tbuckley/cabot-search huggingface dataset:
01.12 Fra-1 transcription factor expression in macrophages foster inflammation during rheumatoid arthritis development
Authors: Nicole Hannemann, Anne Schnelzer, Jutta Jordan, Martin Eberhardt, Ulrike Schleicher, Axel Hueber, Stephen Reid, Sophia Sonnewald, Tobias Bäuerle, Julio Vera, Christian Bogdan, Georg Schett, Aline Bozec
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The polarisation of macrophages leads to diverse populations, which are associated to a complex regulatory network of transcription factors. The activator protein (AP)−1 transcription factor family, specifically FOS proteins can regulate macrophage cytokines production. Because of the production of diverse pro-inflammatory and destructive molecules, macrophages are central players in chronic inflammation and bone destruction of rheumatoid arthritis (RA). Here, we delineate the diverse functions of Fra-1 and Fra-2 in the complex network of macrophage activations during RA development. <h3>Material and methods</h3> To determine Fra-1 and Fra-2 roles during macrophage activation, Fra-1 or Fra-2 deficient peritoneal macrophages were used for microarray and quantitative real-time PCR analysis. In addition, promoter from genes found differentially expressed were analysed by chromatin immunoprecipitation (ChIP) analysis to discover directs targets of Fra-1 or Fra-2 in macrophages. To address the physiological roles of Fra-1 and Fra-2 in macrophages, the serum induced arthritis (K/BxN) model was applied to Fra-1<sup>ΔMx</sup> or Fra-2<sup>ΔLysM</sup> deficient mice. <h3>Results</h3> Microarray analysis and subsequent gene ontology cluster enrichment highlight the specific role of Fra-1 during macrophages activation, whereas Fra-2 seems less essential for macrophage activated pathways. Additionally, the KEGG cluster analysis links Fra-1 expression to autoimmune diseases, such as RA. Applying the K/BxN serum transfer to Fra-2<sup>ΔLysM</sup> or Fra-1<sup>ΔMx</sup> mice, we could show that only Fra-1 deficient mice have a decreased arthritis severity, which was accompanied with a strong increased Arginase-1 (Arg1) expression in mice joints. Mechanistically, ChIP analysis confirmed that Fra-1 but not Fra-2 directly regulates <i>Nos2</i> and <i>Arg1</i> promoters in macrophages. Furthermore, the inhibition of Arg1 by <i>Nω-hydroxy-nor-Arginine</i> (NOHA) rescued the phenotype of Fra-1 mutant mice. Suggesting that Fra-1 promotes arthritic joint inflammation by inhibiting Arg1 expression, this probably leads to an increased resolution of inflammation in RA. <h3>Conclusion</h3> We showed that Fra-1 defines the activation status of macrophages. Physiologically, Fra-1 regulates the Arg1/iNos axis thus promoting inflammation and bone destruction in RA. The role of Fra-1 in macrophages is unique, since Fra-2 cannot recapitulate Fra-1 functions. In conclusion, our data describe a new role of Fra-1 in macrophages activation in the maintenance of inflammation and joint destruction during acute RA.
PTH-034 A novel endoscopic technique to manage buried bumper syndrome in peg: the olympus hookknife
Authors: L Wolpert, D Summers, A Tsang
Journal: Endoscopy (2017)

<h3>Introduction</h3> Buried bumper syndrome (BBS) is an uncommon but serious complication of percutaneous endoscopic gastrostomy (PEG) with an incidence of 0.3%–2.4% per PEG patient year. It involves the internal fixation device, or ‘bumper’, migrating into the gastric wall and subsequent mucosal overgrowth. Symptoms include inability to insert the PEG tube, loss of patency and leakage from the PEG. <h3>Method</h3> We described a case series of four patients with BBS treated with a novel endoscopic technique using a HookKnife between June 2016 and February 2017. The HookKnife is a rotating l-shaped cutting wire designed for hooking tissue and pulling it away from the gastric wall towards the lumen. Patients were selected for treatment following referral for suspected BBS which was then evaluated by endoscopy. <h3>Results</h3> Two patients had the procedure in endoscopy under sedation and two in theatre under general anaesthetic. The indications for PEG feeding were tetraplegia, cerebral palsy, Huntington’s disease and multiple sclerosis. The age range of patients was 28–62 years. In each case the external PEG tubing was cut short approximately 5 cm from the abdominal wall. A 15 mm through the scope (TTS) dilation balloon was passed externally via the PEG tubing and inflated to dilate the mucosal orifice. The orifice was then visualised and the HookKnife was deployed to incise the gastric mucosa over the buried bumper using two to three radial incisions each approximately 5 mm in length. The TTS balloon was inflated inside the tubing at the level of the PEG bumper and the tubing and balloon catheter clamped together using artery forceps. Short but firm controlled pressure was applied towards the gastric lumen to force the bumper into the stomach. The PEG was then removed using a standard snare technique. The HookKnife technique was successful in all four cases with no complications. Each patient was discharged on the day of treatment. <h3>Conclusion</h3> The HookKnife is a manoeuvrable, safe and effective device for endoscopic removal of buried PEG bumpers and allows the avoidance of surgery in a high risk group of patients. The benefit of the HookKnife technique compared with techniques that rely on incising the mucosa towards the gastric wall is that the HookKnife allows elevation of the gastric mucosa away from the bumper. This additional level of control allows a more precise incision, more accurate evaluation of the depth of the bumper migration and reduces the risk of inadvertent gastric perforation. To our knowledge this technique has not been described previously and we suggest that this technique should be added to the treatment algorithms for the management of BBS. <h3>Reference</h3> . Cyrany J, Rejchrt S, Kopacova M, Bures J. Buried bumper syndrome: A complication of percutaneous endoscopic gastrostomy. World J Gastroenterol. 2016Jan 14; 22(2): 618–627 <h3>Disclosure of Interest</h3> None Declared
Race- and Sex-Based Disparities in the Therapy and Outcomes of Squamous Cell Carcinoma of the Anus
Authors: Nivedita Arora, Arjun Gupta, Hong Zhu, Alana Christie, Jeffrey J. Meyer, Saad A. Khan, Muhammad S. Beg
Journal: Journal of the National Comprehensive Cancer Network (2017)

Background: Squamous cell carcinoma of the anus (SCCA) is one of the few cancers with an increasing incidence in the United States. We aimed to characterize race- and sex-based disparities in receipt of therapy and overall survival (OS) of SCCA using the SEER database. Methods: Cases of locoregional SCCA (T2–T4 any N M0) diagnosed between 2000 and 2012 in the SEER database were included. Demographics, tumor characteristics, type of therapy, and outcomes were extracted. Univariable and multivariable Cox proportional hazard models were constructed to test factors associated with OS. Data were reported as hazard ratios (HRs) and 95% CIs. Results: A total of 7,882 cases of locoregional SCCA were identified, with a median age of 58 years, 61.2% of whom were women, and 86.3% were white. Most patients (82.3%) received radiation therapy (RT), with the lowest rate in black men (76.7%) and the highest in white women (86.1%). The median OS was 135 months; OS was lower in elderly patients (age ≥65 years; 68 months), men (108 months), blacks (109 months), and those who did not receive RT (121 months). In multivariable analysis, age (HR, 1.19; 95% CI, 1.17–1.21 per 5 years increase), sex (HR, 1.59; 95% CI, 1.47–1.73, men vs women), race (HR, 1.51; 95% CI, 1.34–1.71, black vs white), and RT (HR, 0.90; 95% CI, 0.82–0.99) were independently associated with OS (P<.05). Conclusions: Significant race- and sex-based disparities exist in survival of patients with locoregional SCCA. Further investigation into the causes of these disparities and methods for elimination are warranted.
A phase II study of intravenous (IV) wild-type reovirus (Reolysin) in the treatment of patients with bone and soft tissue sarcomas metastatic to the lung
Authors: A. C. Mita, K. Sankhala, J. Sarantopoulos, J. Carmona, S. Okuno, S. Goel, R. Chugh, M. C. Coffey, K. Mettinger, M. M. Mita
Journal: Journal of Clinical Oncology (2009)

10524 Background: Reolysin is a Dearing strain, naturally occurring, ubiquitous human reovirus. The PKR (double stranded RNA-activated protein kinase) is inhibited and therefore the virus replicates specifically in transformed cells possessing an activated Ras pathway producing lysis. In vitro and in vivo studies with Reolysin in sarcoma cell lines revealed significant antitumor activity. Methods: This phase II open-label, single agent study was designed to characterize the efficacy and safety of Reolysin given IV every 28 days in patients (pts) with bone or soft tissue sarcoma with lung metastasis using a Simon two-stage design. 38 pts were accrued to the first stage. If 1 or more pts experience clinical benefit (prolonged SD &gt; 6 months, partial or complete response) up to 52 pts could be accrued. The agent will be considered active if 3 or more responses or prolonged SD are observed. Results: Since July 2007, 43 pts age 19–76 (median 49) were enrolled (20 female) and received a total of 141 cycles (range 1–18). All pts had performance status 1 (29 pts) or 0 (14 pts). 38 pts received prior chemotherapy, radiotherapy, biological agents or combinations for their metastatic disease, 15 pts received more than 3 chemotherapy regimens. The sarcoma subtypes included: synovial sarcoma (13 pts), osteosarcoma (7 pts), leiomyosarcoma (7 pts), MFH (5 pts), Ewing/PNET (1 pt), chordoma (1 pt), others (9 pts). Side effects were mild to moderate (grade 1–2) and included constitutional symptoms fever, chills, fatigue. Two pts experienced respiratory side effects (cough and dyspnea) and 2 pts had diarrhea. Hematological side effects included grade 2–3 neutropenia (6 pts) and grade 2 thrombocytopenia (2 pts). One patient experienced grade 2 AST elevation. 33 pts are evaluable for response to date: 14 pts (42%) had SD for 2+ months including 5 pts having SD for more than 6 months. Conclusions: Utilization of single agent reovirus for treatment of sarcoma is a novel and unique therapeutic approach to date. Reolysin is well tolerated and shows promise for the treatment of metastatic sarcoma. Primary efficacy goals have been met. Accrual is ongoing to a total of 52 pts. [Table: see text]
Critical roles of mTORC1 signaling and metabolic reprogramming for M-CSF–mediated myelopoiesis
Authors: Peer W.F. Karmaus, Andrés A. Herrada, Cliff Guy, Geoffrey Neale, Yogesh Dhungana, Lingyun Long, Peter Vogel, Julian Avila, Clary B. Clish, Hongbo Chi
Journal: The Journal of Experimental Medicine (2017)

Myelopoiesis is necessary for the generation of mature myeloid cells during homeostatic turnover and immunological insults; however, the metabolic requirements for this process remain poorly defined. Here, we demonstrate that myelopoiesis, including monocyte and macrophage differentiation, requires mechanistic target of rapamycin complex 1 (mTORC1) signaling and anabolic metabolism. Loss of mTORC1 impaired myelopoiesis under steady state and dampened innate immune responses against Listeria monocytogenes infection. Stimulation of hematopoietic progenitors with macrophage colony-stimulating factor (M-CSF) resulted in mTORC1-dependent anabolic metabolism, which in turn promoted expression of M-CSF receptor and transcription factors PU.1 and IRF8, thereby constituting a feed-forward loop for myelopoiesis. Mechanistically, mTORC1 engaged glucose metabolism and initiated a transcriptional program involving Myc activation and sterol biosynthesis after M-CSF stimulation. Perturbation of glucose metabolism or disruption of Myc function or sterol biosynthesis impaired myeloid differentiation. Integrative metabolomic and genomic profiling further identified one-carbon metabolism as a central node in mTORC1-dependent myelopoiesis. Therefore, the interplay between mTORC1 signaling and metabolic reprogramming underlies M-CSF-induced myelopoiesis.
Reply: Involuntary Smoking and Lung Cancer—Some Object Lessons
Authors: L. Garfinkel, L. Joubert, O. Auerbach
Journal: JNCI Journal of the National Cancer Institute (1986)

Reply: Involuntary Smoking and Lung Cancer—Some Object Lessons Get access L. Garfinkel, L. Garfinkel American Cancer Society, 4 West 35th Street, New York, New York 10001 Search for other works by this author on: Oxford Academic PubMed Google Scholar L. Joubert, L. Joubert American Cancer Society, 4 West 35th Street, New York, New York 10001 Search for other works by this author on: Oxford Academic PubMed Google Scholar O. Auerbach O. Auerbach Veterans Administration, Medical Center, East Orange, New Jersey 07019 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 76, Issue 6, June 1986, Page 1263, https://doi.org/10.1093/jnci/76.6.1263 Published: 01 June 1986
PREVENTIVE EFFECT OF AN ATHLETICS INJURY PREVENTION PROGRAM ON INJURY COMPLAINTS WITH DECREASED PARTICIPATION IN ATHLETICS: A PILOT PROSPECTIVE COHORT STUDY
Authors: Pascal EDOUARD, Emmanuelle CUGY, Romain DOLIN, Nicolas MOREL, Kathrin STEFFEN
Journal: British Journal of Sports Medicine (2017)

Background Athletics practice leads risk of injuries with negative consequences on participation. It is therefore important to develop and validate strategies to prevent it. Objective To determine whether an Athletics Injury Prevention Program (AIPP), targeting the most common athletic injury types (hamstring strain, achilles and patellar tendinopathy, low back pain, ankle sprain), can reduce the occurrence of injury complaints with decreased participation (IC) related to athletics practice. Design Prospective cohort study. Setting Regional- to international-level athletics athletes. Participants A total of 63 athletes, with ≥75% of response rate to a questionnaire with weekly follow-up on AIPP adherence and IC, during one athletics season (43 weeks). Interventions An 8-exercise AIPP, addressing core stability, hamstrings and leg eccentric muscle strengthening and stretching, pelvis balance and stabilizing work. Main Outcome Measurements Adherence to AIPP, incidence of IC and prevalence of weeks with IC. Relative risks (RR) with 95% CI between two groups: “AIPP+” corresponding to athletes executing AIPP≥1/week vs. “AIPP-” corresponding to athletes performing AIPP&lt;1/week. Results At short term (12 weeks, n=63 athletes), there was a significant lower incidence of IC in AIPP+ (n=33; 1.5±0.6 AIPP/week) compared to AIPP- (n=30; 0.5±0.3 AIPP/week) (6.1±2.8 vs. 11.3±4.0 IC per 1000 hours of practice; RR=0.53, 95% CI: 0.30–0.95). At long term (40 weeks, n=40 athletes), there were i) a significant reduction in number of weeks with IC in AIPP+ (n=11; 1.4±0.6 AIPP/week) compared to AIPP− (n=27; 0.6±0.3 AIPP/week) (8.0% vs. 16.4%; RR=0.49, 95% CI: 0.34–0.70), and ii) a significant lower incidence of hamstring IC in AIPP+ compared to AIPP− (1.3±1.3 vs. 2.6±1.2 IC per 1000 hours of practice; RR=0.13, 95% CI: 0.02–0.97). Conclusions An 8-exercise prevention program, based on a scientific evidence and performed more than once a week, resulted in a protective effect on injury complaints with decreased sport participation at both short and long term.
Is Weekend-Only Physical Activity Enough to Compensate for a Sedentary Lifestyle?—Reply
Authors: Gary O’Donovan, Mark Hamer, Emmanuel Stamatakis
Journal: JAMA Internal Medicine (2017)

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Epstein Barr virus, abdominal pain, and jaundice
Authors: Alexandra Khoury, Francois Porté, Masud Haq
Journal: BMJ (2017)

A 22 year old man presented to the emergency department with abdominal pain, jaundice, itching, and fever. His urine was dark and stools pale.

His temperature was 38.7°C and he was icteric with abdominal tenderness, worst in the right upper quadrant with a negative Murphy’s sign. The gall bladder was impalpable. The oropharynx was inflamed with cervical and axillary lymphadenopathy.

Liver function tests (alkaline phosphatase 327, aspartate aminotransferase 358, bilirubin 109) suggested cholestasis. White cell count was high (20.8) and c reactive protein raised (17). Platelets were low (168). Monospot test was positive (Epstein Barr virus), confirmed by positive Epstein Barr virus serology. Hepatitis A, B, and C serology were negative.

Ultrasound revealed splenomegaly with normal hepatopetal flow and a markedly thickened (10 mm) gallbladder wall but no gallstones or sludge (fig 1⇓). The common bile duct was not dilated.



Fig 1  Ultrasound image showing a markedly thickened gallbladder (arrows); no stones visible





### 1. What is the most likely diagnosis?

#### Short answer

Acute acalculous cholecystitis secondary to infectious mononucleosis is the most likely diagnosis in view of the history, blood tests, and ultrasound findings.

#### Discussion

Ultrasound features were consistent with acute acalculous cholecystitis in the absence of gallstones, with marked …
Phase Ib study evaluating safety and pharmacokinetics (PK) of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 monohydrate (LY) when combined with chemoradiotherapy in newly diagnosed malignant gliomas.
Authors: Cristina Suarez, Jordi Rodon, Annick Desjardins, Peter A. J. Forsyth, Ivelina Gueorguieva, Ann Cleverly, Tiana Burkholder, Durisala Desaiah, Michael M. F. Lahn, Wolfgang Wick
Journal: Journal of Clinical Oncology (2013)

2039 Background: Based on preclinical data suggesting an additive antitumor effect of combining TGF-ß inhibitors with temozolomide based chemoradiation (TMZ/RT), a Phase 1b study was initiated to evaluate the safety and PK of LY combined with TMZ/RT in patients with newly diagnosed glioma. Methods: LY was evaluated sequentially in 2 doses (160 mg/day and 300 mg/day) combined with TMZ/RT. TMZ/RT was administered as approved and LY given as intermittent dosing (14 days on/14 days off=1 cycle). Toxicity was assessed using the CTCAE, version 4. The PK profile of LY in combination with TMZ/RT was determined. Results: 19 patients with glioma (16 World Health Organization Grade 4; 3 Grade 3 were treated with LY (160 mg/day, n=10; 300 mg/day, n=9) and TMZ. The median number of cycles was 5 (range 1-13). Regardless of relatedness to study treatment, the following treatment-emergent adverse events (TEAEs) were observed in ≥25% of patients: nausea (n=11), fatigue (n=11), thrombocytopenia (n=11), headache (n=9), vomiting (n=8), lymphopenia (n=6), anorexia (n=6), constipation (n=5), radiation skin injury (n=5), and alopecia (n=5). The following TEAEs were related specifically to at least LY: thrombocytopenia (n=3, 2 Gr 3 and 1 Gr 4), fatigue (n=2), maculopapular rash (n=2, Gr 3), dermatitis acne form (n=3, 1 Gr 3) and in 1 patient each: nausea, vomiting, hypertension, hypersensitivity and leucopenia (Gr 4). No change in the PK profile of LY was shown when LY was combined with TMZ/RT. In the combination therapy, area under the curve (0-∞) at steady state was observed geomean (%CV) to be 5.5 (48%) mg*h/L following 300 mg/day (n=9). Following monotherapy with LY, these exposures were similar with a median (20 th -80 th percentiles) of 4.7 (2.5-8.8) mg*h/L (n=37). Conclusions: No dose-limiting toxicities and no clinically meaningful cardiotoxicities were observed; hence, the treatment of LY at 300 mg/day in combination with standard chemoradiation has a manageable toxicity profile. A Phase 2a trial has been initiated to relate the pharmacodynamic effects with overall survival. Clinical trial information: NCT01220271.
Abstract 11847: Remote Ischemic Conditioning by Single Cuff Inflation Improves Aortic Elastic Properties and Endothelial Glycocalyx Thickness in Acute Myocardial Infarction Patients
Authors: Ignatios Ikonomidis, Dimitrios Vlastos, Ioanna Andreadou, Panagiotis Efentakis, Maria Varoudi, George Pavlidis, George Makavos, Stefanos Vlachos, Dimitrios Mpenas, Helen Triantafyllidi, Eleni Seitanidi, Efstathios K Iliodromitis, John Lekakis
Journal: Circulation (2016)

Background: Remote ischemic conditioning attenuates ischemia-reperfusion injury in patients with STEMI. However, its effects on vascular function and biochemical mechanisms are not fully defined. Methods: We examined 110 patients with STEMI and 30 healthy controls. Patients were randomised in 2 remote ischemic conditioning protocols after a baseline assessment of vascular function (T0), a) one with two ischemic conditioning stimuli by brachial cuff inflation of both arms at 200mmHg for 5 min, separated by 15min, and each followed by vascular assessment (T1,T2), and a final vascular assessment (T3), 25 min after 2nd cuff deflation (double cuff inlation,n=60 ) or b) a second with omission of the second cuff inflation (single cuff inflation-n=50).In both protocols we measured a) the carotid-femoral pulse wave velocity (PWV);b)perfusion boundary region (PBR- micrometers) of the sublingual arterial microvessels as a marker of endothelial glycocalyx thickness;c) plasma malondialdehyde (MDA),NOx, and IL-6 levels as biomarkers of oxidative stress and inflammation. Results: The single cuff inflation protocol resulted in a more uniform aortic elasticity improvement (PWV T0: 12.09m/s, T1:11.74m/s, T2:11.59m/s, T3:11.81m/s),with the greatest difference measured at the last vascular assessment (T3: PWV= 11.8 single cuff vs 13.8 m/s double cuff inflation,p&lt;0.05).A greater glycocalyx integrity restoration was observed in patients with baseline PBR&gt; 2.1 in both protocols (mean difference in PBR improvement=0.5 at T1, p&lt;0.001).Conversely,in healthy controls, PWV and PBR remained unchanged throughout the study (p&gt;0.05).MDA was significantly reduced at T3 compared to baseline in STEMI(2.1 ± 0.15 at T3 vs 2.59 ±0.15 at T0, p&lt; 0.001) in both protocols while it remained unchanged in healthy controls. Additionally, the single cuff inflation protocol promoted a greater increase in NOx levels compared to the double inflation protocol (T0: 8.25± 1.18 to T3: 11.1 ± 2 μμ vs T0: 10.79± 1.18 to T3: 8.91±2 μμ, p&lt; 0.05). IL-6 levels were unaffected. Conclusion: Remote ischemic conditioning by a single 5-min cuff inflation, confers acute short-term improvement of vascular function, likely through oxidative stress reduction and nitrate- nitrite- NO pathway activation.