tbuckley/cabot-search huggingface dataset:
Analysis of newer molecular signatures: Promise of a diagnostic and management assay for breast cancer
Authors: Ashwani Khanna, Alonzo Walker
Journal: Cancer Research (2005)

3127  Hypothesis: A detailed analysis of markers of inflammation, cell cycle control, cell-cell contact and the tissue repair in breast cancer has not been performed. We hypothesize that the changes for these markers in cancerous and normal tissues from the same breast tissue will allow the monitoring of the efficacy of therapy in breast cancer patients. Also, the transcripts of these markers observed in breast tissues are mimicked in immune cells from the same patient. Experimental Design: Using Real Time PCR assay, the analysis for Mammaglobin B, PPAR-alpha, TNF-alpha, NFkB, Il-6, MMP-9, Skp2, Cyclin E was performed on 20 paired tissues (cancerous and normal tissues) from the same breast (obtained from CHTN) and lymphocytes and breast tissues from patients in a blinded fashion (obtained from Fredtert Memorial Lutheran Hospital/Medical College of Wisconsin. We also studied mRNA expression for these markers in normal breast tissues obtained from individuals undergoing breast reduction. RNA samples were prepared from both the lymphocytes and tissue at the same time, reverse transcribed to cDNA and mRNA expression studied by real time PCR assay. Results: The mRNA expression for Mammaglobin B, PPAR-alpha, TNF-alpha, NFkB, Il-6, MMP-9, Skp2, NFKB was significantly higher in cancerous tissues than normal tissues from the same breast. The expression of mammaglobin B was observed only in cancerous tissues not in normal tissues. The expression of PPAR-alpha, Skp2, TNF-alpha and NFKB was also significantly higher in cancerous than paired normal breast tissues. However, the expression varied with the diagnosis. For example in a patient diagnosed with infiltrating ductal carcinoma the fold difference for TNF-alpha mRNA was 5 fold, with moderately differentiating ductal carcinoma 4 fold compared to invasive ductal carcinoma with 80% differentiation a 90 fold increase in mRNA was observed. Similar changes were observed with mRNA expression for other markers. The mRNA expression for these markers was identical in lymphocytes and tissues from these patients, however the quantitative differences for these markers were observed in patients with different diagnosis. The mRNA expression for IL-6 and TNF-alpha in tissue from a patient with benign Phyllodes tumor was not different than normal controls. The mRNA expression for TNF-alpha in patients with Fibroadenoma was not detectable, however for IL-6 was detectable. In sharp contrast, the patient with diagnosed with invasive ductal carcinoma exhibited significantly higher expression for both IL-6 and TNF-alpha mRNA Conclusions: These results demonstrate the ability of these molecular signatures to differentiate malignant tissues from normal tissues and the usefulness of immune cells in detection of cancer. These results provide potential for the development of a multiplex PCR based diagnostic assay for breast cancer.
Microglia affect α-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease
Authors: Sonia George, Nolwen L. Rey, Trevor Tyson, Corinne Esquibel, Lindsay Meyerdirk, Emily Schulz, Steven Pierce, Amanda R. Burmeister, Zachary Madaj, Jennifer A. Steiner, Martha L. Escobar Galvis, Lena Brundin, Patrik Brundin
Journal: Molecular Neurodegeneration (2019)

Cell-to-cell propagation of α-synuclein (α-syn) aggregates is thought to contribute to the pathogenesis of Parkinson's disease (PD) and underlie the spread of α-syn neuropathology. Increased pro-inflammatory cytokine levels and activated microglia are present in PD and activated microglia can promote α-syn aggregation. However, it is unclear how microglia influence α-syn cell-to-cell transfer. We developed a clinically relevant mouse model to monitor α-syn prion-like propagation between cells; we transplanted wild-type mouse embryonic midbrain neurons into a mouse striatum overexpressing human α-syn (huα-syn) following adeno-associated viral injection into the substantia nigra. In this system, we depleted or activated microglial cells and determined the effects on the transfer of huα-syn from host nigrostriatal neurons into the implanted dopaminergic neurons, using the presence of huα-syn within the grafted cells as a readout. First, we compared α-syn cell-to-cell transfer between host mice with a normal number of microglia to mice in which we had pharmacologically ablated 80% of the microglia from the grafted striatum. With fewer host microglia, we observed increased accumulation of huα-syn in grafted dopaminergic neurons. Second, we assessed the transfer of α-syn into grafted neurons in the context of microglia activated by one of two stimuli, lipopolysaccharide (LPS) or interleukin-4 (IL-4). LPS exposure led to a strong activation of microglial cells (as determined by microglia morphology, cytokine production and an upregulation in genes involved in the inflammatory response in the LPS-injected mice by RNA sequencing analysis). LPS-injected mice had significantly higher amounts of huα-syn in grafted neurons. In contrast, injection of IL-4 did not change the proportion of grafted dopamine neurons that contained huα-syn relative to controls. As expected, RNA sequencing analysis on striatal tissue revealed differential gene expression between LPS and IL-4-injected mice; with the genes upregulated in tissue from mice injected with LPS including several of those involved in an inflammatory response. The absence or the hyperstimulation of microglia affected α-syn transfer in the brain. Our results suggest that under resting, non-inflammatory conditions, microglia modulate the transfer of α-syn. Pharmacological regulation of neuroinflammation could represent a future avenue for limiting the spread of PD neuropathology.
Ian James Burns
Authors: Michael Burns
Journal: BMJ (2019)

Ian James Burns was born in Glasgow to parents James Aloysius Burns and Mabel Thomson Dick of Rutherglen. He attended Burnside Primary School and St Aloysius College, Glasgow, before gaining entry to Glasgow School of Medicine in 1949, aged only 17. He qualified in 1955, and spent his preregistration year as house officer at Stonehouse Hospital, Lanarkshire, and Glasgow Western Infirmary A&O, before gaining full medical registration in August 1956.

Ian selected anaesthetics as his specialty and quickly progressed from junior house officer anaesthesia at Glasgow Royal Infirmary to senior house officer at Edinburgh Royal Infirmary in 1957. After three years as registrar anaesthetist at Edinburgh, he moved to Inverness in 1961 as senior registrar anaesthetist at the Royal Northern Infirmary and Raigmore Hospital.

In those early days in Inverness, Ian met Katie McEwan, a young orthopaedic nurse from Perth. They were married in October 1964 and soon moved to Wick, their home to this day. Ian’s primary role for the following 32 years was as specialist anaesthetist to the Caithness hospitals, although in 1970 he started to broaden his expertise; as clinical …
Response to: “Influence of changes in cholesterol levels and disease activity on the 10-year cardiovascular risk estimated with different algorithms in rheumatoid arthritis patients” by Fornaro<i>et al</i>
Authors: Rabia Agca, Sjoerd C Heslinga, S Rollefstad, S Heslinga, Anna Södergren, AG Semb, George D Kitas, Naveed Sattar, Michael T Nurmohamed
Journal: Annals of the Rheumatic Diseases (2019)

Fornaro and colleagues investigated the influence of cholesterol level changes and disease activity on the estimated cardiovascular (CV) risk in rheumatoid arthritis (RA) patients, at baseline, 3 months and 6 months after the start of a tumour necrosis factor-alpha (TNF) inhibitor (n=55), abatacept (n=33) or tocilizumab (n=24).1 The cohort consisted of mainly women (n=86) aged 53±13 years, with a mean disease duration of approximately 59±76 months. CV risk was calculated with QRISK3-2018, Reynolds Risk Score (RRS), Expanded Risk Score (ERS) in RA (ERS-RA) and Progetto Cuore. The Progetto Cuore and RRS scores were multiplied by 1.5 as advocated by the current EULAR recommendations.2 The authors identified a modest but statistically significant change in total cholesterol (TC) at 3 months that returned to baseline at 6 months. Additionally, the ERS-RA and RRS scores significantly decreased during follow-up, while the Progetto Cuore and QRISK3-2018 scores did not change. Thus, the authors argue that QRISK3-2018 and Proguetto Cuore can be used at any time, as they do not seem to be significantly affected by the modest changes in TC levels and disease activity.

Several findings of this interesting study need …
LEAP2 changes with body mass and food intake in humans and mice
Authors: Bharath K. Mani, Nancy Puzziferri, Zhenyan He, Juan A. Rodriguez, Sherri Osborne-Lawrence, Nathan P. Metzger, Navpreet Chhina, Bruce Gaylinn, Michael O. Thorner, E. Louise Thomas, Jimmy D. Bell, Kevin W. Williams, Anthony P. Goldstone, Jeffrey M. Zigman
Journal: Journal of Clinical Investigation (2019)

Acyl-ghrelin administration increases food intake, body weight, and blood glucose. In contrast, mice lacking ghrelin or ghrelin receptors (GHSRs) exhibit life-threatening hypoglycemia during starvation-like conditions, but do not consistently exhibit overt metabolic phenotypes when given ad libitum food access. These results, and findings of ghrelin resistance in obese states, imply nutritional state dependence of ghrelin's metabolic actions. Here, we hypothesized that liver-enriched antimicrobial peptide-2 (LEAP2), a recently characterized endogenous GHSR antagonist, blunts ghrelin action during obese states and postprandially. To test this hypothesis, we determined changes in plasma LEAP2 and acyl-ghrelin due to fasting, eating, obesity, Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), oral glucose administration, and type 1 diabetes mellitus (T1DM) using humans and/or mice. Our results suggest that plasma LEAP2 is regulated by metabolic status: its levels increased with body mass and blood glucose and decreased with fasting, RYGB, and in postprandial states following VSG. These changes were mostly opposite of those of acyl-ghrelin. Furthermore, using electrophysiology, we showed that LEAP2 both hyperpolarizes and prevents acyl-ghrelin from activating arcuate NPY neurons. We predict that the plasma LEAP2/acyl-ghrelin molar ratio may be a key determinant modulating acyl-ghrelin activity in response to body mass, feeding status, and blood glucose.
DN101–004: A multicenter, open label, dose ranging study of DN-101 and docetaxel in patients with stage IIIB or IV non-small cell lung cancer (NSCLC) after platinum-based chemotherapy
Authors: H. J. West, S. Lee, L. Reyno, L. Fehrenbacher, A. L. Cohn, J. O. Hopkins, D. H. Irwin, D. A. Smith, T. E. Boyd, M. R. Olsen
Journal: Journal of Clinical Oncology (2007)

7685 Background: DN-101 is a high-dose oral formulation of calcitriol, the most potent natural ligand of vitamin D receptor. Calcitriol has various anti-neoplastic effects on malignant cells and increases activity of cytotoxic agents, including taxanes. DN-101 in combination with docetaxel was associated with improved survival in a phase II study in androgen-independent prostate cancer and ASCENT 2, a phase III confirmatory study is underway. The objective of the study was to determine the maximum tolerated dose, response rate (ORR), progression-free survival (PFS), and overall survival (OS) of DN-101 in combination with docetaxel in advanced NSCLC patients (pts). Methods: Eligible pts had Stage IIIB or IV NSCLC that progressed on or after platinum-based chemotherapy, ECOG = 1, and measurable disease by RECIST criteria. DN-101 was administered on day 1 in doses of 45 (n=5), 75 (n=4), 135 (n=3), or 180 μg (n=53) in the q21d group, or 180 μg on day 1, followed by 45 (n=5), 90 (n=4), or 180 μg (n=12) on days 8 and 15 in the q7d group. Docetaxel (75 mg/m 2 BSA) was given on day 2 q21d for all pts. Results: A total of 86 pts were treated. No unexpected toxicities were reported with DN-101. Grade 3/4 (G3/4) toxicities and fatal adverse events (AEs) were consistent with the reported toxicity of docetaxel alone. Stomatitis (0% in q7d, 9% in q21d) and G3/4 asthenia and fatigue (5% in q7d, 14% in q21d) were less frequent on DN-101 compared to published reports on docetaxel. No pt on DN-101 q21d developed hypercalcemia while 2 pt on DN-101 q7d (180 μg cohort) developed G3/4 hypercalcemia. Three fatal AEs included 2 on DN-101 q21d (1 lung infiltration, 1 pneumonitis) and 1 on DN-101 q7d (intestinal perforation). The ORR was 5.9% (CI 0.1%, 28.7%) and 6.6% (1.8%, 15.9%), median PFS 14.1 (6.0, 20.0) and 11.6 (8.4, 17.4) weeks, median OS 8.8 (7.1, NA) and 6.9 (5.5, 9.7) months, and 1 year survival rate 40% (15.2%, 64.8%) and 31% (18.9%, 42.2%) for the q7d and q21d group, respectively. Conclusions: DN-101 in combination with docetaxel is well-tolerated in advanced NSCLC. The observation of improved PFS, OS, and 1 year survival with weekly DN-101 administration supports further investigation. [Table: see text]
Incidence and prevalence of synovial sarcoma in the US: An analysis using SEER*Stat.
Authors: Nedra Joseph, Samantha St. Laurent, Jeanenne Joy Nelson, Shan Zheng, Heide Stirnadel-Farrant
Journal: Journal of Clinical Oncology (2019)

e22535 Background: Synovial sarcoma (SS) is a rare and aggressive soft tissue sarcoma which primarily affects the extremities of the arms and legs, and can also occur in the head and neck, lungs and pleura, and the trunk. The disease burden of SS is generally extrapolated from overall soft tissue sarcoma (STS) with SS accounting for 4.5% of all STS (587 cases estimated in 2018 in the US) (Noone, 2018; Siegel, 2018). The objective of this study was to provide disease burden estimates specific to SS in the US. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) 18 Registries, Nov. 2017 (2000-2015) were analyzed using SEER*Stat software (v8.3.5). The incidence and prevalence of SS was estimated by utilizing SS-specific International Classification of Diseases for Oncology, V.3 (ICD-O-3) and histology codes. Data from 2011-2015 were used to project incidence rates (age-specific and age-adjusted), 5-year limited duration prevalence, number of incidence and prevalent cases, and the age distribution of synovial sarcoma for 2018. Results: In the US, the age-adjusted incidence rate of SS was 0.177 per 100,000 (estimated 580 incident cases) in 2018. SS is more frequently manifested in patients aged 20-49 years, with the highest occurrence of new cases in patients between 45-49 years (incidence rate 0.26 per 100,000). The prevalence rate of SS across all ages was 0.65 per 100,000 (estimated 2129 prevalent cases) as of January 1, 2018. Conclusions: We described incidence and prevalence rates of SS, including age-specific and age-standardized rates, and characterized the age distribution of SS. This approach provided more precise estimates that are specific to SS without extrapolation from STS, and which are not available in the literature. References: Noone AM, et al. (ed). SEER CSR, 1975-2015, https://seer.cancer.gov/csr/1975_2015/ . Siegel RL, et al. Cancer statistics, 2018. CA Cancer J Clin 2018;68:7–30.
The <i>MS4A</i> gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk
Authors: Yuetiva Deming, Fabia Filipello, Francesca Cignarella, Claudia Cantoni, Simon Hsu, Robert Mikesell, Zeran Li, Jorge L Del-Aguila, Umber Dube, Fabiana Geraldo Farias, Joseph Bradley, John Budde, Laura Ibanez, Maria Victoria Fernandez, Kaj Blennow, Henrik Zetterberg, Amanda Heslegrave, Per M Johansson, Johan Svensson, Bengt Nellgård, Alberto Lleo, Daniel Alcolea, Jordi Clarimon, Lorena Rami, José Luis Molinuevo, Marc Suárez-Calvet, Estrella Morenas-Rodríguez, Gernot Kleinberger, Michael Ewers, Oscar Harari, Christian Haass, Thomas J Brett, Bruno A. Benitez, Celeste M. Karch, Laura Piccio, Carlos Cruchaga
Journal: Science Translational Medicine (2019)

Common variants in the microglia-specific MS4A gene cluster modify risk for late-onset Alzheimer’s disease and modulate extracellular soluble TREM2.
Concordance of histology type between synchronous and metachronous contralateral breast carcinoma: Is there susceptibility for breast cancer of particular histology?
Authors: Zorica Tomasevic, Dusica Gavrilovic, Zoran Tomasevic, Daniela Kolarevic
Journal: Journal of Clinical Oncology (2012)

e21030 Background: Contra-lateral breast cancer (CBC) is considered to be the most frequent new malignancy after primary breast cancer (PBC) However, there are few reports whether the histology and other major molecular characteristics differs between PBC and CBC. The aim of this paper is toevaluate and compare PBC/CBC histology according to the time to CBC development. Also, age at CBC and major molecular characteristics (tumor grade, estrogen/progesterone receptors, HER2) have been analyzed. Methods: A cohort of 113 patients with CBC, without distant metastases, has been prospectively registered during 28 months. Patients are divided in 2 groups according to the time of CBC diagnose: 1. Synchronous, if the CBC (S-CBC) was diagnosed either simultaneously or within 6 months after PBC; 2. Metachronous (M-CBC) if CBC was diagnosed &gt; 6 months after PBC. Results: Results are presented in Table 1. Median age was calculated at the time of CBC diagnose. Patient with S-CBC are median 7 years older than patients with M- CBC that is statistically significant difference (p-0.007) S-CBC is more likely to be of the same histological type (76%) than M-CBC (56%) (p 0.006) In the whole analyzed group, and each subgroup separately, lobular carcinoma is registered in higher percentage (41%) than expected (~20%) For all other analyzed BC characteristics, statistical difference was not confirmed, however ~ 25% of specimens were not available for testing. Conclusions: Although it is still unclear what could be the clinical significance of these findings, genetic susceptibility to particular histology type of BC might be reasonably speculated. [Table: see text]
How to communicate in science
Authors: Lars Klareskog, Anca Irinel Catrina, Camilla Svensson, Vivianne Malmstrom
Journal: Annals of the Rheumatic Diseases (2019)

Background: In late December of 2019, a novel coronavirus (SARS-CoV-2) was identified in the Chinese city Wuhan among a cluster of pneumonia patients. While it is known that pregnant women have reduced immunity and they are at risk for COVID-19 infection during the current pandemic, it is not clear if the disease manifestation would be different in pregnant women from non-pregnant women. 
Objectives: To describe the maternal and neonatal clinical features as well as outcome of pregnancies complicated with SARS-CoV-2 infection.
Methods: In this retrospective national-based study, we analyzed the medical records of all SARS-CoV-2 positive pregnant patients and their neonates who were admitted to New-Jahra Hospital, Kuwait, between March 15th 2020 and May 31st 2020.  The outcomes of pregnancies were assessed until the end date of follow-up (June 15th 2020). 
Results: A total of 185 pregnant women were enrolled with a median age of 31 years (interquartile range, IQR: 27.5-34), and median gestational age at diagnosis was 29 weeks (IQR: 18-34). The majority (88%) of the patients had mild symptoms, with fever (58%) being the most common presenting symptom followed by cough (50.6%). During the study period, 141 (76.2%) patients continued their pregnancy, 3 (1.6%) had a miscarriage, 1 (0.5%) had intrauterine fetal death and only 2 (1.1%) patients developed severe pneumonia and required intensive care. Most of the neonates were asymptomatic, and only 2 (5%) of them tested positive on day 5 by nasopharyngeal swab testing. 
Conclusion: Pregnant women do not appear to be at higher risk to the COVID-19 than the general population. The clinical features of pregnant women with SARS-CoV-2 infection were similar to those of the general population having SARS-CoV-2 infection. Favorable maternal and neonatal outcomes reinforce the existing evidence and may guide healthcare professionals in the management of pregnancies complicated with SARS-CoV-2 infection.
Restorative design and associated risks for peri‐implant diseases
Authors: Douglas R. Dixon, Robert M. London
Journal: Periodontology 2000 (2019)

Abstract The prevalence of inflammatory conditions around dental implants is significant. Current analysis indicates that the rates for peri‐mucositis and peri‐implantitis may be as high as 40%‐65% and 20%‐47%, respectively. Over the last decade, many risk factors have been associated with peri‐mucositis and peri‐implantitis, creating a multifactorial disease etiology that complicates both diagnosis and treatment. Furthermore, additional considerations such as initial surgical implant placement position, disruption of the biologic interface associated with the implant‐abutment interface manipulation, or prosthetic design may also influence the host response to commonly employed oral prostheses or the diagnosis of inflammatory states. Coupled with the temporal nature of disease progression around implants, understanding and accounting for these additional parameters may help reduce the number of variables that the surgeon/restorative team face when incorporating implant therapy into daily practice. Therefore, this review discusses the importance of surgical and restorative design by reviewing the concepts of natural and prosthetic emergence profile and implant design and position, as well as many other restorative concepts related to potential implant complications and disease. Understanding both the inflammatory nature of peri‐implant disease and additional parameters related to both surgical and prosthetic procedures may provide the best possible approach to reducing the prevalence of both peri‐mucositis and peri‐implantitis within the realm of dental implant therapy.
Influence of Coronary Calcium on Diagnostic Performance of Machine Learning CT-FFR
Authors: Christian Tesche, Katharina Otani, Carlo N. De Cecco, Adriaan Coenen, Jakob De Geer, Mariusz Kruk, Young-Hak Kim, Moritz H. Albrecht, Stefan Baumann, Matthias Renker, Richard R. Bayer, Taylor M. Duguay, Sheldon E. Litwin, Akos Varga-Szemes, Daniel H. Steinberg, Dong Hyun Yang, Cezary Kepka, Anders Persson, Koen Nieman, U. Joseph Schoepf
Journal: JACC. Cardiovascular imaging (2019)
Functional sex differences and signal forms have coevolved with conflict
Authors: D Vaughn Becker, Shelli L Dubbs
Journal: Behavioral and Brain Sciences (2019)

Abstract Evolutionary theory makes further predictions about conflict. It predicts sex differences in the proclivity to attack and defend. It further suggests complementary biases in what we expect of the sexes. Finally, it suggests that the forms of human facial expressions of anger and happiness may have coevolved with the regularity of conflict as a means of signaling, bluffing, and defusing attack.