tbuckley/cabot-search huggingface dataset:
CDK4/6 inhibition and sorafenib: a ménage à deux in HCC therapy?
Authors: Diego Calvisi, Robert Eferl
Journal: Gut (2017)

Hepatocytes are the foreign legionnaires in our body. They are exposed to various xenobiotics, which invigorates them and when transformed into malignant cells, renders them drug resistant. So far, treatment with the multikinase inhibitor sorafenib, which blocks Raf, vascular endothelial growth factor receptor and platelet-derived growth factor receptor signalling, is the only approved targeted therapy for advanced hepatocellular carcinoma (HCC). However, sorafenib extends the average life expectancy of patients only 2.8 months over the placebo,1 which offers room for improvement. Unfortunately, several other drugs and combinatorial therapies, such as sorafenib plus erlotinib failed in clinical trials.1 ,2 In this issue of Gut , Bollard et al 3 tested the combination of sorafenib with palbociclib in preclinical HCC mouse models. Palbociclib (or PD0332991) is a reversible and orally bioavailable low-molecular-weight cyclin-dependent kinase (CDK)4/6 inhibitor without significant off-target effects.4 The history of palbociclib is tightly linked to the decipherment of G1 cell cycle checkpoint regulation that started in 1991 with the discovery of D-type cyclins. CDK4 and CDK6 were discovered soon thereafter. They bind physically to and are enzymatically activated by D-type cyclins, which leads to phosphorylation and inactivation of retinoblastoma (RB1), the key gatekeeper of G1/S transition. Given the importance RB1 in cancer development, pharmacists started to develop CDK4/6 inhibitors such as palbociclib (Pfizer), ribociclib (Novartis) and abemaciclib (Elli Lilly). However, early clinical trials with palbociclib monotherapy dampened the initial enthusiasm for this drug, although tumour regression was observed in some patients with liposarcoma. A breakthrough was achieved when palbociclib was combined with letrozole, an aromatase inhibitor, for the treatment of oestrogen receptor-positive breast …
OA12.05 Noninvasive CT-Based Image Biopsy System (iBiopsy) for Early Stage Lung Adenocarcinoma
Authors: Dawei Yang, Yu Zhu, Charles Powell, Ningfang Wang, Vanbang Le, Bingbing Zheng, Hongcheng Shi, Changwen Zhai, Shaohua Lu, Yingyong Hou, Di Ge, Xinwei Zhang, Jian Zhou, Ming Li, Guozhen Zhang, Chunxue Bai
Journal: Journal of Thoracic Oncology (2017)
S76 Endoplasmic reticulum stress correlates with fibrosis in interstitial lung disease
Authors: H Parfrey, E Moseley, B Beardsley, J Knight, SJ Marciniak, D Rassl
Journal: Thorax (2016)

In interstitial lung disease (ILD), pulmonary fibrosis is associated with a poor prognosis. Distinct histological features differentiate between the ILDs, however it is unknown if there are shared pathogenic mechanisms for the development of fibrosis. Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). In response to ER stress, cells trigger the integrated stress response and upregulate chaperones, such as BiP, and the phosphatase GADD34, which can regulate EMT, cell proliferation and survival. <h3>AIMS</h3> We hypothesise that ER stress may be involved in the pathogenesis of fibrosis in all interstitial lung diseases. Paraffin embedded lung biopsy sections from 8 patients with familial pulmonary fibrosis, 11 sporadic idiopathic pulmonary fibrosis (IPF), 12 non-specific interstitial pneumonia (NSIP) and 10 hypersensitivity pneumonitis (HP) were evaluated for BiP and GADD34 by immunohistochemistry. Using light microscopy, 6 high power fields were scored for fibrosis, inflammation, BiP and GADD34 using semi-quantitative analysis by 2 blinded, independent investigators. Data were analysed by linear regression using Prism software. BiP and GADD34 were localised to reactive type II pneumocytes and columnar epithelium within areas of fibrosis. GADD34 was also evident in the endothelium. No staining was detected in fibroblasts. Epithelial GADD34 correlated with extent of fibrosis in familial pulmonary fibrosis (r<sup>2</sup> = 0.72, p &lt; 0.001), IPF (r<sup>2</sup> = 0.51, p &lt; 0.0001) and NSIP (r<sup>2</sup> = 0.46, p &lt; 0.0001). In contrast, BiP was associated with fibrosis in IPF (r<sup>2</sup> = 0.49, p &lt; 0.0001) and HP (r<sup>2</sup> = 0.59, p &lt; 0.0001). These data show that ER stress and the unfolded protein response are associated with fibrosis in ILD. Hence targeting ER stress may be a novel therapeutic option for pulmonary fibrosis.
Better referrals and funding are needed for preserving fertility
Authors: Yazan Abdallah, Jonathan Briggs, Cheryl T Fitzgerald
Journal: BMJ (2017)

We agree with Anderson and Davies that provision of fertility preservation is haphazard across the UK.1 We cannot agree, however, that the number of women undergoing fertility preservation is unknown. We recently carried out a UK-wide survey to examine the provision of oocyte and embryo cryopreservation before …
Imaging as the Nidus of Precision Cerebrovascular Health
Authors: David S. Liebeskind, Konark Malhotra, Jason D. Hinman
Journal: JAMA Neurology (2017)

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 Neurology 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 Neurology journal
P3.02b-027 Detection of EGFR Mutations in Plasma of Lung Adenocarcinoma Patients Using Real-Time PCR and Mass Spectrometry
Authors: Rossella Bruno, Elisabetta Macerola, Vincenzo Condello, Cristiana Lupi, Alessandro Ribechini, Antonio Chella, Greta Alì, Gabriella Fontanini
Journal: Journal of Thoracic Oncology (2017)
P3.02b-050 A Phase I/II Study of Erlotinib, Carboplatin, Pemetrexed and Bevacizumab for Advanced Non-Squamous NSCLC Harboring EGFR Mutation
Authors: Takashi Yokoi, Takayasu Kurata, Yoshitaro Torii, Naoko Satsutani, Kayoko Kibata, Maiko Niki, Shosaku Nomura
Journal: Journal of Thoracic Oncology (2017)
Indoleamine 2,3-Dioxygenase (IDO) Is Associated with High Incidence of Chemorefractory Disease in Acute Myeloid Leukemia (AML) Patients
Authors: Sarah Parisi, Sara Trabanelli, Darina Ocadlikova, Stefania Paolini, Cristina Papayannidis, Emanuela Ottaviani, Giovanni Martinelli, Michele Baccarani, Roberto Massimo Lemoli, Antonio Curti
Journal: Blood (2012)
S120 Asthma in fire fighter applicants: burden of disease and factors predicting successful application
Authors: J Szram, SJ Schofield, B Fitzgerald, P Cullinan
Journal: Thorax (2016)

<h3></h3> Asthma is of concern to UK fire services that need to maintain maximal operational capability; current guidance suggests specialist respiratory review of applicants with a history of asthma, including tests of non-specific airway responsiveness. We present data from our occupational lung disease clinic over a 17 year period. Between March 1999 and January 2016, 112 firefighters were assessed; 90 of these completed histamine provocation testing allowing measurement of non-specific bronchial hyper-responsiveness using PC20 to histamine. Retrospective case note review was undertaken to look for predictors of PC20 from clinical history in this cohort. Subsequent follow up included recorded outcome of application and reported symptoms on future employment in the fire service. Unsurprisingly the majority of applicants were male (87.8%, n = 79) and atopic (78.6% n = 66). Around one third had experienced symptoms 27 (31.8) or taken treatment 32 (38.0) in the last year. Most patients were taking no asthma therapy at the time of assessment (64.4%, n = 58) with the majority of those on therapy taking a reliever only (n = 20, 22.2%). Three quarters (75.6%) had normal bronchial reactivity at the time of assessment (PC20 &gt; 16 mg/ml histamine; n = 68) and 85.6% borderline normal airway responsiveness (PC20 &gt; 8 mg/ml histamine; n = 77). Complete data on follow up was available for 86% of those assessed (n = 90); 64 of these had a recorded PC20. Table 1 shows the predictive factors for successful application in this cohort. Applicants were more likely to be rejected if they were older at time of application; reported recent asthma symptoms or use of treatment in the last year, had a history of childhood asthma or a measured PC20 of less than 16 mg/ml. The findings of this study suggest that a history of asthma in this occupational group remains a concern to occupational health teams focusing on operational capability of workforces with safety critical roles. Further follow-up of this cohort or a wider prospective study could provide applicants with asthma and their recruiters with useful guidance on individual suitability for employment as a fire fighter.
OA05.07 Prognostic Value of Circulating Tumor Cells in Limited-Disease Small Cell Lung Cancer Patients Treated on the CONVERT Trial
Authors: Fabiola Fernandez-Gutierrez, Victoria Foy, Katy Burns, Jackie Pierce, Karen Morris, Lynsey Priest, Jonathan Tugwood, Linda Ashcroft, Corinne Faivre-Finn, Caroline Dive, Fiona Blackhall
Journal: Journal of Thoracic Oncology (2017)
P3.04-029 A Prospective Randomized Trial of Perioperative Administration of Neutrophil Elastase Inhibitor in Patients with Interstitial Pneumonias
Authors: Mariko Fukui, Kazuya Takamochi, Shiaki Oh, Takeshi Matsunaga, Kazuhiro Suzuki, Katsutoshi Ando, Kenji Suzuki
Journal: Journal of Thoracic Oncology (2017)
ARID5B Genetic Polymorphisms Contribute to Racial Disparities In Childhood Acute Lymphoblastic Leukemia: A Children's Oncology Group Study
Authors: Jun Yang, Heng Xu, Cheng Cheng, Meenakshi Devidas, Deqing Pei, Yiping Fan, Wenjian Yang, Geoffrey A. Neale, Naomi J. Winick, Paul L Martin, Cheryl L. Willman, Bruce M. Camitta, Gregory H. Reaman, William L. Carroll, Mignon Loh, Stephen P. Hunger, William E. Evans, Mary V. Relling
Journal: Blood (2010)
P2.06-030 Optimum Duration of Vitamin B12/Folate Supplementation in NSCLC Patients on Pemetrexed Based Chemotherapy: The PEMVITASTART Randomized Trial
Authors: Navneet Singh, Milind Baldi, Jyotdeep Kaur, Rakesh Kapoor, Digambar Behera
Journal: Journal of Thoracic Oncology (2017)
P1.03-062 Lung Cancer Screening with Low-Dose CT in China: Study Design and Baseline Results from the First Round Screening Arm
Authors: Huimin Wang, Yanwei Zhang, Jiajun Teng, Qunhui Chen, Jianding Ye, Jiatao Lou, Rong Shi, Liyan Jiang, Aiqin Gu, Yizhuo Zhao, Bo Jin, Xueyan Zhang, Jianlin Xu, Yuqing Lou, Fangfei Qian, Wenjia Yang, Baohui Han
Journal: Journal of Thoracic Oncology (2017)
Impact of Myeloablative Versus Reduced Intensity Conditioning Regimens on Early Lymphocyte Recovery and Its Impact on Transplant Outcomes after Allogeneic Peripheral Blood Stem Cell Transplantation in Adult Patients with Hematologic Malignancies.
Authors: Dong Hwan (Dennis) Kim, Gizelle Popradi, John Kuruvilla, Vikas Gupta, Mark Minden, Jeffrey H. Lipton, Hans A. Messner
Journal: Blood (2007)
Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis
Authors: Anneline S.J.M. te Riele, Esperanza Agullo-Pascual, Cynthia A. James, Alejandra Leo-Macias, Marina Cerrone, Mingliang Zhang, Xianming Lin, Bin Lin, Eli Rothenberg, Nara L. Sobreira, Nuria Amat-Alarcon, Roos F. Marsman, Brittney Murray, Crystal Tichnell, Jeroen F. van der Heijden, Dennis Dooijes, Toon A.B. van Veen, Harikrishna Tandri, Steven J. Fowler, Richard N.W. Hauer, Gordon Tomaselli, Maarten P. van den Berg, Matthew R.G. Taylor, Francesca Brun, Gianfranco Sinagra, Arthur A.M. Wilde, Luisa Mestroni, Connie R. Bezzina, Hugh Calkins, J. Peter van Tintelen, Lei Bu, Mario Delmar, Daniel P. Judge
Journal: Cardiovascular Research (2016)

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is often associated with desmosomal mutations. Recent studies suggest an interaction between the desmosome and sodium channel protein Nav1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding Nav1.5) in ARVD/C. We performed whole-exome sequencing in six ARVD/C patients (33% male, 38.2 ± 12.1 years) without a desmosomal mutation. We found a rare missense variant (p.Arg1898His; R1898H) in SCN5A in one patient. We generated induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CMs) from the patient's peripheral blood mononuclear cells. The variant was then corrected (R1898R) using Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 technology, allowing us to study the impact of the R1898H substitution in the same cellular background. Whole-cell patch clamping revealed a 36% reduction in peak sodium current (P = 0.002); super-resolution fluorescence microscopy showed reduced abundance of NaV1.5 (P = 0.005) and N-Cadherin (P = 0.026) clusters at the intercalated disc. Subsequently, we sequenced SCN5A in an additional 281 ARVD/C patients (60% male, 34.8 ± 13.7 years, 52% desmosomal mutation-carriers). Five (1.8%) subjects harboured a putatively pathogenic SCN5A variant (p.Tyr416Cys, p.Leu729del, p.Arg1623Ter, p.Ser1787Asn, and p.Val2016Met). SCN5A variants were associated with prolonged QRS duration (119 ± 15 vs. 94 ± 14 ms, P < 0.01) and all SCN5A variant carriers had major structural abnormalities on cardiac imaging. Almost 2% of ARVD/C patients harbour rare SCN5A variants. For one of these variants, we demonstrated reduced sodium current, Nav1.5 and N-Cadherin clusters at junctional sites. This suggests that Nav1.5 is in a functional complex with adhesion molecules, and reveals potential non-canonical mechanisms by which Nav1.5 dysfunction causes cardiomyopathy.
New year message
Authors: D L Crosby
Journal: BMJ (1988)

There is now increasing use of dopamine agonists as effective early monotherapy in the treatment of Parkinson’s disease (PD). Dopamine agonists can induce an antiparkinsonian effect through actions on either D<sub>1</sub>-like or D<sub>2</sub>-like dopamine receptors, and the multiple receptor subtypes present in the brain may provide further opportunities to improve the treatment of PD. Functional interactions exist between D<sub>1</sub>- and D<sub>2</sub>-like receptors, and adaptive changes occur after denervation and repeated administration of a dopamine agonist. Long-acting dopamine agonists produce a lower incidence of dyskinesia than levodopa (l-dopa) when they are used as monotherapy in either PD or in drug-naïve 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates. Continuous dopaminergic stimulation appears less likely to prime basal ganglia for involuntary movements compared with drugs, such as l-dopa, that produce pulsatile stimulation. However, once priming has occurred, dopamine agonists produce dyskinesia identical to that of l-dopa. Continuous administration of long-acting dopamine agonists may reverse the priming process initiated by l-dopa, markedly decreasing dyskinesia intensity with a minimal loss of antiparkinsonian activity, at least in MPTP-treated primates. Dopamine receptors in brain areas other than the striatum, such as the globus pallidus and subthalamic nucleus, and in the mesolimbic and mesocortical regions may also contribute to antiparkinsonian activity of dopamine agonists and their associated side effects. The future potential of dopamine agonists may lie in the selective stimulation of dopamine receptor subtypes in different brain areas and through the actions of partial dopamine agonists and drugs that normalize dopamine receptor function.
Diversity in Dermatology Clinical Trials
Authors: Alexandra Charrow, Fan Di Xia, Cara Joyce, Arash Mostaghimi
Journal: JAMA Dermatology (2017)

Though there have been significant shifts in US demographic data over the past 50 years, research cohorts lack full racial and ethnic representation. There is little data available regarding the diversity of dermatology research cohorts with respect to sex, race, and ethnicity.To characterize and assess the representation of racial and ethnic minorities and women in randomized controlled trials across a range of dermatologic conditions.All randomized clinical trials (RCTs) were identified between July 2010 and July 2015 within the PubMed database using the following keywords: "psoriasis," "atopic dermatitis," "acne," "vitiligo," "seborrheic dermatitis," "alopecia areata," and "lichen planus." Diverse study populations were defined as including a greater than 20% racial or ethnic minority participants based on US census data. The distributions of sex and race groups in studies were compared by journal type, disease type, and funding source.Of the 626 articles reporting RCTs included in this analysis, 532 (85.0%) reported the sex of study participants. Overall, 52 of 626 international (11.3%) studies and 58 of 97 studies (59.8%) conducted exclusively within the United States reported on the racial or ethnic demographics of study participants. Across all RCTs exclusively recruited within the United States that reported race, 74.4% of study participants were white. Disease type was significantly associated with the degree of racial diversity (P < .001) within a study cohort: 30.0% of US-based psoriasis had more than 20% racially or ethnically diverse research participants as compared with 73.9% of acne studies and 91.7% of eczema studies.Dermatologic clinical trials within the United States reflect the growing diversity of the US population. Reporting of both sex and racial/ethnic diversity of research cohorts is still lacking, especially among studies conducted outside of the United States.
P1.07-039 Insulinoma-Associated 1 (INSM1) Immunohistochemical Expression in Lung Neuroendocrine Tumors
Authors: Rie Sakakibara, Kentaro Inamura, Hironori Ninomiya, Yasuyuki Shigematsu, Tomoyo Kakita, Daisuke Noma, Yoshifumi Hirata, Yosuke Matsuura, Masayuki Nakao, Mingyon Mun, Makoto Nishio, Sakae Okumura, Yuichi Ishikawa
Journal: Journal of Thoracic Oncology (2017)
P2.04-031 Predictors of Pathological Complete Response (TRG=1) among Esophageal Cancer Cases; NCI Pooled Data
Authors: M. Rahouma, Fatma Abou Elkassem, Iman Loay, Maha Yehia, Mostafa Rahouma, Abdelrahman Abdelrahman
Journal: Journal of Thoracic Oncology (2017)
Identification and differentiation of major components in three different “Sheng-ma” crude drug species by UPLC/Q-TOF-MS
Authors: Mengxue Fan, Kunming Qin, Fei Ding, Yuting Huang, Xiaoli Wang, Baochang Cai
Journal: Acta Pharmaceutica Sinica B (2017)

Cimicifugae Rhizoma (Sheng ma) is a Ranunculaceae herb belonging to a composite family and well known in China. has been widely used in traditional Chinese medicine. The Pharmacopoeia of the People׳s Republic of China contains three varieties (Cimicifuga dahurica (Turcz.), Cimicifuga foetida L. and Cimicifuga heracleifolia Kom.) which have been used clinically as "Sheng-ma". However, the chemical constituents of three components of "Sheng-ma" have never been documented. In this study, a rapid method for the analysis of the main components of "Sheng-ma" was developed using ultra-high performance liquid chromatography with quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF-MS). The present study reveals the major common and distinct chemical constituents of C. dahurica, C. foetida and C. heracleifolia and also reports principal component and statistical analyses of these results. The components were identified by comparing the retention time, accurate mass, mass spectrometric fragmentation characteristic ions and matching empirical molecular formula with that of the published compounds. A total of 32 common components and 8 markers for different "Sheng-ma" components were identified. These findings provide an important basis for the further study and clinical utilities of the three "Sheng-ma" varieties.
David Oliver: Is NHS “candour” on a break for winter?
Authors: David Oliver
Journal: BMJ (2017)

Winter seems more difficult each year in NHS acute care, and 2016-17 is no exception. Vocal public support from national leadership bodies would be a welcome New Year gift. It would certainly beat attempts at news management to limit reputational damage and appease politicians’ reported wishes to keep hospital crises out of the headlines.1

Looking at NHS performance statistics,2 media reports of clinicians’ tales from around the country,3 or statements from their medical colleges and societies,45 it’s been more like the Apocalypse than the Christmas story. Demand for urgent care is high, …
P1.03-040 Beliefs Surrounding Lung Cancer Screening among Physicians and Lay Populations: Results from the EDIFICE Survey
Authors: Alexis Cortot, Sébastien Couraud, François Eisinger, Chantal Touboul, Jean-Yves Blay, Jérôme Viguier, Christine Lhomel, Xavier Pivot, Jean-François Morere, Laurent Greillier
Journal: Journal of Thoracic Oncology (2017)
Adaptive design of VALOR, a phase III trial of vosaroxin or placebo in combination with cytarabine for patients with first relapsed or refractory acute myeloid leukemia.
Authors: C. R. Mehta, G. Michelson, M. Salganik, J. Feaster, R. Allen, A. L. Cahill, J. A. Fox, S. B. Ketchum, F. Ravandi, H. P. Erba, G. J. Schiller, R. K. Stuart, N. Vey, E. J. Feldman
Journal: Journal of Clinical Oncology (2011)

TPS201 Background: Median overall survival (OS) for patients with relapsed or refractory AML remains short (3-6 mos) with current treatments. Vosaroxin (formerly voreloxin) with cytarabine had a promising activity/tolerability profile in phase II in this population (N=69): median OS 7.1 mos, combined CR rate 29%, current median leukemia-free survival 14.4 mos, 30-day all-cause mortality 3% (Stuart Chem Found Symp 2010), supporting phase III trial design. VALOR (NCT01191801) is a phase III, randomized, controlled, double-blind, multinational trial of the efficacy and safety of vosaroxin and cytarabine versus placebo and cytarabine in patients with first relapsed or refractory AML; OS is the primary endpoint. VALOR enrollment initiated in December 2010. Methods: Adaptive Design: Base case assumed 40% improvement in median OS, from 5 mos for the placebo + cytarabine arm to 7 mos for the vosaroxin + cytarabine arm (hazard ratio, HR=0.71); 375 OS events are required to provide 90% power at a 2-sided alpha of 0.05 with 1 interim look allowed at 50% OS events. The interim result is partitioned into zones based on conditional power: futility, unfavorable, promising, favorable and efficacy. The Data and Safety Monitoring Board (DSMB) can recommend stopping early for futility or efficacy or completing per base case if the interim result is either unfavorable or favorable. However, if the result falls into the promising zone, the DSMB can recommend a one time sample size adjustment, increasing the final number of events and sample size by 50% (from 450 to 675 evaluable patients) in order to detect a smaller but relevant treatment effect (HR > 0.71) (Mehta, Pocock, Stat Med 2010). For example, if the HR is 0.77 rather than 0.71, the 50% increase in sample size boosts the conditional power within the promising zone from approximately 70% to slightly greater than 90%. A key advantage of VALOR’s design is the 50% increase is recommended only if the interim result demonstrates that the increase substantially reduces the risk of failing to detect a clinically meaningful OS benefit. This design satisfies the statistical and operational requirements of the FDA Draft Guidance on Adaptive Design.