisingly, no ATP receptors were differentially expressed in bone metastases compared to other sites. However, enzymes that degrade ATP into adenosine (CD39/ENTPD1 and CD73/NT5E) were upregulated, as was the ADORA3 adenosine receptor (Limma, p=0.037, 0.016, 0.0019, respectively). We next investigated whether this expression signature in primary tumors predicts bone metastasis. In primary ER+ breast cancer, which predominately metastasizes to bone, high expression of these genes is correlated with lower distant metastasis-free survival (HR = 1.97, 1.49, 2.03, logrank p=0.0017, 0.0004, 0.0012). Moreover, this expression pattern is correlated with a bone metastasis signature (Spearman R=0.28, p=1.2 × 10−20). In a pharmacologic screen of 750 cancer cell lines, breast cancer lines and especially ER+ ones, are uniquely sensitive to a pan-adenosine receptor inhibitor (Limma, p=2.9 × 10−5) and ADORA3/2B inhibitor (p=5.4 × 10−5). Our findings suggest that an expression program to convert ATP to adenosine facilitates bone metastasis and begins in the primary tumor. ADORA3 inhibition is proposed as a pharmacologic strategy for preventing or treating bone metastasis. Furthermore, bone metastases should be analyzed in anti-CD39 and CD73 clinical trials. Citation Format: Daniel B Shropshire, Jaime Benavides, Jean X Jiang. Ectonucleotidase ATP hydrolysis facilitates breast cancer bone metastasis [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 P3-01-27.
Screening of patients with overload to identify hemochromatosis and porphyria cutanea tarda.
Authors: FM O'Reilly, C Darby, J Fogarty, William Tormey, W Kay, M Leader, GM Murphy
Journal: JAMA Dermatology (1997)

Results: Of 4127 patients tested, 240 patients with an elevated serum ferritin level were identified, of whom 74 had an elevated serum ferritin level of more than 500 \g=m\g/L.Of the latter group, 17.5% had hemochromatosis and 6.7% had PCT. The incidence of PCT in the hemochromatosis group was 23%; HLA typing revealed the presence of at least 1 of the hemochromatosis markers. Conclusions: A high serum ferritin level in the absence of evident cause should prompt investigation for both hemochromatosis and PCT. The HLA heterozygosity for hemochromatosis in some patients with PCT may be a cause of hepatic siderosis.
Exposure to Air Pollution during Pregnancy and Childhood, and White Matter Microstructure in Preadolescents
Authors: Małgorzata J. Lubczyńska, Ryan L. Muetzel, Hanan El Marroun, Xavier Basagaña, Maciej Strak, William Denault, Vincent W.V. Jaddoe, Manon Hillegers, Meike W. Vernooij, Gerard Hoek, Tonya White, Bert Brunekreef, Henning Tiemeier, Mònica Guxens
Journal: Environmental Health Perspectives (2020)

Background: Air pollution has been related to brain structural alterations, but a relationship with white matter microstructure is unclear. Objectives: We assessed whether pregnancy and childhood exposures to air pollution are related to white matter microstructure in preadolescents. Methods: We used data of 2,954 children from the Generation R Study, a population-based birth cohort from Rotterdam, Netherlands (2002–2006). Concentrations of 17 air pollutants including nitrogen oxides (NOX), particulate matter (PM), and components of PM were estimated at participants’ homes during pregnancy and childhood using land-use regression models. Diffusion tensor images were obtained at child’s 9–12 years of age, and fractional anisotropy (FA) and mean diffusivity (MD) were computed. We performed linear regressions adjusting for socioeconomic and lifestyle characteristics. Single-pollutant analyses were followed by multipollutant analyses using the Deletion/Substitution/Addition (DSA) algorithm. Results: In the single-pollutant analyses, higher concentrations of several air pollutants during pregnancy or childhood were associated with significantly lower FA or higher MD (p&lt;0.05). In multipollutant models of pregnancy exposures selected by DSA, higher concentration of fine particles was associated with significantly lower FA [−0.71 (95% CI: −1.26, −0.16) per 5 μg/m3 fine particles] and higher concentration of elemental silicon with significantly higher MD [0.06 (95% CI: 0.01, 0.11) per 100 ng/m3 silicon]. Multipollutant models of childhood exposures selected by DSA indicated significant associations of NOX with FA [−0.14 (95% CI: −0.23, −0.04) per 20-μg/m3 NOX increase], and of elemental zinc and the oxidative potential of PM with MD [0.03 (95% CI: 0.01, 0.04) per 10-ng/m3 zinc increase and 0.07 (95% CI: 0.00, 0.44) per 1-nmol DTT/min/m3 oxidative potential increase]. Mutually adjusted models of significant exposures during pregnancy and childhood indicated significant associations of silicon during pregnancy, and zinc during childhood, with MD. Discussion: Exposure in pregnancy and childhood to air pollutants from tailpipe and non-tailpipe emissions were associated with lower FA and higher MD in white matter of preadolescents. https://doi.org/10.1289/EHP4709
Association of Sex With Repair Type and Long-term Mortality in Adults With Abdominal Aortic Aneurysm
Authors: Niveditta Ramkumar, Bjoern D. Suckow, Shipra Arya, Art Sedrakyan, Todd A. Mackenzie, Philip P. Goodney, Jeremiah R. Brown
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Sex-based differences exist in the prevalence and clinical presentation of abdominal aortic aneurysm (AAA). However, it is unclear if sex is associated with AAA repair type and long-term mortality. <h3>Objective</h3> To investigate whether a sex-related difference exists in mortality risk after AAA repair owing to differences in repair type. <h3>Design, Setting, and Participants</h3> This cohort study uses data from the Vascular Quality Initiative, a national clinical registry, and Medicare claims to investigate endovascular and surgical repair procedures performed between January 1, 2003, and September 30, 2015, in patients aged 65 years or older with AAA. The data were analyzed from October 1, 2018, to November 19, 2019. <h3>Exposure</h3> Sex of the patient. <h3>Main Outcomes and Measures</h3> Endovascular (EVR) or open surgical AAA repair type and subsequent long-term, all-cause mortality. <h3>Results</h3> In this cohort study of 16 386 patients, 12 757 (77.9%) were men and 3629 (22.1%) were women. Women were more likely than men to be older (mean [SD] age, 77 [6.5] years vs 75 [6.6] years;<i>P</i> &lt; .001), active smokers (33% vs 28%;<i>P</i> &lt; .001), and to have smaller aneurysms (mean [SD] diameter, 57 [11.7] mm vs 59 [17.7] mm;<i>P</i> &lt; .001). Surgical AAA repair was performed in 27% (983 of 3629) of women compared with 18% (2328 of 12 757) of men (<i>P</i> &lt; .001). After inverse probability weighting for risk adjustment, women were more likely to receive open surgical repair than EVR repair (risk ratio, 1.65; 95% CI, 1.51-1.80). The 10-year unadjusted survival rate after EVR repair was 14% lower in women than in men (23% vs 37%; log-rank<i>P</i> &lt; .001), but the rates were comparable after open surgical repair (36% in men vs 32% in women; log-rank<i>P</i> = .22). Risk-adjusted analysis showed that women were associated with higher mortality rates after EVR repair (hazard ratio, 1.13; 95% CI, 1.03-1.24), whereas both men and women had a similar risk of death after open surgical repair (hazard ratio, 0.94; 95% CI, 0.84-1.06). After further stratification by symptom severity, higher risk of mortality among women was limited to elective EVR and open surgical repair for ruptured AAA. <h3>Conclusions and Relevance</h3> In this study, women were 65% more likely than men to undergo open surgical repair. After EVR repair, women were 13% more likely to die than men, although no sex-based difference in mortality was found after open surgical repair. The differential treatment benefit of EVR repair in women is concerning given the shift toward an EVR-first approach to AAA repair.
Sleep in Parkinson's disease: A systematic review and meta-analysis of polysomnographic findings
Authors: Ye Zhang, Rong Ren, Larry D. Sanford, Linghui Yang, Junying Zhou, Lu Tan, Taomei Li, Jihui Zhang, Yun-Kwok Wing, Jie Shi, Lin Lu, Xiangdong Tang
Journal: Sleep Medicine Reviews (2020)
Multifocal Atrial Tachycardia
Authors: Jane F. Desforges, John A. Kastor
Journal: New England Journal of Medicine (1990)

TWENTY-TWO years ago in the Journal, the term "multifocal atrial tachycardia" was first applied systematically to an arrhythmia characterized by irregularity, different forms of P waves, and (in adults) a rather grim prognosis.1 In this article, I shall discuss our current knowledge of the incidence, clinical setting, electrocardiographic and electrophysiologic features, treatment, and prognosis of the arrhythmia.Multifocal atrial tachycardia occurs relatively infrequently as compared with other arrhythmias. Investigators have reported finding evidence of the condition in 0.05 to 0.32 percent of electrocardiograms interpreted in general hospitals1 2 3 4 and in 0.36 percent of patients admitted to a hospital.5 Clinical Setting . . .