tbuckley/cabot-search huggingface dataset:
Impact of chemotherapy dose intensity in the geriatric population with locally advanced breast cancer treated in neoadjuvant setting at the National Cancer Institute, Mexico City.
Authors: Claudia Arce, Leticia Mendoza-Galindo, Gabriela Alamilla, Rebeca Ramirez-Morales, Alberto Alvarado-Miranda, Fernando Lara-Medina
Journal: Journal of Clinical Oncology (2014)

e11500 Background: Breast cancer in older women is usually undertreated, this population is considered fragile, they receive dose of chemotherapy below standards. The aim fo the study is to evaluate the relation of dose intensity with complete pathological response (cPR) in geriatric patients, and its impact on survival. Methods: Retrospective analysis of patients treated with neoadjuvant anthracyclines, taxanes, or combination regimen from 2005 to 2010. Case-control design with proportion 1:3. pCR was evaluated in the surgical specimen. Survival analysis was made with Kaplan-Meier method. Results: 317 were eligible, were divided into two subgroups 79 elderly-women (>65 years-old) and 238 younger-women (<64 years-old). The median age at diagnosis was 71.7 years old for the elderly group (65-87yr old) and 51 years old for the younger group (28-64). Median tumor size of 6 cm in both groups. ER+ was 73.4% and 62.2%; HER2+ 16.5% and 21.4% and 15.4% and 19% were identified as triple negative, respectively (p=0.2).Most patients were treated with 8 cycles of anthracyclines and taxanes, before surgery. The group of elderly women had more cases <80% of anthracyclines planned dose compared with the group of young women (17.3% vs 0.4%) and P=0.000. pCR was 12.7% in elderly group vs 23.6% in younger group (P=0.000). DFS was according with dose intensity was 88.4% for dose-intensity >80% and 71.4% for dose-intensity <80%, both with a Log-rank of 0.012. There was no difference in adverse events grade 3-4. Conclusions: Breast cancer in older women has the same clinical and pathological presentation as younger women. Older group was undertreated respect to chemotherapy dose intense, with impact in pathological complete response and disease free survival.
Evaluation of CLASI by paediatric dermatologists and rheumatologists
Authors: C.J. Kushner, M. Tarazi, R.G. Gaffney, R. Feng, K. Ardalan, H.A. Brandling‐Bennett, L. Castelo‐Soccio, J.C. Chang, Y.E. Chiu, S. Gmuca, R.D. Hunt, P.J. Kahn, A.M. Knight, J. Mehta, D.R. Pearson, J.R. Treat, J. Wan, A.C. Yeguez, J.S.S. Concha, B. Patel, J. Okawa, L.M. Arkin, V.P. Werth
Journal: British Journal of Dermatology (2019)

The term ‘lupus erythematosus’ refers to a range of related disorders. As many as 70–80% of lupus patients will develop skin lesions (abnormal patches) at some point during the course of their disease. Types of lupus affecting the skin are collectively known as cutaneous lupus erythematosus (CLE). The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) is a tool for classifying how severe the skin symptoms are in people with CLE. Being able to accurately and reliably measure skin lesions is an important way to monitor any improvement or worsening of the disease, which is useful in clinical trials to see if a treatment is working. It is already known that the CLASI is a reliable (accurate) measure in adults, but researchers based in the USA conducted this study to validate the reliability of the CLASI in the pediatric (child) population, where CLE can appear differently than in adults. This validation will allow clinical trials to reliably assess treatment efficacy in CLE. The researchers recruited 11 pediatric patients with active CLE, 6 dermatologists, and 6 rheumatologists to attend a one-day event at the University of Pennsylvania. Physicians were trained to use the CLASI as well as another scoring system called the Physician Global Assessment (PGA) to allow for comparison. Physicians (doctors) individually rated all patients using both tools. Each physician reassessed two randomly selected patients. CLASI proved to be a reliable and valid measurement tool and superior to the PGA for pediatric CLE, and the researchers conclude that it can be used in future clinical trials.
Proto-oncogene Ets-1 is pathologically expressed in low-grade astrocytomas and glioblastomas in a tissue and location specific pattern and correlates with patient survival.
Authors: Susanne Antje Kuhn, Sabine Pfeifenbring, Anne Schirrmeister, Tobias Kratzsch, Uwe Traeger, Uwe Karsten Hanisch, Hannes Haberl
Journal: Journal of Clinical Oncology (2014)

e13016 Background: Ets-1 regulates migration & angiogenesis and is active in malignomas. Methods: We investigated Ets-1 in 60 glioblastomas WHO IV° & 40 astrocytomas WHO II° and evaluated its prognostic value. Results: Ets-1 was upregulated in astrocytomas (p=.002) & glioblastomas (p<.001). In astrocytomas, endothelial Ets-1 was highest within the invasion zone, followed by the peritumoral brain and the tumor center (p<.001). Nuclear, transcriptionally active Ets-1 was mainly found in the invasion zone, whereas cytoplasmic Ets-1 was dominant in the tumor center. We found a statistically positive correlation of high Ets-1 with high mitosis indices (r=.603; p<.001). Real-time PCR revealed a tendency of increased Ets-1-downstream-gene matrix metalloproteinase 9 with an increasing Ets-1 in astrocytoma tissue. Similar results were obtained for glioblastomas. Ets-1 was strongest within the invasion zone followed by the tumor center (p<.001); and Ets-1 in glioblastomas was higher than in low-grade astrocytomas and tumor-free controls (p<.001). Endothelial Ets-1 of glioblastomas was highest within neoangiogenic vessels of the invasion zone followed by the tumor center (p=.003). Ets-1 correlated positively with the number of mitoses (r=.742; p=.004). In glioblastomas, real-time PCR revealed the supposed positive relationship between Ets-1 and MMP-9 (r=.770; p<.001). Further, we asked for correlation between Ets-1 and patient survival. The astrocytoma recurrence was correlated to higher Ets-1 within the invasion zone (p=.036) and within the peritumoral brain parenchyma (p=.032). Further, malignant transformation of astrocytoma WHO II° occurred in tumors with higher Ets-1 (p=.029). Median progression-free survival was 21.5 months for high Ets-1 versus 81 months for low Ets-1 (p=.025). Finally, patient overall survival was shorter with increasing Ets-1 in astrocytoma WHO II° (p=.019, HR 1.067, CI (95%) 1.01-1.12). Conclusions: Our results imply a role of Ets-1 in glioma invasion, neoangiogenesis, and malignant transformation, which correlates with prognostic factors like mitoses and has a significant impact on patient survival.
Chemotherapy infusion reaction training for medical oncology fellows: A checklist-based simulation exercise.
Authors: Jennifer Jill Dacus, Nathan M. Shumway, Kate Ida Lathrop, Elizabeth P. Hernandez, Maria Miller, Anand B. Karnad
Journal: Journal of Clinical Oncology (2014)

e17683 Background: The ability to recognize and treat a chemotherapy infusion reaction (IR) is essential for quality cancer care. Anaphylaxis is a severe allergic reaction that can lead to significant morbidity and even death. There is little data to guide how best to teach treatment of IR to medical oncology fellows (MOF). To improve our teaching of the subject, we conducted a PI project using simulation (SIM) and the use of checklists (CKL) to assess our MOF skills pertaining to IR. Methods: Program directors from 2 training sites in San Antonio, TX created a 10-minute SIM lab using a standardized patient and a standardized nurse during a chemotherapy IR. MOF from both institutions were asked to respond to a patient with severe hypersensitivity reaction (hypotensive) while receiving carboplatin for ovarian cancer. Half the MOF were given an IR checklist prior to their SIM encounter based upon NCCN guidelines. All encounters were videotaped and data recorded by 2 faculty. Results: 17 MOF (6 PGY-4s, 6 PGY-5s, and 5 PGY-6s) participated and had video reviewed. 8/17 were given CKL prior to their encounter. The mean time to stop the carboplatin infusion was 83 sec (±58) in the entire cohort. The mean time to stop the infusion in the CKL group was 53 sec (±53) vs. 110 sec (±51) in those without a CKL (p=0.04). The mean Infusion reaction checklist total score (9 items) was 5 (±1.7) in the checklist group compared to 4.8 (±1.2) in the group with no checklist. No fellows (0/17) performed all 9 CKL items. 63% of MOF checked vital signs (VS) up front in the CKL group compared to 67% without the CKL. 100% of fellows with a CKL gave H1 blockers versus 88% in group without CKL. 63% of fellows with CKL gave H2 blockers compared to 44% without. 100% of fellows (17/17) gave steroids. 50% of MOF with CKL gave EPI versus 22% without a CKL. Only 2/17 MOF (12%) verbalized the correct dose of EPI. Conclusions: CKL led to more immediate intervention and an increased use of H1 and H2 blockers. Our project suggests that we should focus our efforts on teaching MOF the importance of stopping the infusion immediately, monitoring of vital signs, and consideration of EPI for patients who have IR associated with hypotension.
Abstract 18118: Overexpression of Angiotensin-Converting Enzyme 2 in the Rostral Ventrolateral Medulla Inhibits the Neuroinflammation in Hypertensive Rats
Authors: Weizhong Wang, Yang-Kai Wang, Yu Deng
Journal: Circulation (2013)

Neuroinflammation has been reported to contribute to cardiovascular dysfunction in hypertension. Gene transfer of angiotensin-converting enzyme 2 (ACE2) into the rostral ventrolateral medulla, a key region for controlling the sympathetic outflow, leads to a significant reduction in blood pressure and sympathetic activity in hypertension. The goal of the present work is to determine the effect of ACE2 overexpression in the RVLM on neuroinflammation in spontaneously hypertensive rats (SHRs). SHRs was received lentiviral-mediated overexpression of ACE2 (lenti-ACE2) or lenti-enhanced green fluorescent protein (lenti-GFP) control. It was found that a significant reduction in blood pressure and heart rate in the SHRs 3 weeks after lenti-ACE2 injected into the RVLM. Activation of microglia in the RVLM was confirmed in the SHR-GFP, but it was significantly reduced in SHR-ACE2. Content and mRNA expression of the proinflammatory cytokine interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha in the RVLM was significantly (P&lt;0.05) decreased in the SHRs that treated with injection of lenti-ACE2 compared with lenti-GFP. In normotensive WKY rats, we also found that overexpression of ACE2 in the RVLM significantly (P&lt;0.05) reduced the increases in mRNA expression of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha evoked by intracerebraventricular infusion of lipopolysaccharides (4 weeks). Based on the present data, it is suggested that ACE2 gene transfer into the RVLM inhibits neuroinflammation in hypertensive rats, which may be responsible for the beneficial effects of central ACE2 on hypertension. (This work is supported by NSCF 81070214 and 81170240).
Identification and targeting of M-phase progression downstream of HER2 in trastuzumab-sensitive and -resistant breast cancer cell lines.
Authors: E. Aubrey Thompson, Brian M. Necela, Jennifer M. Carr, Jennifer M. Kachergus, Daniel Serie, Krishna R. Kalari, Yan W. Asmann, Edith A. Perez
Journal: Journal of Clinical Oncology (2014)

612 Background: It is generally accepted that therapeutic response to HER2-targeted therapy involves both immunological and cell autonomous (signaling) events. We have used a genomic approach to define signaling processes that occur downstream of HER2 in trastuzumab-sensitive and –resistant human breast cancer cells in culture, with a view towards defining downstream effectors that could be exploited as potential therapeutic targets in tumors that are resistant to inhibition of HER2 signaling. Methods: RNA-seq analysis was carried out with trastuzumab-sensitive cell lines (BT474 and SKBR3), resistant variants selected from such cells, and cells that exhibit de novo resistance (MDAMB453 and HCC1954). Changes in mRNA abundance were quantified after trastuzumab treatment and after shRNA-mediated knockdown of ERBB2. Network analysis was carried to define biological processes associated with abrogation of HER2 signaling. Both pharmacological and genetic knockdown were used to test candidate downstream effectors of trastuzumab. Results: A prominent cohort of M-phase progression genes was consistently downregulated in sensitive but not resistant cells. These genes included PLK1, AURKB, ECT2, MCM10, BUB1, and PBK. Knockdown of PLK1 inhibited growth of both sensitive and resistant cultures. Since both PLK1 and paclitaxel inhibit process associated with the mitotic spindle, we tested for synergy between paclitaxel and the PLK inhibitor BI2536 in sensitive and resistant cell lines. At EC50 concentrations, both inhibitors significantly reduced culture growth rates. However, when both drugs were combined at EC50 concentrations, culture growth was completely obliterated. Conclusions: Regulation of M-phase progression is a significant component of ERBB2 signaling in HER2+ breast cancer cells. Combined therapy with low concentrations of drugs that target mitotic spindle formation by different mechanisms appears to provide a potential mechanism to target HER2+ tumors irrespective of sensitivity to HER2-targeted therapy.
Abstract 15544: GRK2 RGS Domain-Specific Interaction With Gαq Inhibits Hypertrophy and Cardiac Dysfunction During Pressure Overload
Authors: Sarah M Schumacher, Erhe Gao, Maya Cohen, Melissa Lieu, J. Kurt Chuprun, Walter J Koch
Journal: Circulation (2015)

G protein-coupled receptor (GPCR) kinases (GRK) play a critical role in cardiac function through regulation of GPCR activity. Canonically, GRK2 phosphorylates active GPCRs leading to desensitization and down-regulation of the receptors to regulate signaling in the heart. Mounting evidence, however, supports non-canonical regulation of cardiac function by GRK2 through a dynamic “interactome” in which GRK2 can uncouple GPCRs via novel protein-protein interactions. Several GRK2 interacting partners are important for adaptive and maladaptive myocyte growth including Gq, the signaling trigger for maladaptive cardiac hypertrophy, leading to HF. Importantly, GRK2 contains a putative amino-terminal Regulator of G protein Signaling (RGS) domain, that directly interacts with Gq and appears to inhibit signaling without altering Gq enzymatic activity. In the present study we generated transgenic (Tg) mice with cardiac-specific expression of the RGS domain of GRK2 (βARKrgs) and subjected them to a trans-aortic constriction (TAC) model of pressure overload hypertrophy. The βARKrgs Tg mice exhibited a marked anti-hypertrophic effect, with reduced left ventricular wall thickness and hypertrophic gene expression relative to their littermate controls. Use of genetically engineered lines demonstrated that this was through an interaction of the βARKrgs peptide with Gq-mediated signaling that inhibited hypertrophy as well as the progression to heart failure (HF). These data support our hypothesis that the RGS domain of GRK2 may serve as a non-canonical inhibitor of Gq-mediated hypertrophic signaling in the heart and highlight how this research may pave the way for novel GRK2-based therapeutic approaches to prevent hypertrophy and HF.
The Next Generation of Diabetes Translation: A Path to Health Equity
Authors: Debra Haire-Joshu, Felicia Hill-Briggs
Journal: Annual Review of Public Health (2019)

Disparities in diabetes burden exist in large part because of the social determinants of health (SDOH). Translation research and practice addressing health equity in diabetes have generally focused on changing individual behavior or providing supportive approaches to compensate for, rather than directly target, SDOH. The purpose of this article is to propose a pathway for addressing SDOH as root causes of diabetes disparities and as an essential target for the next generation of interventions needed to achieve health equity in diabetes prevention and treatment. This review describes ( a) the current burden of diabetes disparities, ( b) the influence of SDOH on diabetes disparities, ( c) gaps in and implications of current translation research, and ( d) approaches to achieving health equity in the next generation of diabetes translation.
Maintenance chemotherapy (MC) in advanced non-small cell lung cancer (NSCLC): A meta-analysis.
Authors: Tiago Biachi De Castria, Gilberto Castro, Paulo Marcelo Hoff
Journal: Journal of Clinical Oncology (2014)

e19020 Background: MC, either as switch or continuation therapy, has been shown to improve progression-free (PFS) and overall survival (OS) in advanced NSCLC. In order to clarify the survival benefits of MC in advanced NSCLC, we conducted a meta-analysis including only randomized trials. Methods: We collected data “as available”, from studies published between 1990 and 2013 that compared chemotherapy (CT) with best supportive care (BSC) or placebo, after a platinum-based induction CT. We excluded studies with monoclonal antibodies or small-molecule tyrosine kinase inhibitors. We retrieved studies from Medline, Cochrane Database, ASCO Annual Meetings and ClinicalTrials.gov. Two reviewers independently assessed eligibility and the quality of studies using Jadad scale. We extracted hazard ratios (HR) for PFS and OS from studies, or computed them from median times or Kaplan-Meier curves. We obtained the overall HR through the generic inverse variance method, using random-effects models. We assessed variability across trials using Cochran Q tests , with analyses conducted using Review Manager v5.2. Results: We included 8 studies, enrolling 2,458 patients (pts) (1461 MC and 997 controls). Only one trial (Paz-Ares et al., 2012) included only pts with non-squamous histology. Regarding PFS, 7 trials (2203 pts) were included, with an overall HR of 0.60 (95% CI 0.54 – 0.66, I2 5%). For OS, 8 trials (2458 pts) were included, with an overall HR of 0.84 (95% CI 0.77 – 0.93, I2 0%). Both switch and continuation MC were associated with a superior PFS (HR 0.56, 0.45 - 0.71, I2 59% and HR 0.63, 055 - 0.72, I2 0%) and OS (HR 0.80, 0.69 - 0.93, I2 0% and HR 0.87, 0.77 - 0.99, I2 0%, respectively). Pemetrexed-based MC improved PFS (HR 0.57, 0.47 - 0.69, I2 31%) and OS (HR 0.80, 0.69 - 0.91, I2 0%). Gemcitabine and taxanes improved PFS (HR 0.58, 0.48 - 0.70, I2 0% and HR 0.67, 0.56 - 0.81, I2 0%) but not OS (HR 0.91, 0.76 - 1.09, I2 0% and HR 0.84, 0.77 - 0.93, I2 0%, respectively). Among published studies, Jadad score was 5 in 2 studies, 3 in 2 studies and 2 in 3 studies. Conclusions: MC, either as switch or continuation, improves PFS and OS in advanced NSCLC after platinum-based induction CT, in both non-squamous and squamous histologies. Only pemetrexed was shown to improve OS.
Efficacy of Lenalidomide and Bortezomib for Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) Relapsing after Allogeneic Stem Cell Transplantation
Authors: Andrew M. Brunner, Traci M. Blonquist, Malgorzata McMasters, Gabriela S. Hobbs, Steven L McAfee, Jacalyn Rosenblatt, Philip C. Amrein, Christine Connolly, Aura Y. Ramos, Kaleb Mikami, Emma Logan, Bimalangshu R Dey, Thomas Spitzer, David E. Avigan, Yi-Bin Chen, Karen K. Ballen, Areej El-Jawahri, Amir T. Fathi
Journal: Blood (2018)
Programmed death receptor ligand-1 (PD-L1) expression in a thymoma (T) tissue microarray (TMA).
Authors: Sukhmani Kaur Padda, Jonathan Riess, Erich Jurgen Schwartz, Lu Tian, Holbrook Edwin Kohrt, Joel W. Neal, Yasodha Natkunam, Robert B. West, Heather A. Wakelee
Journal: Journal of Clinical Oncology (2014)

7606 Background: Thymomas (T) contain lymphocytic infiltrates, and as they arise from an immune organ confer a unique tumor microenvironment. Tumor expression of the immune checkpoint ligand, PD-L1, is a known mechanism for immune evasion. Here, we evaluated T expression of PD-L1. Methods: A TMA was constructed from 69 Ts, with 15 thymic controls (C) (including 8 paired normal thymuses adjacent to tumor), at Stanford University. The pathologist was blinded to clinical data and sample identity. The TMA was stained with a monoclonal antibody (clone 15, Sino Biological) to human PD-L1 using human placenta for staining titration. To distinguish PD-L1 expression on epithelial cells from that on lymphocytes, a CK5/6 cytokeratin stain was used. An intensity scale of 0, 1, 2, and 3 representing no, equivocal, weak, and intermediate-strong staining, respectively, was used. Positive PD-L1 expression was defined as ≥2 staining intensity on thymic epithelial cells. A two-sample Wilcoxon rank sum test was used to compare the average intensity between Ts and Cs, and a Kruskal-Wallis rank test was used to compare the average intensity between type A, B, and AB histologies. A two-sided p-value ≤0.05 was considered statistically significant. Results: Characteristics for 69 patients: 36M/33F; mean age 54 years (2-86); WHO histology: 7 A, 17 AB, 8 B unspecified, 9 B1, 18 B2, 4 B3, 3 C, and 3 NOS. There were no PD-L1 intensity scores of 0 or 1 in either Ts or Cs. The majority of lymphocytic infiltrates did not stain for PD-L1. Ts had a higher frequency of more intense PD-L1 staining compared to Cs [T: 22.4% (2)/77.6% (3) v. C: 58.1% (2)/41.9% (3); p=0.007]. PD-L1 staining intensity also varied between histologic subtypes: B>AB>A (p=0.0002). The difference between A v. B was the most striking [A: 66.7% (2)/33.3% (3) v. B: 9.2% (2)/90.8% (3); p=0.0001]. Conclusions: To our knowledge, Ts have not been previously examined for PD-L1 expression. Although both Ts and Cs expressed PD-L1, Ts generally stained more intensely than Cs. There was also higher PD-L1 staining intensity in lymphocyte dominant histologies (i.e. type B). This finding is highly translatable as several PD-1 and PD-L1 inhibitors are in clinical trials.
Immune System Profiling of Waldenstrom Macroglobulinemia (WM) and Immunoglobulin M Monoclonal Gammopathy of Undetermined Significance (IgM MGUS) Using Mass Cytometry (CyTOF)
Authors: Jonas Paludo, Jose Villasboas Bisneto, Anne J Novak, Morie A. Gertz, Prashant Kapoor, Aneel Paulus, Sikander Ailawadhi, Esteban Braggio, Craig B. Reeder, Shahrzad Jalali, Francis K. Buadi, Robert A. Kyle, Stephen M. Ansell
Journal: Blood (2018)
Abstract 16586: The Intermediate-Conductance Ca2+-activated K+ Channel KCa3.1 Regulates Proliferation of Human Coronary Smooth Muscle Cells
Authors: Dan Bi, Vincent LemaÎtre, Jun Takai, Hiroto Miura
Journal: Circulation (2012)

Introduction: Vascular smooth muscle cell (VSMC) proliferation is a pathological process occurring in vascular remodeling. We have previously demonstrated that the intermediate-conductance Ca2+-activated K+ channel KCa3.1 is upregulated in proliferating VSMCs, and the blockade, knockdown and deficiency of KCa3.1 suppress VSMC proliferation. Here we further explored the mechanism by which KCa3.1 regulates VSMC proliferation. Methods and Results: Platelet-derived growth factor-BB (PDGF, 20 ng/ml)-induced proliferation (using a BrdU incorporation assay) of human coronary artery VSMCs was attenuated by lowering intracellular Ca2+ concentration ([Ca2+]i) with BAPTA (30 μ M, an intracellular Ca2+ chelator) and was enhanced by a forced rise in [Ca2+]i with A23187 (0.1 to 1 nM, a Ca2+ ionophore). KCa3.1 blockade with TRAM-34 (100 nM, a specific blocker of KCa3.1) or siRNA knockdown reduced proliferation by inhibiting the rise in [Ca2+]i, as assessed in fluorescence microscopy with Fluo-4 (a Ca2+-sensitive dye), a...