tbuckley/cabot-search huggingface dataset:
Abstract 396: GRK5-mediated Exacerbation of Ischemic Heart Failure Involves Cardiac Immune-Inflammatory Responses
Authors: Claudio de Lucia, Laurel A Grisanti, Jessica Ibetti, Anna M Lucchese, Erhe Gao, Douglas G Tilley, Dario Leosco, Nicola Ferrara, Giuseppe Rengo, Walter J Koch
Journal: Circulation Research (2017)

Rationale: Coronary artery disease and subsequent myocardial ischemia (MI) are the most common cause of heart failure (HF) in the US. G protein-coupled receptor (GPCR) kinase 5 (GRK5) has been shown to be upregulated in failing human myocardium. While the canonical role of GRKs is to desensitize receptors via phosphorylation, it has been shown that GRK5 can also locate to the nucleus of cardiomyocytes where it can exert GPCR-independent effects that promote maladaptive cardiac hypertrophy after hypertrophic stress. Despite numerous data indicating the importance of GRK5 in hypertrophy, it is still unknown if GRK5 has a role in ischemic heart disease. Objective: In this study, we investigated the critical role that GRK5 plays after myocardial ischemic injury with a novel aspect being the regulation of immune and inflammatory responses including recruitment of immune cells to the injured heart. Methods and Results: Cardiac-specific GRK5 transgenic mice (Tg-GRK5) and non-transgenic littermate (NLC) control mice were subjected to MI. Tg-GRK5-HF mice showed decreased cardiac function (both global and segmental contractility) as well as augmented left ventricular diameters and volumes compared to NLC-HF mice. Heart weight (HW) to body weight or tibia length ratios as well as mRNA expression of all major adverse remodeling-associated biomarkers (ANF, BNP, b-MHC) were increased in the TgGRK5-HF compared to NLC-HF. Cardiac fibrosis in the border zone (BZ) area as well as mRNA levels of Collagen-1 (Col-1), Col-3, MMP2 and CTGF were higher in TgGRK5-HF compared to NLC-HF, strongly suggesting increased adverse remodeling. Inflammatory Cytokines (IL-6 and IL-1beta) were augmented in TgGRK5-HF compared to NLC-HF and contribute at least in part to increased immune cell recruitment in the heart. In fact, we found both Neutrophils and T-lymphocytes (T- cells) augmented in the BZ and infarct zone. Conclusions: Our study shows that cardiac GRK5 has a detrimental effect during ischemic HF. GRK5 overexpression causes reduced cardiac function and increased immune cell recruitment/inflammation. Further, these results suggest GRK5 as a potential therapeutic target to limit HF development after ischemic injury.
Modification of titanium surface via Ag-, Sr- and Si-containing micro-arc calcium phosphate coating
Authors: Mariya B. Sedelnikova, Ekaterina G. Komarova, Yurii P. Sharkeev, Anna V. Ugodchikova, Tatiana V. Tolkacheva, Julietta V. Rau, Evgeny E. Buyko, Vladimir V. Ivanov, Vladimir V. Sheikin
Journal: Bioactive Materials (2019)

The current research is devoted to the study of the modification of the titanium implants by the micro-arc oxidation with bioactive calcium phosphate coatings containing Ag or Sr and Si elements. The coatings' microstructure, phase composition, morphology, physicochemical and biological properties were examined by scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX) and X-ray diffraction (XRD). Ag-containing and Sr-Si-incorporated coatings were formed in alkaline and acid electrolytes, respectively. The formation of the coatings occurred at different ranges of the applied voltages, which led to the significant difference in the coatings properties. The trace elements Ag, Sr and Si participated intensively in the plasma-chemical reactions of the micro-arc coatings formation. Ag-containing coatings demonstrated strong antibacterial effect against Staphylococcus aureus AТСС 6538-P. MTT in vitro test with 3T3-L1 fibroblasts showed no cytotoxicity appearance on Sr-Si-incorporated coatings.
Cancer control in the Pacific: big challenges facing small island states
Authors: Diana Sarfati, Rachel Dyer, Filipina Amosa-Lei Sam, Michael Barton, Freddie Bray, Eka Buadromo, Alec Ekeroma, Sunia Foliaki, James Fong, Josephine Herman, Linda Huggins, Kiki Maoate, Ineke Meredith, Glen Mola, Neal Palafox, Viliami Puloka, Hai-Rim Shin, Jane Skeen, Wendy Snowdon, Malama Tafuna'i, Andrea Teng, David Watters, Paula Vivili
Journal: The Lancet Oncology (2019)
Immunohistochemical expression of phospho-mTOR protein in breast carcinoma tissues and correlation with clinicopathologic parameters.
Authors: Vasiliki Michalaki, M Frangou-Plemenou, Agathi Kondi-Pafiti, Konstantinos Gennatas
Journal: Journal of Clinical Oncology (2012)

e13556 Background: The mammalian target of rapamycin (m-TOR) kinase plays a central role in coordinating cell growth in response to mitogens, amino acid and energy sufficiency. The pathway leading to mTOR activation by these factors, is important for the regulation of protein synthesis and cell survival with implications in carcinogenesis. For these reasons, mTOR is currently under investigation as a potential target for anti-cancer therapy. The aim of this study was to determine the phospho-mTOR (p-mTOR) kinase expression in breast cancer tissues and the relationships with clinicopathological parameters of the breast tumors. Methods: We investigated the status of p-mTOR, in 140 breast carcinomas by immunohistochemistry. Western blot analysis was performed to verify the expression levels of p-mTOR. The relationship of protein expression with clinicopathological data and the correlations of protein expression levels were explored. Multiple logistic regression analyses with stepwise method was used in order to find independent factors associated wth p-mTOR. Results: 47.1% of the patients were p-mTOR positive. In univariate analyses a greater proportion of p-mTOR positive patients was found in those having progesterone receptors, in those hving higher grades of differentiation. When multiple analysis was conducted the only factor that was independently associated with p-mTOR kinase was the tumors grade of differentiation adjusted for age. Subjects with moderate grade of differentiation had greater likelihood for being p-mTOR positive compared to those with low grade of differentiation with odds ratio equal to 3.869 (95% CI: 1.35-11.04, p=0.012). Conclusions: The kinase p-mTOR was found in the neoplastic cells of almost half of the patients were enrolled. Overexpression of p-mTOR was correlated with well-to-moderately differentiated tumors (p&lt;0.001) Our results indicate that dysregulation of the p-mTOR pathway may have an important role in the development of breast carcinoma, but not necessarily in the progression of the disease.
Machine learning and data mining frameworks for predicting drug response in cancer: An overview and a novel in silico screening process based on association rule mining
Authors: Konstantinos Vougas, Theodore Sakellaropoulos, Athanassios Kotsinas, George-Romanos P. Foukas, Andreas Ntargaras, Filippos Koinis, Alexander Polyzos, Vassilios Myrianthopoulos, Hua Zhou, Sonali Narang, Vassilis Georgoulias, Leonidas Alexopoulos, Iannis Aifantis, Paul A. Townsend, Petros Sfikakis, Rebecca Fitzgerald, Dimitris Thanos, Jiri Bartek, Russell Petty, Aristotelis Tsirigos, Vassilis G. Gorgoulis
Journal: Pharmacology & Therapeutics (2019)
Incidence of febrile neutropenia and effectiveness of pegfilgrastim prophylaxis in patients with advanced-stage solid tumors receiving chemotherapy.
Authors: Jeffrey Crawford, Maureen Reiner, Phuong Khanh H. Morrow, Gary H. Lyman
Journal: Journal of Clinical Oncology (2013)

e20564 Background: Advanced disease stage has been identified as an independent risk factor for the development of febrile neutropenia (FN), which continues to be associated with substantial morbidity. We report here results from two clinical trials on the impact of pegfilgrastim (PEG) in patients with advanced stage solid tumors. Methods: Patients were pooled from two placebo-controlled trials: a) a phase III trial of 928 patients with breast cancer, randomized to placebo or PEG 6 mg on day 2 of each 21-day cycle (Vogel CL, et al. JCO 23:1178-84, 2005); and b) a phase II trial of 241 patients with colorectal cancer (CRC), randomized to placebo or PEG 6 mg on day 4 of each 14-day cycle (Hecht JR et al. Clin CRC 9:95-101, 2010). Patients were grouped by disease stage at baseline: advanced (stage III, IIIA, IIIB, IV) or limited (stage I, II, IIA, IIB). Grade 3/4FN was defined as a temperature of ≥ 38.2°C and an ANC of &lt;1.0 x 10 9 /L. The Cochran-Mantel-Haenszel test was used to evaluate the association between PEG and grade 3/4 FN, odds ratio (OR) for FN was estimated by logistic regression, and a trend in the number of FN events per patient was estimated using a Cochran-Armitage test. Results: Characteristics of the 982 patients with advanced stage cancer are shown in the table. PEG was associated with significantly fewer grade 3/4 FN events (p &lt; 0.001), with OR for PEG vs placebo of 0.12 (95% CI: 0.07, 0.22). The percentage of patients with 0, 1, and ≥ 2 FN events was 97%, 3%, and 0% with PEG and 81%, 18%, and 0.4% with placebo, and PEG significantly reduced the number of FN events (p&lt; 0.001). Conclusions: Patients with advanced stage cancer are at considerable risk for developing FN, and PEG prophylaxis reduced that risk. Assessment of FN risk is essential in the advanced/metastatic treatment setting. [Table: see text]
Interrogation of polymorphisms in drug metabolism or transport genes and peripheral neuropathy during paclitaxel treatment.
Authors: Daniel Louis Hertz, Elizabeth Claire Dees, Alison A. Motsinger-Reif, Amy Drobish, Siddharth Roy, Howard L. McLeod, Lisa A. Carey
Journal: Journal of Clinical Oncology (2012)

10515 Background: Peripheral neuropathy is the most common severe toxicity in patients treated with paclitaxel. Putative genetic mutations in genes relevant to drug metabolism, distribution, and elimination may explain the differences in risk of neurotoxicity among patients. Using a genotyping platform that interrogates nearly 2,000 known variants in drug exposure genes, we hypothesized that polymorphisms could be identified which modulate a patient’s risk of neuropathy during paclitaxel treatment. Methods: Subjects included in this study were treated for breast cancer with paclitaxel-containing regimens. Clinical data, including patient characteristics and toxicity, was collected prospectively in an observational registry. Blood was collected at diagnosis and genotyped using the Affymetrix DMET Plus chip at Gentris. The primary endpoint was grade 2+ neuropathy as defined by NCI CTC criteria. Statistical analysis was carried out using Fisher’s exact test for each SNP, without assumption of a specific genetic model. For this hypothesis-generating study, a p-value of &lt;0.001 was selected for significance. Results: 412 breast cancer patients treated with paclitaxel were included in the analysis. The median age was 50, 107 (26%) were African-American, and 48 (12%) had preexisting diabetes. The prevalence of grade 2+ neuropathy was 18.5% in the cohort. After exclusion of SNPs based on call rate, Hardy-Weinberg equilibrium, and allele frequency, 564 SNPs were interrogated for an association with grade 2+ neuropathy. Two SNPs, rs3788007 (ABCG1_43706676G&gt;A[Intron]) and rs6163 (CYP17A1_195G&gt;T[S65S]), were associated with grade 2+ neurotoxicity p=0.0003 (OR=3.54, 95% CI: 1.77-7.72) and p=0.0008 (OR=0.35, 95%CI: 0.18-0.66), respectively. Conclusions: We identified two SNPs, both in genes not previously investigated in paclitaxel pharmacogenetic studies, which were associated with modified risk of paclitaxel-induced neuropathy. Both genes are implicated in endogenous steroid biology, which is thought to be relevant to neuropathy development, and one SNP (rs6163) is in high LD (r 2 =0.93) with a SNP recently reported to be associated with bortezomib-induced neuropathy.
Upper limb function: Comparison of postmenopause women with and without a history of early breast cancer.
Authors: Nasim Foroughi, Mi-Joung Lee, Sharon Kilbreath
Journal: Journal of Clinical Oncology (2013)

e20578 Background: Long term upper limb impairments following early breast cancer treatment are commonly reported in women years following surgery. However, the extent to which the symptoms are related to menopause and ageing, rather than cancer, has not been explored. This study aimed to compare upper limb strength, shoulder forward flexion range of motion (FF RoM), and presence of impairments in post menopausal women with and without a history of breast cancer. Methods: Community–dwelling age and body mass index (BMI)-matched post menopausal women with (n=40) and without a history of early breast cancer treatment (n=40) participated. Women with other types of cancer, metastatic cancer, and significant neurological or musculoskeletal history unrelated to breast cancer were excluded. Peak shoulder muscle strength was assessed using pneumatic resistance machines and FF RoM with a digital inclinometer. Participants completed the Disability of arm, shoulder and hand (DASH) questionnaire. Between groups comparison were made using analysis of co-variance with age and BMI as confounding variables. Results: Upper limb strength (206.22±45.0 vs. 225.36±86.9 Nm/kg, p=0.091) and FF RoM (166.75±7.9◦ vs. 170.14±6.9◦, p=0.259) were not significantly different between the study and the control group. There were no significant differences between the groups on any of the DASH sub scores (pain: 9.18±8.1 vs. 8.62±8.2, P=0.770). Conclusions: Upper limb impairments are often presumed to be a consequence of surgical procedures in women with breast cancer. However, some of the symptoms women perceive years following surgery may be related to the changes due to aging or menopause rather than cancer treatment.
Response to the recently published guidelines on lower gastrointestinal bleeding
Authors: Samuel Snelling, Rania Ghaffar, Stephen Thomas Ward
Journal: Gut (2019)

In response to the recently published national guideline on lower GI bleeding written by Oakland et al ,1 we have audited our practice at the Queen Elizabeth Hospital, Birmingham (QEHB). We were most interested by the general recommendation for CT angiography and for the use of ‘Shock Index’ to select patients for CT angiography, with the aim to identify the source of bleeding.

When retrospectively analysing 4 years of admissions (905) for lower GI bleeding, we found that 74 patients underwent CT angiography, with a total of 91 scans. This 8% rate is higher than the national 5.9%.1 

Our most interesting finding was the identification of bleeding points …
Changes in Both CD4+CD25+Foxp3+ Regulatory T Cells and CD3-CD56+ NK Cells in Patients with Chronic Myeloid Leukemia Treated with a Tyrosine Kinase Inhibitor
Authors: Fumihito Tajima, Koji Adachi, Toshio Kawatani, Takaya Nishio, Junji Suzumiya
Journal: Blood (2018)
Abstract P310: Effect of Static Stretching Exercise on Aortic Pulse Wave Velocity
Authors: Jeongok G Logan, Suk-Sun Kim, Mijung Lee, SeonAe Yeo
Journal: Circulation (2017)

Introduction: Large-artery stiffness (i.e., aortic stiffness) is an independent predictor of hypertension which is a leading cause of excess cardiovascular morbidity and mortality. Carotid-femoral pulse wave velocity (cf-PWV) is considered the ‘gold-standard’ measure of arterial stiffness because it measures along the aorto-iliac pathway, which buffers blood pressure (BP) the most. While there is well-documented evidence on the health benefits of aerobic and resistance exercise, the information for the effect of stretching on aortic stiffness is limited. Previous studies have shown that arterial stiffness is associated with trunk flexibility. Stretching exercise targeted to improve flexibility may exert a beneficial effect on reducing aortic stiffness. Objectives: This study aimed to examine effects of a single bout of a structured static stretching exercise on aortic stiffness as well as trunk flexibility, blood pressure (BP), and heart rate (HR). Method: This study has a pretest-postest design without a control group. Thirty healthy women from the community were instructed to follow a video demonstration of a structured whole-body static stretching lasting 30 minutes. Each stretching was designed to improve range of motion and enhance flexibility in 10 body areas, and all stretching motions were performed in the sitting position. Aortic stiffness was measured by cf-PWV using the SphygmoCor system (AtCor medical, AU). Trunk Flexibility was measured by the sit and reach method. BP and HR were measured using the WelchAllyn Monitor (WelchAllyn, USA). Results: After stretching exercise, cf-PWV (m/s) was significantly reduced (M=6.93, SD=1.54 vs M=6.29, SD=1.17; t(29)=2.708, p =.011). In addition, HR (bpm) was significantly decreased (M=64.88, SD=6.29 vs M=61.77, SD=6.29; t(29) = 7.170, p=.000). A significant increase of lumbar flexibility (inches) was also detected (M=13.37, SD=4.3 vs M=16.45, SD=4.79; t(29) = 12.248, p=.000). Systolic BP and diastolic BP (mmHg) were decreased after stretching exercise from M=107.87 (SD 10.75) to M=106.82 (SD 12.48), from M=63.37 (SD 6.71) to M=61.88 (SD 6.47), respectively; however, the differences did not reach the statistical significance. Conclusions: Findings of the current study highlight the potential benefit of static stretching exercise on aortic stiffness independent of BP. The results also demonstrate that HR was significantly decreased after the stretching exercise. Given no sign of over-activity of sympathetic function, a structured static stretching exercise may be prescribed as an effective intervention to reduce aortic stiffness for the people with high risk of cardiac events. In addition, stretching motions that were conducted in the sitting position can be cautiously utilized as an effective intervention for stroke patients, post-surgery patients, and people who have unsteady walking.
Impact of race on survival of prostate cancer patients treated with noncurative intent
Authors: D. Hatcher, A. E. Rose, P. J. Christos, M. Mazumdar, M. John, S. S. Taneja, P. Lee, I. Osman
Journal: Journal of Clinical Oncology (2009)

5069 Background: We previously reported that African American (AA) men have a higher recurrence rate than Caucasian (CA) men treated with radical prostatectomy at the New York Veteran Administration Medical Center (NY-VAMC), an equal access to care facility (J Urol. 2006). In the current study, we attempted to examine the differences in survival of AA and CA prostate cancer (PC) patients with clinically detected localized disease treated with non curative intent. We hypothesized that comparing patients whose PC was not altered by primary treatment might give a better idea about the difference, if any, of the natural history of PC in AA compared to CA patients. Methods: Men diagnosed with PC at NY-VAMC during 1990–2005 were identified. Inclusion criteria were: 1) biopsy confirmed PC; 2) no evidence of metastatic disease within 6 months after diagnosis; 3) no curative intent treatment. Results: The study included 530 men (288 AA and 242 CA) with median follow-up of 8.1 years (range: 0.6–17.6 years). AA men presented with significantly higher PSA compared to CA patients (median 18.5 versus 11.4 respectively, p = 0.004), however, there were no differences in age at presentation (median 73 versus 74, p = 0.98) or Gleason score (23% of AA and CA had Gleason &gt;7, p = 0.92). Of the 530 patients, 198 (37%) are alive with disease, 67 (13%) died of prostate cancer, 206 (39%) died of other causes, and 59 (11%) died of unknown causes. AA patients had shorter median overall survival compared to CA patients (8 versus 9 years, respectively), however, the difference was not significant (p = 0.29). Factors most predictive of mortality by Cox regression multivariable analysis were PSA at diagnosis (p = 0.001), Gleason score (p = 0.04), and age of patient at diagnosis (p &lt; 0.0001). Race was not an independent predictor of mortality in this model (p = 0.37). Competing risk analysis distinguishing the types of death is underway. Conclusions: The extended follow up available for our study cohort points to non PC related mortality as the major cause of death in patients treated with non-curative intent. No significant financial relationships to disclose.
Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer
Authors: Mark P. Labrecque, Ilsa M. Coleman, Lisha G. Brown, Lawrence D. True, Lori Kollath, Bryce Lakely, Holly M. Nguyen, Yu C. Yang, Rui M. Gil da Costa, Arja Kaipainen, Roger Coleman, Celestia S. Higano, Evan Y. Yu, Heather H. Cheng, Elahe A. Mostaghel, Bruce Montgomery, Michael T. Schweizer, Andrew C. Hsieh, Daniel W. Lin, Eva Corey, Peter S. Nelson, Colm Morrissey
Journal: Journal of Clinical Investigation (2019)

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with diverse drivers of disease progression and mechanisms of therapeutic resistance. We conducted deep phenotypic characterization of CRPC metastases and patient-derived xenograft (PDX) lines using whole genome RNA sequencing, gene set enrichment analysis and immunohistochemistry. Our analyses revealed five mCRPC phenotypes based on the expression of well-characterized androgen receptor (AR) or neuroendocrine (NE) genes: (i) AR-high tumors (ARPC), (ii) AR-low tumors (ARLPC), (iii) amphicrine tumors composed of cells co-expressing AR and NE genes (AMPC), (iv) double-negative tumors (i.e. AR-/NE-; DNPC) and (v) tumors with small cell or NE gene expression without AR activity (SCNPC). RE1-silencing transcription factor (REST) activity, which suppresses NE gene expression, was lost in AMPC and SCNPC PDX models. However, knockdown of REST in cell lines revealed that attenuated REST activity drives the AMPC phenotype but is not sufficient for SCNPC conversion. We also identified a subtype of DNPC tumors with squamous differentiation and generated an encompassing 26-gene transcriptional signature that distinguished the five mCRPC phenotypes. Together, our data highlight the central role of AR and REST in classifying treatment-resistant mCRPC phenotypes. These molecular classifications could potentially guide future therapeutic studies and clinical trial design.
A phase II trial of epirubicin (E), estramustine phosphate (EP), and celecoxib (C) as second line treatment of patients (pts) with hormone resistant prostate cancer (HRPC)
Authors: F. Zhong, B. Kasimis, V. Chang, N. Sambamoorthi, S. Srinivas, J. Cogswell, E. Morales, M. Gonzalez, L. Duque, M. Blumenfrucht
Journal: Journal of Clinical Oncology (2006)

14567 Background: Celecoxib, epirubicin, and estramustine phosphate affect prostate cancer cells through different mechanisms. All three could be synergistic. We studied the effects of this combination on PSA, response, toxicity and survival in pts with HRPC. Methods: Pts after progression from first line taxane-based chemotherapy with rising PSA and radiographic progression were eligible. Treatment was E30 mg/m 2 iv on day 1 and 8 of each 4 week cycle; EP 280 mg po bid daily × 3 days every wk × 2 followed by 2 wks rest; C 400 mg po bid daily for 28 days. All pts were assessed for response every 2 cycles. Dose modifications for hematologic and hepatorenal toxicity were made. RECIST criteria and PSA decline&gt;50% were used to define response. Results: Sixteen pts enrolled, and 13 are evaluable for toxicity and response. Two withdrew before treatment and one for toxicity. The Median (M) age was 71.5 yrs (59–87), ECOG PS 1 (0–1), Gleason score 7 (4–9), LDH 172 (131–244), Hgb 11.1 (8.8–11.9), PSA 75 (6–814). Pts received M 4 cycles (2–10). Nine (69%) pts had soft tissue and 12 (92%) pts had bone metastases. For radiographic response, 11 pts were evaluable; 6 had stable disease and 2 had complete response by CT. Two pts had response by bone scan. Nine (69%) pts had PSA response. The M survival was 441 days (10–995). There were 5 SAE - DVT, diarrhea, bowel obstruction, cord compression and myocardial infarction. There was good renal and cardiac tolerance. Conclusions: This combination was safe and showed good and durable response as a second line regimen. [Table: see text]