tbuckley/cabot-search huggingface dataset:
Local and Distant Input Controlling Excitation in Layer II of the Medial Entorhinal Cortex
Authors: Elke C. Fuchs, Angela Neitz, Roberta Pinna, Sarah Melzer, Antonio Caputi, Hannah Monyer
Journal: Neuron (2015)

Layer II (LII) of the medial entorhinal cortex (MEC) comprises grid cells that support spatial navigation. The firing pattern of grid cells might be explained by attractor dynamics in a network, which requires either direct excitatory connectivity between phase-specific grid cells or indirect coupling via interneurons. However, knowledge regarding local networks that support in vivo activity is incomplete. Here we identified essential components of LII networks in the MEC. We distinguished four types of excitatory neurons that exhibit cell-type-specific local excitatory and inhibitory connectivity. Furthermore, we found that LII neurons contribute to the excitation of contralateral neurons in the corresponding layer. Finally, we demonstrated that the medial septum controls excitation in the MEC via two subpopulations of long-range GABAergic neurons that target distinct interneurons in LII, thereby disinhibiting local circuits. We thus identified local connections that could support attractor dynamics and external inputs that likely govern excitation in LII.
Continental Differences in Clinical Characteristics, Management, and Outcomes in Patients Hospitalized With Worsening Heart Failure
Authors: John E.A. Blair, Faiez Zannad, Marvin A. Konstam, Thomas Cook, Brian Traver, John C. Burnett, Liliana Grinfeld, Holly Krasa, Aldo P. Maggioni, Cesare Orlandi, Karl Swedberg, James E. Udelson, Christopher Zimmer, Mihai Gheorghiade
Journal: Journal of the American College of Cardiology (2008)
Interaction between body mass index and bone turnover during aromatase inhibition: Evidence from the letrozole (L), exemestane (E), and anastrozole (A) pharmacodynamics (LEAP) trial
Authors: E. McCloskey, R. Hannon, G. Lakner, G. Clack, A. Miyamoto, R. Eastell
Journal: Journal of Clinical Oncology (2007)

560 Background: High body mass index (BMI) protects against postmenopausal osteoporotic fracture, mediated in part by higher endogenous levels of oestradiol. Third-generation aromatase inhibitors (AIs) show superior efficacy and tolerability than tamoxifen in the adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer. We examined the interactions between BMI and bone turnover during treatment with 3 aromatase inhibitors in the LEAP trial, an open, randomized, pharmacodynamic study in postmenopausal women. Methods: Healthy volunteers from the UK and Hungary with normal bone density and BMI between 18 and 34 kg/m 2 were randomized to receive A (1 mg/day), L (2.5 mg/day), or E (25 mg/day) orally, once daily for 24 weeks. Effects on bone resorption (log transformed serum C-telopeptide crosslinks, CTX) and bone formation (bone alkaline phosphatase and propeptide of type I procollagen, PINP) were compared. Changes in biochemical markers of bone resorption and formation during treatment were all statistically inter- correlated (p&lt;0.01) with no notable differences between the 3 agents studied, so that the groups were pooled for analysis. Spearman correlation coefficients and the p-values were computed. Results: A total of 90 participants were evaluable at baseline and at 24 weeks (29 A, 29 L, 32 E). As expected, baseline BMI correlated with pre-treatment circulating endogenous oestradiol (r=0.28, p=0.007) and both BMI and oestradiol negatively correlated with baseline serum CTX (r=-0.32, p=0.0025 and r=-0.35, p=0.0007 respectively) and PINP (r=-0.30, p=0.004 and r=-0.26, p=0.016 respectively). Baseline BMI and oestradiol were significantly correlated with the increase in serum CTX (r=0.26, p=0.015 and r=0.23, p=0.032 respectively) and BMI also correlated significantly with the increase in serum PINP (r=0.23, p=0.030). Conclusions: Steroidal and non-steroidal AIs increase bone turnover with the greatest increase in women with high BMI and higher oestradiol levels at baseline. As increased bone turnover is an independent risk factor for fracture, a high BMI may not confer a reduced fracture risk in the setting of AI use in early breast cancer. No significant financial relationships to disclose.
Elucidating the role of Neuropilin-1 in intra-tumoral regulatory T cell stability
Authors: Abigail E Overacre, Maria Chikina, Greg M Delgoffe, Dario AA Vignali
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Regulatory T cells (Tregs) play an integral role in the adaptive immune system through suppression of self-reactive immune responses in order to prevent autoimmunity and maintain homeostasis. However, they are deleterious in cancer through suppression of the anti-tumor immune
Abstract 3232: CEP-37440, a highly selective and potent dual inhibitor of ALK and FAK1 inhibits the proliferation of inflammatory breast cancer cells
Authors: Israa Salem, Lucy Aburto, Sankar Addya, Inna Chervoneva, Zhaomei Mu, Bruce Ruggeri, Massimo Cristofanilli, Sandra V. Fernandez
Journal: Cancer Research (2015)

Abstract Inflammatory breast cancer (IBC) is a very aggressive type of advanced breast cancer with a poor prognosis. Due to its propensity to rapidly metastasize, IBC is responsible for a disproportionate number of breast cancer-related deaths; 15% of all breast cancer deaths result from this disease. Approximately 30% of IBC patients have distant metastases at time of diagnosis, in contrast to 5% of patients with non-IBC breast cancers. Currently, there is no adequate adjuvant therapy to reduce the risk of recurrence and mortality in IBC patients. We recently found that FAK1, also known as PTK2, is amplified, up-regulated and phosphorylated (active) in some inflammatory breast cancer cells [1]. The focal adhesion kinase FAK1 is a cytoplasmic tyrosine kinase that localizes to focal adhesions, and controls a number of cell pathways including proliferation, viability and survival. Activated FAK1 is absent or low in normal tissue and benign neoplasms and up-regulated in invasive and metastatic tumors. In this study, we investigated a new dual FAK1/ALK inhibitor, CEP-37440, in vitro and in vivo using preclinical models of IBC. We found that 300 nM CEP-37440 was able to decrease the proliferation of the triple negative FC-IBC02 cell line and, 1000 nM CEP-37440 was able to complete inhibit the proliferation of these cells. SUM190 showed a 50% decreased in proliferation when these cells were treated with 1000 nM CEP-37440. Genes involved in functions such as cellular growth and proliferation, cell cycle, cell death and survival and cellular movement and cell-to cell signaling and interaction were differentially regulated by CEP-37440 in sensitive IBC cell lines. Among them, TGFβ1 and MMP3 were down-regulated and DKK3, CAV1 and TFPI2 were up-regulated by CEP-37440. In FC-IBC02 orthotopic breast cancer xenograft models, CEP-37440 was able to reduce the growth of the primary tumor and inhibit the development of spontaneous metastases in brain. In conclusion, CEP-37440 was highly effective in reducing the proliferation in vitro and in vivo of IBC cells that expressed high levels of phospho-FAK (Tyr397). References 1. Fernandez S, Robertson F, Pei J, Aburto-Chumpitaz L, Mu Z, Chu K, Alpaugh K, Huang Y, Cao Y, Ye Z et al: Inflammatory breast cancer (IBC): clues for targeted therapies. Breast Cancer Res Treat 2013, 140:23-33. Citation Format: Israa Salem, Lucy Aburto, Sankar Addya, Inna Chervoneva, Zhaomei Mu, Bruce Ruggeri, Massimo Cristofanilli, Sandra V. Fernandez. CEP-37440, a highly selective and potent dual inhibitor of ALK and FAK1 inhibits the proliferation of inflammatory breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3232. doi:10.1158/1538-7445.AM2015-3232
Conflicts of interest in dermatology: a medical student and mentor perspective
Authors: K.A. Ashack, K.A. Burton, J.M. Kilgour, R.P. Dellavalle
Journal: British Journal of Dermatology (2015)

Conflict of interest (COI) in medicine is well defined, but is seldom discussed in the field of dermatology. This perspective sheds light on this topic in dermatology and provides suggestions on how better to approach COI in medical school and residency.
Integration of Th17- and Lymphotoxin-Derived Signals Initiates Meningeal-Resident Stromal Cell Remodeling to Propagate Neuroinflammation
Authors: Natalia B. Pikor, Jillian L. Astarita, Leslie Summers-Deluca, Georgina Galicia, Joy Qu, Lesley A. Ward, Susan Armstrong, Claudia X. Dominguez, Deepali Malhotra, Brendan Heiden, Robert Kay, Valera Castanov, Hanane Touil, Louis Boon, Paul O’Connor, Amit Bar-Or, Alexandre Prat, Valeria Ramaglia, Samuel Ludwin, Shannon J. Turley, Jennifer L. Gommerman
Journal: Immunity (2015)
CDK4 is an essential insulin effector in adipocytes
Authors: Sylviane Lagarrigue, Isabel C. Lopez-Mejia, Pierre-Damien Denechaud, Xavier Escoté, Judit Castillo-Armengol, Veronica Jimenez, Carine Chavey, Albert Giralt, Qiuwen Lai, Lianjun Zhang, Laia Martinez-Carreres, Brigitte Delacuisine, Jean-Sébastien Annicotte, Emilie Blanchet, Sébastien Huré, Anna Abella, Francisco J. Tinahones, Joan Vendrell, Pierre Dubus, Fatima Bosch, C. Ronald Kahn, Lluis Fajas
Journal: Journal of Clinical Investigation (2015)

Insulin resistance is a fundamental pathogenic factor that characterizes various metabolic disorders, including obesity and type 2 diabetes. Adipose tissue contributes to the development of obesity-related insulin resistance through increased release of fatty acids, altered adipokine secretion, and/or macrophage infiltration and cytokine release. Here, we aimed to analyze the participation of the cyclin-dependent kinase 4 (CDK4) in adipose tissue biology. We determined that white adipose tissue (WAT) from CDK4-deficient mice exhibits impaired lipogenesis and increased lipolysis. Conversely, lipolysis was decreased and lipogenesis was increased in mice expressing a mutant hyperactive form of CDK4 (CDK4R24C). We performed a global kinome analysis and found that mice lacking Cdk4 had impaired insulin signaling in the adipose tissue. Interestingly, our results demonstrated that insulin activates the cyclin D3-CDK4 complex, which, in turn, phosphorylates the insulin receptor substrate 2 (IRS2) at the Ser 388, likely creating a positive feedback loop to maintain adipocyte insulin signaling. Furthermore, we found that CCND3 expression and IRS2 serine 388 phosphorylation are increased in human obese subjects. Together, our results demonstrate that CDK4 is a major regulator of insulin signaling in WAT.
Regulation of ubiquitous expression of the human growth hormone receptor (hGHR) gene
Authors: Gurvinder Kenth, Cynthia Goodyer
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4389 

Growth hormone (hGH) is known to play an essential role in normal growth and metabolism but has also been associated with the progression of several cancers (e.g. breast, colon, prostate), often linked with increased expression of its receptor (hGHR) and IGF-I. Our research goal is to characterise the mechanism(s) regulating hGHR expression as the first step towards determining what causes its aberrant production in cancer tissues. The hGHR gene has a complex 5’untranslated region (5’UTR): fourteen variant mRNAs are expressed from different 5’UTR exons but all splice into the same site upstream of the translation start site and, thus, code for the same protein. Seven of these exons are clustered within two small regions: V2-V9-V3 (Module A) and V7-V1-V4-V8 (Module B). Module A-derived mRNAs are ubiquitously expressed while those from Module B are expressed in a tissue-, tumor- and developmental-specific fashion (only in normal postnatal liver), indicating that at least two different regulatory mechanisms are involved. One striking difference is that Module A promoters contain response elements (REs) for factors common amongst ubiquitously expressed genes, while Module B contains REs for liver-enriched factors. Secondly, CpG islands surround all three exons of Module A but not Module B. These differential features are conserved in the ovine, bovine, mouse and rat GHR genes.

Studies of proximal promoter regions for Module A exons showed significant activity in HEK293, CV1, HepG2 and Huh7 cell lines. However, when the constructs were partially or fully methylated there was partial or complete loss of promoter activity, respectively. The methylation status of the promoter regions was examined in genomic DNA of two hepatoma cell lines (HepG2, Huh7) as well as human adult and fetal livers. Southern blot analyses for V2 and V9 showed partial methylation in fetal liver (in which hGHR levels are less abundant compared to adult liver), suggesting that expression of the ubiquitous hGHR mRNAs may be regulated by a methylation-specific mechanism.

A second unique feature of Module A is that the promoter regions of each exon have a putative Sp1 binding site. Overexpression of a dominant-negative Sp1 in HEK293 cells showed a significant decrease in promoter activity for all three exons. Parallel experiments in drosophila SL2 cells indicate that overexpression of Sp1 or Sp3 has a stimulatory effect, primarily on a site within the V2 exon. Currently, Sp1 RE deletion and EMSA assays are being done to confirm which Sp1 sites play a significant role in regulating expression of the ubiquitous hGHR mRNAs.

In summary, this study highlights important elements involved in regulating ubiquitous expression of the hGHR and, thus, sensitivity to hGH. This is a first step towards understanding aberrant expression of hGHR in cancer cells.
Relationship between the influence of exposure to tobacco smoke and max-IMT, ABI, ratio of EPA / AA in COPD patients
Authors: Akinori Ebihara, Akifumi Watanabe, Asuka Nagai, Takayuki Nakano, Tokuzen Iwamoto, Ichiro Kuwahira
Journal: European Respiratory Journal (2013)

[Background]COPD is positioned as a systemic inflammatory disease. We have previously reported that COPD from early exposure to tobacco smoke may cause an increase of maximum value of the intima media thickness (max-IMT) that correlates with the increase in the prevalence of smoke-related vascular comorbidities. Analyzing the data of the ratio of serum Eicosapentaenoic Acid to Arachidonic Acid (EPA/AA) and Ankle Brechial Pressure Index(ABI), which were useful as an indicator of arteriosclerosis, we examined the correlation between them in this study. [Methods]We identified potential subjects from Erimo town clinic into two groups: G1) history of COPD and sever exposure to tobacco smoke; G2) subjects without COPD and analyzed the measurements max-IMT, EPA/AA and ABI. We defined severe smoke as that Brinkman Index more than 600. [Results]A total of 118 subjects (male 77, female 41) were enrolled into the study after informed consents were obtained. G1 and 2 consisted of 60 subjects (46, 14), 58 subjects (31,27), respectively. Max-IMT in G1 was 1.52 ± 1.29 mm, G2 was 1.38 ± 1.55mm. ABI in G1:G2 (0.84±1.23: 0.92±1.73), EPA / AA in G1: G2 (0.44± 0.37: 0.47±0.23). G1 had higher max-IMT when compared with G2. Furthermore, G1 demonstrated significant decline in ABI and EPA/AA, when compared with G2. [Conclusions]In subjects with COPD, sever exposure to smoke in addition to rise in max-IMT, declined ABI and EPA/AA, that promoted atherosclerotic changes, which may increase the likelihood of smoke-related vascular comorbidities such as cardiovascular and cerberovascular diseases.
From ASCO 2016
Authors: Lisa Hutchinson
Journal: Nature Reviews Clinical Oncology (2016)

At this year's ASCO meeting, much excitement and anticipation surrounded Vice President Joe Biden's address regarding the National Cancer Moonshot Initiative.Resonating with the ASCO theme of Collective Wisdom, Biden highlighted how we need a change of mindset to tackle cancer, in which we combine diverse disciplines and place more emphasis on the importance of prevention, access, and affordability.The first Cancer Moonshot Summit will convene in late June, and Biden made a plea to the ASCO audience that he needs our help in shaping the answers to fundemental societal challenges on cancer, and invited the audience to submit suggestions.Two abstracts, with full findings published in the New England Journal of Medicine, showed that for women with early stage breast cancer, the risk of disease recurrence was reduced by 34%, when hormonal therapy with aromatase inhibitors was extended for 5 years (to 10 years in total), without compromising patients' quality of life.A large-scale genomic analysis showed that the mutational profiles of circulating tumour cells (CTCs) closely mirrored the genetic changes detected in traditional biopsy samples.Samples from 15,191 patients with lung, breast, and colorectal cancer, among others, were compared with biopsy specimens and, in 94-100% of situations, the same mutations were present in CTCs, indicating that so-called liquid biopsies provide an accurate indication of the genomic landscape of the tumour.Elderly patients with glioblastoma have a poor survival duration, but the results of a randomized phase III trial provide new hope for this population.The addition of temozolomide chemotherapy to short-course radiation treatment, followed by maintenance temozolomide, significantly improved patient survival (33% reduced risk of death), without compromising quality of life.
Safety and Efficacy Of Obinutuzumab (GA101) Plus CHOP Chemotherapy In First-Line Advanced Diffuse Large B-Cell Lymphoma: Results From The Phase 2 Gather Study (GAO4915g)
Authors: Andrew D Zelenetz, Mehrdad Mobasher, Luciano J Costa, Ian Flinn, Christopher R. Flowers, Mark S. Kaminski, Thomas Sandmann, Kerstin Trunzer, Charlotte Vignal, Andres Forero-Torres
Journal: Blood (2013)
Mid Staffordshire trust is fined £500 000 for “corporate failure” linked to four deaths
Authors: Clare Dyer
Journal: BMJ (2015)

Mid Staffordshire NHS Foundation Trust has been fined £500 000 (€690 000; $745 000) and ordered to pay £35 000 in prosecution costs for a “corporate failure” linked to the deaths of four elderly patients treated at Stafford Hospital.

Three of the patients, who were known to be vulnerable to falls, died after falling, and the fourth was given penicillin despite relatives’ repeated warnings to staff that she was allergic to the drug. Last month …
Rituximab, gemcitabine and oxaliplatin (R-GEMOX): A promising regimen for refractory/relapsed B-cell lymphoma
Authors: T. El Gnaoui, B. Joly, J. Dupuis, K. Belhadj, A. Rahmouni, C. Copie-Bergman, A. Allain, I. Tabah-Fisch, F. Reyes, C. Haioun
Journal: Journal of Clinical Oncology (2004)

6592 Background: High-dose therapy with autologous stem cell support (HDT) is now an established treatment for chemosensitive relapse in aggressive lymphoma. However, not all patients are candidates for HDT because of age, comorbidities or previous HDT. Effective and well-tolerated salvage therapies with minimal toxicities are needed. Methods: We designed the R-GEMOX regimen, with rituximab 375mg/m2 d1, gemcitabine 1000 mg/m2 d2 and oxaliplatin 100 mg/m2 d2 (recycling on d15). Between January 2002 and August 2003, 24 patients with refractory/relapsing B-cell lymphoma not eligible for HDT were enrolled in an open unicenter pilot study whose primary objective was to determine the overall response rate (ORR) after 4 cycles of R-GEMOX. Patients were planned to receive 8 cycles if a good response (at least PR) was observed after 4 cycles. Median age was 64 years (range: 43–77) and histological subtypes were : diffuse large B-cell lymphoma (n=16), follicular (n=6) and mantle cell (n=2). Prior treatment included anthracyclin (n=22), rituximab (n=11) and HDT (n=6). The median number of prior treatments was 2 (range : 1 to 5) and 8 patients had received at least 3 prior regimens. Results: 172 cycles were given. The dose administered was 100% of the intended dose for the three drugs in all patients but 4, for whom the dose of oxaliplatin was reduced due to neurotoxicity (n=3) or preexisting renal insufficiency (n=1). Two patients progressed after 3 cycles. After 4 cycles, observed responses were: 6 CR, 4 CRu, 11 PR and 1 failure resulting in an ORR of 88 %. Among the 21 responders after 4 cycles, 17 achieved CR or CRu, 2 remained in PR after completion of 8 cycles. Treatment was stopped after 5 cycles in 2 patients because of physician decision. As of December 2003, 22 patients are alive, 15 in continuous complete remission, 3 in CRu, 2 in PR and 2 in progression. NCIC grade 3–4 neutropenia and thrombocytopenia were reported in 50% and 21% of cycles. Two patients developed a grade 4 infection. There was no renal toxicity. Conclusion: The R-GEMOX regimen shows promising activity with an acceptable toxicity. It is evaluated in an ongoing multicentric phase II study. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi-Synthelabo
The epidemiological transition of first-ever stroke among low-income population in China: a population-based study from 1992 to 2014
Authors: Xianjia Ning, Yihe Yang, Li Yang, Zhongping An, Bin Li, Wenjuan Zhao, Hongfei Gu, Changqing Zhan, Jun Tu, Lingling Bai, Jinghua Wang
Journal: The Lancet (2015)
Interleukin-15 potentiates human natural killer cells to resist tumor-induced suppression through mTOR-regulated metabolic control
Authors: Andreas Lundqvist, Yumeng Mao, Xiaonan Zhang, Erik Wennerberg, Vincent Van Hoef, Ola Larsson, Stig Linder, Rolf Kiessling
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts In cancer patients, anti-tumor functions of NK cells are severely impaired by a variety of immunosuppressive mechanisms. Interleukin (IL)-2 and -15 are two essential cytokines regulating the development and function of human natural killer (NK) cells. Here, we compared the role of
Selection of circulating PD-1+ lymphocytes from cancer patients enriches for tumor-reactive and mutation-specific lymphocytes
Authors: Alena Gros, Eric Tran, Maria R Parkhurst, Pasetto Anna, Sadia Ilyas, Todd D Prickett, Jared J Gartner, Paul F Robbins, Jessica S Crystal, Kasia Trebska-Mcgowan, John R Wudnerlich, James C Yang, Steven A Rosenberg
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts T cells targeting unique somatic mutations appear to play an important role in the antitumor responses observed following T cell transfer, and isolation of mutation-specific lymphocytes and T-cell receptors has become a major obstacle to the development of more effective