tbuckley/cabot-search huggingface dataset:
MiR-16 regulates the pro-tumorigenic potential of lung fibroblasts through the inhibition of HGF production in an FGFR-1- and MEK1-dependent manner
Authors: Francesca Andriani, Maria Teresa Majorini, Miguel Mano, Elena Landoni, Rosalba Miceli, Federica Facchinetti, Mavis Mensah, Enrico Fontanella, Matteo Dugo, Mauro Giacca, Ugo Pastorino, Gabriella Sozzi, Domenico Delia, Luca Roz, Daniele Lecis
Journal: Journal of Hematology & Oncology (2018)

Fibroblasts are crucial mediators of tumor-stroma cross-talk through synthesis and remodeling of the extracellular matrix and production of multiple soluble factors. Nonetheless, little is still known about specific determinants of fibroblast pro-tumorigenic activity in lung cancer. Here, we aimed at understanding the role of miRNAs, which are often altered in stromal cells, in reprogramming fibroblasts towards a tumor-supporting phenotype. We employed a co-culture-based high-throughput screening to identify specific miRNAs modulating the pro-tumorigenic potential of lung fibroblasts. Multiplex assays and ELISA were instrumental to study the effect of miRNAs on the secretome of both primary and immortalized lung fibroblasts from lung cancer patients and to evaluate plasmatic levels of HGF in heavy smokers. Direct mRNA targeting by miRNAs was investigated through dual-luciferase reporter assay and western blot. Finally, the pro-tumorigenic activity of fibroblasts and their conditioned media was tested by employing in vitro migration experiments and mouse xenografts. We identified miR-16 as a master regulator of fibroblast secretome and showed that its upregulation reduces HGF secretion by fibroblasts, impairing their capacity to promote cancer cell migration. This effect is due to a pleiotropic activity of miR-16 which prevents HGF expression through direct inhibition of FGFR-1 signaling and targeting of HGF mRNA. Mechanistically, miR-16 targets FGFR-1 downstream mediator MEK1, thus reducing ERK1/2 activation. Consistently, chemical or genetic inhibition of FGFR-1 mimics miR-16 activity and prevents HGF production. Of note, we report that primary fibroblast cell lines derived from lungs of heavy smokers express reduced miR-16 levels compared to those from lungs not exposed to smoke and that HGF concentration in heavy smokers' plasma correlates with levels of tobacco exposure. Finally, in vivo experiments confirmed that restoration of miR-16 expression in fibroblasts reduced their ability to promote tumor growth and that HGF plays a central role in the pro-tumorigenic activity of fibroblasts. Overall, these results uncover a central role for miR-16 in regulating HGF production by lung fibroblasts, thus affecting their pro-tumorigenic potential. Correlation between smoking exposure and miR-16 levels could provide novel clues regarding the formation of a tumor-proficient milieu during the early phases of lung cancer development.
Long term survival, health, social functioning, and education in patients with European Lyme neuroborreliosis: nationwide population based cohort study
Authors: Niels Obel, Ram B Dessau, Karen A Krogfelt, Jacob Bodilsen, Nanna S Andersen, Jens K Møller, Casper Roed, Lars H Omland, Claus B Christiansen, Svend Ellermann-Eriksen, Jette M Bangsborg, Klaus Hansen, Thomas L Benfield, Kenneth J Rothman, Henrik T Sørensen, Christian Ø Andersen, Anne-Mette Lebech
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To estimate long term survival, health, and educational/social functioning in patients with Lyme neuroborreliosis compared with the general population. <h3>Design</h3> Nationwide population based cohort study using national registers. <h3>Setting</h3> Denmark. <h3>Participants</h3> All Danish residents diagnosed during 1986-2016 as having Lyme neuroborreliosis (n=2067), defined as a positive <i>Borrelia burgdorferi</i> intrathecal antibody test and a clinical diagnosis of Lyme borreliosis, and a comparison cohort from the general population matched on sex and date of birth (n=20 670). <h3>Main outcome measures</h3> Mortality rate ratios, incidence rate ratios of comorbidities, and differences in educational and social outcomes. <h3>Results</h3> Mortality among patients with Lyme neuroborreliosis was not higher than in the general population (mortality rate ratio 0.90, 95% confidence interval 0.79 to 1.03). Lyme neuroborreliosis patients had increased risk of haematological (incidence rate ratio 3.07, 2.03 to 4.66) and non-melanoma skin cancers (1.49, 1.18 to 1.88). At diagnosis, Lyme neuroborreliosis patients had slightly higher employment and lower disability pension rates. After five years, patients and comparison cohort members had similar numbers of hospital contacts (difference −0.22, 95% confidence interval −0.45 to 0.02, in-hospital days/year; 0.37, −0.10 to 0.83, outpatient visits/year), employment rates (difference 1.5%, −2.1% to 5.1%), income (difference −1000, −20 000 to 18 000, Danish kroner), days of sick leave (difference −0.3, −3.5 to 3.0, per year), rates of receipt of a disability pension (difference −0.9%, −3.2% to 1.3%), and number of children (difference –0.10, −0.27 to 0.08). More patients were married (difference 4.8%, 2.2% to 7.4%) and had completed high school education (difference 7%, 1% to 12%). <h3>Conclusion</h3> A verified diagnosis of Lyme neuroborreliosis had no substantial effect on long term survival, health, or educational/social functioning. Nevertheless, the diagnosis decreased labour market involvement marginally and was associated with increased risk of haematological and non-melanoma skin cancers.
Introduction of new and reinforcement of existing compulsory vaccinations in Italy: first evaluation of the impact on vaccination coverage in 2017
Authors: Fortunato D’Ancona, Claudio D’Amario, Francesco Maraglino, Giovanni Rezza, Walter Ricciardi, Stefania Iannazzo
Journal: Eurosurveillance (2018)

In June 2017, a decree-law to increase the number of mandatory vaccinations from 4 to 10 for minors up to 16-years-old was issued in Italy. The vaccination coverage for 2017 showed a positive impact for all the vaccines, particularly for the measles, mumps and rubella vaccine at 91.6% for the year 2017, showing a 4.4% increase compared with 2016 (87.2%). Continued monitoring is needed to evaluate the medium to long-term effects of the law.
JAK inhibitors in autoinflammation
Authors: Hal M. Hoffman, Lori Broderick
Journal: Journal of Clinical Investigation (2018)

Interferonopathies are a subset of autoinflammatory disorders with a prominent type I IFN gene signature. Treatment of these patients has been challenging, given the lack of response to common autoinflammatory therapeutics including IL-1 and TNF blockade. JAK inhibitors (Jakinibs) are a family of small-molecule inhibitors that target the JAK/STAT signaling pathway and have shown clinical efficacy, with FDA and European Medicines Agency (EMA) approval for arthritic and myeloproliferative syndromes. Sanchez and colleagues repurposed baricitinib to establish a significant role for JAK inhibition as a novel therapy for patients with interferonopathies, demonstrating the power of translational rare disease research with lifesaving effects.
Efficacy of primary prophylactic GCSF in patients receiving docetaxel based chemotherapy for breast cancer.
Authors: Jamal M Zekri, Azhar Nawaz, Haleem J. Rasool, Imran Ahmad, Hossam Abdel Rahman, Ahmed Allithy, Ehab Mosaad Abdelghany, Kamel Farag, Refaei Belal Ibrahim, Mohamed Youssef Deibas, Mohamed Kamal Kamel, Reyad Dada
Journal: Journal of Clinical Oncology (2018)

e12516 Background: Primary prophylactic Granulocyte Colony Stimulating Factor (PP-GCSF) is recommended for patients receiving single agent docetaxel (SAD) and docetaxel combination regimens (DCR) to reduce risk of febrile neutropenia (FN). This study aims to investigate the benefit of PP-GCSF in these patients in real life daily setting. Methods: All consecutive patients (n = 276) with breast cancer who received SAD or DCR between years 2015 and 2017 were included. Starting dose of Docetaxel was 80 mg/m2 in SAD and was variable in different DCRs. Data was collected retrospectively. Chi-square and Mann–Whitney–Wilcoxon tests were used as appropriate to detect significance of differences. The outcome presented in this abstract is limited to findings related to 1st and 2nd cycles of chemotherapy. Results of comprehensive analyses will be presented at the conference. Results: Median age was 50 (21-75) years. Treatment intent was curative in 233 (84.4%) and palliative in 43 (15.6%) patients. 193 (69.9%) received PP-GCSF after first cycle of chemotherapy while 83 (30.1%) did not. FN was less frequent in patients who received SAD (P = 0.046) and in those who received primary PP-GCSF (P = 0.02) compared to DCR and no GCSF prophylaxis respectively (Table). There was a tendency to shorter admission days after FN (P = 0.098) and less cycle 2 chemotherapy dose reduction (P = 0.525) and delays (P = 0.256) in patients who received PP-GCSF compared to those who did not. Conclusions: PP-GCSF significantly reduces the risk of FN in patients receiving docetaxel based chemotherapy. It may also shorten duration of admission after 1st cycle of docetaxel based therapy and enables more optimal subsequent treatment delivery. Number Rate of FN after 1st cycle Mean duration (range) of admission for FN in days Cycle 2 dose reduction Cycle 2 dose delay All patients 276 25 (9.1%) 4.56 (1-15) 60/265 (22.6%) 39/265 (14.7%) SAD 138/276 (50%) 8/138 (5.8%) 4 (1-6) 29/131 (22.1%) 19/131 (14.5%) DCR 138/276 (50%) 17/138 (12.3%) 4.82 (1-15) 31/134 (23.1%) 20/134 (14.9%) Received PP-GCSF 193 (69.9%) 12/193 (6.2%) 3.67 (1-7) 40/185 (21.6%) 24/184 (13%) No PP-GCSF 83 (30.1%) 13/83 (15.7%) 5.38 (1-15) 20/80 (25%) 15/79 (19%)
Women and Sleep
Authors: Anita Rajagopal, Ninotchka Liban Sigua
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

How does the menstrual cycle affect a woman's sleep?Women report disrupted sleep a week prior to their menses (period) and during menses.This is due to changes in the levels of the hormones progesterone and estrogen that can lead to menstrual symptoms such as cramping, moodiness, cravings, and irritability.During the menstrual period, it is common to have an increase in nighttime awakenings and an increase in vivid dreams.Normally, these sleep problems resolve after the start of the period, though some women may have continuing sleep problems such as insomnia.Hormone therapy may alter a woman's sleep and various symptoms associated with sleep disorders.This should be discussed with your provider prior to initiating therapy so that you know what changes to expect. How does pregnancy affect a woman's sleep?About 66% to 94% of pregnant women report some form of sleep change during the course of pregnancy.A woman's sleep may vary by the time period in pregnancy as follows:
G1T38, an oral CDK4/6 inhibitor, dosed continuously in combination with fulvestrant for HR+ breast cancer: Preliminary phase 1b results.
Authors: Iurie Bulat, Marina Maglakelidze, Carmen Murias, Galina Petrova Kurteva, Rebecca Roylance, Maia Gogiladze, Adrian Crijanovschi, Amy McCullough, Elizabeth Shearin, Jessica Sorrentino, Christina Sipes, Zhao Yang, Yaping Cai, Rajesh K. Malik, Andrew Paul Beelen
Journal: Journal of Clinical Oncology (2018)

1061 Background: CDK4/6 inhibition has demonstrated significant improvements in PFS when combined with fulvestrant (F) in patients with breast cancer (BC). G1T38 (38) is a potent, selective oral CDK4/6 inhibitor with best-in-class potential. Continuous daily dosing in preclinical models inhibits tumor growth and leads to a dose-dependent ANC decline and subsequent plateau. A completed Phase 1 trial supports this Phase 1b/2a trial (NCT02983071) in BC patients. Methods: Patients with metastatic or locally advanced HR+ HER2(-) BC who had progressed following endocrine therapy are eligible. Patients receive 38 QD or BID continuously with 500 mg F. Primary objectives are to evaluate DLTs, safety, and tolerability and to determine the RP2D and schedule of 38 administered with F. Results: To date, 24 patients (median age 55.5) have enrolled and received 38 doses ranging from 200-500 mg QD and 100-150 mg BID for up to 367 days. Dose escalation is ongoing. 38 is well tolerated: no 38-related SAEs have been reported and no patient has withdrawn due to an AE. 1 DLT of Grade 4 neutropenia occurred at 200 mg QD. The most common 38-related TEAEs are cytopenias and GI AEs. There have been no reports of VTE, QT prolongation, or DILI. Incidence/severity of diarrhea is less than abemaciclib, and similar to palbociclib and ribociclib. The degree of neutropenia is consistent with effective CDK4/6 inhibition with 79% all-grade neutropenia. Following an initial decline, ANCs plateau beginning at Week 5, which is consistent with preclinical findings. The % ANC change at Week 5 ranges from -48% (200 mg QD) to -74% (500 mg QD). Confirmed PR rate is 20% in evaluable patients, with a median time to response of 12 weeks. The CBR (CR + PR + SD ≥ 24 weeks) is 57%. Conclusions: G1T38 is a potential best-in-class CDK4/6 inhibitor. Continuous daily dosing with G1T38 + F is well tolerated with non-dose-limiting ANC decrease that plateaus at week 5, thus eliminating the need for a drug holiday. Early efficacy results are encouraging, and data support continued dose escalation and dose expansion. Combinations of G1T38 in other indications are anticipated; a Phase 1/2a trial of G1T38 + Tagrisso in EGFRm NSCLC will initiate in March 2018. Clinical trial information: NCT02983071.
A phase 1b/2 study of ARRY-382, an oral inhibitor of colony stimulating factor 1 receptor (CSF1R), in combination with pembrolizumab (Pembro) for the treatment of patients (Pts) with advanced solid tumors.
Authors: Wael A. Harb, Melissa Lynne Johnson, Jonathan Wade Goldman, Amy M. Weise, Justin Anthony Call, Arkadiusz Z. Dudek, Rene Gonzalez, C. Lance Cowey, P. Taylor Eves, Ashwin Gollerkeri, Justin F. Gainor
Journal: Journal of Clinical Oncology (2017)

TPS3110 Background: CSF1, which signals via CSF1R, regulates tumor-associated macrophages and myeloid-derived suppressor cells, both critical drivers of immune escape in the tumor microenvironment. ARRY-382 is a highly selective, oral inhibitor of the CSF1R intracellular tyrosine kinase. The first-in-human study of ARRY-382 monotherapy identified the maximum tolerated dose (MTD) of 400 mg QD, with biologic activity at doses ≥200 mg QD (Bendell JC et al. Mol Cancer Ther. 2013;12:A252). Preclinical data supports combining a PD-1 inhibitor with a CSF1R inhibitor (Zhu Y et al. Cancer Res. 2014;74:5057-69). This study is designed to evaluate ARRY-382 in combination with pembro, a potent and highly selective humanized monoclonal antibody that targets PD-1. Methods: This is an open-label, multicenter, phase 1b/2 study (NCT02880371) to determine the MTD and/or recommended phase 2 dose (RP2D) of ARRY-382 + pembro and to evaluate the activity of the combination in select indications. In phase 1b (Part A), the primary objective is to identify the MTD/RP2D. Up to 18 pts with select advanced solid tumors (Part A) will be enrolled in 2 successive cohorts evaluating ARRY-382 at doses of 200 mg QD and 400 mg QD, respectively, in combination with pembro 2 mg/kg Q3W. Once the MTD/RP2D has been determined in phase 1b, phase 2 will concurrently evaluate the combination in up to 20 pts with advanced unresectable/metastatic melanoma (Part B) and in up to 33 pts with PD-L1-positive (tumor proportion score ≥50) non-small cell lung cancer (NSCLC) (Part C). The primary objective of Part B is to assess the pharmacodynamics and antitumor activity of ARRY-382 + pembro in pts with advanced unresectable/metastatic melanoma, and the endpoints include effects of treatment on circulating growth factors and cytokines, markers of bone resorption, and objective response rate (ORR). The primary objective of Part C is to assess the efficacy of ARRY-382 + pembro in pts with PD-L1–positive NSCLC (Part C). The primary endpoint is ORR. Immune-related response rate and safety will be evaluated in all pts in the study. Clinical trial information: NCT02880371.
Abstract 14779: A Simple, Highly-Sensitive Clinical Prediction Rule to Exclude Acute Coronary Syndrome in a Population with a High Burden of Cardiac Risk Factors
Authors: Alexander C Fanaroff, Ryan D Schulteis, Sunil V Rao, L K Newby
Journal: Circulation (2014)

Background:  A minority of patients presenting to emergency departments (ED) with chest pain have acute coronary syndrome (ACS). The ADAPT study showed that patients with TIMI Risk Score (TRS) of 0, no ischemic ECG changes and contemporary sensitive troponin assays below the 99th percentile on 2 assessments 2 hours apart were at low risk for 30-day ischemic events. We hypothesized that older patients with traditional cardiac risk factors (and thus, TRS > 0) could also be identified as being low risk if they had troponin I (TnI) levels below the limit of detection (LOD) of the assay, no ischemic ECG changes and no history of coronary artery disease (CAD), and potentially could be discharged without stress testing.   Methods:  We performed a single-center retrospective cohort study of 246 consecutive patient care episodes in which a first TnI was drawn in the ED and a second TnI was drawn 4 to 12 hours later. Patients were categorized as potentially eligible for discharge from the ED without stress testing if they had no known CAD, no ischemic ECG changes and both TnI measurements were below the LOD, irrespective of other clinical risk factors. We determined the 30-day incidence of major cardiac events (MI, revascularization, or cardiovascular death).   Results:  The median age of our population was 64 years, 95% were male, 54% had pre-existing CAD, and 27% had TRS ≤ 1. At 30 days, 23% had a major cardiac event and 40% underwent stress testing and/or left heart catheterization (LHC) before discharge. Applying our rule (no CAD, no ischemic ECG changes and 2 TnI determinations below LOD), 22% (n=55/246) of patients would have been eligible for discharge without stress testing; 44% of these patients eventually underwent stress testing and/or LHC. The negative predictive value for 30-day cardiac events in this subset was 98%. By comparison, the ADAPT rule identified 8% (p    Conclusions:  If validated in prospective studies, applying this risk model to ED chest pain patients could reduce the number of stress tests performed and identify patients who can be safely discharged from the ED.
Randomized web-based physical activity intervention in adolescent survivors of childhood cancer.
Authors: Carrie R Howell, Kevin R. Krull, Robyn Partin, MS, Nina S. Kadan-Lottick, Leslie L. Robison, Melissa M. Hudson, Kirsten K. Ness
Journal: Journal of Clinical Oncology (2018)

102 Background: This study of adolescent survivors of childhood cancer evaluated the initial efficacy of a web-delivered, interactive, rewards-based physical activity intervention that aimed to increase moderate to vigorous physical activity (MVPA) and improve fitness, neurocognitive and health-related quality of life (HRQoL) outcomes over 24 weeks. Methods: Survivors (aged ≥ 11 to &lt; 15 years) who were not undergoing active cancer treatment, were physically active &lt; 60 minutes/day and were treated at a single institution were randomized (2:1) to a rewards-based physical activity intervention delivered via the internet or a control group. The intervention group received educational materials, an activity monitor, and access to an interactive website designed to motivate increased physical activity via rewards (e.g. t-shirts, stickers, gift cards) and the control group received only the activity monitor and educational materials. Physical activity, fitness, neurocognitive and HRQoL outcomes were assessed at baseline and 24-weeks. Mean changes in outcomes were compared between groups using paired t-tests. Results: Of 97 survivors enrolled, 78 completed the study (53 in the intervention group, 25 in the control group), the mean age was 12.7 (SD 1.1), 80% were white, and 55.1% were female. The intervention group increased their MVPA over time (mean change in weekly MVPA: 4.7 minutes [SD 119.9]), while the control group steadily decreased their weekly MVPA (-24.3 minutes [SD 89.7]) (p = 0.30). In the intervention group, mean change in hand grip strength (p = 0.01), number of sit-ups (p &lt; 0.01) and push-ups (p &lt; 0.01), neurocognitive measures (e.g. verbal executive function, p &lt; 0.01), and HRQoL outcomes (e.g. overall HRQoL, p = 0.01; physical function, p = 0.01) improved over time; no change was observed in the control group. Conclusions: These preliminary findings indicate that increasing MVPA via an intervention designed to increase motivation to exercise may have positive effects on fitness, neurocognitive and HRQoL outcomes in adolescent survivors of childhood cancer. Clinical trial information: NCT01778127.
AMPA-ergic regulation of amyloid-β levels in an Alzheimer’s disease mouse model
Authors: Jane C. Hettinger, Hyo Lee, Guojun Bu, David M. Holtzman, John R. Cirrito
Journal: Molecular Neurodegeneration (2018)

Extracellular aggregation of the amyloid-β (Aβ) peptide into toxic multimers is a key event in Alzheimer's disease (AD) pathogenesis. Aβ aggregation is concentration-dependent, with higher concentrations of Aβ much more likely to form toxic species. The processes that regulate extracellular levels of Aβ therefore stand to directly affect AD pathology onset. Studies from our lab and others have demonstrated that synaptic activity is a critical regulator of Aβ production through both presynaptic and postsynaptic mechanisms. AMPA receptors (AMPA-Rs), as the most abundant ionotropic glutamate receptors, have the potential to greatly impact Aβ levels.In order to study the role of AMPA-Rs in Aβ regulation, we used in vivo microdialysis in an APP/PS1 mouse model to simultaneously deliver AMPA and other treatments while collecting Aβ from the interstitial fluid (ISF). Changes in Aβ production and clearance along with inflammation were assessed using biochemical approaches. IL-6 deficient mice were utilized to test the role of IL-6 signaling in AMPA-R-mediated regulation of Aβ levels.We found that AMPA-R activation decreases in ISF Aβ levels in a dose-dependent manner. Moreover, the effect of AMPA treatment involves three distinct pathways. Steady-state activity of AMPA-Rs normally promotes higher ISF Aβ. Evoked AMPA-R activity, however, decreases Aβ levels by both stimulating glutamatergic transmission and activating downstream NMDA receptor (NMDA-R) signaling and, with extended AMPA treatment, acting independently of NMDA-Rs. Surprisingly, we found this latter, direct AMPA pathway of Aβ regulation increases Aβ clearance, while Aβ production appears to be largely unaffected. Furthermore, the AMPA-dependent decrease is not observed in IL-6 deficient mice, indicating a role for IL-6 signaling in AMPA-R-mediated Aβ clearance.Though basal levels of AMPA-R activity promote higher levels of ISF Aβ, evoked AMPA-R signaling decreases Aβ through both NMDA-R-dependent and -independent pathways. We find that evoked AMPA-R signaling increases clearance of extracellular Aβ, at least in part through enhanced IL-6 signaling. These data emphasize that Aβ regulation by synaptic activity involves a number of independent pathways that together determine extracellular Aβ levels. Understanding how these pathways maintain Aβ levels prior to AD pathology may provide insights into disease pathogenesis.