tbuckley/cabot-search huggingface dataset:
A phase I trial and pharmacokinetic study of non-pegylated liposome-encapsulated doxorubicin citrate (NPLD) plus carboplatin in patients with recurrent gynecological and primary peritoneal tumors.
Authors: Andres Poveda, Ana Oaknin, Ignacio Romero, Angel Guerrero, Laura Calabuig, Jose Maria Del Campo
Journal: Journal of Clinical Oncology (2015)

5544 Background: Pegylated liposomal doxorubicin (PLD) plus carboplatin is one of the standard treatments for platinum-sensitive recurrent ovarian patients (pts). PLD shortage during 2012 and 2013 was determining in the need to search for an alternative doxorubicin combination with carboplatin. Non-pegylated Liposome-Encapsulated Doxorubicin Citrate (NPLD, Myocet) has been developed in the past decades with proved activity and limited skin-cardiac toxicity. Methods: This open multicentric dose-escalation phase I trial aimed to determine the maximum-tolerated dose (MTD) and the pharmacokinetic (PK) profile of Carboplatin+NPLD using a traditional 3+3 design. Main eligibility criteria: measurable or evaluable recurrent gynecological and primary peritoneal cancer (ca), ECOG: 0-2, normal organ function, no limited number of prior regimens, left ventricular ejection fraction (LVEF) > 50%. Prior anthracycline therapy permitted only for previous responders. Dose Limiting Toxicity (DLT) was defined as G4 hematologic and/or G3 febrile neutropenia and/or ³ G3 non-hematologic toxicity (NCI-CTCAE v4.03). If more than one DLT occurred at a specific dose level the previous dose level was defined as the MTD. Results: 22/23 evaluable pts were treated with NPLD (40, 50, 60, 70 mg/m2) and carboplatin (AUC 5) every 21 days. ECOG 0:14, 1: 8, 2:1. Median age: 57y (40-79). 9 pts had epithelial ovarian, 9 cervical, 5 endometrial ca. Number of prior regimens: 3 (1-7). Previous anthracycline: 7/22. MTD was LEDC 60mg/m2 + Carboplatin AUC 5. DLT were: NPLD 40mg/m2: G3 febrile neutropenia, (1/6); 50mg/m2: G4 thrombocytopenia (1/6); 60 mg/m2: G4 thrombocytopenia (1/6); 70mg/m2: G4 thrombocytopenia (1/4), G3 febrile neutropenia, (1/4). Other non-hematologic G2 toxicities were (%): asthenia (16), infection (7) and anorexia (5). No cardiotoxicity was reported. 1PR and 17SD at 8 weeks were observed. PK data will be presented at the Meeting. Conclusions: The MTD for NPLD when combined with carboplatin AUC 5 is 60mg/m2. The regimen is well tolerated, antitumor activity was observed. A phase-II study is ongoing. Clinical trial information: EudraCT: 2012-003173-25.
Optimizing personalized treatment sequences in metastatic castration resistant prostate cancer using tumor-biomarker based computational modeling.
Authors: Shilpa Gupta, Jill Gallaher, Conor Lynch, Leah Cook, Arturo Araujo, Jacob Scott, Jasreman Dhillon, Julio Pow-Sang, David Basanta
Journal: Journal of Clinical Oncology (2015)

e16014 Background: CRPC is a heterogeneous disease, and it is challenging to determine optimal treatment sequences. Mathematical modeling can integrate diverse clinical and biological data to offer personalized treatment for patients based on tumor characteristics. Methods: We considered AR, AKT, and JAK2/STAT5 mutations, which are frequently expressed in CRPC bone metastases and tested their IHC expression on 35 CRPC bone metastases samples collected between 2000 and 2010. Chart review was done for clinical information. A computational model was generated to predict response to standard and targeted therapies against these targets. The model captures tumor heterogeneity with regards to these targets, assuming up to 8 subpopulations based on presence or absence of AR, JAK2/STAT5, or AKT. The impact of hormones, chemotherapy, AKT inhibitor and JAK2 inhibitor were evaluated by solving simple ordinary differential equations (ODEs), which represent the number of each cell type, hormone level, and amount of bone formation over time. The model was validated and parameterized with our patient cohort. A genetic algorithm (GA) was used to optimize treatment options, personalizing them to the specific mCRPC patient. Results: The ODE system describes changes in CRPC bone metastases tumor population and bone microenvironment over time while the GA predicted the best treatment sequence based on biomarker features. The GA was applied repeatedly to evolve new, better solutions until the best fitness (best OS) for a specific patient was reached. These results were compared to the clinical outcomes of patients after standard of care therapies. Preliminary results recapitulate clinical findings and suggest the scope of identifying personalized treatment sequences. Conclusions: Our novel mathematical model may be a useful tool to determine the best treatment sequence to give mCRPC patients based on biomarkers involved in their disease progression. This tool should be further validated in prospective biomarker based studies in mCRPC to understand how best to sequence novel targeted drugs with standard therapies and improve outcomes.
‘Try to make good hay in the shade – it won't work!’ A qualitative interview study on the perspectives of Bavarian farmers regarding primary prevention of skin cancer
Authors: A. Zink, M. Schielein, M. Wildner, E.A. Rehfuess
Journal: British Journal of Dermatology (2019)

Extensive exposure to solar ultraviolet radiation (UVR) is the main risk factor for keratinocyte carcinoma (KC), making outdoor workers, including farmers, a high-risk population for KC. The use of sun protection is crucial for KC prevention but is not typically implemented by outdoor workers during their daily tasks.To explore the attitudes of Bavarian farmers regarding sun-protective measures in their daily work and to understand perceived barriers and unmet needs.Farmers were recruited through the Bavarian Farmers Association in Bavaria, Southern Germany. Qualitative semi structured interviews were conducted with participants between December 2017 and March 2018. Interviews were recorded, transcribed verbatim and analysed using qualitative content analysis.Twenty farmers (11 women, nine men; nine aged 18-30 years, 11 aged > 60 years) participated. Knowledge and awareness of UVR exposure and KC, perceived individual barriers to implementing sun-protective measures, individual experiences and farm life-specific circumstances emerged as key areas influencing the perspectives of farmers regarding the primary prevention of KC. Female farmers tended to take a more positive stance on sun protection, whereas male farmers showed a lower overall interest.Knowledge and awareness of KC and UVR exposure is very limited in Bavarian farmers with serious perceived barriers due to the demands of daily agricultural work. Further qualitative studies are needed to identify intervention options that can increase skin cancer awareness and that can successfully overcome real barriers to implementing sun protection.
Sustained release of exendin-4 from tannic acid/Fe (III) nanoparticles prolongs blood glycemic control in a mouse model of type II diabetes
Authors: Zhiyu He, Yizong Hu, Zaizhi Gui, Yang Zhou, Tianqi Nie, Jinchang Zhu, Zhijia Liu, Kuntao Chen, Lixin Liu, Kam W. Leong, Peng Cao, Yongming Chen, Hai-Quan Mao
Journal: Journal of Controlled Release (2019)
Intercepting the Lipid-Induced Integrated Stress Response Reduces Atherosclerosis
Authors: Umut I. Onat, Asli D. Yildirim, Özlem Tufanli, Ismail Çimen, Begüm Kocatürk, Zehra Veli, Syed M. Hamid, Kenichi Shimada, Shuang Chen, Jon Sin, Prediman K. Shah, Roberta A. Gottlieb, Moshe Arditi, Ebru Erbay
Journal: Journal of the American College of Cardiology (2019)

Eukaryotic cells can respond to diverse stimuli by converging at serine-51 phosphorylation on eukaryotic initiation factor 2 alpha (eIF2α) and activate the integrated stress response (ISR). This is a key step in translational control and must be tightly regulated; however, persistent eIF2α phosphorylation is observed in mouse and human atheroma. Potent ISR inhibitors that modulate neurodegenerative disorders have been identified. Here, the authors evaluated the potential benefits of intercepting ISR in a chronic metabolic and inflammatory disease, atherosclerosis. The authors investigated ISR’s role in lipid-induced inflammasome activation and atherogenesis by taking advantage of 3 different small molecules and the ATP-analog sensitive kinase allele technology to intercept ISR at multiple molecular nodes. The results show lipid-activated eIF2α signaling induces a mitochondrial protease, Lon protease 1 (LONP1), that degrades phosphatase and tensin-induced putative kinase 1 and blocks Parkin-mediated mitophagy, resulting in greater mitochondrial oxidative stress, inflammasome activation, and interleukin-1β secretion in macrophages. Furthermore, ISR inhibitors suppress hyperlipidemia-induced inflammasome activation and inflammation, and reduce atherosclerosis. These results reveal endoplasmic reticulum controls mitochondrial clearance by activating eIF2α-LONP1 signaling, contributing to an amplified oxidative stress response that triggers robust inflammasome activation and interleukin-1β secretion by dietary fats. These findings underscore the intricate exchange of information and coordination of both organelles’ responses to lipids is important for metabolic health. Modulation of ISR to alleviate organelle stress can prevent inflammasome activation by dietary fats and may be a strategy to reduce lipid-induced inflammation and atherosclerosis.
Urban air quality and health: two steps forward, one step back
Authors: Frank J. Kelly
Journal: European Respiratory Journal (2019)

Air pollution in the form of particulate matter (PM), nitrogen dioxide (NO2) and ground level ozone (O3) all cause harm to human health. Across Europe, high concentrations of these air pollutants continue to have a negative impact on citizens, especially those living in urban areas. Air pollution also has marked economic impacts, leading to shorter lives, increased medical costs and reduced productivity. Air pollution also negatively impacts ecosystems, damaging lakes and rivers, and reduces agricultural yields. Those who question the basis of the WHO health-based air quality guidelines need to consider the totality of evidence <http://ow.ly/aOpE30nVtuZ>
Radium 223 treatment in metastatic castrate-resistant prostate cancer: Impact of sequencing on survival—Real-world outcomes from a single United Kingdom center.
Authors: Xue Yan Jiang, Sarah Atkinson, Sam Cuming, Alexander Burns, Rachel Anne Pearson, John A. Frew, Ashraf S. Azzabi, Rhona Margaret McMenemin, Ian David Pedley
Journal: Journal of Clinical Oncology (2019)

223 Background: Radium 223 (Ra-223) is a FDA and EMA approved alpha particle radiopharmaceutical used to treat men with metastatic castrate resistant prostate cancer (mCRPC) with symptomatic bone metastasis. In view of emerging systemic options, new EMA 2018 licence indication is for 3 rd line onwards. We aim to evaluate the impact of systemic therapy sequencing on survival outcomes from a heterogeneous cohort of 228 patients treated with Ra-223 in a single UK centre. Methods: We prospectively collected data from 228 men underwent Ra-223 therapy for mCRPC between April 2014 and August 2018. Survival outcomes in relation to sequence of systemic treatment used prior to Ra-223 were analysed. Results: Medium age = 72 (51-87) years. Most patients (n = 142, 69%) received at least one systemic agent prior to Ra-223: docetaxel and/or cabaxitaxel chemotherapy (n = 60, 29%), abiraterone (n = 62, 30.1%) and enzalutamide (n = 67, 32.5%) in various sequences. No patients received concurrent Ra-223 /systemic treatment other than LHRH analogue. Key findings are summarized in table below. Conclusions: Our data demonstrated better survival trend in patients who received Ra-223 early. Patients who received prior chemotherapy have worse survival compared with those who were chemo-naïve likely due to bone marrow depletion. Ra-223 should not be offered to patients who have already had both cabaxitaxel and docetaxel as their medium survival is too poor to justify a treatment which takes 6 months to complete.[Table: see text]
Evaluating the clinical, environmental, genetic, and genomic profile of men with early-onset aggressive prostate cancer (PCa).
Authors: Ahmad Zarzour, Alicia K. Morgans, Philip Palmbos, Borko Jovanovic, Scott A. Tomlins, David James VanderWeele, Ximing J Yang, Edward M. Schaeffer, Roohollah Sharifi, Joshua J Meeks, Sarki Abdulkadir, Maha H. A. Hussain
Journal: Journal of Clinical Oncology (2020)

e17517 Background: Although PCa incidence has stabilized/decreased in most age groups, the incidence of metastatic disease has increased among men 50-69 years-old. The incidence of fatal PCa has decreased for most age groups, it has remained unchanged in men under 55 years-old. Studies have described genetic abnormalities in aggressive localized or end-stage PCa, but early-onset cases are not included or are under-represented. The primary objective of this study is to characterize the clinical, environmental, genetic and genomic features of high-risk advanced PCa. Methods: Study cohort includes men with PCa ≤ 60 years old with N1 or M1 stage at diagnosis or who develop metastases in 5-years after local therapy. Clinical (race, family history (Hx), environmental exposure), laboratory,/pathology, cell-free DNA germline analysis were collected. Primary/metastatic tumor tissue tested via the Tempus-Xe platform (DNA sequencing, whole transcriptome expression profiling, copy number analysis, comprehensive fusion gene analysis and calculation of tumor mutational burden). We report interim analysis. Results: Study completed accrual with 30 pts. Median age 55 years (41-60), 87% are white, 13% are black, 77% had a family Hx of malignancy in 1-6 family members, including 40% with family hx of PCa. Only 33% had Hx of smoking. Median Gleason score 9. Only 27% had nodal disease, and 73% had metastatic disease at diagnosis. Molecular data are available in 25 pts. Most common germline mutations: BRCA2 (12%), ATM (12%), RB1 (8%), MSH3 (8%) and MYBPC3 (8%). Most common somatic mutations:TP53 (40%), TMPRSS2-ERG fusion (32%), MUC4 (16%), PTEN (12%), C2CD4D (12%), SPOP (12%), OBSCN (12%), MXRA5 (12%), and MYO15A (12%). Microsatellite stability status was available in 15 pts and all were stable. Tumor mutational burden was low in all pts, ranging between 0.7 to 2.7 mutations/megabase. Conclusions: Our preliminary data suggest high rates of germline mutations in early onset lethal PCa. This aggressive subset of disease requires further studying to better characterize the underlying clinical/genomic factors driving this disease.
Prognostic value of HPV detection with three primer sets in 255 Head-Neck cancers.
Authors: Cristiana Lo Nigro, Daniela Vivenza, Martino Monteverde, Mirella Fortunato, Nerina Denaro, Laura Lattanzio, Federica Tonissi, Valentina Astesana, Elvio Russi, Marco Carlo Merlano
Journal: Journal of Clinical Oncology (2015)

6045 Background: HPV-related patients (pts) with locally advanced head and neck cancers (LA-HNCs) have a better prognosis than the HPV-negative ones. This study aimed to investigate the prevalence of HPV infection in a series of LA-HNCs and to compare the prognostic value of E1, E6 and L1 genomic viral fragments, each other, in order to find the best prognosticator among them in terms of Overall Survival (OS) and Progression Free Survival (PFS). Methods: HPV was searched in 255 LA-HNC pts, 89 Oropharyngeal cancers (OPCs) and 166 non-OPCs, by DNA-PCR on formalin-fixed paraffin-embedded (FFPE) tissues using three specific primer pairs for type 16. Each pt was analysed simultaneously for the three viral primer sets and for a housekeeping gene to determinate the integrity of tumour DNA samples. Results: One hundred and thirty six out of 255 pts (53.3%) were HPV positive with at least one of the primer pairs used; pos E6 (51%) and L1 (29.8%) samples were the most common; while pos E1 samples were lower (13.7%). OPCs showed a significant higher % of pos samples compared to non-OPCs for each primer set tested and the prevalence proportions for each fragment analysed were kept in both groups, with the highest for E6 and the lowest for E1. Therefore each pt highlighted variable positivity for E1, L1 and E6 viral fragments. In this sense OPCs showed the higher % of pos pts for the three viral fragments concurrently (31.5%) compared to non-OPCs (4.2%), moreover E1 detection was always associated with E6 and L1 one. In term of prognostic value analysed for each fragment by itself, only E1 pos OPC pts showed improved OS (p = 0.012) and PFS (p = 0.036), while pos L1 and E6 ones did not show any gain according with either viral status. Conclusions: Though prevalence in HPV infection by DNA-PCR was significantly higher for E6 and L1 primer sets, the detected pos viral fragments seemed very weak prognosticators; on the contrary E1 might become a stronger prognostic marker for OS and PFS in OPC pts. In conclusion E1 by DNA-PCR appears to be clinically relevant in the present series of pts.
Assessment of Employee Susceptibility to Phishing Attacks at US Health Care Institutions
Authors: William J. Gordon, Adam Wright, Ranjit Aiyagari, Leslie Corbo, Robert J. Glynn, Jigar Kadakia, Jack Kufahl, Christina Mazzone, James Noga, Mark Parkulo, Brad Sanford, Paul Scheib, Adam B. Landman
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Cybersecurity is an increasingly important threat to health care delivery, and email phishing is a major attack vector against hospital employees. <h3>Objective</h3> To describe the practice of phishing simulation and the extent to which health care employees are vulnerable to phishing simulations. <h3>Design, Setting, and Participants</h3> Retrospective, multicenter quality improvement study of a convenience sample of 6 geographically dispersed US health care institutions that ran phishing simulations from August 1, 2011, through April 10, 2018. The specific institutions are anonymized herein for security and privacy concerns. <h3>Exposures</h3> Simulated phishing emails received by employees at US health care institutions. <h3>Main Outcomes and Measures</h3> Date of phishing campaign, campaign number, number of emails sent, number of emails clicked, and email content. Emails were classified into 3 categories (office related, personal, or information technology related). <h3>Results</h3> The final study sample included 6 anonymized US health care institutions, 95 simulated phishing campaigns, and 2 971 945 emails, 422 062 of which were clicked (14.2%). The median institutional click rates for campaigns ranged from 7.4% (interquartile range [IQR], 5.8%-9.6%) to 30.7% (IQR, 25.2%-34.4%), with an overall median click rate of 16.7% (IQR, 8.3%-24.2%) across all campaigns and institutions. In the regression model, repeated phishing campaigns were associated with decreased odds of clicking on a subsequent phishing email (adjusted OR, 0.511; 95% CI, 0.382-0.685 for 6-10 campaigns; adjusted OR, 0.335; 95% CI, 0.282-0.398 for &gt;10 campaigns). <h3>Conclusions and Relevance</h3> Among a sample of US health care institutions that sent phishing simulations, almost 1 in 7 simulated emails sent were clicked on by employees. Increasing campaigns were associated with decreased odds of clicking on a phishing email, suggesting a potential benefit of phishing simulation and awareness. With cyberattacks increasing against US health care systems, these click rates represent a major cybersecurity risk for hospitals.
A phase Ib study of the anti-cancer stem cell agent demcizumab (DEM) &amp; gemcitabine (GEM) +/- paclitaxel protein bound particles (nab-paclitaxel) in pts with pancreatic cancer.
Authors: Manuel Hidalgo, Prasad Cooray, Michael B. Jameson, Alfredo Carrato, Francis Parnis, Mark Jeffery, Peter S. Grimison, Robert J. Stagg, Ann M. Kapoun, Jakob Dupont, Niall C. Tebbutt
Journal: Journal of Clinical Oncology (2015)

4118 Background: Delta-like ligand 4 (DLL4) activates the Notch pathway. DEM is a humanized IgG2anti-DLL4 antibody that inhibits tumor growth & decreases cancer stem cell frequency in human tumor xenograft models. In addition, DEM has an antiangiogenic effect & synergistic activity when combined with GEM & nab-paclitaxel in pt derived xenograft models of pancreatic cancer. Methods: Pts with 1st line pancreatic cancer were enrolled. Pts in cohorts 1-3 received DEM (2.5 every 2 or 4 wks or 5 mg/kg every 4 wks including 3 truncated pts) & GEM 1000 mg/m2 7 of 8 wks, then 3 of 4 wks. Pts in cohorts 4, 5 & 6 received truncated DEM (2.5, 3.5 or 5 mg/kg every 2 wks through Day 70) & nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m23 of 4 wks. The primary objective was to determine the MTD. Other objectives were safety, efficacy, immunogenicity, PK & biomarkers. Results: 47 pts were enrolled; 8, 8, 8, 6, 8 & 9 pts received 2.5 mg/kg every 2 wks, 2.5 mg/kg every 4 wks, 5 mg/kg every 4 wks, 2.5 mg/kg every 2 wks (truncated), 5 mg/kg every 2 wks (truncated) & 3.5 mg/kg every 2 wks (truncated), respectively. Related AEs in > 20% of pts were fatigue (38%), nausea (34%), vomiting (28%), decreased appetite (21%), hypertension (21%) & diarrhea (21%). Hypertension was managed with anti-hypertensives. Increased BNP is an early indicator of the cardiac effects of DEM & mildly elevated values were used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. One pt who received 5 mg/kg continuously developed reversible pulmonary hypertension & heart failure on day 143. As a result, DEM was limited to 70 days in cohorts 4, 5 & 6. In cohorts 1-3, 4 of 16 (25%) pts had a PR & 7 had SD. In cohorts 4, 5 & 6, 9 of 22 (41%) pts had a PR & 10 had SD. The median PFS for 2.5 & 5 mg/kg every 4 wks & 2.5 mg/kg, 2.5 mg/kg (truncated), 3.5 (truncated) & 5 mg/kg (truncated) every 2 wks were 1.7, 7, 3.4, 9.1, not reached & not reached, respectively. Conclusions: This therapy was generally well tolerated with fatigue, nausea & vomiting being the most common related AEs. Encouraging clinical activity was observed. Biomarker analysis showed pharmacodynamic modulation of the Notch pathway. Final data will be presented. Clinical trial information: NCT01189929.
Reversal of multidrug resistance by silencing ABCB1 using RNAi in the epirubicin-resistant gastric cancer cell subline AGS/EPI.
Authors: Nora Manoukian Forones, Aledson Vitor Felipe, Andrea Aparecida Moraes, Juliana Oliveira, Tiago Donizetti Silva
Journal: Journal of Clinical Oncology (2015)

e15046 Background: Gastric cancer (GC) is one of the most common malignancies worldwide. Acquired resistance to chemotherapy is an obstacle on GC therapy. Epirubicin (EPI) is extensively used despite its tendency to induce multidrug resistance (MDR) by overexpression of ABCB1 efflux pump. Modulating MDR and the disruption of the overexpression of drug-transporter proteins such as ABCB1 can be specifically done using RNA interference (RNAi) mechanism. Aim: to attempt the reverse of MDR by silencing ABCB1 expression using siRNAs in the EPI-resistant GC cell subline AGS/EPI. Methods: The AGS/EPI cells subline was developed exposing AGS cells to increasing concentrations of EPI. ABCB1 protein localization and evaluation of siRNA transfection efficiency were measured. The localization and fluorescence spectral properties of epirubicin were verified by Laser scanning confocal microscopy analysis. The relative mRNA expression of ABCB1 was determined using qRT-PCR. In vitro cytotoxicity assays were performed by MTT colorimetric assay. Apoptosis was measured by DNA fragmentation analysis, and trypan blue exclusion staining. Results: The ABCB1 mRNA expression levels in AGS/EPI cell subline was 1.9 times higher than AGS cells. In contrast, the ABCB1 gene knockdown cell line (AGS/EPI-siRNA) was 0.37 less resistant than AGS. The AGS/EPI cells showed low sensitivity to EPI and the AGS/EPI-siRNA showed a significant reduction of chemoresistance to EPI. We have clearly demonstrated that MDR can be reversed in the AGS/EPI cells, and these results can help future design for studies of chemoresistance in vitro in GC. Conclusions: ABCB1 knockdown using siRNA technology increases EPI sensitivity due to reduced EPI efflux in GC cells. These findings can be effectively applied to the development of siRNA therapies to reverse EPI resistance.