tbuckley/cabot-search huggingface dataset:
Abstract 2785: The role of heat shock factors for cancer stem cell regulation
Authors: Ankita Thakkar, Bin Wang, Tan A. Ince
Journal: Cancer Research (2016)

Abstract Introduction: Heat shock factor family is a group of transcription factors that can bind specifically to heat shock elements (HSE) within the promoter region of heat shock protein (HSP). The HSF pathway activation helps cells survive under stress by preventing protein misfolding and aggregation. Three heat shock factors (HSF1, HSF2 and HSF4) have been identified in humans, among them, HSF1, which is believed to be the master regulator of cellular response to stress, is by far the best-characterized member of the HSF family. We first identified that high HSF1 is associated with high tumor grade and poor survival in multiple cancer models including breast, ovarian, lung and colon cancers. In addition, our recent data indicate that HSF1 drives a distinct transcription program that is unrelated to heat shock response in malignant tumors, and this HSF1 “non-heat shock related transcription program” correlates with poor outcome in breast cancer patients. Moreover, we confirmed that HSF1 drives the Cancer Stem Cell (CSC) phenotype in multiple breast cancer cell lines and facilitate chemo-treatment resistance by increasing CSC frequency in breast cancer cells. Previous studies have shown that HSF2 and HSF4 may play a role in cancer progression either on their own or through interaction with HSF1. HSF2 forms hetero-trimers with HSF1 and facilitate its function in response to heat shock. Inactivation of HSF4 in p53 null mouse models causes cell senescence and suppression of tumorigenesis, with great similarities to HSF1-/- p53 null mice. Results: In an attempt to investigate how HSF1 is activated to regulate CSC phenotype, we constructed phospho HSF1 at three different sites. We observed that there is no correlation of phospho activation of HSF1 with CSC phenotype. In follow-up work to the studies above, we found that both HSF2 and HSF4 are also significantly up-regulated in CSCs, suggesting that they may cooperate with HSF1 in regulating CSCs. Moreover, we discovered that HSF4 is over-expressed in breast cancers compared to normal mammary gland, and over-expression of HSF4 induces tumorsphere formation in breast cancer cells. Conclusion: These observations indicated that in order to gain a complete understanding of the role of the HSFs in cancer it is now necessary to study all three HSFs together. Citation Format: Ankita Thakkar, Bin Wang, Tan A. Ince. The role of heat shock factors for cancer stem cell regulation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2785.
Making a Difference With Diabetes Research and Care
Authors: Hertzel C. Gerstein
Journal: Diabetes Care (2016)

Type 1 and type 2 diabetes are serious diseases because they can cause a wide variety of health consequences that may reduce both the quality and/or length of life. Almost every body system can be adversely affected by diabetes, including the eyes, kidneys, nerves, skin, heart, brain, liver, circulatory system, skeleton, and reproductive system (1). Type 1 and type 2 diabetes are clearly caused by different processes and have different risk factors and natural histories. Regardless of these differences, both diseases share the same glycemic thresholds for diagnosis (2) and manifest a similar relationship between the extent of hyperglycemia and the risk to the integrity of the organ systems listed above (1). Moreover, for both diseases many of these long-term risks can be mitigated by chronically reducing the degree of hyperglycemia (3,4), by detection and treatment of other risk factors for many of these consequences (e.g., hypertension, smoking, and dyslipidemia), and by appropriate screening and aggressive therapy of early evidence of these consequences (e.g., retinal, renal, neurological, and cardiovascular disease) (5,6).

The Diabetes Control and Complications Trial (DCCT) and its long-term follow-up study (Epidemiology of Diabetes Interventions and Complications [EDIC]) comprise the most definitive body of evidence regarding the short- and long-term benefits of managing hyperglycemia in people with type 1 diabetes (7). The DCCT recruited 1,441 individuals of mean age 27 years with 1–15 years’ duration of type 1 diabetes who had no cardiovascular disease, hypertension, or dyslipidemia and randomly allocated them …
Role of Glycated Proteins in the Diagnosis and Management of Diabetes: Research Gaps and Future Directions
Authors: Kerry J. Welsh, M. Sue Kirkman, David B. Sacks
Journal: Diabetes Care (2016)

Blood oligosaccharides are attached to many proteins after translation, forming glycoproteins. Glycosylation refers to an enzyme-mediated modification that alters protein function, for example, their life span or their interactions with other proteins (1). By contrast, glycation refers to a monosaccharide (usually glucose) attaching nonenzymatically to the amino group of a protein. Glycated hemoglobin is formed by the condensation of glucose with select amino acid residues, commonly lysine, in hemoglobin to form an unstable Schiff base (aldimine, pre-HbA1c) (Fig. 1). The Schiff base may dissociate or may undergo an Amadori rearrangement to form a stable ketoamine.



Figure 1 
Formation of glycated protein. A reversible interaction between a primary amino group (depicted as NH2) of a protein and the carbonyl group of d-glucose yields a labile intermediate, called a Schiff base. This can undergo a slow and spontaneous Amadori rearrangement to form a stable ketoamine. HbA1c is formed if glucose attaches to the N-terminal valine of the β-chain of hemoglobin. If the glucose attaches to proteins in the plasma, fructosamine or glycated albumin results. RBC, red blood cell.



Glycated hemoglobin, particularly HbA1c, has for decades been widely incorporated into the management (and, more recently, the diagnosis) of patients with diabetes. An important attribute is that glycation occurs continuously over the lifetime of the protein, so the concentration of the glycated protein reflects the average blood glucose value over a period of time. This contrasts with the measurement of blood glucose, which reveals the glucose concentration at the instant blood is sampled and which is acutely altered by multiple factors such as hormones, illness, food ingestion, and exercise (2). While HbA1c is by far the most extensively used—and studied—glycated protein (2–4), other glycated proteins that have been evaluated in clinical studies include fructosamine, glycated albumin, and …
Case 47-1962
Authors: Frederic M. Blodgett, Benjamin Castleman
Journal: New England Journal of Medicine (1962)

Presentation of Case*A two-year-old boy was admitted to the hospital because of fever and hyperpnea.Three days previously a generalized skin rash characteristic of varicella appeared. The child was otherwise asymptomatic until the day before entry, when there was an episode of retching. On the day of admission a high fever, lethargy, twitching and rapid respiration suddenly developed. A total of 300 mg. of aspirin was given at home, and the child was brought to the hospital. Upon arrival a generalized tonic-clonic convulsive seizure occurred and subsided within three minutes after 100 mg. of phenobarbital was given intravenously. Cyanosis . . .
Abstract LB-376: Hormone therapy use and DNA methylation in breast tissue
Authors: Sophia Harlid, Zongli Xu, Erin L. Kirk, Lauren E. Wilson, Melissa A. Troester, Jack A. Taylor
Journal: Cancer Research (2016)

Abstract The association between use of hormone therapy (HT) and breast cancer risk has been consistently replicated in epidemiologic studies, but the biological effects of HT on breast tissue are poorly understood. We hypothesized that postmenopausal exposure to HT leads to changes in DNA methylation in breast tissue. We used fresh frozen samples from the Normal Breast Study (NBS), a hospital based study conducted between 2009 and 2013 at the University of North Carolina in Chapel Hill. Women undergoing breast surgery for reduction mammoplasty, prophylactic resection, or tumor resection donated samples of histologically normal-appearing breast tissue. Out of 474 enrolled participants 106 reported ever using hormone therapy, 37 of which had used it within one year of surgery (classified as current users) and 17 of which had used HT within 1-5 years prior to surgery (classified as recent users). Current and recent users were compared with 36 age frequency-matched controls that had never used HT. Frozen tissue DNA samples from these 90 women were evaluated using the Illumina HumanMethylation450 BeadChip. Genome wide DNA methylation data was analyzed using the reference-free cell mixture method to test for associations between HT-use and the methylation level at each CpG site. In the model we adjusted for SVA derived surrogate variables, to control for unobserved confounders, and multiple comparisons using the false discovery rate (FDR). Although methylation differences between current and never users were small in magnitude (β&amp;lt;0.05), 290 CpGs were significantly differentially methylated (FDR, q&amp;lt;0.05). The top CpG was located in an intronic region of the DDX10 gene (p = 7.9E-10, q = 0.0003), previously known to be translocated in estrogen receptor-negative (ER-) breast cancer. Our results extend the evidence base for hormonally derived epigenetic changes in breast tissue. Citation Format: Sophia Harlid, Zongli Xu, Erin L. Kirk, Lauren E. Wilson, Melissa A. Troester, Jack A. Taylor. Hormone therapy use and DNA methylation in breast tissue. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-376.
The effects of obesity on recovery after endometrial cancer surgery.
Authors: Keayra Morris, Stephen L. Rose, Meredith E. Rumble, Christopher L. Coe, Hollis Moore, Kaitlin H. White, Manish S. Patankar, David M. Kushner, Erin S. Costanzo
Journal: Journal of Clinical Oncology (2015)

e20640 Background: Excess body fat is a risk factor for endometrial cancer. However, its effects on recovery and quality of life following surgery for endometrial cancer have not yet been determined. The present study examined the extent to which body mass index (BMI) predicted depression, insomnia, and fatigue, three of the most common and distressing quality of life concerns following surgery. We also considered type of surgery, physical activity, and inflammation as potential mediators of relationships between BMI and quality of life. Methods: Women who underwent surgical resection of endometrial cancer (N = 85) were evaluated at 1, 4 and 16 weeks post-surgery. At each assessment, participants completed validated self-report measures of depression, insomnia, and fatigue. Wrist actigraphy assessed average activity level (mesor) as determined through traditional cosinor analysis, and inflammatory cytokine levels in peripheral blood were quantified with an electrochemiluminescence platform. BMI was assessed at the time of surgery. Mixed-effects linear regression models covarying for age and disease stage tested the significance of relationships between BMI and outcomes. Results: Participants with higher BMIs reported greater depression (z= 2.69, p= .007) and fatigue (z= 2.50, p= .013) at all post-surgical assessments. There was no significant association between BMI and insomnia. Those with higher BMIs were more likely to have a laparotomy versus laparoscopic surgery (p= .048), had lower mean activity levels (z= -2.73, p= .006), and had higher circulating IL-6 levels (z= 2.43, p= .015). Mean activity level mediated the relationship between BMI and fatigue. Surgery and IL-6 levels did not mediate relationships between BMI and quality of life outcomes. Conclusions: The findings indicate that obesity is a risk factor for a slower recovery following treatment for endometrial cancer, particularly with respect to mood and fatigue, two critical aspects of quality of life. The level of physical activity mediates the relationship between BMI and fatigue, offering a potential intervention target for women of all body sizes to improve quality of life following surgery.
Abstract 3092: Physiological mimicry to characterize the average topology of the MYC and VEGF promoter G-quadruplexes
Authors: Rhianna K. Morgan, Tracy A. Brooks
Journal: Cancer Research (2016)

Abstract DNA G-quadruplexes (G4s) have become increasingly present in modern drug discovery efforts. The main focus centers on cancer therapeutic development, as G4s are more concentrated in oncogenic promoters than the rest of the genome. Two of the most well described G4s to date are within the MYC and the VEGF promoters; stabilization of either structure fosters transcriptional silencing. Downregulation of MYC decreases cell proliferation and alters metabolism; it is promising for a number of cancers, such lymphomas, leukemia, colorectal cancer and more. VEGF downregulation would modulate angiogenesis, which is of therapeutic benefit for almost all solid tumors. The physiological structure of both of these promoter G4s has been elucidated using plasmid DMS footprinting, which incorporates DNA supercoiling in addition to stabilizing cations or molecules. The current study examines a variety of anhydrous or crowding co-solvents for their ability to recapitulate the physiological structure in single-stranded ex vivo conditions. The co-solvents tested included glucose, acetonitrile, polyethylene glycol, dextran sulfate, sucrose, ficoll, and extracted nucleoplasm, ranging from 0-40%. Significant changes in structure, including loop directionality and number of competing isoforms, were examined by electronic circular dichroism. Electromobility shift assays differentiated inter- and intra-molecular structures, further distinguishing the distribution of isoforms. DMS footprinting with select molecular crowding and dehydrating agents was performed and compared to plasmid footprints, to validate physiological mimicry ex vivo. Ongoing studies examining the physiological conditions regulating G4 stability and function include moving from plasmid to in cell DMS footprinting in order to most completely identify the physiologic isoform, and to using optimized co-solvents to examine the effects of small molecules ex vivo and better predict active hits for in vitro evaluation. Overall the VEGF and MYC promoter G4 structures are promising therapeutic targets for anti-angiogenic and anti-proliferative therapy, respectively. This comprehensive understanding of physiological principles governing the above G4 formation will best inform future drug discovery efforts for these and other oncogenic promoters. Citation Format: Rhianna K. Morgan, Tracy A. Brooks. Physiological mimicry to characterize the average topology of the MYC and VEGF promoter G-quadruplexes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3092.
Evaluation d’une nouvelle prothèse métallique de 12 mm de diamètre couverte dans les sténoses biliaires malignes: une étude de faisabilité
Authors: L. Heyries
Journal: Endoscopy (2016)

La prothèse biliaire métallique est actuellement le standard du traitement palliatif de l’ictère néoplasique. Les problèmes à long terme des prothèses métalliques couvertes sont la migration duodénale et l’obstruction. Pour prévenir la migration duodénale l’industrie a mis au point une prothèse munie d’ailerons latéraux mais ces derniers provoqueraient des lésions intra canalaires Le largage de la prothèse au-dessus de la papille semble prévenir la migration duodénale. L’obstruction de la prothèse est le deuxième problème et ce phénomène est corrélé au reflux duodéno-biliaire qui favorise le développement d’un biofilm bactérien, la sédimentation biliaire et l’impaction d’aliments. Bien qu’une étude sur 84 patients n’ait pas confirmé cette hypothèse, des prothèses métalliques avec système anti-reflux ont été également testées.
Abstract 4100: Stromalcell suppression of estrogen receptor in growth-arrested breast cancer cellsand promotion of outgrowth of estrogen-independent clones
Authors: Richard Steinman, Jingjing Huang, Paul Woods, Daniel Normolle, Julie Goff, Christine Stehle
Journal: Cancer Research (2016)

Abstract Breast cancers have a poorer prognosis if estrogen receptor expression was lost during recurrence. It is unclear whether this conversion is cell autonomous or whether it can be promoted by the microenvironment during cancer dormancy. Bone marrow is the most common site for luminal breast cancer recurrence. We explored whether the HS5 bone marrow stromal cell line that is known to arrest co-cultured breast cancer cells could suppress estrogen receptor alpha (ER) expression during arrest, and whether it could prime the emergence of estrogen-independent breast cancer clones. We demonstrated that paracrine signaling from HS5 cells downregulated ER at the mRNA level and also decreased ER protein stability in T47D and MCF7 breast cancer cells. Conditioned medium (CM) from HS5 arrested the cells in G0/G1 in part through interleukin-1 (IL1), inhibiting mammosphere formation and 2D-growth despite activation of proliferative pathways (Erk and AKT) by the CM. Reversal of stromal-induced growth arrest by blockade of signaling by IL1 in HS5-CM enabled the outgrowth of ER-negative breast cancer cells that were fulvestrant-resistant and estrogen-independent. Outgrowth depended on AKT signaling. Our results describe pro- and anti-proliferative paracrine signals arising from a bone marrow stromal cell line. Blockade of the growth suppressive signaling unmasked stromal facilitation of ER conversion and anti-estrogen resistance in breast cancer cells. Citation Format: Richard Steinman, Jingjing Huang, Paul Woods, Daniel Normolle, Julie Goff, Christine Stehle. Stromalcell suppression of estrogen receptor in growth-arrested breast cancer cellsand promotion of outgrowth of estrogen-independent clones. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4100.
Factors influencing the career decisions of United States hematology oncology fellows training at NCI- and NCCN-designated cancer centers.
Authors: L. Horn, E. Koehler, Y. Shyr, J. Gilbert, D. H. Johnson
Journal: Journal of Clinical Oncology (2010)

6144 Background: Factors influencing hematology-oncology fellows' choice of academic medicine as a career are not well defined. Moreover, it appears that trainees' interest in academic medicine wanes as they progress through fellowship training. To better understand the factors that impact on career choices we undertook a survey of hematology-oncology fellows at National Cancer Institute (NCI) and National Comprehensive Cancer Network (NCCN) designated cancer centers. Methods: Program directors at all NCI and NCCN cancer centers were emailed and invited to participate in the study. Surveys were distributed through the offices of all participating programs. Results: A total of 422 fellows were surveyed;236 responded (62.3% RR). 58% were male, 64% were PGY2 and PGY3, 46% had > $100,000 in debt, 22% had a second post-graduate degree and 15% intended to pursue an additional degree after training. 98% had participated in a research project during training; 45% in clinical research, 17% basic science research and 29% in both a clinical and a basic science research project. Fellows choosing an academic career were more likely to have presented (78% vs. 57%; p = 0.001) their research at a scientific meeting. They were also more likely to have published (78% vs. 50%; p < 0.0001). Additional factors associated with choosing an academic career included perceived status (p < 0.0001), faculty mentorship (p < 0.0001), perceived support of research interests (p < 0.000) and desire to teach (p < 0.0001). Regardless of career path fellows ranked job satisfaction, consistency with personality and experience with patients, among the most important factors in their career decisions. Fellows choosing nonacademic careers listed lifestyle factors such as on-call and work hours and time for leisure among the most important factors in their career decision. Conclusions: Strategies are needed to increase fellows' interest in pursuing academic careers. Our data suggest increased opportunities for research and publication along with improved mentorship are key factors necessary to attract fellows into academic careers. In addition, lifestyle issues, real or perceived, require more attention and study. No significant financial relationships to disclose.
Advances in Robotic Vena Cava Tumor Thrombectomy: Intracaval Balloon Occlusion, Patch Grafting, and Vena Cavoscopy
Authors: Chandan Kundavaram, Andre Luis de Castro Abreu, Sameer Chopra, Giuseppe Simone, Rene Sotelo, Monish Aron, Mihir M. Desai, Michele Gallucci, Inderbir S. Gill
Journal: European Urology (2016)