tbuckley/cabot-search huggingface dataset:
Inositol Trisphosphate Receptor Type 3-mediated Enhancement of EGFR and MET Cotargeting Efficacy in Non–Small Cell Lung Cancer Detected by 18F-fluorothymidine
Authors: Francesca Iommelli, Viviana De Rosa, Cristina Terlizzi, Marcello Monti, Mariarosaria Panico, Rosa Fonti, Silvana Del Vecchio
Journal: Clinical Cancer Research (2018)

Purpose: Our aim was to test whether imaging with 18F-fluorothymidine (18F-FLT) PET/CT was able to detect the combined effects of EGFR and MET inhibitors in oncogene-driven non-small cell lung cancer (NSCLC) and to elucidate the mechanisms underlying the enhanced efficacy of drug combination.Experimental Design: NSCLC cells bearing MET amplification (H1993 and H820) were treated with EGFR and MET inhibitors either alone or in combination and then tested for cell viability and inhibition of signaling. Nude mice bearing H1993 tumors underwent 18F-FLT PET/CT scan before and after treatment with erlotinib and crizotinib alone or in combination (1:1 ratio) and posttreatment changes of 18F-FLT uptake in tumors were determined. The role of inositol trisphosphate receptor type 3 (IP3R3) in mediating the combined action of EGFR and MET inhibitors was tested by transfecting NSCLC cells with IP3R3-targeted siRNA.Results: Imaging studies showed a significant reduction of 18F-FLT uptake in response to combined treatment with EGFR and MET inhibitors that was higher than that obtained with single agents (ANOVA, F-ratio = 6.215, P = 0.001). Imaging findings were confirmed by analysis of surgically excised tumors. Levels of IP3R3 were significantly reduced in both cells and tumors after treatment with crizotinib, whereas EGFR inhibitors caused a reduction of IP3R3 interaction with K-Ras mainly through dephosphorylation of serine residues of K-Ras.Conclusions: Our findings indicate that 18F-FLT PET/CT is able to detect the enhanced efficacy of EGFR and MET inhibitors in oncogene-driven NSCLC and that such enhancement is mediated by IP3R3 through its interaction with K-Ras. Clin Cancer Res; 24(13); 3126-36. ©2018 AACR.
<i>Vital Signs</i>: Containment of Novel Multidrug-Resistant Organisms and Resistance Mechanisms — United States, 2006–2017
Authors: Kate Russell Woodworth, Maroya Spalding Walters, Lindsey M. Weiner, Jonathan Edwards, Allison C. Brown, Jennifer Y. Huang, Sarah Malik, Rachel B. Slayton, Prabasaj Paul, Catherine Capers, Marion A. Kainer, Nancy Wilde, Alicia Shugart, Garrett Mahon, Alexander J. Kallen, Jean Patel, L. Clifford McDonald, Arjun Srinivasan, Michael Craig, Denise M. Cardo
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Approaches to controlling emerging antibiotic resistance in health care settings have evolved over time. When resistance to broad-spectrum antimicrobials mediated by extended-spectrum β-lactamases (ESBLs) arose in the 1980s, targeted interventions to slow spread were not widely promoted. However, when Enterobacteriaceae with carbapenemases that confer resistance to carbapenem antibiotics emerged, directed control efforts were recommended. These distinct approaches could have resulted in differences in spread of these two pathogens. CDC evaluated these possible changes along with initial findings of an enhanced antibiotic resistance detection and control strategy that builds on interventions developed to control carbapenem resistance.Infection data from the National Healthcare Safety Network from 2006-2015 were analyzed to calculate changes in the annual proportion of selected pathogens that were nonsusceptible to extended-spectrum cephalosporins (ESBL phenotype) or resistant to carbapenems (carbapenem-resistant Enterobacteriaceae [CRE]). Testing results for CRE and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are also reported.The percentage of ESBL phenotype Enterobacteriaceae decreased by 2% per year (risk ratio [RR] = 0.98, p<0.001); by comparison, the CRE percentage decreased by 15% per year (RR = 0.85, p<0.01). From January to September 2017, carbapenemase testing was performed for 4,442 CRE and 1,334 CRPA isolates; 32% and 1.9%, respectively, were carbapenemase producers. In response, 1,489 screening tests were performed to identify asymptomatic carriers; 171 (11%) were positive.The proportion of Enterobacteriaceae infections that were CRE remained lower and decreased more over time than the proportion that were ESBL phenotype. This difference might be explained by the more directed control efforts implemented to slow transmission of CRE than those applied for ESBL-producing strains. Increased detection and aggressive early response to emerging antibiotic resistance threats have the potential to slow further spread.
Lung function trajectories from pre-school age to adulthood and their associations with early life factors: a retrospective analysis of three population-based birth cohort studies
Authors: Danielle C M Belgrave, Raquel Granell, Steve W Turner, John A Curtin, Iain E Buchan, Peter N Le Souëf, Angela Simpson, A John Henderson, Adnan Custovic
Journal: The Lancet Respiratory Medicine (2018)
KLRG1+ Effector CD8+ T Cells Lose KLRG1, Differentiate into All Memory T Cell Lineages, and Convey Enhanced Protective Immunity
Authors: Dietmar Herndler-Brandstetter, Harumichi Ishigame, Ryo Shinnakasu, Valerie Plajer, Carmen Stecher, Jun Zhao, Melanie Lietzenmayer, Lina Kroehling, Akiko Takumi, Kohei Kometani, Takeshi Inoue, Yuval Kluger, Susan M. Kaech, Tomohiro Kurosaki, Takaharu Okada, Richard A. Flavell
Journal: Immunity (2018)
Uses of H.P. Acthar Gel in the Clinical Setting—Reply
Authors: Daniel M. Hartung, Dennis N. Bourdette, David M. Cohen
Journal: JAMA Internal Medicine (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Long-term Accuracy of Breast Cancer Risk Assessment Combining Classic Risk Factors and Breast Density
Authors: Adam R. Brentnall, Jack Cuzick, Diana S. M. Buist, Erin J. Aiello Bowles
Journal: JAMA Oncology (2018)

Accurate long-term breast cancer risk assessment for women attending routine screening could help reduce the disease burden and intervention-associated harms by personalizing screening recommendations and preventive interventions.
Role of the impulse oscillometry in the evaluation of tracheal stenosis
Authors: R. Linhas, F. Lima, D. Coutinho, J. Almeida, S. Neves, A. Oliveira, I. Ladeira, R. Lima, S. Campainha, M. Guimarães
Journal: Pulmonology (2018)

Tracheal stenosis is a rare and challenging disease. Bronchoscopy is the gold standard for diagnosis and assessment but brings inherent risks. Spirometry is commonly used to access obstructions but is not always feasible due to patient related factors. We therefore considered impulse oscillometry (IOS) as a non-invasive method to quantify airway obstruction and its potential use for diagnosis and follow-up of tracheal stenosis. Patients with confirmed tracheal stenosis were recruited between January 1st, 2015 and December 31st, 2016. Before bronchoscopy, all subjects underwent IOS and spirometry; for patients submitted to interventional bronchoscopy the same techniques were also performed after the procedure. We assessed the correlation between IOS measurements and airway narrowing as well as between IOS and spirometry values. Twenty-one patients were included. Tracheal narrowing was inversely correlated with X5% (r −0.442, p 0.045) and positively correlated with FEV1/PEF (r 0.467, p 0.033). The stenosis length was inversely correlated with PEF and PEF% (r −0.729, p = 0.001 and r −0.707, p = 0.002, respectively). There was a strong correlation between spirometric and IOS values. We did not find any significant differences between pre- and post-intervention IOS values for patients assessed after interventional bronchoscopy. Our study showed a weak correlation between X5% and tracheal narrowing making it unclear whether IOS can be used for physiological assessment of patients with tracheal stenosis. Stenosis length correlated with PEF making it a potential predictor of successful surgical approach. The correlation between IOS and spirometric values makes IOS a potential alternative in patients with suspected tracheal stenosis who are not able to perform spirometry. Larger scale studies should clarify the role of IOS in this pathology.
Combination anti-Aβ treatment maximizes cognitive recovery and rebalances mTOR signaling in APP mice
Authors: Angie C.A. Chiang, Stephanie W. Fowler, Ricky R. Savjani, Susan G. Hilsenbeck, Clare E. Wallace, John R. Cirrito, Pritam Das, Joanna L. Jankowsky
Journal: The Journal of Experimental Medicine (2018)

Drug development for Alzheimer’s disease has endeavored to lower amyloid β (Aβ) by either blocking production or promoting clearance. The benefit of combining these approaches has been examined in mouse models and shown to improve pathological measures of disease over single treatment; however, the impact on cellular and cognitive functions affected by Aβ has not been tested. We used a controllable APP transgenic mouse model to test whether combining genetic suppression of Aβ production with passive anti-Aβ immunization improved functional outcomes over either treatment alone. Compared with behavior before treatment, arresting further Aβ production (but not passive immunization) was sufficient to stop further decline in spatial learning, working memory, and associative memory, whereas combination treatment reversed each of these impairments. Cognitive improvement coincided with resolution of neuritic dystrophy, restoration of synaptic density surrounding deposits, and reduction of hyperactive mammalian target of rapamycin signaling. Computational modeling corroborated by in vivo microdialysis pointed to the reduction of soluble/exchangeable Aβ as the primary driver of cognitive recovery.
The tangled web of agency
Authors: Alain Pe-Curto, Julien A. Deonna, David Sander
Journal: Behavioral and Brain Sciences (2018)

Abstract We characterize Doris's anti-reflectivist, collaborativist, valuational theory along two dimensions. The first dimension is social entanglement , according to which cognition, agency, and selves are socially embedded. The second dimension is disentanglement , the valuational element of the theory that licenses the anchoring of agency and responsibility in distinct actors. We then present an issue for the account: the problem of bad company .
Mutual Risks of Cutaneous Melanoma and Specific Lymphoid Neoplasms: Second Cancer Occurrence and Survival
Authors: Megan M Herr, Sara J Schonfeld, Graça M Dores, Diana R Withrow, Margaret A Tucker, Rochelle E Curtis, Lindsay M Morton
Journal: JNCI Journal of the National Cancer Institute (2018)

It is unclear whether the established association between cutaneous melanoma (CM) and lymphoid neoplasms (LNs) differs across LN subtypes. This study quantifies risk for developing CM after specific LNs and, conversely, for developing specific LNs after CM, as well as assessing clinical impact.We identified a cohort of Caucasian adults (age 20-83 years) initially diagnosed with CM or LN, as reported to 17 US population-based cancer registries, 2000-2014. Standardized incidence ratios (SIRs) quantified second cancer risk. We assessed impact of second cancer development on risk of all-cause mortality using Cox regression.Among 151 949 one-or-more-year survivors of first primary LN, second primary CM risk was statistically significantly elevated after chronic lymphocytic leukemia/small lymphocytic lymphoma (SIR = 1.96, 95% confidence interval [CI] = 1.74 to 2.21), follicular lymphoma (SIR = 1.32, 95% CI = 1.09 to 1.58), and plasma cell neoplasms (SIR = 1.33, 95% CI = 1.07 to 1.63). Risks for these same subtypes were statistically significantly elevated among 148 336 survivors of first primary CM (SIR = 1.44, 95% CI = 1.25 to 1.66; SIR = 1.47, 95% CI = 1.21 to 1.77; SIR = 1.25, 95% CI = 1.06 to 1.47; respectively). Risk for CM was statistically significantly elevated after diffuse large B-cell lymphoma (SIR = 1.22, 95% CI = 1.02 to 1.45) and Hodgkin lymphoma (SIR = 1.75, 95% CI = 1.33 to 2.26), but the reciprocal relationship was not observed. There were no statistically significant associations between marginal zone lymphoma and CM. Among survivors of most LN subtypes, CM statistically significantly increased risk of death (hazard ratio [HR] range = 1.52, 95% CI = 1.25 to 1.85, to 2.46, 95% CI = 1.45 to 4.16). Among survivors of CM, LN statistically significantly increased risk of death (HR range = 1.75, 95% CI = 1.15 to 2.65, to 6.28, 95% CI = 5.00 to 7.88), with the highest risks observed for the most aggressive LN subtypes.Heterogeneous associations between CM and specific LN subtypes provide novel insights into the etiology of these malignancies, with the mutual association between CM and certain LN suggesting shared etiology. Development of second primary CM or LN substantially reduces overall survival.
Co-inhibitory Molecule B7 Superfamily Member 1 Expressed by Tumor-Infiltrating Myeloid Cells Induces Dysfunction of Anti-tumor CD8+ T Cells
Authors: Jing Li, Younghee Lee, Yanjian Li, Yu Jiang, Huiping Lu, Wenjuan Zang, Xiaohong Zhao, Liguo Liu, Yang Chen, Haidong Tan, Zhiying Yang, Michael Q. Zhang, Tak W. Mak, Ling Ni, Chen Dong
Journal: Immunity (2018)
Doctor with list of “bad guys” he blamed for dismissal is jailed for 12 years
Authors: Clare Dyer
Journal: BMJ (2018)

A former NHS accident and emergency consultant has been jailed for 12 years for possessing firearms with intent to endanger life.

Martin Watt, 62, was sacked from his job at Monklands Hospital in Airdrie, North Lanarkshire, in 2012 after disciplinary proceedings. Police raided his home in 2015 after a tip off about a parcel containing a submachine gun addressed to him.

Police found three submachine guns, two pistols, ammunition, a silencer, and homemade gunpowder, along with an envelope labelled “bad guys,” with names, addresses, and car registration numbers of former colleagues and NHS managers he blamed for his dismissal.

He was found guilty last month …
Prognostic impact of PD-L1 and PD-1 expression by primary tumor location in colorectal cancer.
Authors: Jonna Berntsson, Anna Larsson, Bjorn Nodin, Jakob Eberhard, Karin Jirstrom
Journal: Journal of Clinical Oncology (2018)

628 Background: A plethora of studies report abundant expression of programmed death-ligand 1 (PD-L1) on tumors to be associated with poor outcome in several cancer forms, whereas immune cell-specific expression of PD-L1 has been associated with improved prognosis in colorectal cancer. However, none of these studies have investigated the association with prognosis according to primary tumor location. This study aimed to investigate the clinicopathological correlates and prognostic impact of PD-L1 and its receptor PD-1 in colorectal cancer, with particular reference to the anatomical subsite of the primary tumor. Methods: Immunohistochemical expression of PD-L1 and PD-1 was analysed in tissue microarrays with tumors from 557 incident cases of CRC from a prospective population-based cohort. Kaplan-Meier and Cox regression analyses were applied to determine the impact of biomarker expression on 5-year overall survival (OS), in the entire cohort and in subgroup analysis of right colon, left colon, and rectum. Results: High PD-L1 expression on tumor-infiltrating immune cells correlated significantly with an improved 5-year OS in univariable and multivariable analysis, adjusted for age, sex, TNM stage, differentiation grade, and vascular invasion, in the full cohort (HR = 0.49; 95 % CI 0.35-0.68), and in primary tumors of the right (HR = 0.43; 95 % CI 0.25-0.74) and the left colon (HR = 0.28; 95 % CI 0.13-0.61), but not in rectal cancer. High tumor-specific PD-L1-expression was not significantly associated with prognosis in neither the full cohort nor according to primary tumor location. High expression of PD-1 on tumor-infiltrating immune cells was significantly associated with an improved 5-year overall survival in the entire cohort (HR = 0.42; 95 % CI 0.21-0.87), but not in subsite analysis according to primary tumor location. Conclusions: This study is, to the best of our knowledge, the first to investigate the prognostic impact of PD-L1 and PD-1 expression according to primary tumor site in colorectal cancer. Dense infiltration of PD-L1+ immune cells was found to be an independent favorable prognostic factor in primary tumors of the right and left colon, but not in the rectum.
STOPS trial versus Costa<i>et al</i>: a more accurate analysis
Authors: Jon J Ford, Andrew John Hahne, Luke D Surkitt, Alexander Y P Chan, Matthew C Richards, Sarah L Slater, Tania Pizzari, Megan Davidson, Nicholas F Taylor
Journal: British Journal of Sports Medicine (2018)

We thank Travers et al 1 for highlighting the results of the Specific Treatment of Problems of the Spine (STOPS) trial.2 However, a number of their assertions are factually wrong, and we strongly disagree with their interpretation of our results.

Travers et al argue that the recovery trajectory of the STOPS comparison group (guideline-based advice) was worse than for participant data from a meta-analysis of cohort studies by Costa et al .3 They propose the reason for this was our advice group receiving a pathoanatomical explanation as a component of the advice intervention, which may have had a negative effect. Travers et al conclude that the lower than expected recovery trajectory for the STOPS advice group renders our statistically and likely clinically important results favouring the STOPS primary intervention (individualised physiotherapy) over advice as potentially invalid.

Practitioners4 and researchers5 understand that the validity and utility of research for clinical practice are influenced by the complexity of low back disorders (LBD).6 It is therefore essential that interpretation and comparison of research data are conducted using the principle of ‘apples for apples’. Travers et al suggest that the participants in the Costa et al meta-analysis were ‘broadly comparable’ with those in the STOPS trial. A closer analysis reveals that this is not the case.

Travers et al compare the Costa et al recovery trajectories for ‘acute/subacute’ LBD with the STOPS participants. However, this comparison is based on the authors’ erroneous assertion that the Costa et al ’s acute group had a symptom duration of 0–12 …
Factors associated with delayed bleeding after resection of large nonpedunculated colorectal polyps
Authors: Timothy Elliott, Zacharias Tsiamoulos, Siwan Thomas-Gibson, Noriko Suzuki, Leonidas Bourikas, Ailsa Hart, Paul Bassett, Brian Saunders
Journal: Endoscopy (2018)

Abstract Background Delayed bleeding is the most common significant complication after piecemeal endoscopic mucosal resection (p-EMR) of large nonpedunculated colorectal polyps (NPCPs). Risk factors for delayed bleeding are incompletely defined. We aimed to determine risk factors for delayed bleeding following p-EMR. Methods Data were analyzed from a prospective tertiary center audit of patients with NPCPs ≥ 20 mm who underwent p-EMR between 2010 and 2012. Patient, polyp, and procedure-related data were collected. Four post p-EMR defect factors were evaluated for interobserver agreement and included in analysis. Delayed bleeding severity was reported in accordance with guidelines. Predictors of bleeding were identified. Results Delayed bleeding requiring hospitalization occurred after 22 of 330 procedures (6.7 %). A total of 11 patients required blood transfusion; of these, 4 underwent urgent colonoscopy, 1 underwent radiological embolization, and 1 required surgery. Interobserver agreement for identification of the four post p-EMR defect factors was moderate (kappa range 0.52 – 0.57). Factors associated with delayed bleeding were visible muscle fibers (P = 0.03) and the presence of a “cherry red spot” (P = 0.05) in the post p-EMR defect. Factors not associated with delayed bleeding were American Association of Anesthesiologists class, aspirin use, polyp size, site, and use of argon plasma coagulation. Conclusions Visible muscle fibers and the presence of a “cherry red spot” in the resection defect were associated with delayed bleeding after p-EMR. These findings suggest evaluation and photodocumentation of the post p-EMR defect is important and, when considered alongside other patient and procedural factors, may help to reduce the incidence and severity of delayed bleeding.
Population pharmacokinetic (PopPK) and exposure-response (ER) modeling of cabozantinib (C) in patients (pts) with renal cell carcinoma (RCC) in the phase 3 METEOR study.
Authors: Steven Lacy, Matthew M Hutmacher, Bei Yang, Robert J. Motzer, Bernard J. Escudier, Thomas Powles, Toni K. Choueiri, Dale Miles, Jace Nielsen
Journal: Journal of Clinical Oncology (2016)

2565 Background: PopPK and ER models were developed to characterize the C concentration-time profile and the relationship between C exposure and efficacy endpoints in pts with RCC. Methods: The PopPK model was developed using nonlinear mixed effects modeling methodology (NONMEM v7.3) and incorporated 1650 measurable PK concentrations from 63 healthy volunteers (HV) and 282 pts with RCC. An extensive PK sampling strategy was employed for HV whereby C was administered as a single 20, 40 or 60 mg dose, while a single steady-state sample was collected at Day 29 and Day 57 for RCC pts initially receiving 60 mg C qd. Time-to-event Cox proportional hazard ER models were developed to characterize the relationship between various individual predicted C exposure measures and the relative hazard for specified efficacy endpoints including progression-free survival (PFS). Results: A 2-compartment model with first-order elimination and two parallel (fast and slow), lagged first-order absorption processes adequately described the C concentration data. The oral clearance, terminal phase volume of distribution, and terminal half-life were estimated to be 2.23 L/hr, 319 L, and 99 hours, respectively, for a White male subject. Inter-individual variability of CL/F was estimated to be 46% CV. A statistically significant relationship was identified between the rate of progressive disease (PD) or death and the time-varying average daily C concentration. Increases in C concentration were predicted to decrease the rate of PD or death in a nonlinear manner. The best Emax model (p < 0.001) was achieved with EC50 = 100 ng/mL, a value below the typical individual predicted steady-state average concentration at 60 (1125 ng/mL) or 20 (375 ng/mL) mg/day. Conclusions: Based on the ER analysis, C was efficacious at all doses evaluated in METEOR, including those resulting from dose reductions, with higher exposures predicted to correlate with improved PFS. Clinical trial information: NCT02496208.
Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease
Authors: Jaebok Choi, Matthew L. Cooper, Karl Staser, Kidist Ashami, Kiran R. Vij, Bing Wang, Lynne Marsala, Jessica Niswonger, Julie Ritchey, Bader Alahmari, Samuel Achilefu, Ikuo Tsunoda, Mark A. Schroeder, John F. DiPersio
Journal: Leukemia (2018)