tbuckley/cabot-search huggingface dataset:
TMOD-04. DETERMINING THE NEUROANATOMICAL AND CELLULAR ORIGIN OF BRAFV600E MUTANT CDKN2A DELETED GLIOMAS AND MECHANISMS OF TRANSFORMATION BY BRAFV600E EXPRESSION IN TRANSGENIC MICE
Authors: Sista Sugiarto, Robin G Lerner, Brian Reichholf, Martin McMahon, Charles David James, Claudia K Petritsch
Journal: Neuro-Oncology (2019)

Expression of the constitutively active BRAFV600E-mutant kinase occurs in pediatric and predominantly young adult high-grade glioma patients (Cancer Res. 2010, 70:512; Acta Neuropathol. 2011, 121:397). BRAFV600E expression frequently coincides with CDKN2A deletion and marks a subgroup of predominantly hemispheric tumors with epigenetic similarities to pleomorphic xanthastrocytoma (PXA) and histologic features of grade IV astrocytoma (Cancer Cell 2018, 33:829). The origin of BRAFV600E mutant astrocytoma is under investigation. Here, we are using transgenic mice to assess neuroanatomical aspects and effects on differentiation of BRAFV600E expression. In previous studies, expression of BRAFV600E in astroglial cells and neural stem cells of the developing brain led to hyperplasia in transgenic mice. To circumvent the early postnatal lethality associated with BRAFV600E expression during development, my lab injected adenovirus expressing Cre recombinase into the corpus callosum of BRAFCA Ink4a/Arf floxed young adult mice. In these mice, Cre expression induces BRAFV600E expression and deletion of Ink4a/Arf, the mouse locus homologous to human CDKN2A. This approach showed that BRAFV600E expression and CDKN2A (Ink4a/Arf) deficient corpus callosum cells form high-grade astrocytoma-like tumors in young adult mice (Proc Natl Acad Sci. 2012, 109:8710). To further investigate the neuroanatomical aspects of tumor formation we directed cre expression to distinct neuroanatomical areas, including the cortex, of the young adult mouse brain. Histo-pathologic and survival analyses showed that each injected area was susceptible to tumor formation albeit with different latency. Induction of BRAFV600E expression in Ink4a/Arf-deleted neurospheres in vitro decreased the capacity for neuronal and glial differentiation and led to expansion of oligodendrocyte progenitor-like cells (OPC). Ongoing studies investigate directly the extent to which BRAFV600E expression in Ink4a/Arf-deleted OPC in transgenic mice cause tumor formation. Results from cell of origin studies are expected to inform which mouse model most faithfully recapitulates the human diseases.
Diagnostic Performance of Creatinine-Based Equations for Estimating Glomerular Filtration Rate in Adults 65 Years and Older
Authors: Luciano da Silva Selistre, Dener L. Rech, Vandréa de Souza, Jean Iwaz, Sandrine Lemoine, Laurence Dubourg
Journal: JAMA Internal Medicine (2019)

Estimating glomerular filtration rate (GFR) is useful in many clinical conditions. However, very few studies have evaluated the performance of GFR-estimating equations in older adults at various degrees of kidney impairment.To determine the performance of plasma-creatinine-based equations Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI), Lund-Malmö Revised, (LMR), full age spectrum (FAS), and Berlin Initiative Study (BIS) 1 in older adults across a broad spectrum of GFRs.Single-center cross-sectional study performed in France including 2247 participants aged 65 to 90 years who underwent inulin GFR measurements from July 1, 2003, to July 30, 2017, for suspected or established renal dysfunction, for renal risk, before kidney donation, or after kidney transplant.The main outcome measure was GRF measured by inulin clearance. Equation performance criteria considered bias (difference between estimated and measured GFR), precision (interquartile range of the median difference), and accuracy P30 (percentage of estimated GFRs lying between [measured GFR - 30% of measured GFR] and [measured GFR + 30% of measured GFR]).The mean (SD) age of the 2247 participants was 71.5 (5) years and 1192 (53.0%) were male. The difference in median (95% CI) bias was significant between CKD-EPI vs LMR (-4.0 [-4.0 to -3.5 mL/min/1.73 m2; P < .001]) and CKD-EPI vs FAS (-2.0 [-3.5 to -2.5] mL/min/1.73 m2, P < .001) but not significant between CKD-EPI vs BIS 1 (0.0 [-1.5 to 0.5], P = .07, Mood test). In patients aged 65 to 74 years with measured GFR<45 mL/min/1.73 m2, the difference in median P30 (95% CI) was not significant between CKD-EPI vs LMR (P = .08) and CKD-EPI vs FAS (P = .48) but significant vs BIS 1 (P = .004, McNemar test). In subjects 75 years and older, with measured GFR less than 45 mL/min/1.73 m2, LMR and BIS 1 were more accurate than CKD-EPI and FAS (P30 = 74.5 [70.0-79.5] and 73.0 [68.0-78.0] vs 69.0 [64.5-74.0] and 69.0 [65.5-72.0]). In all patients, despite small statistical differences, the performance of CKD-EPI equation was not clinically different from that of LMR, FAS, or BIS 1.In a referral group of patients 65 years and older who had GFR estimated using CDK-EPI, LMR, BIS 1, and FAS equations, a comparison with renal inulin clearance found that none of the equations had a superior diagnostic performance. Each had limitations regarding accuracy.
Immune response in malignant ascites from a melanoma patient treated with anti-CTLA-4 mAb
Authors: Helena Harlin, Amy C. Peterson, Thomas F. Gajewski
Journal: Cancer Research (2004)

708  Generating an efficient T cell anti-tumor response resulting in clearance of tumor is the goal of immunotherapy strategies. For this to occur, tumor antigen-specific T cells need to become activated, traffic to the tumor site, recognize the tumor, and perform their effector function. We have studied an unusual patient with metastatic melanoma who developed large volume ascites after anti-CTLA-4 antibody therapy. By cytologic analysis and real-time RT-PCR for melanoma antigens, it was clear that the ascites contained tumor cells. In addition, large numbers of lymphocytes were present in the fluid, which by flow cytometric analysis were predominantly T cells and NK cells. A substantially greater percentage of activated T cells was present in the ascites compared to peripheral blood, and these cells produced high levels of effector cytokines after short-term activation with PMA + ionomycin in vitro. Peptide/HLA-A2 tetramer staining revealed significant numbers of CD8+ T cells specific for peptides derived from melanoma antigens Melan-A and NA17-A, but also from EBV, arguing that activated T cells regardless of specificity were preferentially recruited into the peritoneal space. Upon in vitro restimulation of ascites cells with Melan-A, NA17-A and EBV peptides, only EBV peptide resulted in IFN-γ production as measured by ELISpot. The discrepancy between tetramer staining and ELISpot data might suggest induction of a hyporesponsive state among the tumor antigen-specific T cells in the patient. To infer the mechanism of vast lymphocyte recruitment into the ascites, a cytokine protein array that detects 79 independent factors was utilized. Multiple chemokines were detected, including IP-10, MIP-1β, MCP-1, IL-8, CCL18, and eotaxin-2. Of note, no T cell-specific cytokines were detected, and IL-10 was present. Our results suggest that malignant melanoma cells in the peritoneum of this patient established an environment rich in chemokines that recruited large number of lymphocytes yet failed to support productive activation of anti-tumor T cells.
Correction: Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer
Authors: Valerie M. Jansen, Neil E. Bhola, Joshua A. Bauer, Luigi Formisano, Kyung-Min Lee, Katherine E. Hutchinson, Agnieszka K. Witkiewicz, Preston D. Moore, Mónica Valéria Estrada, Violeta Sánchez, Paula G. Ericsson, Melinda E. Sanders, Paula R. Pohlmann, Michael J. Pishvaian, David A. Riddle, Teresa C. Dugger, Wenyi Wei, Erik S. Knudsen, Carlos L. Arteaga
Journal: Cancer Research (2019)
Revision surgery after endoscopic sutured gastroplasty
Authors: Jagtap Nitin, Kalapala Rakesh, D. Nageshwar Reddy
Journal: Endoscopy (2019)

Letter to: Endoscopic gastric reduction with an endoluminal suturing device: a multicenter prospective trial with 1-year follow-upEndoscopy 2018; 50(12): 1156-1162DOI: 10.1055/a-0630-1224
Peanut immunotherapy increases allergic and anaphylactic reactions, finds review
Authors: Susan Mayor
Journal: BMJ (2019)

Oral immunotherapy for peanut allergy, in which patients are exposed to gradually increasing doses of allergen over time, increases the risk of allergic and anaphylactic reactions despite inducing desensitisation, a review has found.1

“Our study synthesises all randomised clinical trials comparing peanut oral immunotherapy with no immunotherapy,” said lead author Derek Chu, from McMaster University, Hamilton, Canada.

“It shows that current peanut oral immunotherapy regimens can achieve the immunological goal of desensitisation, but that this outcome does not translate into less allergic reactions and anaphylaxis over time. Instead, the opposite occurs, with more allergic and adverse reactions with oral immunotherapy compared with avoidance or placebo.”

Peanut allergy is common, affecting 2% of children and 1% of adults in high income countries, …
Serotonin Receptor 1A Variation Is Associated with Anxiety and Agonistic Behavior in Chimpanzees
Authors: Nicky Staes, Chet C Sherwood, Hani Freeman, Sarah F Brosnan, Steven J Schapiro, William D Hopkins, Brenda J Bradley
Journal: Molecular Biology and Evolution (2019)

Serotonin is a neurotransmitter that plays an important role in regulating behavior and personality in humans and other mammals. Polymorphisms in genes coding for the serotonin receptor subtype 1A (HTR1A), the serotonin transporter (SLC6A4), and the serotonin degrading enzyme monoamine oxidase A (MAOA) are associated with anxiety, impulsivity, and neurotic personality in humans. In primates, previous research has largely focused on SLC6A4 and MAOA, with few studies investigating the role of HTR1A polymorphic variation on behavior. Here, we examined variation in the coding region of HTR1A across apes, and genotyped polymorphic coding variation in a sample of 214 chimpanzees with matched measures of personality and behavior. We found evidence for positive selection at three amino acid substitution sites, one in chimpanzees-bonobos (Thr26Ser), one in humans (Phe33Val), and one in orangutans (Ala274Gly). Investigation of the HTR1A coding region in chimpanzees revealed a polymorphic site, where a C/A single nucleotide polymorphism changes a proline to a glutamine in the amino acid sequence (Pro248Gln). The substitution is located in the third intracellular loop of the receptor, a region important for serotonin signal transduction. The derived variant is the major allele in this population (frequency 0.67), and is associated with a reduction in anxiety, decreased rates of male agonistic behavior, and an increase in socio-positive behavior. These results are the first evidence that the HTR1A gene may be involved in regulating social behavior in chimpanzees and encourage further systematic investigation of polymorphic variation in other primate populations with corresponding data on behavior.
Needle-based confocal laser endomicroscopy for real-time diagnosing and staging of lung cancer
Authors: Lizzy Wijmans, Joey Yared, Daniel M. de Bruin, Sybren L. Meijer, Paul Baas, Peter I. Bonta, Jouke T. Annema
Journal: European Respiratory Journal (2019)

Diagnosing lung cancer in the absence of endobronchial abnormalities is challenging. Needle-based confocal laser endomicroscopy (nCLE) enables real-time microscopic imaging of cells. We assessed the feasibility and safety of using nCLE for real-time identification of lung cancer. In patients with suspected or proven lung cancer scheduled for endoscopic ultrasound (EUS), lung tumours and mediastinal lymph nodes were imaged with nCLE before fine-needle aspiration (FNA) was performed. nCLE lung cancer characteristics were identified by comparison with pathology. Multiple blinded raters validated CLE videos of lung tumours and mediastinal nodes twice. EUS-nCLE-FNA was performed in 22 patients with suspected or proven lung cancer in whom 27 lesions (six tumours, 21 mediastinal nodes) were evaluated without complications. Three nCLE lung cancer criteria (dark enlarged pleomorphic cells, dark clumps and directional streaming) were identified. The accuracy of nCLE imaging for detecting malignancy was 90% in tumours and 89% in metastatic lymph nodes. Both inter-observer agreement (mean κ=0.68, 95% CI 0.66–0.70) and intra-observer agreement (mean± sd κ=0.70±0.15) were substantial. Real-time lung cancer detection by endosonography-guided nCLE was feasible and safe. Lung cancer characteristics were accurately recognised.
Increase in Measles Cases — United States, January 1–April 26, 2019
Authors: Manisha Patel, Adria D. Lee, Susan B. Redd, Nakia S. Clemmons, Rebecca J. McNall, Amanda C. Cohn, Paul A. Gastañaduy
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

As of April 26, 2019, CDC had reported 704 cases of measles in the United States since the beginning of 2019, representing the largest number of cases reported in the country in a single year since 1994, when 963 cases occurred, and since measles was declared eliminated* in 2000 (1,2). Measles is a highly contagious, acute viral illness characterized by fever and a maculopapular rash; complications include pneumonia, encephalitis, and death. Among the 704 cases, 503 (71%) were in unvaccinated persons and 689 (98%) occurred in U.S. residents. Overall, 66 (9%) patients were hospitalized. Thirteen outbreaks have been reported in 2019, accounting for 663 cases, 94% of all reported cases. Six of the 13 outbreaks were associated with underimmunized close-knit communities and accounted for 88% of all cases. High 2-dose measles vaccination coverage in the United States has been critical to limiting transmission (3). However, increased global measles activity poses a risk to U.S. elimination, particularly when unvaccinated travelers acquire measles abroad and return to communities with low vaccination rates (4). Health care providers should ensure persons are up to date with measles, mumps, rubella (MMR) vaccine, including before international travel, and rapidly report all suspected cases of measles to public health authorities.
Surgical‐site infections after full‐thickness skin grafting
Authors: J. Palmgren, J. Paoli, A. Schmidtchen, K. Saleh
Journal: British Journal of Dermatology (2019)

The authors of this paper from Sweden note that there are more than 30 definitions of surgical site infection (SSI, or post‐operative infection), and that even the most widely used is open to interpretation. To look at consistency in diagnosing SSI, they sent eight standardised photographs to dermatologists around the world. Each photograph showed a patient one week after a skin graft on the face, and in each case the dermatologists were asked if they thought the wound looked infected. (The investigators first assessed the photographs themselves, using a scoring system to explain why an SSI might be suspected.) At the time of photography, no patient had pain, heat, or pus coming from the wound. All wounds were also assessed in person by the same investigator and swabbed to see if bacteria could be grown. There were 393 responses from 27 countries. The degree of agreement as to whether the photographs showed an SSI was only slight. Three wounds were interpreted as infected by 70%, 65% and 33% of responders, respectively, and these were the same three that were assessed as infected by the investigator in person. Fewer than 25% of responders thought the other five wounds were infected. The feature that made most responders diagnose infection was redness. The dermatologist responders were also asked how they would manage an SSI. Topical antibiotics were favoured by 14%, even though evidence for effectiveness is lacking. The authors conclude that diagnosing SSI is difficult using current guidance, at least when examining photographs.
Burden of Coronary Artery Disease as a Cause of Sudden Cardiac Arrest in the Young
Authors: Victor Waldmann, Nicole Karam, Wulfran Bougouin, Ardalan Sharifzadehgan, Florence Dumas, Kumar Narayanan, Christian Spaulding, Alain Cariou, Xavier Jouven, Eloi Marijon
Journal: Journal of the American College of Cardiology (2019)
Abstract 12451: Achievement of Weight Loss With Hypertension Control Among Adults With Incident Hypertension
Authors: Heather M Johnson, Christie M Bartels, Carolyn T Thorpe, Nancy Pandhi, Elizabeth A Jacobs, Maureen A Smith
Journal: Circulation (2014)

Background: Being overweight or obese independently contributes to the development of target organ damage among adults with hypertension. Weight loss and hypertension control are critical to reduce morbidity in this population. The purpose of this study is to evaluate rates and predictors of weight loss among adults with incident hypertension who achieve hypertension control. Methods: We conducted an analysis of overweight or obese ≥18 year-olds with incident hypertension receiving regular primary care in a large, academic group practice from 2008-2011. Patients with a previous hypertension diagnosis or antihypertensive prescription were excluded. Patients (n=4,913) were followed until hypertension control. Patients were classified by body mass index (BMI) at baseline as overweight or class I, II, or III obese. Weight was assessed at study entry and within 30 days of achieving hypertension control. Kaplan-Meier analysis estimated the probability of any weight loss (≥2.0 kg). Cox proportional-hazard models (HR; 95% CI) were fit to identify predictors of weight loss at the time of hypertension control. Results: Patients were followed a mean 12.4 (SD 10.3) months. Overall, 32% (n=1,567) had ≥2.0 kg weight loss at the time of hypertension control, almost half (n=718) lost ≥5.0 kg. Patients with lower BMI at study entry had lower weight loss rates at the time of hypertension control. Compared to class III obese (BMI ≥40 kg/m2), overweight patients had a 37% lower rate of losing &gt;2.0 kg (HR: 0.63; 0.55-0.73), class I obese had 27% lower rates (HR: 0.73; 0.64-0.85) and class II obese had 16% lower rates (HR 0.84; 0.71-0.98). Middle-aged adults (40-59 years old) had 27% lower weight loss (HR 0.83; 0.73-0.94) compared to ≥60 year-olds. Females (HR: 0.90; 0.81-0.99), patients with higher health care utilization (HR 0.86; 0.75-0.99), and Stage 1 hypertension (HR: 0.87; 0.77-0.98) had lower weight loss rates. Socioeconomic and provider factors did not predict weight loss. Conclusions: Among overweight and obese patients that achieved hypertension control, only 32% had ≥2.0 kg weight loss and 15% achieved ≥5.0 kg weight loss. Effective weight loss interventions are needed to maintain hypertension control and decrease target organ damage in this population.
Liraglutide in Children and Adolescents with Type 2 Diabetes
Authors: William V. Tamborlane, Margarita Barrientos-Pérez, Udi Fainberg, Helle Frimer-Larsen, Mona Hafez, Paula M. Hale, Muhammad Y. Jalaludin, Margarita Kovarenko, Ingrid Libman, Jane L. Lynch, Paturi Rao, Naim Shehadeh, Serap Turan, Daniel Weghuber, Timothy Barrett
Journal: New England Journal of Medicine (2019)

Metformin is the regulatory-approved treatment of choice for most youth with type 2 diabetes early in the disease. However, early loss of glycemic control has been observed with metformin monotherapy. Whether liraglutide added to metformin (with or without basal insulin treatment) is safe and effective in youth with type 2 diabetes is unknown.
Obituary: Peter Ormerod
Authors: Nigel Horsfield
Journal: Thorax (2019)

Peter Ormerod has died at the age of 68. A past president of the British Thoracic Society (BTS), his research helped define drug treatment, public health measures and a national strategy to reduce tuberculosis (TB) in the UK. These guidelines adopted nationally were also regarded internationally as the definitive standards. Given that he was working as a general physician in a busy district general hospital (Blackburn Royal Infirmary, later the Royal Blackburn Hospital), his achievements were quite remarkable.

Lawrence Peter Ormerod was born in Rossendale, Lancashire on 28 August 1950, the oldest of three sons of Milton and Dorothy Ormerod. He attended Bacup and Rawtenstall Grammar School where his father taught chemistry.

He attended the University of Manchester Medical School and graduated with an intercalated BSc in Pharmacology and MB ChB with honours in 1974. After training posts in Manchester, he passed the MRCP examination in April 1977 and then worked at East Birmingham Hospital for a year. He returned to Manchester as a senior …
THER-17. BRAF-V600E DEGRADATION AS A THERAPEUTIC STRATEGY IN BRAF-V600E MUTANT GLIOMAS
Authors: Guisheng Zhao, Daniel Muldoon, Xiulei Mo, Cong Tang, Haian Fu, W Clay Gustafson, William A Weiss, Theodore Nicolaides
Journal: Neuro-Oncology (2019)

INTRODUCTION: Oncogenic, driver BRAF-V600E mutations are frequently found in pediatric gliomas. While small molecule inhibitors of BRAF and/or MEK kinases are showing early clinical efficacy against these tumors, no experimental strategies thus far have focused on the degradation of the mutant BRAF protein itself. Members of our team have recently discovered that in contrast to wildtype BRAF protein, BRAF-V600E protein binds to aurora kinase A. We therefore hypothesized that CD532, a novel small molecule allosteric aurora kinase A inhibitor, would preferentially degrade BRAF-V600E over wildtype BRAF, and lead to decreased cell growth in BRAF-V600E gliomas. METHODS: We used an isogenic system of 3T3 fibroblasts transduced with empty vector, wildtype BRAF, KIAA1549:BRAF fusion, and BRAF-V600E, as well as established glioma cell lines AM38 (BRAF-V600E homozygous), DBTRG (BRAF-V600E heterozygous), U87 (BRAF wildtype), LN229 (BRAF wildtype with NF1 deficiency) and immortalized normal human astrocytes (NHA, BRAF wildtype). We performed cell cycle and viability assays, as well as immunoblot analyses for wildtype BRAF and BRAF-V600E. Cells were treated with CD532 at doses of 0.5 and 1 uM. RESULTS: The OncoPPi network mapping revealed that aurora kinase A binds to only BRAF-V600E but not wildtype BRAF protein. BRAF-V600E mutant cell lines showed a dramatic decrease in BRAF-V600E expression level after CD532 treatment. This was accompanied by a significant decrease in growth rate. Cells containing only wildtype BRAF or KIAA1549:BRAF did not show any changes in BRAF expression and had less inhibited growth after treatment with CD532. CONCLUSIONS: Degradation of BRAF-V600E mutant protein through inhibition of aurora kinase A shows preclinical efficacy against BRAF –V600e gliomas.