tbuckley/cabot-search huggingface dataset:
Experimental modulation of mood by acoustic stimulation and its effect on exertional dyspnoea
Authors: Pramod Sharma, Liam Hall, Norman R Morris, Surendran Sabapathy, Lewis Adams
Journal: Thorax (2019)

We examined the interactions between acoustically driven mood modulation and dyspnoea. Following familiarisation, 18 healthy participants attended three experimental sessions on separate days performing two 5 min treadmill tests with a 30 min interval per session while listening to either a positive, negative or neutral set of standardised International Affective Digitised Sounds (IADS). Participants rated intensity and affective domains of dyspnoea during the first exercise test and mood during the second. Mood valence was significantly higher when listening to positive (mean (95% CI): 6.5 (5.9–7.2)) compared with negative sounds (3.6 (2.9–4.4); p&lt;0.001). Dyspnoea intensity and affect were statistically significantly lower when listening to positive (2.4 (1.8–2.9) and 1.3 (0.7–1.9)) compared with negative IADS (3.2 (2.3–3.7), p=0.013 and 2.3 (1.3–3.3), p=0.009). These findings indicate that acoustically induced mood changes influence exertional dyspnoea.
The Abnormal Expression and Mutation of Recombination Signal Binding Protein-Jk Gene Mightbe Contribute to the Proliferation of CD59- Clone in Paroxysmal Nocturnal Hemoglobinuria Patients
Authors: Rong Fu, Liyan LI, Zhaoyun Liu, Hui Liu, Honglei Wang, Yingying Chen, Zonghong Shao
Journal: Blood (2018)
Urine cell flow cytometry analysis of PD-L1 expression and DNA content for bladder cancer.
Authors: Pin-I Chen, Alice (Xiaoyang) Wang, Mustafa Deebajah, Shaheen Alanee, Bruce Kendrick Patterson
Journal: Journal of Clinical Oncology (2019)

466 Background: Bladder cancer is the fifth most common cancer in the United States. PD-1/PD-L1, a pathway used by cancer cells to evade immune response, correlates with bladder cancer severity and has emerged as a target in bladder cancer treatment. Chromosomal instability is also a prominent feature associated with the development of bladder cancer. A method to unbiasedly analyze PD-L1 expression and DNA content in cells from urine samples will help us better understand bladder cancer. Methods: To evaluate the PD-L1 expression and DNA content, we developed a 4-color flow assay. Cells in urine samples were pelleted, fixed/permeabilized (in incellMAX, IncellDx Inc.) and stained with antibodies against pan-cytokeratin (CK), CD45, PD-L1 and a cell cycle dye. The stained samples were analyzed by a flow cytometer alongside stained control cells. Results: Fifty bladder cancer patient and 15 normal donor urine samples were collected and tested with this assay. We could distinguish epithelial cells (pan-CK+) and white blood cells (WBCs, CD45+) in urine samples and obtain PD-L1 expression and DNA content information simultaneously from these cell populations. The patient samples showed a significantly higher percentage of WBCs with substantial PD-L1 expression. The percentage of PD-L1 positive epithelial cells was not distinguishable between normal donor and patient samples. However, increased post G1 epithelial cells ( &gt; 5%) were observed in a majority of bladder cancer patients, with around 25% of samples showing a DNA index above 1.05. In addition, a comparison of urine collection fixatives showed that incellMAX-fixed samples had the best single cell recovery and DNA content measurement, as shown by lower cell cycle dye staining variability (lower rCV). Statistically significant differences were found between cancer patients and normal samples. Conclusions: We developed a flow cytometry-based method to investigate PD-L1 and DNA content simultaneously in cells from urine samples. Comparing urine samples from bladder cancer patients and normal yielded statistically significant differences that could provide valuable information for bladder cancer patient management.
Impact of disagreement between the IMDC and MSKCC risk groups on prognosis in patients with metastatic renal cell carcinoma.
Authors: Shingo Hatakeyama, Toshiaki Tanaka, Yoshinori Ikehata, Naoki Fujita, Hayato Yamamoto, Takahiro Yoneyama, Yasuhiro Hashimoto, Naoya Masumori, Hiroshi Kitamura, Chikara Ohyama
Journal: Journal of Clinical Oncology (2019)

556 Background: As the clinical implication of the risk group disagreement between the risk models remains unclear, we aimed to investigate the impact of the risk group disagreement between the Memorial Sloan Kettering Cancer Center (MSKCC) and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) models on prognosis. Methods: We retrospectively evaluated 176 patients with metastatic renal cell carcinoma (mRCC) who were treated with tyrosine kinase inhibitors as first-line therapy in five hospitals between October 2008 and August 2018. The risk group classification differences between the MSKCC and the IMDC models were evaluated using criteria of agreement (identical risk group in both the MSKCC and IMDC models) and disagreement (not identical risk group in both the MSKCC and IMDC models). The agreement of risk stratification between the MSKCC and IMDC models was evaluated using Cohen’s k coefficient. Oncological outcomes were compared between the agreement and disagreement groups. Results: The number of patients with agreement, upgrade, and downgrade was 135/176 (77%), 39/176 (22%), and 2/176 (1.1%), respectively. Of 41 patients with disagreement, reclassification from the MSKCC-intermediate to the IMDC-poor-risk group was most frequent (n = 34/176, 19%). The Cohen’s k coefficient for agreement of the two risk models was substantial with k value of 0.613 ( P &lt; 0.001). Significantly poorer prognosis was observed in patients with disagreement than in those with agreement. Conclusions: Disagreement between the MSKCC and IMDC models may have a negative impact on prognosis in patients with mRCC. Further study is necessary to validate our findings.
Abstract P348: Validation of <i>SGCD</i> (rs2116737) Genotype-Discrimination Interaction as a Determinant of Blood Pressure Variation in the Jackson Heart Study
Authors: Leanne Dumeny, Chu Hsiao, Adam P Bress, Larisa H Cavallari, Dayna A Johnson, Connie J Mulligan, Daichi Shimbo
Journal: Circulation (2019)

Introduction: Previous anthropological studies have demonstrated the utility of integrating genetic and psychosocial data, such as discrimination, to understand complex phenotypes such as blood pressure (BP). In these studies, including both single nucleotide polymorphisms (SNP) and psychosocial measures in the model only revealed significant SNPs after accounting for gene by social environment interactions. Methods: We sought to externally validate SNPs associated with BP in African Americans (AAs) identified in a study by Quinlan et al. in 2016 that incorporated novel measures of unfair treatment/discrimination and revealed new genes and biological pathways relevant to BP variation. Our validation was done using a larger cohort study of AAs, the Jackson Heart Study (JHS). Systolic and diastolic BP were measured twice in the same visit using a random-zero mercury sphygmomanometer and averaged. During this visit, perceived discrimination was assessed as lifetime occurrence of unfair treatment in nine social domains using the JHS discrimination instrument. Using available GWAS data, 28 significant SNPs were imputed from 1000 Genomes Project Phase 1 (version 3). Our analysis was conducted separately on participants who reported use of BP medications (n= 1532) and those who did not (n=1407). We similarly tested for associations of SNPs with BP using 3 linear regression models adjusting for global ancestry, sex, age, education, BMI, and relatedness. Model 1 tested only the SNPs, model 2 tested the SNPs and discrimination, and model 3 tested an interaction between SNPs and discrimination. Results: JHS participants were 62% female, with a mean age of 55 years, mean BMI of 32, mean systolic BP of 127 and mean diastolic BP of 76. Participants on average experienced unfair treatment in three domains in their lifetime. In participants not on BP medications, we found that rs2116737, in the gene SGCD , achieved Bonferroni-corrected significance (p &lt; 0.004) with systolic BP in a recessive genotype model (β= 11.92; p =2.00х10 -4 ) and was only identified through model 3, the gene-discrimination interaction model. No significant findings were seen in patients using BP medications. Conclusions: rs2116737 was validated in the JHS for a gene-discrimination interaction. rs2116737 is an intronic variant in SGCD , a gene that is highly expressed in arterial tissue, suggesting vascular regulation as a possible mechanism behind the interaction. In conclusion, the findings suggest accounting for a gene by social environment interaction can identify new SNPs that deserve further investigation in understanding BP variation.
Measurement science of the androgen receptor splice variant-7 protein in primary and castration-resistant prostate cancer tissue.
Authors: Adam Sharp, Ilsa Coleman, Jon Welti, Maryou B. Lambros, Wei Yuan, Daniel Nava Rodrigues, Cynthia Sprenger, David Dolling, Joshua Russo, Ines Figueiredo, Antje Neeb, Takuma Uo, Colm Morrissey, Suzanne Carreira, Peter S Nelson, Steven P. Balk, Lawrence D. True, Jun Luo, Stephen R Plymate, Johann S. De Bono
Journal: Journal of Clinical Oncology (2019)

151 Background: Liquid biopsies demonstrate the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced benefit from endocrine therapies in castration resistant prostate cancer (CRPC). These studies provide little information pertaining to AR-V7 expression in PC tissue. Methods: AR-V7 protein expression was determined for 358 primary PC samples and 293 metastatic CRPC biopsies by immunohistochemistry. Associations with disease progression, full length AR (AR-FL) expression, response to therapy, gene expression, and circulating tumor cell (CTC) AR-V7 status were investigated. Results: AR-V7 protein is rarely expressed ( &lt; 1% of 358 cases) in primary PC but is frequently detected (75% of 40 cases) following primary androgen deprivation therapy (ADT) alone (H-score 40; interquartile range 1.25-92.5), with a further significant (p = 0.020) increase following abiraterone or enzalutamide therapy (90; 20-150). In CRPC, AR-V7 expression is mainly nuclear (94% of 144 cases), correlates with AR-FL expression (p = &lt; 0.001), and is homogeneous within single metastases (p = 0.997) but heterogeneous in different metastases from the same patient (p &lt; 0.001). In addition, AR-V7 expression correlates with a 59-gene signature, including HOXB13, a co-regulator of AR-V7 function. Moreover, AR-V7 negative disease associates with better PSA response (p = 0.03) and overall survival (p = 0.02) from endocrine therapies. Finally, CTC+/AR-V7+ blood samples had significantly (p = 0.004) higher AR-V7 protein expression (100; 62.5-147.5) in paired tissue biopsy compared to CTC+/AR-V7- blood samples (15; 0.0-112.5), and AR-V7 protein expression is frequently detected (63% of 16 samples) in tissue of patients with CTC- blood samples. Conclusions: AR-V7 protein is not expressed until castration resistance and occurs after primary ADT alone. Levels of AR-V7 protein vary between metastases, and although AR-V7 associates with response to endocrine therapies, this suggests multiple resistance mechanisms exist in the same patient. If developed, agents targeting AR-V7 may be best explored earlier in the course of disease and in combination with other therapies.
Abstract 10976: Preoperative Right Ventricular Function and Residual Mitral Regurgitation After LVAD Implantation Determines the Incidence of Postoperative Right Ventricular Failure
Authors: Paul C Tang, Jonathan W Haft, Abbas Bitar, Reema Hasan, Keith Aaronson, Francis D Pagani
Journal: Circulation (2018)

Introduction: Impact of residual significant mitral regurgitation (MR) on outcomes following durable left ventricular assist device (LVAD) is unclear. Hypothesis: Persistent MR following LVAD is as...
Thirty-month follow-up of the phase III CheckMate 214 trial of first-line nivolumab + ipilimumab (N+I) or sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC).
Authors: Nizar M. Tannir, Osvaldo Arén Frontera, Hans J. Hammers, Michael Anthony Carducci, David F. McDermott, Pamela Salman, Bernard Escudier, Benoit Beuselinck, Asim Amin, Camillo Porta, Saby George, Sergio Bracarda, Scott S. Tykodi, Thomas Powles, Brian I. Rini, Yoshihiko Tomita, M. Brent McHenry, Sabeen Fatima Mekan, Robert J. Motzer
Journal: Journal of Clinical Oncology (2019)

547 Background: N+I showed superior OS v S in ITT (IMDC any risk) and intermediate/poor-risk (I/P) pts with aRCC in CheckMate 214 at 17.5 mo min follow-up. Methods: Pts with clear cell aRCC were randomized 1:1 to N3 mg/kg + I1 mg/kg Q3W×4 and then N3 mg/kg Q2W, or S 50 mg daily for 4 wk on, 2 wk off. Co-primary endpoints were OS, RECISTv1.1 ORR and PFS per IRRC in I/P pts. PFS and ORR were assessed by investigator (inv) at 30 mo. Results: At 30 mo min follow-up, OS remains significantly improved in ITT and I/P pts with N+I v S; the HR for OS in favorable (fav) risk pts has improved for N+I v the previous analysis (1.22 [95% CI 0.73–2.04] v 1.45 [99.8% CI 0.51‒4.12]). Per previous IRRC ORR (N+I, 42% [95% CI 37‒47]; S, 27% [95% CI 22‒31]), ORR per inv was higher with N+I v S in ITT and I/P pts. ORR CIs overlapped in fav pts, CR was doubled with N+I v S. Increasing PFS benefit with N+I v S is emerging in ITT and I/P pts; PFS CIs between arms remain overlapping in fav pts (Table). 15% v 9% of N+I and S ITT pts remain on therapy, and 48% v 61% have received 2nd-line systemic therapy; 39% of S pts received subsequent immune-checkpoint inhibitor therapy. Among pts who were alive with CR, 50% v 10% remain on treatment with N+I (n = 56) v S (n = 10). 5 N+I and 7 S additional pts developed Gr 3–4 drug-related AEs; 1 N+I and 3 S additional pts had AEs leading to discontinuation. No new drug-related deaths occurred. Conclusions: At 30 mo min follow-up, OS and ORR remain improved with N+I v S in ITT and I/P CheckMate 214 pts. No new safety signals emerged with longer follow-up. Clinical trial information: NCT02231749. [Table: see text]
Quality of life in colorectal cancer patients during chemotherapy in the era of monoclonal antibody therapies.
Authors: Idris Yucel
Journal: Journal of Clinical Oncology (2015)

e14525 Background: Quality of life (QoL) is increasingly being used as primary outcome measure in clinical studies. This study was designed to gain knowledge about QoL during chemotherapy among different lines and regimens. Methods: The study comprised 101 CRC outpatients receiving chemotherapy who completed the EORTC QLQ-C30 questionnaire. The Shapiro-Wilk, Kruskal-Wallis, and Mann-Whitney U tests were used for statistical analyses. A p value was accepted as significant in all the statistical analysis. Results: The median patient age was 57.8 years and was similar between (neo) adjuvant and metastatic patients. Male patients predominated (58%). More than half of the patients (64.3%) had colon cancer and the remaining (35.7%) had rectal cancer. The most distinctive symptom was fatigue (fa) with a mean value of 45±28.5 points, and the lowest was dyspnea with a mean value of 14±21 points. The patient demographics were evaluated for QoL. Prior surgery/radiotherapy, working status, stage, comorbidity and sex had no effect on global health status in CRC patients, although some other demographics such as education, monthly income, age and type of chemotherapy regimen did have an effect on global health status. Role functioning was worse in older than in younger ones (p < 0.05). Nausea and vomiting and appetite loss were better in adjuvant patients (p < 0.05). According to chemotherapy regimen, the best QoL was observed in patients receiving FUFA regimen. In the palliative setting; FOLFOX/Bevacizumab were associated with the best QoL scores whereas FOLFIRI/Cetuximab were associated with the worst QoL scores. Conclusions: In this study, there was no QoL difference between chemotherapy lines in metastatic patients (p > 0.05). This means that further chemotherapy did not negatively affect QoL this group of patients. Different chemotherapy regimens resulted different QoL scores. There was no statistically difference between different chemotherapy regimens in terms of global health status in the palliative setting. Patients received FOLFOX/Bevacizumab had the best QoL scores in this group of patients.
Results of a phase II study to evaluate the safety and efficacy of RX-0201 in combination with everolimus in subjects with metastatic renal cell carcinoma (mRCC).
Authors: Neeraj Agarwal, Sumanta K. Pal, Richard C. Lauer, Gurkamal S. Chatta, Sanjay Goel, Parminder Singh, Srinath Sundararajan, Callie Heaton, Christine Peterson, Ely Benaim, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2019)

646 Background: RX-0201 is a novel 20-mer oligonucleotide that binds to mRNA coding for AKT-1, preventing AKT-1 expression and limiting the amount of downstream p-AKT. In vitro RX-0201, in combination with everolimus, additively inhibited Caki-1 cell growth. RX-0201, in combination with everolimus, to treat mRCC was evaluated in a Phase 1b/2 clinical study. Methods: This Phase 1b/2 study (2‐stage design, NCT02089334 ) evaluated the efficacy and safety of RX‐0201 in combination with everolimus in eligible subjects with mRCC. Eligible subjects must have had confirmed histologic or cytologic evidence of renal cancer with a clear cell component, measurable disease as defined by RECIST, received at least 1 course of therapy with a VEGFR inhibitor and progressed within 6 months of planned first dose of on study treatment. In Phase 1 subjects were enrolled at increasing doses of RX-0201 (delivered via continuous IV for 14 days) in combination with 10 mg/day everolimus in a modified 3+3 design. The target dose of RX-0201 identified in Phase 1, 250 mg/m 2 /day, was further evaluated in Phase 2. Primary objectives included the safety and efficacy at the recommended Phase 2 dose. The Phase 2 primary endpoint was progression free survival (PFS) benefit for at least 4.5 months. Results: Eleven subjects (7 males, 4 females) with mRCC were treated with RX-0201 (250 mg/m 2 /day) + everolimus (10 mg/ day) in Phase 2. The median age was 63 years, ECOG performance status at screening was 0 to 1, and 55% received ≥ 3 prior therapies. The median PFS in evaluable subjects was 4.9 months. Four subjects had stable disease after 6 months of treatment. The most frequent related adverse events ( &gt; 15%) were G1/2 epistaxis, G3 fatigue, G1/2 nausea and G1 vomiting. Conclusions: In this mRCC population with extensive prior therapy, RX‐0201 in combination with everolimus was safe, well-tolerated, and showed promising efficacy. The results also support the therapeutic significance of the AKT-1/mTOR pathway in mRCC. Clinical trial information: NCT02089334.
Abstract 157: Alterations in Signaling Pathways During Regression of Pathological Cardiac Hypertrophy
Authors: Deanna Langager, Leslie Leinwand
Journal: Circulation Research (2017)

Introduction: Cardiac hypertrophy is initially, a compensatory mechanism to maintain cardiac output when there is an increased load on the heart. However, if cardiac hypertrophy persists for an extended time, there can be maladaptive changes to the myocardium. Even when the underlying cause of hypertrophy is treated, regression is often minimal or absent. Clinical cases of cardiac regression do exist, including patients receiving bariatric surgery or a left ventricular assist device. While many of the mechanisms leading to cardiac hypertrophy are well understood, little is known about the mechanisms of reversal of hypertrophy and why it is sometimes irreversible. We hypothesized that a reversal of isoproterenol (Iso) induced cardiac hypertrophy in the mouse will be observed within 7 days following the removal of the stimulus and we will be able to identify alterations in signaling pathways. Methods: We induced pathological cardiac hypertrophy with Iso for 7 days, at which peak hypertrophy is achieved. To identify if/when regression occurs, the Iso treatment was stopped and the mice were monitored for 7 days. Heart weights were measured at peak hypertrophy, post-drug days 1, 2, 3 &amp; 7, along with vehicle treated mice (8/group). We used left ventricle tissue for protein analysis and protein degradation activity assays. Results: Regression from cardiac hypertrophy occurs by post-drug day 7 (p=0.016) in the Iso mouse model. p-Akt is increased with Iso treatment and returns to vehicle control levels by post-drug day 7. There is a decrease in p-mTOR and an increase in LC3-II levels at post-drug day 7, indicating a possible role of autophagy in cardiac regression. In addition, there was a decrease in cell size when neonatal rat ventricular myocytes were treated with the Akt inhibitor, Wortmannin, following phenylephrine induced hypertrophy. Conclusion: Regression of Iso-induced cardiac hypertrophy occurs in the mouse after 7 days following the removal of the stimulus. The Akt pathway is activated with Iso treatment and when this pathway is inactivated during regression, autophagy is activated, which may be an important mechanism to degrade proteins and lead to a decrease in cardiac hypertrophy. Finally, when the Akt pathway is inhibited in vitro , hypertrophic cells regress.
Immunotoxin therapy in animal model of HuD antigen positive small cell lung cancer.
Authors: Bo Wang, Wei Lu, Peter Dowling
Journal: Journal of Clinical Oncology (2015)

3033 Background: Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer. Most patients exhibit clinically detectable metastases at diagnosis and have an extremely poor prognosis despite combined modality therapy. HuD-antigen is a neuronal RNA-binding protein that is expressed in 100% of SCLC tumor cells. High levels of circulating anti-HuD antibodies in patients appear to be linked to spontaneous remission of their SCLC. This suggests that the HuD-antigen might be a potential molecular target for SCLC immunotargeting therapy. Methods: We constructed a new antibody-toxin compound (BW-2) comprised of mouse-anti-human-HuD mAb bound to saporin and tested the compound in vitro in the NCI-H69 SCLC cell line. In vivo SCLC experiments utilized male athymic nude mice (NCRNUM) xenografted with NCI-H69 cells. Tumor xenografted mice received a single intravenous or intratumoral injection of BW-2, while control tumor xenografted mice were treated with either anti-HuD antibody or saporin alone. Normal C57BL/6 mice were used to test for potential neurological side effects from BW-2. Results: In vitro experiments showed a high level of HuD+ tumor cell specific cytotoxicity in the presence of BW-2 immunotoxin and minimal HuD- cell cytotoxicity only at much higher concentrations of BW-2. Immunotoxin therapy in a nude mouse model of human SCLC demonstrated clear tumor shrinking while control tumor xenografted mice demonstrated rapid tumor volume expansion. Tumor volume in immunotoxin treated mice regressed for several weeks. Neurological testing revealed no manifestations of neurological disease in normal C57BL/6 mice even at doses of BW-2 as high as 10mg/kg. Conclusions: Our findings demonstrate in vitro and in vivo effectiveness of anti-HuD immunotoxin therapy for HuD+ SCLC. This approach to tumor antigen specific immunotargeting therapy may one day provide an additional treatment for SCLC.
Single-Cell RNA Sequencing Reveals Distinct Transcriptomic Profiles of Multiple Myeloma with Implications for Personalized Medicine
Authors: David Melnekoff, Alessandro Lagana, Wissam Hamou, Kimaada Allette, Itai Beno, Violetta Leshchenko, Deepak Perumal, Deepu Madduri, Ajai Chari, Hearn Jay Cho, Bart Barlogie, Sundar Jagannath, Joel Dudley, Robert Sebra, Samir Parekh
Journal: Blood (2017)