tbuckley/cabot-search huggingface dataset:
Protein-protein interactions between the multifunctional protein CAD and protein phosphatase 1 in breast cancer
Authors: Elizabeth Masko, Meenal Mhaskar, Deborah Heyl-Clegg, Hedeel Guy-Evans, David Evans
Journal: Cancer Research (2008)

2732  CAD is a multifunctional protein that catalyzes the first three reactions in de novo pyrimidine biosynthesis, a pathway essential for cell division and proliferation. Uncontrolled cell proliferation, a hallmark of cancer, is invariably associated with CAD activation. CAD is up-regulated by Erk1/2 MAP kinase, and down-regulated by protein kinase A (PKA). The protein is phosphorylated by MAP kinase just prior to the S phase of the cell cycle and is simultaneously translocated into the nucleus. Interestingly, CAD found in malignant MCF-7 cells is persistently phosphorylated by ERK1/2 and is resistant to phosphorylation by PKA, leading to continuous activation of pyrimidine biosynthesis. The levels of CAD in the nucleus are also much higher in MCF-7 cells as compared to cells from the immortalized MCF-10A line. The mechanisms that control the timing of these events are not well understood. For example, the phosphorylation of CAD by MAPK does not coincide with the activation of the kinase, but is delayed until just before the onset of DNA synthesis. Our hypothesis is that the timing of the activation and nucleocytoplasmic dynamics of CAD is controlled by signaling complexes with kinases and phosphatases. The formation of a stable complex between CAD and PP1 has been demonstrated by far-western analysis, co-immunoprecipation and pull down experiments. Interestingly, the sole consensus sequence for PP1 targeting proteins is located immediately adjacent to Thr456, the residue phosphorylated by MAP kinase, suggesting that the binding of PP1 would mask the MAP kinase phosphorylation site. Conversely, phosphorylation of Thr456 might be expected to impair the binding of PP1. To test this idea, a polypeptide was synthesized corresponding to residues 444-460 of CAD that encompasses both the PP1 consensus sequence and Thr456, as well as two mutant peptides in which Thr456 was replaced with Ala or Asp. The wild type peptide and Ala mutant bind to PP1 while the Asp mutant, which mimics phosphorylated CAD, does not. Moreover, PP1 assays have shown that the CAD peptide effectively competes with the PP1 inhibitor, I-2, for a common binding site on PP1. In contrast, the Asp mutant peptide does not impede the binding of I-2 to PP1. Fluorescence microscopy of mammalian cells transfected with full length CAD, Thr456Ala, or Thr456Glu mutants suggest that PP1 colocalizes with wild type CAD and the Ala mutant but not with the Glu mutant. A plausible interpretation of these results is that the association with PP1 may block the premature activation of CAD in the cytoplasm until it is translocated into the nucleus, whereupon PP1 dissociates and CAD is activated by MAP kinase. Understanding the control mechanisms that are involved in the up and down regulation of the pathway may lead to the development of more efficacious chemotherapeutic drugs that target specific signaling complexes rather than the individual pathway enzymes.
Hospital Length of Stay and Clinical Outcomes in Older STEMI Patients After Primary PCI
Authors: Rajesh V. Swaminathan, Sunil V. Rao, Lisa A. McCoy, Luke K. Kim, Robert M. Minutello, S. Chiu Wong, David C. Yang, Paramita Saha-Chaudhuri, Harsimran S. Singh, Geoffrey Bergman, Dmitriy N. Feldman
Journal: Journal of the American College of Cardiology (2015)
A clinicopathological prediction model for recurrence in patients with early-stage hormone-receptor-positive, HER2-negative breast cancer at King Chulalongkorn Memorial Hospital.
Authors: Suleepon Uttamapinan, Kroongpong Iampenkhae, Thanapoom Rattananupong, Nattaya Poovorawan, Virote Sriuranpong, Napa Parinyanitikul
Journal: Journal of Clinical Oncology (2017)

e12015 Background: Genetic recurrent score has been increasingly applied in combination with clinicopathology for predicting recurrence and guiding the potential role of adjuvant chemotherapy in patients with early breast cancer. However, lack of accessibility limits its use for clinical practice especially in developing countries. Our study aims to formulate model for predicting risk of recurrence in patients with hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. Methods: Five hundred and twenty nine HR-positive, HER2-negative early breast cancer patients who were diagnosed during 2005 to 2015 in King Chulalongkorn Memorial Hospital were retrospectively reviewed. All potentially clinicopathologic prognostic factors for recurrence were analyzed using multivariable logistic regression. Results: Ninety eight HR-positive, HER2-negative early breast cancers developed distant recurrences after a median follow-up of 65.7 months (IQR, 41.2 - 92.3). There was no difference among recurrent and non-recurrent groups in term of age and menopausal status. However, greater number of patients in non-recurrent group had earlier stage (stage I or II). Most of patients in both groups received hormonal therapy, while more patients in the recurrent group received adjuvant (82.7% vs. 70.8%; P = 0.017) and neoadjuvant chemotherapy (35.1% vs. 11.2 %; P &lt; 0.001). From multiple logistic regression using clinical and pathologic variables, lymphovascular invasion (LVI), percentage of Ki-67, and tumor size were independent predictors of recurrence (OR 3.04; P &lt; 0.001, OR 1.02; P = 0.001, and OR 1.18; P= 0.05, respectively). The prediction model for 10-year recurrent risk appears as “log (odd) = - 3.535 + 0.020 (percentage of Ki-67) + 0.165 (Tumor size in cm) + 1.111 (LVI)”. Probability of recurrence is defined as odd / (1+odd). This model yields a C statistic above 0.7 on validation in independent population. Conclusions: A new clinicopathologic prediction model provides comprehensive recurrent risk estimation for Thai patients with HR-positive, HER2-negative early breast cancer.
In severe aortic stenosis with intermediate surgical risk, TAVR was noninferior to SAVR for death or disabling stroke
Authors: Frederick A. Spencer, Gordon H. Guyatt
Journal: Annals of Internal Medicine (2017)

Source Citation Reardon MJ, Van Mieghem NM, Popma JJ, et al; SURTAVI Investigators. Surgical or transcatheter aortic-valve replacement in intermediate-risk patients. N Engl J Med. 2017;376:1321-31. 28304219
Mitochondria and Golgi Apparatus of Induced and Spontaneous Hepatomas in the Mouse
Authors: Albert J. Dalton, Jesse E. Edwards
Journal: JNCI Journal of the National Cancer Institute (1942)

Journal Article Mitochondria and Golgi Apparatus of Induced and Spontaneous Hepatomas in the Mouse Get access Albert J. Dalton, Albert J. Dalton cytologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Jesse E. Edwards Jesse E. Edwards research fellow National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 2, Issue 6, June 1942, Pages 565–575, https://doi.org/10.1093/jnci/2.6.565 Published: 01 June 1942
Quantitative evaluation of enhancement of drug delivery for focused ultrasound with contrast agent by cadmium-selenide nanoparticles
Authors: Chung Lin
Journal: Clinical Cancer Research (2007)

A29  Purpose:To employ cadmium-selenide (CdSe) nanoparticles to quantitatively evaluate the in vivo enhancement of high intensity focused ultrasound (HIFU) with ultrasound contrast agent (UCA) on drug delivery at target locations.  Method:The nanoparticle was composed of CdSe with a coating layer of cholesterol and lipid and resulted the particle size of 150 nm. 1 MHz HIFU was applied with 10 ms burst length, 1% duty cycle, 1 Hz repetition frequency and 2 min sonication duration. The acoustic pressure at the focal location was 0.9 or 1.2 MPa. In in vivo experiments, 30 tumor-bearing male Balb/c mice were injected UCA (30 μL/Kg, SonoVue) first, then sonicated at the tumor locations, and finally injected 0.25 μg/g of body weight CdSe nanoparticles Intravenously. 5 tumor-bearing Balb/c mice were in control group. The mice were sacrificed after 24 h, and Atomic Absorption Spectroscopy (AA) was used to assay the cadmium amount in the tumors and organs.  Result:The in vivo experiment showed that HIFU with UCA could significantly enhance the nanoparticle dosage in the sonicated tumor region when compared with control group (P
Outcomes of women with small, early-stage breast cancer in Manitoba from 2006-2011.
Authors: Hanbo Zhang, Pascal J Lambert, Aly-Khan A. Lalani, Katherine Fradette, Rashid Ahmed, Debjani Grenier, Marshall W. Pitz
Journal: Journal of Clinical Oncology (2017)

e12000 Background: The incidence of early-stage breast cancers has increased dramatically over the past decades. Treatment decisions for patients with stage I breast cancers are challenging, as there are significant variations in outcomes based on biologic subtypes. The objectives were to describe the distribution, molecular phenotypes, management, and long-term outcomes of women with early-stage breast cancer (T1mic/T1a/T1b N0 M0) in Manitoba from 2006-2011. Methods: Using the Manitoba Cancer Registry, we created a retrospective cohort of patients with primary breast cancer of ≤1.0 cm, diagnosed between 2006 and 2011. Data included patient demographics, tumour size, treatment modalities (surgery, radiotherapy, chemotherapy and trastuzumab), estrogen-receptor (ER) and progesterone-receptor (PR) status, and human epidermal growth factor receptor 2 (HER2) status. Node-positive cancers were excluded. Patient outcomes were evaluated, including rates of recurrence and overall survival using univariate and multivariable models. Kaplan-Meier curves and cumulative incidence curves were used to illustrate overall survival and recurrence, respectively. Results: Our study included 733 women. Mean age at diagnosis was 62. ER/PR positivity and HER2 positivity (HER2+) were 84% and 8.9%, respectively. Tumours were: T1mic in 14.0%, T1a in 19.1%, and T1b in 66.9%. 98% of patients had surgery, 60% had adjuvant radiation, 3.8% received trastuzumab, and 11% received chemotherapy. The adjusted hazard ratio (HR) for disease recurrence for patients with HER2+ versus HER2- status was 4.31 (95% CI, 2.18 to 8.50; P = 0.0001), and the HR for overall survival was 1.63 (95% CI, 0.72 to 3.67; P = 0.2402). The HR for disease recurrence in HER2+ patients receiving trastuzumab versus HER2+ patients who did not receive trastuzumab was 1.92 (95% CI, 0.61 to 5.97; P = 0.2621). Conclusions: HER2-positivity appears to be an important risk factor for recurrence in small, early-stage breast cancers. In our cohort, trastuzumab did not appear to reduce the risk of recurrence compared to those who did not receive it. This may be due to limited power and selection bias, in which patients with higher risk cancers received trastuzumab.
Age and Gender Associations of Virus Positivity in Merkel Cell Carcinoma Characterized Using a Novel RNA <i>In Situ</i> Hybridization Assay
Authors: Lisha Wang, Paul W. Harms, Nallasivam Palanisamy, Shannon Carskadon, Xuhong Cao, Javed Siddiqui, Rajiv M. Patel, Sylvia Zelenka-Wang, Alison B. Durham, Douglas R. Fullen, Kelly L. Harms, Fengyun Su, Sudhanshu Shukla, Rohit Mehra, Arul M. Chinnaiyan
Journal: Clinical Cancer Research (2017)

Purpose: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine tumor of the skin. Merkel cell polyomavirus (MCPyV) plays an oncogenic role in the majority of MCCs. Detection of MCPyV in MCCs has diagnostic utility and prognostic potential. We investigated whether RNAscope, an RNA in situ hybridization (ISH) assay for detection of RNA transcripts in tissues, is useful for MCPyV detection.Experimental Design: We applied an RNAscope probe targeting MCPyV T antigen transcripts on tissue microarrays (TMA) and whole-tissue sections encompassing 87 MCCs from 75 patients, 14 carcinomas of other types, and benign tissues. For comparison, qPCR was performed on 57 cases of MCC from 52 patients.Results: RNA-ISH demonstrated the presence of MCPyV in 37 of 75 cases (49.3%). Notably, tumors from younger patients (<73 years) had a significantly higher virus positivity than those from elderly patients (≥73 years; 64.9% vs. 34.2%, P = 0.011). Female patients had a higher positive rate of MCPyV than male patients (66.7% vs. 39.6%, P = 0.032). Data from both RNA-ISH and qPCR were available for 57 samples. Considering MCPyV qPCR as the gold standard for determining MCPyV status, RNAscope had 100% sensitivity and 100% specificity. There was a strong correlation between qPCR copy number and RNA-ISH product score (Spearman correlation coefficient R2 = 0.932, P < 0.0001).Conclusions: RNA-ISH is comparably sensitive to qPCR for detection of MCPyV and allows for correlation with tissue morphology. This study also reveals a significant association between age, gender, and MCPyV positivity. Clin Cancer Res; 23(18); 5622-30. ©2017 AACR.
Abstract P162: Granulocyte Colony-Stimulating Factor Administration Reduced the Inducibility of Ventricular Tachyarrhythmias in Cardiac Hypertrophied Rats Through Phosphorylated Connexin-43
Authors: Nobutake Shimojo, Takeshi Machino, Donzhu Xu, Taizo Kimura, Rumi Koshitsuka, Yuri Kameda, Satoshi Sakai, Kazutaka Aonuma
Journal: Circulation Research (2011)

Introduction: Cardiac hypertrophy is an independent risk factor for sudden cardiac death from ventricular tachyarrhythmias (VT). Granulocyte colony-stimulating factor (G-CSF) has recently been reported to suppress VT after myocardial infarction by modulating the function of gap junctions between cardiomyocytes via maintaining Connexin-43 (Cx43). We hypothesized that the G-CSF could also regress an enhanced vulnerability to VT in the cardiac hypertrophy without ischemic fibrosis through regulating Cx43. Methods: Dahl salt-sensitive rats were maintained for a 6 week-period on a high-salt diet as left ventricular hypertrophy models (LVHs) and a low-salt diet as controls (CONs). After 3-time subcutaneous injection (50 μ g/kg) of G-CSF and vehicle, the inducibility of VT was evaluated by rapid ventricular burst pacing. The electrical pulses for the induction of VT were square waves with 6 ms width at 6 V and delivered at 25 Hz for 30 sec. White blood cell was counted to confirm a response to the G-CSF treatment. Expression levels of phosphorylated and total Cx43 in the rat ventricles were analyzed by immunoblotting. Results: The LVHs showed apparent cardiac hypertrophy without pathological fibrotic changes. The G-CSF reduced the inducibility of VT compared to the vehicle in the LVHs (11 % vs. 63 %, p=0.04). Furthermore, the G-CSF eliminated the inducibility of VT in the CONs, although a difference in the inducibility of VT between with and without the G-CSF treatment did not reach statistical significance in the CONs (0 % vs. 33 %, p=0.60). White blood cell count in one microliter of blood was elevated by the G-CSF treatment in both LVHs (15083±4397 vs. 6976±1308, p&lt;0.01) and CONs (19370±1174 vs. 7700±2335, p&lt;0.01). The G-CSF increased phosphorylated Cx43 levels compared to the vehicle in both LVHs (1.4-fold vs. 1.2-fold, p&lt;0.01) and CONs (1.4-fold vs. 1.0-fold, p=0.04), whereas the G-CSF did not affect total Cx43 levels in all groups. Conclusion: We demonstrated that the G-CSF administration ameliorated the electrophysiological stability in the rat model of cardiac hypertrophy by modulating the function of gap junctions through accelerating phosphorylation of Cx43.
The Effect of Variable Dose and Release Kinetics on Neointimal Hyperplasia Using a Novel Paclitaxel-Eluting Stent Platform
Authors: Patrick W. Serruys, Georgios Sianos, Alexandre Abizaid, Jiro Aoki, Peter den Heijer, Hans Bonnier, Pieter Smits, Dougal McClean, Stefan Verheye, Jorge Belardi, Jose Condado, Michel Pieper, Louise Gambone, Marco Bressers, Janette Symons, Eduardo Sousa, Frank Litvack
Journal: Journal of the American College of Cardiology (2005)
Microglia limit the expansion of β-amyloid plaques in a mouse model of Alzheimer’s disease
Authors: Ruohe Zhao, Wanling Hu, Julia Tsai, Wei Li, Wen-Biao Gan
Journal: Molecular Neurodegeneration (2017)

Microglia are known as resident immune cells in the brain. β-amyloid (Aβ) plaques in the brain of Alzheimer's disease (AD) are surrounded by microglia, but whether and how microglia affect the formation and maintenance of plaques remains controversial. We depleted microglia by injecting diphtheria toxin (DT) in CX 3 CR1 CreER/+ :R26 DTR/+ (CX 3 CR1-iDTR) mice crossed with APPswe/PSEN1dE9 (APP/PS1) mice. Intravital time-lapse imaging was performed to examine changes in the number and size of Congo Red-labeled amyloid plaques over 1–2 weeks. We also examined spine density and shaft diameter of dendrites passing through plaques in a PSAPP mouse model of AD (PS1 M146L line 6.2 × Tg2576) crossed with Thy1 YFP H-line mice. We found that DT administration to CX 3 CR1-iDTR mice efficiently ablated microglia within one week and that microglia repopulated in the second week after DT administration. Microglia depletion didn't affect the number of amyloid plaques, but led to ~13% increase in the size of Aβ plaques within one week. Moreover, microglia repopulation was associated with the stabilization of plaque size during the second week. In addition, we found dendritic spine loss and shaft atrophy in the distal parts of dendrites passing through plaques. Our results demonstrate the important role of microglia in limiting the growth of Aβ plaques and plaque-associated disruption of neuronal connection.
Lineage-specific rediploidization is a mechanism to explain time-lags between genome duplication and evolutionary diversification
Authors: Fiona M. Robertson, Manu Kumar Gundappa, Fabian Grammes, Torgeir R. Hvidsten, Anthony K. Redmond, Sigbjørn Lien, Samuel A. M. Martin, Peter W. H. Holland, Simen R. Sandve, Daniel J. Macqueen
Journal: Genome biology (2017)

The functional divergence of duplicate genes (ohnologues) retained from whole genome duplication (WGD) is thought to promote evolutionary diversification. However, species radiation and phenotypic diversification are often temporally separated from WGD. Salmonid fish, whose ancestor underwent WGD by autotetraploidization ~95 million years ago, fit such a ‘time-lag’ model of post-WGD radiation, which occurred alongside a major delay in the rediploidization process. Here we propose a model, ‘lineage-specific ohnologue resolution’ (LORe), to address the consequences of delayed rediploidization. Under LORe, speciation precedes rediploidization, allowing independent ohnologue divergence in sister lineages sharing an ancestral WGD event. Using cross-species sequence capture, phylogenomics and genome-wide analyses of ohnologue expression divergence, we demonstrate the major impact of LORe on salmonid evolution. One-quarter of each salmonid genome, harbouring at least 4550 ohnologues, has evolved under LORe, with rediploidization and functional divergence occurring on multiple independent occasions >50 million years post-WGD. We demonstrate the existence and regulatory divergence of many LORe ohnologues with functions in lineage-specific physiological adaptations that potentially facilitated salmonid species radiation. We show that LORe ohnologues are enriched for different functions than ‘older’ ohnologues that began diverging in the salmonid ancestor. LORe has unappreciated significance as a nested component of post-WGD divergence that impacts the functional properties of genes, whilst providing ohnologues available solely for lineage-specific adaptation. Under LORe, which is predicted following many WGD events, the functional outcomes of WGD need not appear ‘explosively’, but can arise gradually over tens of millions of years, promoting lineage-specific diversification regimes under prevailing ecological pressures.
An open-label, phase II study of rucaparib, a PARP inhibitor, in HER2- metastatic breast cancer patients with high genomic loss of heterozygosity: RUBY.
Authors: Anne Patsouris, Cecile Vicier, Loic Campion, Wilfried Gouraud, Marta Jimenez, Veronica Pezzella, Andrea Loehr, Mitch Raponi, Ivan Bieche, Celine Callens, Fabrice Andre
Journal: Journal of Clinical Oncology (2017)

TPS1117 Background: BRCA1 and/or BRCA2 mutations confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). In addition to BRCA1/2, alterations of other genes (PALB2, RAD51C….) implicated in homologous recombination repair (HRR) pathways leads to a BRCAness phenotype that is also associated with PARPi sensitivity. Rucaparib, a potent oral PARP-1, -2 and -3 inhibitor, has shown activity in a phase 1 study of patients (pts) with homologous recombination deficient (HRD) breast cancer (Kristeleit, RS. J Clin Oncol 32:5s, 2014 [suppl; abstr 2573]). This single arm, open-label, multicenter phase II study (NCT02505048) is evaluating the efficacy and safety of rucaparib in pts with HER2- metastatic breast cancer (MBC) associated with a BRCAness phenotype determined by “high tumor genomic LOH” score and/or a somatic BRCAmutation. Methods: Pts with HER2- MBC exhibiting a BRCAness phenotype will receive oral rucaparib 600 mg BID continuously in 21-day cycles until disease progression. The primary endpoint is clinical benefit rate (CBR), defined by complete and partial response and stable disease lasting for at least 16 weeks and, if CBR is significant, the objective response rate (ORR). Secondary endpoints include progression-free survival, overall survival, safety, and the prognostic value of the BRCAness signature. Targeted enrollment is 41 pts using a Simon two-stage design. Eligibility: Women with HER2- MBC with a BRCAness phenotype who received 1-4 prior chemotherapy regimens are eligible. ECOG PS 0-1 and adequate organ function is required. The BRCAness phenotype is defined by high tumor genomic LOH (LOH cutoff of 18%) that can identify HRD tumors, including both known BRCA1 methylation and unknown genetic/epigenetic mechanisms and somatic BRCA1/2 mutations. Pts with a known BRCA1 and/or BRCA2 germline mutation are excluded. “high tumor genomic LOH” score will be generated from the CytoScan HD SNP array, which is available from the SAFIR02 protocol or other molecular programs. To date, 13 pts have been enrolled, with enrollment ongoing. This trial design is intended to establish proof-of-concept that rucaparib can improve ORR in HER2- MBC with HRD. Clinical trial information: NCT02505048.
Trends in Breastfeeding Among Infants Enrolled in the Special Supplemental Nutrition Program for Women, Infants and Children — New York, 2002–2015
Authors: Furrina Lee, Lynn S. Edmunds, Xiao Cong, Jackson P. Sekhobo
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Breastfeeding is widely accepted as the optimal method of infant feeding (1,2). New York Special Supplemental Nutrition Program for Women, Infants and Children (WIC) has prioritized the promotion of breastfeeding. To assess breastfeeding trends among New York WIC infants, indicators for measuring breastfeeding practices reported by the New York Pediatric Nutrition Surveillance System (PedNSS) during 2002-2015 were examined. The prevalence of breastfeeding initiation increased from 62.0% (2002) to 83.4% (2015), exceeding the Healthy People 2020 (HP2020)* objective of 81.9% in 2014, with improvements among all racial/ethnic groups. The percentage of New York WIC infants who breastfed for ≥6 and ≥12 months increased from 30.2% and 15.0% (2002) to 39.5% and 22.8% (2015), respectively. The prevalence of exclusive breastfeeding for ≥3 and ≥6 months increased from 8.9% and 2.9% (2006) to 14.3% and 8.0% (2015), respectively. Despite improvements in breastfeeding initiation, increasing the duration of breastfeeding and of exclusive breastfeeding among infants enrolled in the New York WIC program remains challenging. Identifying targeted strategies to support continued and exclusive breastfeeding should remain priorities for the New York WIC program.