tbuckley/cabot-search huggingface dataset:
Imaging of Prostate-Specific Membrane Antigen with Small-Molecule PET Radiotracers: From the Bench to Advanced Clinical Applications
Authors: Steven P. Rowe, Michael A. Gorin, Martin G. Pomper
Journal: Annual Review of Medicine (2019)

In recent years, small-molecule inhibitors of prostate-specific membrane antigen (PSMA) labeled with radionuclides that allow for positron emission tomography (PET) imaging have been extensively studied in many clinical contexts in men with prostate cancer (PCa). The high sensitivity and specificity of these agents for identifying sites of PCa has quickly led to their widespread adoption as a de facto clinical standard of care throughout much of the world. PSMA-targeted PET radiotracers have been particularly well-studied in preoperatively staging men with high-risk PCa, evaluating biochemical recurrence following definitive therapy, and guiding metastasis-directed therapy in patients suspected of having oligorecurrent/oligometastatic disease. Furthermore, the expression of PSMA on the tumor neovasculature of many nonprostate malignancies has enabled a burgeoning subfield concentrated on delineating the potential utility of PSMA-targeted PET agents for imaging other cancers. In this review, we highlight the preclinical development of key small molecules that are now being clinically utilized for PCa imaging, discuss the roles of PSMA-targeted agents in guiding patient management, and consider the role these compounds may play in imaging nonprostate cancers.
Engineering of CD19-Specific Chimeric Antigen Receptor T Cells with the Integrin CD103 Results in Augmented Therapeutic Efficacy Against Human Lymphoma in a Preclinical Model
Authors: Hongxing Sun, Shan He, Lijun Meng, Ying Wang, Hanghang Zhang, Yongnian Liu, Jian Wang, Min Tao, Stefan Klaus Barta, Essel D. Al-Saleem, Henry C. Fung, Jean-Pierre Issa, Leizhen Zheng, Yi Zhang
Journal: Blood (2018)
Cancer neoantigens targeted by adoptive T cell transfer: private no more
Authors: Enrico Lugli, Pia Kvistborg, Giovanni Galletti
Journal: Journal of Clinical Investigation (2019)

Effector T cell responses directed toward cancer neoantigens mediate tumor regression following checkpoint blockade or adoptive T cell immunotherapy, but are generally "private", thus requiring considerable effort for their identification. In this issue of the JCI, Malekzadeh et al. show that a fraction of patients with epithelial cancers mount antigen-specific T cell responses to "hot spot" p53 mutations that in some cases are shared among patients. This work suggests that other genes frequently mutated in human cancer can be immunogenic, thus offering a rapid way to screen for cancer neoantigens that can be targeted by subsequent T cell–based therapies.
Combined BCL-2 and HDAC Targeting Has Potent and TP53 Independent Activity in AML
Authors: Jessica M Salmon, Giovanna Pomilio, Donia M Moujalled, Sarah Macraild, Charis E Teh, Sewa Riajl, Adam Ivey, Tse-Chieh Teh, Paul G Ekert, Laurence Kraus-Berthier, Ioana Kloos, Marie Schoumacher, Daniel Gray, Andrew H Wei
Journal: Blood (2018)
Cystic fibrosis – How we reach adult life
Authors: I. Serras, J.A. Oliveira, L. Pereira, C. Barreto
Journal: Pulmonology (2019)

Copyright © 2019 Sociedade Portuguesa de Pneumologia. Published by Elsevier Espana, S.L.U. This is an open access article under the CCBY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Asymptomatic Isolated Vulvar Metastasis in Old Treated Case of Carcinoma Rectum—Diagnosis and Treatment Response Evaluation by 18F-FDG PET/CT Scan
Authors: Ram Kumar Elumalai, Ritu Verma, Dharmender Malik, Ethel Shangne Belho
Journal: Clinical Nuclear Medicine (2019)

Abstract We report a clinically asymptomatic, old treated case of carcinoma rectum, presenting with raised serum carcinoembryonic antigen level, referred for 18 F-FDG PET/CT scan for restaging. Whole-body PET/CT scan revealed an isolated FDG-avid lesion in the left labia majora region, which on histopathology was found to be metastasis from carcinoma rectum. Subsequent 18 F-FDG PET/CT done after 4 cycles of chemotherapy revealed favorable response to therapy. 18 F-FDG PET/CT facilitates the detection of unusual site of metastasis and its subsequent response evaluation in the index case.
What is the role of the anti-angiogenic therapy in BRAF (V600E) mutant metastatic colorectal cancer patients in a real-world setting?
Authors: Nieves Martinez Lago, Marta Covela Rúa, Elena Brozos Vazquez, Ana Fernandez Fernandez Montes, Juan Cruz De La Camara Gomez, Carlos Méndez Méndez, Mónica Jorge Fernández, Antia Cousillas Castiñeira, Begoña Graña Suárez, Guillermo Alfonso Quintero Aldana, Sonia Candamio Folgar, Mercedes Salgado Fernandez, Maria Luz Pellon Augusto, Paula Gonzalez Villarroel, Elena Gallardo Martin, Marta Carmona Campos, Francisca Vazquez Rivera, Carlos Grande Ventura, Alberto Carral Maseda, Margarita Reboredo Lopez
Journal: Journal of Clinical Oncology (2019)

620 Background: Activating B-type Raf kinase (BRAF) mutations, mostly missense V600E, occur in approximately 8% to 12% of patients with metastatic colorectal cancer (mCRC). BRAF (V600E) mt is a strong predictor of a poor prognosis, with distinct clinical and pathological features. However, it is unknown whether this mutation is predictive of any treatment benefit in a real world setting. Methods: We conducted an observational, retrospective, multicentric study of patients with BRAF V600E-mt mCRC treated at nine university Spanish hospitals in NW Spain, belonging to GITuD (Galician Research Group on Digestive Tumors). Demographic, clinic and pathological characteristics, overall survival (OS) and first-line progression free survival (PFS) were retrospectively collected and analyzed. Results: Data from 65 patients treated between November 2010 to June 2018 were recorded in this study. Median age was 62.8 years (range 30-83 years), 55.4 % female, 75.4% ECOG PS0-1, 49.2% right-sided, 35.2% high grade, 69.2% synchronous presentation, 66.2% primary tumor resection and median metastatic locations was 2 (range 1-5). With a median follow up of 64.6 months, median OS was 12.9 months (95% CI, 9.8-16.0 months) and first line PFS was 4.1 months (95% CI, 2.7-5.5 months). First line PFS according treatment: Bev+Triplet-CT/Bev+Doublet-CT/antiEGFR+Doublet-CT/Doublet-CT: 6.2 vs 4.8 vs 2.9 vs 2.1 months (p = 0.020). Bevacizumab based chemotherapy was associated with a prolonged first line PFS (median 5.0 vs. 2.1 months, HR, 0.406; 95% CI, 0.20-0.81; p = 0.005). Nevertheless, no statistical differences between bevacizumab based regimes, (Triplet-CT vs Doublet-CT (HR 0.830; 95% CI 0.4-1.9; p = 0.666)) or between Doublet-CT with or without a antiEGFR were found (HR 0.511; 95% CI 0.2-1.6; p = 0.223). Conclusions: Our study confirms the negative prognostic impact of BRAF V600E mt in mCRC and encourage the use of anti-angiogenic based chemotherapy in this subgroup of patients.
Drug Combinations Co-Targeting Myeloid Cell Leukemia-1 (Mcl-1) Protein Can Overcome Microenvironmentally-Induced Multi-Drug Tolerance in Non-Hodgkin Lymphomas
Authors: Kallesh D. Jayappa, Craig A. Portell, Vicki L. Gordon, Goutham Narla, Timothy P. Bender, Michael E. Williams, Michael J. Weber
Journal: Blood (2018)
Government review on illicit drug use and violence will not look at decriminalisation
Authors: Jacqui Wise
Journal: BMJ (2019)

Carol Black, who has led a number of medical organisations and chaired government reviews on work and health, will lead a “wide ranging” review of how illicit drug use fuels serious violence. But the review, which will publish its initial findings this summer, will not look at the decriminalisation of drugs.

The review, which has been commissioned by the Home Office, will look at who drug users are, what they are taking, and who is supplying the drugs. It will also examine the harms of drugs and the best ways to prevent their misuse.

The formal terms of reference will be published shortly, but …
Nrf2 metagene as a prognostic biomarker across all stages of colorectal cancer (CRC).
Authors: Sean Micheal O'Cathail, Chieh-Hsi Wu, Annabelle Lewis, Tim Maughan, Maria A Hawkins
Journal: Journal of Clinical Oncology (2019)

557 Background: Keap1/Nrf2 is an important intracellular canonical stress response pathway, with Nrf2 acting as a potent transcription factor. Lung cancer is known to acquire constitutive activation of the pathway thus promoting survival, resisting chemo-radiation and dysregulating metabolism. Mechanisms of pathway activation include methylation of KEAP1, somatic mutation and direct activation by KRAS, BRAF and MYC. Its role in CRC is unknown. Due to its role as a transcription factor, activated in many ways, we hypothesise a metagene of Nrf2 regulated genes would act as a prognostic biomarker in CRC. Methods: Using a candidate gene approach and publicly available data (GSE17536), we derived and trained a 36 gene metagene to aggregate Nrf2 pathway expression, using principal component analysis and cox proportional hazard models. GSE14333 was used for validation in stage I/II/III CRC. The first line metastatic FOCUS trial was used for validation in Stage IV disease. Results: 601 patients are included in the validation analysis. Nrf2 metagene expression is associated with worse DFS outcomes in stage I/II/III disease in Cox PH model comparisons (LRT, p = 0.00175) and worse OS in stage IV disease (LRT, p = 0.00574). On multivariate analysis, Nrf2 expression remained significant when adjusted for known prognostic factors of adjuvant chemotherapy and Duke’s stage in stage I/II/III disease (ANOVA, p = 0.03), BRAF V600E and sidedness in stage IV disease (ANOVA, p = 0.00255). Using the median cut point, high expression has a HR 2.36 (C.I 1.27-4.38) in stage I/II/III disease and HR 1.39 (C.I 1.12-1.72) in metastatic disease. Conclusions: Nrf2 expression is a novel, robust prognostic biomarker of poor prognosis across all stages of colorectal cancer. Greater understanding of its mechanistic role could lead to targeted strategies to improve outcomes in CRC. [Table: see text]
Cadherin-related Family Member 3 Gene is a Candidate Gene for Preschool Wheezing and Lung Function as well as Childhood Asthma
Authors: Ting Fan Leung, Man Fung Tang, Tak Chi Liu, Alice Pik Shan Kong, Agnes Sze Yin Leung, Wan Yi Chan, Hing Yee Sy, Gary Wing Kin Wong
Journal: Journal of Allergy and Clinical Immunology (2019)
Identification of genes functionally involved in the detrimental effects of mutant histone H3.3-K27M in Drosophila melanogaster
Authors: Johannes Berlandi, Amel Chaouch, Nicolas De Jay, Isabel Tegeder, Katharina Thiel, Margret Shirinian, Claudia L Kleinman, Astrid Jeibmann, Paul Lasko, Nada Jabado, Martin Hasselblatt
Journal: Neuro-Oncology (2019)

Recurrent specific mutations in evolutionarily conserved histone 3 (H3) variants drive pediatric high-grade gliomas (HGGs), but little is known about their downstream effects. The aim of this study was to identify genes involved in the detrimental effects of mutant H3.3-K27M, the main genetic driver in lethal midline HGG, in a transgenic Drosophila model.Mutant and wild-type histone H3.3-expressing flies were generated using a φC31-based integration system. Genetic modifier screens were performed by crossing H3.3-K27M expressing driver strains and 194 fly lines expressing short hairpin RNA targeting genes selected based on their potential role in the detrimental effects of mutant H3. Expression of the human orthologues of genes with functional relevance in the fly model was validated in H3-K27M mutant HGG.Ubiquitous and midline glia-specific expression of H3.3-K27M but not wild-type H3.3 caused pupal lethality, morphological alterations, and decreased H3K27me3. Knockdown of 17 candidate genes shifted the lethal phenotype to later stages of development. These included histone modifying and chromatin remodeling genes as well as genes regulating cell differentiation and proliferation. Notably, several of these genes were overexpressed in mutant H3-K27M mutated HGG.Rapid screening, identification, and validation of relevant targets in "oncohistone" mediated pathogenesis have proven a challenge and a barrier to providing novel therapies. Our results provide further evidence on the role of chromatin modifiers in the genesis of H3.3-K27M. Notably, they validate Drosophila as a model system for rapid identification of relevant genes functionally involved in the detrimental effects of H3.3-K27M mutagenesis.
Abstract 21290: Adipose Tissue Factors and the Adipokine Resistin-Induce Vascular Endothelial Dysfunction via Arginase Upregulation
Authors: Reem T Atawia, Jijun Chen, Haroldo A Toque, Tahira Lemtalsi, Ruth B Caldwell, Robert W Caldwell
Journal: Circulation (2017)

Introduction: Obesity is a major contributor to cardiovascular disorders, for which endothelial cell (EC) dysfunction is a hallmark. Obesity-induced EC dysfunction has been linked to dysregulation of the visceral adipose tissue (VAT) resulting in increased secretion of the pro-inflammatory cytokine resistin and alterations in endothelial nitric oxide (NO) producing capacity. However, mechanisms underlying this pathology are not well understood. Hypothesis: Resistin impairs vascular EC function via upregulation of endothelial arginase1 (ARG1) expression and activity, thus limiting L-arginine availability for NO synthesis. Methods: To determine the effect of obesity on EC function, conditioned media prepared from VAT (VAT CM) of high fat diet-induced obese mice, VAT CM from lean mice or resistin (100 ηg/ml) were used to treat mouse aortic endothelial cells (MAEC) and aortic rings for 24 hr. Results: VAT CM from obese mice increased endothelial ARG1 mRNA by 34% and decreased NO level by 32% (p&lt;0.05), vs VAT CM from lean mice. Aortic rings incubated with obese VAT CM markedly reduced endothelium-dependent vasorelaxation (EDV) to acetylcholine. Moreover, resistin levels were 143% higher in obese VAT CM compared to lean VAT CM. In MAEC, resistin increased ARG1 mRNA by 30% and decreased NO production by 39% (p&lt;0.05). Co-treatment with the specific ARG inhibitor (ABH, 100 μM) or supplementing EC with L-arginine increased NO to near normal levels. Incubation of aortic rings with resistin also impaired EDV. This dysfunction was largely prevented by co-treatment with ABH or in aortic rings from EC specific-ARG1 knockout mice. The resistin-induced increase in ARG1 expression in MAEC is attributed to Toll-like receptor 4 (TLR4)-induced activation of p38 MAPK pathway as co-treatment with specific TLR4 inhibitor (CLI-095) inhibited p38 activation and ARG1 expression (34% and 33%, respectively, p&lt;0.05) and increased NO production by 38% (p&lt;0.05). Additionally, co-treatment with a specific p38 inhibitor prevented resistin-induced increase in endothelial ARG1 expression. Conclusions: VAT factors and particularly resistin induce vascular endothelial dysfunction via elevated arginase expression/activity. Support : NIH EY11766 &amp; HL70215 &amp; AHA fellowship
Abstract 16885: Resuscitation Trends in Survival Rate and Get With the Guidelines Resuscitation Award Recognition
Authors: Anand Ramanathan, Jolanta Gargano, Pam Madrid, Kathie Thomas, Art Miller, Gary Myers, Kathleen O'Neill
Journal: Circulation (2017)

Background and Objectives: Over 200,000 adults each year experience in-hospital cardiac arrest. The overall survival to discharge has remained relatively unchanged for several decades and survival ...
Abstract 17206: Osteopontin Levels in Patients at High Cardiovascular Risk
Authors: Gerfried Pesau, Florian Obendorf, Carsten Thilo Herz, Clemens Hoebaus, Renate Koppensteiner, Gerit Schernthaner
Journal: Circulation (2015)

Introduction: Proteins which are involved in the bone metabolism have recently been discovered to have significant implications in the development of vascular disease and complications. Osteopontin (OPN) has been suggested as a biomarker of atherosclerosis and vascular calcification. Hypothesis: OPN levels may be used for risk stratification in patients with peripheral artery disease (PAD). Methods: 361 patients suffering from PAD were studied and followed-up for five years. 60 outcome events, defined as death, non-fatal myocardial infarction or non-fatal stroke, were observed. Multiplex bead array technology was used to measure serum levels of OPN at baseline. For basic analysis, the patients were divided into quartiles according to OPN levels. A Cox regression model was used to identify confounding variables. Results: A significantly different event-free survival could be observed between all groups (log-rank: p=0.049). When comparing the highest quartile to the rest of the cohort, a further increase in significance could be observed (log-rank: p=0.017). A cut-off point accommodating the most favorable sensitivity (50.0%) and specificity (66.4%) was determined for regression analysis. The hazard ratio was 2.13 (1.26-3.60) in the unadjusted model and reached 2.16 (1.21-3.84) after adjustment for age, gender, diabetes, low-density lipoprotein cholesterol, blood pressure, smoking, c-reactive protein and renal function. Conclusions: Our results suggest an association between OPN levels and the rate of cardiovascular events in high risk patients. In our observations this relation was independent of established risk factors.
The Impact of Obesity on the Incidence of Type 2 Diabetes Among Women With Polycystic Ovary Syndrome
Authors: Nadira S. Kakoly, Arul Earnest, Helena J. Teede, Lisa J. Moran, Anju E. Joham
Journal: Diabetes Care (2019)

OBJECTIVE The nature of the independent relationship between polycystic ovary syndrome (PCOS) and type 2 diabetes remains unclear. Few studies have aimed to clarify this relationship independent of obesity in longitudinal population-based cohorts. RESEARCH DESIGN AND METHODS We used the Australian Longitudinal Study on Women’s Health (ALSWH) (2000–2015) database to estimate nationwide incidence rates and predictors of type 2 diabetes among women aged 18–42 using person-time and survival analysis. RESULTS Over a follow-up of 1,919 person-years (PYs), 186 women developed type 2 diabetes. The incidence rate was 4.19/1,000 PYs and 1.02/1,000 PYs (P &amp;lt; 0.001) in PCOS and control subjects. On subgroup analyses across healthy-weight, overweight, and obese categories of women, the incidence rates for type 2 diabetes were 3.21, 4.67, and 8.80, whereas incidence rate ratios were 4.68, 3.52, and 2.36 (P &amp;lt; 0.005) in PCOS versus age-matched control subjects. PCOS was one of the most influential predictors for type 2 diabetes in the entire cohort (hazard ratio 3.23, 95% CI 2.07–5.05, P &amp;lt; 0.001) adjusting for BMI, education, area of residence, and family history of type 2 diabetes. CONCLUSIONS Women with PCOS are at an increased risk of type 2 diabetes, irrespective of age and BMI. The incidence of type 2 diabetes increases substantially with increasing obesity; yet, PCOS adds a greater relative risk in lean women. Based on the overall moderate absolute clinical risk demonstrated here, guideline recommendations suggest type 2 diabetes screening every 1–3 years in all women with PCOS, across BMI categories and age ranges, with frequency influenced by additional type 2 diabetes risk factors.
Re: Bernard H. Bochner, Guido Dalbagni, Karim H. Marzouk, et al. Randomized Trial Comparing Open Radical Cystectomy and Robot-assisted Laparoscopic Radical Cystectomy: Oncologic Outcomes. Eur Urol 2018;74:465–71
Authors: Siebren Dijkstra, Carl J. Wijburg
Journal: European Urology (2019)
Patient-reported outcomes are important elements of psoriasis treatment decision making: A discrete choice experiment survey of dermatologists in the United States
Authors: Steven R. Feldman, Stephane A. Regnier, Alexandra Chirilov, Felix Hey, Isabelle Gilloteau, David Cella
Journal: Journal of the American Academy of Dermatology (2019)

Psoriasis Area and Severity Index (PASI) response rates have been the benchmark for evaluating treatment efficacy in trials involving moderate-to-severe psoriasis.To understand how dermatologists assess biologics and which trade-off rules they apply when planning psoriasis treatment.Two online surveys of 130 and 129 US dermatologists (surveys 1 and 2, respectively) were conducted with use of direct and indirect elicitation via discrete choice experiment. Respondents were asked to choose hypothetical biologics on the basis of 6 attributes (a ≥75% reduction from baseline in PASI score or a ≥90% reduction from baseline in PASI score, infection risk, dosing frequency, and 3 patient-reported outcomes [PROs] [relief of depression, relief of itching, and impact on usual activities]).Most dermatologists (74% in survey 1 and 76% in survey 2) reported using both PASI and PROs when selecting a biologic. PASI response rate was the most important attribute (35%-38% of overall decision weight), whereas combined PRO attributes had similar importance (36% of decision weight). Infection risk and dosing frequency influenced the decision to a lesser extent.Potential bias in considering 3 PROs versus 1 PASI rate and 1 safety attribute.PASI is most important for dermatologists selecting biologics, but PROs are also considered, especially when PASI response rate is similar between treatments. PRO data should be collected in trials involving moderate-to-severe psoriasis.
Outcomes in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): Longer-Term Follow-up Demonstrates Poor Outcomes in Patients with Skin-Only Presentation
Authors: Naveen Pemmaraju, Hagop M. Kantarjian, Joseph David Khoury, Susan M. O'Brien, Jorge E. Cortes, Guillermo Garcia-Manero, Elias J. Jabbour, Nitin Jain, Phyu Aung, C. Cameron Yin, Sergej Naumovich Konoplev, Keyur Patel, Sherry A. Pierce, Lingsha Zhou, Marina Y. Konopleva
Journal: Blood (2018)
The prognostic role of soluble transforming growth factor-β (sTGFb) and soluble programmed death-ligand 1 (sPDL1) in biliary tract cancer patients treated with binimetinib and capecitabine.
Authors: Jin Won Kim, Kyung-Hun Lee, Ji-Won Kim, Koung Jin Suh, Ah-Rong Nam, Ju-Hee Bang, Yung-Jue Bang, Do-Youn Oh
Journal: Journal of Clinical Oncology (2019)

257 Background: Transforming growth factor (TGF) -β signaling is important for tumor growth and metastasis in biliary tract cancer (BTC). TGF-β attenuates tumor response to programmed death-ligand 1 (PD-L1) blockade. This study aimed to evaluate a correlation between soluble TGF-β (s TGF-β) and soluble PD-L1 (sPD-L1) and its prognostic role in BTC. Methods: Study population consisted of 34 patients enrolled in phase Ib clinical trial of binimetinib (MEK inhibitor) with capecitabine in gemcitabine-pretreated BTC (ClinicalTrials.gov: NCT02773459). Blood samples at screening, after first cycle, after second cycle, and at disease progression were prospectively collected. Plasma sTGF-β and sPD-L1 values were measured by using an enzyme-linked immunosorbent assay. Results: In total 34 patients, 25 (73.5%) and 9 patients (26.5%) were second-line and third-line setting, respectively. Median progression-free survival (PFS) and overall survival (OS) were 4.1 and 7.8 months. The mean baseline sTGF-β and sPD-L1 were 18.7 ng/ml and 3.1 ng/ml. There was a positive correlation between sTGF-β and sPD-L1 value (pearson correlation = 0.596, p &lt; 0.001). Mean baseline value was likely to be higher in best response of progressive disease, followed by stable disease and partial response. Similarly, higher baseline sTGF-β showed significantly shorter PFS (3.4 vs 5.1 months (m), p = 0.047) and OS (5.4 vs 9.7 m, p = 0.042). Higher baseline sPD-L1 also had a trend for poor PFS and OS (PFS: 3.0 vs 4.3 m, p = 0.220; OS: 6.4 vs 9.7 m, p = 0.140). Regarding changes from baseline to after first cycle, sTGF-β change of &gt; 3.6 ng/ml demonstrated significantly shorter OS (5.9 vs 10.8 m, p = 0.020), although PFS did not differ according to sTGF-β change (p = 0.210). In contrast, OS did not differ according to sPD-L1 change (p = 0.190). sPD-L1 change &gt; -1.7 ng/ml even had longer PFS (5.1 vs 2.2 m, p = 0.005). Conclusions: In BTC patients with binimetinib and capecitabine, there is a positive correlation between sTGF-β and sPD-L1 value and higher baseline sTGF-β and sPD-L1 indicate a worse prognosis. The early change of sTGF-β and sPD-L1 during treatment could predict the survival.