tbuckley/cabot-search huggingface dataset:
Molecular design opportunities presented by solvent‐exposed regions of target proteins
Authors: Xiangyi Jiang, Ji Yu, Zhongxia Zhou, Jacob Kongsted, Yuning Song, Christophe Pannecouque, Erik De Clercq, Dongwei Kang, Vasanthanathan Poongavanam, Xinyong Liu, Peng Zhan
Journal: Medicinal Research Reviews (2019)

Abstract Solvent‐exposed regions, or solvent‐filled pockets, within or adjacent to the ligand‐binding sites of drug‐target proteins provide opportunities for substantial modifications of existing small‐molecular drug molecules without serious loss of activity. In this review, we present recent selected examples of exploitation of solvent‐exposed regions of proteins in drug design and development from the recent medicinal‐chemistry literature.
MPL nano-liposomal vaccine containing P5 HER2/neu-derived peptide pulsed PADRE as an effective vaccine in a mice TUBO model of breast cancer
Authors: Parvin Zamani, Jamshid Gholizadeh Navashenaq, Amin Reza Nikpoor, Mahdi Hatamipour, Reza Kazemi Oskuee, Ali Badiee, Mahmoud Reza Jaafari
Journal: Journal of Controlled Release (2019)
EHA Research Roadmap on Hemoglobinopathies and Thalassemia: An Update
Authors: Achille Iolascon, Lucia De Franceschi, Martina Muckenthaler, Ali Taher, David Rees, Mariane de Montalembert, Stefano Rivella, Androulla Eleftheriou, Maria Domenica Cappellini
Journal: HemaSphere (2019)

Abstract The inherited disorders of hemoglobin, which include sickle cell disease and thalassemias, are the most common and widespread distributed monogenic disorders. Due to a selective advantage in malaria regions, these hemoglobin defects are particularly frequent in Africa, Asia, or in the Mediterranean areas, where malaria was endemic until the last century. In recent decades, the globalization of migration has contributed to generate multiethnic European societies. Due to migration from countries or regions with high hemoglobinopathy frequencies such as Africa, Middle East, or Asia, large numbers of patients with these disorders are living in almost every European country today. Furthermore, the numbers are increasing because of increasing refugee flows toward Europe. Additional requirements are the development of European recommendations and guidelines for diagnosis and effective therapeutic approaches. These, together with the advancement of clinical trials using new drugs and therapeutic procedures could ameliorate the quality of life of patients affected with these diseases and increase their life expectancy. Lastly, coordinated efforts should be made to develop diagnostic pathways for thalassemias and hemoglobinopathies, in order to plan interventions, including prenatal diagnosis and cure. For these reasons, the development of new tools to reliably diagnose anemias is urgently needed and fits well with the needs of personalized medicine. In the last 15 years, hematology research has made many big leaps forward. Our general aim will be to solve several hematologic problems using these new approaches. We expect that the development of such a diagnostic tool will improve timely diagnosis throughout Europe, especially in those countries where it is difficult to gain access to “classical” diagnostic tests.
A Pilot Study of Liposomal Doxorubicin Combined with Bevacizumab followed by Bevacizumab Monotherapy in Patients with Advanced Kaposi Sarcoma
Authors: Ramya Ramaswami, Thomas S. Uldrick, Mark N. Polizzotto, Kathleen M. Wyvill, Priscila Goncalves, Anaida Widell, Kathryn Lurain, Seth M. Steinberg, William Douglas Figg, Giovanna Tosato, Denise Whitby, Robert Yarchoan
Journal: Clinical Cancer Research (2019)

VEGF-A is important in the pathogenesis of Kaposi sarcoma, and bevacizumab has a response rate of 31%. We explored the combination of bevacizumab with liposomal doxorubicin in patients with Kaposi sarcoma.
Non-invasive and repeatable EGFR analysis using novel enrichment method for circulating tumor cells.
Authors: Dong-Hyoung Lee, Sung Ho Choi, Du Yeol Han, Cham Han Lee, Soo Jeong Lee, Mi So Choi, Hyun Kyung Lee, Ga-Yun Kim, Pyeong-Soo Park, Jinseon Lee, Sung Man Yoon, Byung Hee Jeon
Journal: Journal of Clinical Oncology (2015)

e22033 Non-invasive and repeatable EGFR analysis using novel enrichment method for circulating tumor cells Background: The first-line treatment in confirmed NSCLC (non-small cell lung cancer) patients harboring EGFR mutation is the epidermal growth factor receptor inhibitors (EGFR-TKIs) therapy. A bronchoscopy with transbronchial biopsy or CT guided needle biopsy for EGFR mutation screening may accompany complication, such as infection, bleeding or pneumothorax. However, use of enriched circulating tumor cells (CTCs) from patients’ blood might overcome these risks by means of non-invasive and repeated EGFR mutation analysis. Methods: The blood samples (10 ml) were obtained from NSCLC patients harboring EGFR mutation, and processed through Cytogen Protocolto enrich CTCs. In brief, peripheral blood mononuclear cell fraction was passed through micro fabricated porous filter (CytoGen), and EpCAM antibody was used for positive selection. The identification of enriched CTC was performed by immunofluorescent staining for EpCAM, CD45 and DAPI. The DNAs were extracted from enriched CTCs and used as templates for multi-step real-time PCR. The LOD (limit of detection) values were optimized in spike-in experiments. And, the mutation was identified by both EGFR dependent Real-time PCR and sequencing. Results: The recovery rate by micro fabricated porous filters was about 80% in spike-in experiments for establishing platform. The EGFR mutations were detected by multi-step Real-time PCR method in as low as 10~20 cells per ml of blood. The DNAs ( > 350 ng) were obtained from enriched CTCs through micro fabricated porous filter, pre-amplified, and analyzed for at least 7 mutations using real-time PCR. Among other EGFR mutations, deletion of exon 19 and L858R point mutation are commonly detected. However, the mutation relevant to exon 18 was not detected. Conclusions: In this study, we showed that CTCs enriched using micro fabricated porous filter can be used for EGFR mutation analysis. This new approach may provide insight establishing the personalized cancer therapeutic strategies based on them to molecular profiles in NSCLC. Background: Methods: Results: Conclusions:
SAT-319-Fibroblast growth factor 21 is independently associated with severe hepatic steatosis in non-obese HIV-infected patients
Authors: Michael Praktiknjo, Djayadi Natalie, Bischoff Jenny, Mohr Raphael, Robert Schierwagen, Alessandra Pohlmann, Carolynne Schwarze-Zander, Jan-Christian Wasmuth, Christoph Boesecke, Jürgen Rockstroh, Jonel Trebicka
Journal: Journal of Hepatology (2019)
Safety of biosimilar filgrastim in patients with breast cancer undergoing neutropenia-inducing chemotherapy: A subanalysis of the NEXT study.
Authors: Stephane Leprêtre, Frederic Maloisel, Didier Kamioner, Christian Berthou, Helene Albrand
Journal: Journal of Clinical Oncology (2015)

e20711 Background: Febrile neutropenia (FN) is a major risk factor for infection-related morbidity/mortality as well as a dose-limiting toxicity in patients (pts) undergoing chemotherapy (CT). Biosimilar filgrastim (Nivestim, Hospira Inc.) is a granulocyte-colony stimulating factor licensed for the treatment of neutropenia and FN induced by myelosuppressive CT. NEXT (Nivestim safety profile in patiEnts treated with cytotoXic CT in real-life clinical pracTice) assessed the safety of biosimilar filgrastim in pts undergoing CT for malignancies. Methods: NEXT was a prospective, non-interventional, longitudinal, multicentre study conducted in France to evaluate the safety of biosimilar filgrastim. Recorded data included demographic and clinical characteristics, biosimilar filgrastim treatment-related data on efficacy and safety, such as adverse events (AEs) and FN. Pts were monitored for 1–6 CT cycles with three visits at inclusion, during treatment, and following CT. Here we present data for pts with breast cancer. Results: 2114 pts were enrolled in the study; 463 pts with breast cancer were included in this analysis. Mean age ± standard deviation was 58.4±12.0 years (97.0% female). At inclusion, 74.8% of pts had a stage 0, I, II or III tumour and 19.4% had a metastatic tumour. The most common CT regimen was FEC-D. The majority (98.1%) of pts received prophylactic biosimilar filgrastim. In the prophylactic group (n = 454), median time to initiation of biosimilar filgrastim was 2 days after the last CT dose; mean treatment duration was 5.6±2.6 days. In this group, 4.7% experienced FN and 1.6% had an infection; FN and/or infection led to hospitalisation of 4.7% of pts (mean duration: 4.6±2.5 days), a CT dose reduction in 2.7% and a CT delay in 5.2% of pts. In this analysis, 26.1% of pts had ≥ 1 AE; 18.5% reported musculoskeletal disorders. Pts with breast cancer displayed similar rates of FN but had more AEs and bone, chest and muscle pains vs the overall population (4.9%, 20.4% and 12.7%, respectively in the overall population). Conclusions: Biosimilar filgrastim was effective and well-tolerated in breast cancer pts and is an alternative therapeutic option for CT-induced neutropenia. Clinical trial information: NCT01574235.
Real-world experience of ALK positive NSCLC from India
Authors: M. Malhotra, V. Noronha, A. Joshi, V. Patil, S. Wadhwa, K. Prabhash
Journal: Annals of Oncology (2019)

Background: ALK gene rearranged lung cancer is a rare subset of NSCLC. However, treatment with ALK inhibitors leads to a drastic improvement in outcomes. In this study, we have audited the outcomes of patients with ALK-rearranged NSCLC at our institute. Methods: We conducted an audit of patients with ALK-rearranged NSCLC diagnosed between November 2011–December 2017 from a prospective database of lung cancer patients maintained by the authors. The basic demographic characteristics, treatment received, and the outcomes were noted. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan Meier method. This study was approved by the institutional ethics committee and was carried out in accordance with good clinical practice guidelines and the Declaration of Helsinki. Results: We diagnosed 318 ALK-positive patients during November 2011–December 2017. The median age was 50 years (23-77 years); 189 patients (59.4%) were male and 129 (41.6%) were female. Only 57 (17.9%) were smokers. The ECOG PS was 0-1 in 195 patients (61.3%), 2 in 46 (14.5) and 3-4 in 33 (10.4%). Data on PS was missing in 44 patients (13.8%). The median number of sites of metastasis was 2 (0-7); brain metastases were seen in 38 patients (11.9%). The first line treatment received was as follows: crizotinib (either upfront or as a switch after a few cycles of doublet chemotherapy) in 202 patients (63.5%), pemetrexed platinum in 72 (22.6%), taxane platinum in 5 (1.6%), gemcitabine platinum in 5 (1.6%) and others in 33 (10.7%). The median PFS and median OS for the entire cohort was 11.0 months and 34.2 months, respectively. The hazard ratio (HR) favoured using crizotinib upfront (0.5, 95% CI 0.38-0.67, p < 0.001). Patients receiving upfront crizotinib had better PFS compared to those who received crizotinib as a switch after a few cycles of chemotherapy (HR: 0.66 (0.44-0.99) p-0.040). However, the median OS was similar between the two treatment strategies for crizotinib (p-0.964). The median OS in patients who never received crizotinib was 11.0 months while OS was not reached in patients who received crizotinib in any line (p< 0.001). The 5-year OS in patients receiving crizotinib in any line was 50.0%. Conclusions: Crizotinib substantially improves outcomes in patients with ALK-rearranged NSCLC and is a suitable option where other ALK inhibitors are not available. Legal entity responsible for the study: IEC, TMH. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
FRI-158-Bone and renal safety are improved in chronic HBV patients switched to tenofovir alafenamide (TAF) after either 2 or 3 years of prior tenofovir disoproxil fumarate (TDF) treatment
Authors: Maria Buti, Namiki Izumi, Young-Suk Lim, Harry Janssen, Jia-Horng Kao, Adrian Streinu-Cercel, Elena Nurmukhametova, Xiaoli Ma, Tabak Fehmi, Maciej Jablkowski, Vithika Suri, John F. Flaherty, Audrey Lau, Anuj Gaggar, Shuyuan Mo, Abhijit Chaudhuri, Scott Fung, Wan-Long Chuang, Edward Gane
Journal: Journal of Hepatology (2019)
Pilot project to determine the predictive value of microRNAs in breast cancer brain metastases.
Authors: Zarah Dulce Francisco Lucas, Narayan Shivapurkar, Akash Mukherjee, Anton Wellstein, Sameer Desale, Pia Maarit Herbolsheimer
Journal: Journal of Clinical Oncology (2015)

e22059 Background: Brain metastases are more common in HER2-positive and triple-negative breast cancer patients. Biomarkers, such as microRNA, may help predict which breast cancer patients will develop brain metastases. The aim of our study was to identify a microRNA signature in the primary breast tumor that predicts subsequent development of brain metastases. Methods: Formalin-fixed, paraffin-embedded (FFPE) primary breast tissue samples were collected from breast cancer patients diagnosed from 3 centers between years 2000-2011 who fell into the following subgroups: Triple negative breast cancer (TNBC) with brain metastases, Her2-positive breast cancer with brain metastases, TNBC with non-brain metastases and Her2-positive breast cancer with non-brain metastases. Total RNA was extracted using Qiagen’s miRNeasy FFPE kit. MicroRNA expression profiling was done through hybridization using Exiqon’s miRCURY LNA microRNA Array system. MicroRNA profiles from patients with brain metastases were compared to those with non-brain metastases using t-test. Cox proportional regression analysis was applied to determine association of microRNA with time to metastases and death. Results: Of 47 samples collected, 36 met criteria for concentration and RNA quality by absorption ratio using Nanodrop. Of the 36 samples, 8 were TNBC with brain metastases, 6 were Her2-positive with brain metastases, 12 were TNBC with non-brain metastases and 10 were Her2-positive with non-brain metastases. MicroRNA profiling did not identify significant differentially expressed microRNAs in the brain metastases compared to non-brain metastases samples out of 947 microRNAs analyzed. There was also no significant association between microRNA expression and time to metastases or death. Comparison of all TNBC to all Her2-positive samples revealed 62 microRNAs differentially expressed between the groups. Conclusions: MicroRNA profiling did not identify a signature that would predict development of brain metastases. The results may be due to small sample size. MicroRNAs were significantly different between the TNBC and Her2-positive samples, which are expected due to different genetic drivers of the tumorigenesis.
Implementation of organized lung cancer screening program in Korea
Authors: Y. Kim
Journal: Annals of Oncology (2019)

Background: Lung cancer is the leading cause of cancer mortality worldwide and has a low survival rate due to difficulties cocnerning early detection. The Korean Lung Cancer Screening demonstration project (K-LUCAS) was started in February 2017. K-LUCAS will assess the effectiveness, harm, and feasibility of lung cancer screening in order to implement a population-based screening program. K-LUCAS will evaluate the validation of the new standard of reporting form of low-dose computed tomography (LDCT) and the quality of lung cancer screening by a web-based network system using computer-aided nodule detection program (CAD). Methods: K-LUCAS is a population-based single arm trial conducted in 14 cancer hospitals that targets a high-risk population aged 55-74 years with at least 30 pack-year smoking history within the last 15 years. Participants were recruited when visiting the national cancer screening center or smoking cessation clinics based on a lung cancer risk evaluation questionnaire. Lung cancer screening was provided by LDCT with at least a 16-row multidetector CT scanner and screening results were reported by Lung Imaging Reporting and Data System (Lung-RADS). All participants should have their results explained to them by a physician and current smokers should receive smoking cessation counselling. Results: Up until November 2018, 13,491 participants had joined K-LUCAS. The positive screening rate (categories 3 and 4 in Lung-RADS) was 15.3%. Among these, 69 lung cancers were detected and stage I and II lung cancers were 53.6% and 15.9%, respectively. CAD detects more positive findings but decreases the variation of positive rate among screening units. About 75% of abnormal findings, including emphysema, coronary artery calcification etc. besides lung nodules, were detected in K-LUCAS. Conclusions: K-LUCAS shows promising results in effective detection of early stage lung cancer and controlling diagnosis quality by a web-based network system. Based on the observations from K-LUCAS, a decision will be made as to whether lung cancer screening will be included in national cancer screening program. Clinical trial identification: NCT03394703. Legal entity responsible for the study: The author. Funding: Ministry of Health and Welfare, Republic of Korea. Disclosure: The author has declared no conflicts of interest.
Non-small cell lung carcinoma (NSCLC) patients with baseline brain imaging: A prospective observational study
Authors: N. Gundu, P.S. Malik, S. Khurana, S. Pathy, M. Yadav, D. Jain, H. Kancharla
Journal: Annals of Oncology (2019)

Background: Brain metastases in NSCLC patients is the major cause of the poor survival and quality of life. Symptomatic brain metastasis at baseline are present in 5-10% of NSCLC and over the time course about 40% patients develop brain metastasis. Screening for asymptomatic brain metastasis in advanced NSCLC is controversial. Here we present our initial experience of mandatory brain imaging of all NSCLC patients irrespective of CNS symptoms and stage. Methods: It is a prospective observation study of NSCLC patients with mandatory baseline brain imaging. Data was analysed for patients enrolled in the study from Jan 2018- Nov 2018. All patients with histology proven NSCLC were incuded irrespective of stage. Brain imaging was performed by CECT. A comprehensive CNS examination was performed at diagnosis. All statistical analysis was done by STATA version 13.Univariate analysis was done by Cox regression model. Results: There were 238 patients enrolled. Median age was 58yrs (range 26-83yrs) with male predominance (n = 183, 76.9%). Smokers were 65.1% (n = 153) and majority had ECOG PS 1&2 (82%). Most common histology was adenocarcinoma - 64.6% (n = 151). EGFR mutation could be tested in 98 of adenocarcinoma patients and was positive in 32 (32.6%). ALK (IHC-D5F3) was tested in 78 patients and was positive in 11 (14.1%). Majority patients had stage 4 disease, 74.8% (n = 176). There was upstaging to stage 4 after brain imaging in 8% (n = 20) patients. Brain metastases was present in 22.7% (n = 54) of which 52% (n = 28) were asymptomatic. Majority had solitary lesion - 48% (n = 26), predominatly located supratentorially - 66% (n = 36). Majority of these patients received chemotherapy - 46.2% (n = 25), TKI -27.7% (n = 15), WBRT -14.8%(n = 8), BSC -22.2% (n = 12). Univariate analyses was done for age, sex, histological subtype, EGFR and ALK status, out of which younger age (<40 yrs) and adenocarcinoma histology were found to be significant predictors for presence brain metastases. Conclusions: Brain metastasis with mandatory baseline brain imaging (atleast CECT) were found in 22.7% patients in our study and resulted in upstaging of disease in 8%. Frequency of brain metastasis were significantly higher in adenocarcinoma histology and younger age (<40 yrs). Legal entity responsible for the study: All India Institute of Medical Sciences. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
The ERUS Curriculum for Robot-assisted Partial Nephrectomy: Structure Definition and Pilot Clinical Validation
Authors: Alessandro Larcher, Geert De Naeyer, Filippo Turri, Paolo Dell’Oglio, Umberto Capitanio, Justin W. Collins, Peter Wiklund, Henk Van Der Poel, Francesco Montorsi, Alexandre Mottrie
Journal: European Urology (2019)
Risk Factors for Major Adverse Cardiovascular Events in Phase <scp>III</scp> and Long‐Term Extension Studies of Tofacitinib in Patients With Rheumatoid Arthritis
Authors: Christina Charles‐Schoeman, Ryan DeMasi, Hernan Valdez, Koshika Soma, Lie‐Ju Hwang, Mary G. Boy, Pinaki Biswas, Iain B. McInnes
Journal: Arthritis & Rheumatology (2019)

Objective Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis ( RA ). This study was undertaken to evaluate the risk of major adverse cardiovascular events ( MACE ) in patients with RA receiving tofacitinib. Methods Data were pooled from patients with moderately to severely active RA receiving ≥1 tofacitinib dose in 6 phase III and 2 long‐term extension studies over 7 years. MACE (myocardial infarction, stroke, cardiovascular death) were independently adjudicated. Cox regression models were used to evaluate associations between baseline variables and time to first MACE . Following 24 weeks of tofacitinib, changes in variables and time to future MACE were evaluated after adjusment for age, baseline values, and time‐varying tofacitinib dose. Hazard ratios and 95% confidence intervals were calculated. Results Fifty‐two MACE occurred in 4,076 patients over 12,873 patient‐years of exposure (incidence rate 0.4 patients with events per 100 patient‐years). In univariable analyses of baseline variables, traditional cardiovascular risk factors and glucocorticoid and statin use were associated with MACE risk; disease activity and inflammation measures were not. In subsequent multivariable analyses, baseline age, hypertension, and the total cholesterol to high‐density lipoprotein ( HDL ) cholesterol ratio remained significantly associated with risk of MACE . After 24 weeks of treatment, an increase in HDL cholesterol and a decrease in the total to HDL cholesterol were associated with decreased MACE risk; changes in total cholesterol, low‐density lipoprotein ( LDL ) cholesterol, and disease activity measures were not. Increased erythrocyte sedimentation rates trended with increased future MACE risk. Conclusion In this post hoc analysis, after 24 weeks of tofacitinib treatment, increased HDL cholesterol, but not increased LDL cholesterol or total cholesterol, appeared to be associated with lower future MACE risk. Further data are needed to test the cardiovascular safety of tofacitinib.
TCTAP A-092 Non-invasive Evaluation of Global and Territorial Coronary Vascular Function: Association with Diastolic Function
Authors: Bryan M.H. Keng, Felix Y.J. Keng, X.F. Teng, Loy L. Shan, Ru San Tan, L Baskaran, Terrance S.J. Chua, Angela S. Koh
Journal: Journal of the American College of Cardiology (2019)