tbuckley/cabot-search huggingface dataset:
Phase IB Study of Osimertinib in Combination with Navitoclax in <i>EGFR</i>-mutant NSCLC Following Resistance to Initial <i>EGFR</i> Therapy (ETCTN 9903)
Authors: Erin M. Bertino, Ryan D. Gentzler, Sarah Clifford, Jill Kolesar, Alona Muzikansky, Eric B. Haura, Zofia Piotrowska, D. Ross Camidge, Thomas E. Stinchcombe, Christine Hann, Jyoti Malhotra, Liza C. Villaruz, Cloud P. Paweletz, Christie L. Lau, Lynette Sholl, Naoko Takebe, Jeffrey A. Moscow, Geoffrey I. Shapiro, Pasi A. Jänne, Geoffrey R. Oxnard
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Osimertinib is an effective therapy in EGFR-mutant non–small cell lung cancer (NSCLC), but resistance invariably develops. Navitoclax is an oral inhibitor of BCL-2/BCL-xL that has exhibited synergy with osimertinib in preclinical models of EGFR-mutant NSCLC. In hematologic malignancies, BCL-2 family inhibitors in combination therapy effectively increase cellular apoptosis and decrease drug resistance. Patients and Methods: This single-arm phase Ib study evaluated safety, tolerability, and feasibility of osimertinib and navitoclax, including dose expansion in T790M-positive patients at the recommended phase II dose (RP2D). Eligible patients had advanced EGFR-mutant NSCLC with prior tyrosine kinase inhibitor exposure. Five dose levels were planned with osimertinib from 40 to 80 mg orally daily and navitoclax from 150 to 325 mg orally daily. Results: A total of 27 patients were enrolled (18 in the dose-escalation cohort and nine in the dose-expansion cohort): median age 65, 67% female, 48% exon 19 del, and 37% L858R, median one prior line of therapy. The most common adverse events were lymphopenia (37%), fatigue (22%), nausea (22%), and thrombocytopenia (37%). No dose-limiting toxicities were seen in dose-escalation cohort; osimertinib 80 mg, navitoclax 150 mg was chosen as the RP2D. Most patients (78%) received &amp;gt;95% of planned doses through three cycles. In expansion cohort, objective response rate was 100% and median progression-free survival was 16.8 months. A proapoptotic effect from navitoclax was demonstrated by early-onset thrombocytopenia. Conclusions: Oral combination therapy with navitoclax and osimertinib was safe and feasible at RP2D with clinical efficacy. Early thrombocytopenia was common, supporting an target engagement by navitoclax. Further study of BCL-2/BCL-xL inhibition to enhance osimertinib activity is warranted.
Dissecting the effects of preconditioning with inflammatory cytokines and hypoxia on the angiogenic potential of mesenchymal stromal cell (MSC)-derived soluble proteins and extracellular vesicles (EVs)
Authors: Cansu Gorgun, Davide Ceresa, Raphaelle Lesage, Federico Villa, Daniele Reverberi, Carolina Balbi, Sara Santamaria, Katia Cortese, Paolo Malatesta, Liesbet Geris, Rodolfo Quarto, Roberta Tasso
Journal: Biomaterials (2020)
Will Cholesteryl Ester Transfer Protein Inhibition Succeed Primarily by Lowering Low-Density Lipoprotein Cholesterol?: Insights From Human Genetics and Clinical Trials⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Sekar Kathiresan
Journal: Journal of the American College of Cardiology (2012)
Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1–associated membranous nephropathy
Authors: George Haddad, Johan M. Lorenzen, Hong Ma, Noortje de Haan, Harald Seeger, Christelle Zaghrini, Simone Brandt, Malte Kölling, Urs Wegmann, Bence Kiss, Gábor Pál, Péter Gál, Rudolf P. Wüthrich, Manfred Wuhrer, Laurence H. Beck, David J. Salant, Gérard Lambeau, Andreas D. Kistler
Journal: Journal of Clinical Investigation (2020)

Primary membranous nephropathy (pMN) is a leading cause of nephrotic syndrome in adults. In most cases, this autoimmune kidney disease is associated with autoantibodies against the M-type phospholipase A2 receptor (PLA2R1) expressed on kidney podocytes, but the mechanisms leading to glomerular damage remain elusive. Here, we developed a cell culture model using human podocytes and found that anti-PLA2R1–positive pMN patient sera or isolated IgG4, but not IgG4-depleted sera, induced proteolysis of the 2 essential podocyte proteins synaptopodin and NEPH1 in the presence of complement, resulting in perturbations of the podocyte cytoskeleton. Specific blockade of the lectin pathway prevented degradation of synaptopodin and NEPH1. Anti-PLA2R1 IgG4 directly bound mannose-binding lectin in a glycosylation-dependent manner. In a cohort of pMN patients, we identified increased levels of galactose-deficient IgG4, which correlated with anti-PLA2R1 titers and podocyte damage induced by patient sera. Assembly of the terminal C5b-9 complement complex and activation of the complement receptors C3aR1 or C5aR1 were required to induce proteolysis of synaptopodin and NEPH1 by 2 distinct proteolytic pathways mediated by cysteine and aspartic proteinases, respectively. Together, these results demonstrated a mechanism by which aberrantly glycosylated IgG4 activated the lectin pathway and induced podocyte injury in primary membranous nephropathy.
Modeling human brain tumors in flies, worms, and zebrafish: From proof of principle to novel therapeutic targets
Authors: Uswa Shahzad, Michael S Taccone, Sachin A Kumar, Hidehiro Okura, Stacey Krumholtz, Joji Ishida, Coco Mine, Kyle Gouveia, Julia Edgar, Christian Smith, Madeline Hayes, Xi Huang, W Brent Derry, Michael D Taylor, James T Rutka
Journal: Neuro-Oncology (2020)

For decades, cell biologists and cancer researchers have taken advantage of non-murine species to increase our understanding of the molecular processes that drive normal cell and tissue development, and when perturbed, cause cancer. The advent of whole-genome sequencing has revealed the high genetic homology of these organisms to humans. Seminal studies in non-murine organisms such as Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio identified many of the signaling pathways involved in cancer. Studies in these organisms offer distinct advantages over mammalian cell or murine systems. Compared to murine models, these three species have shorter lifespans, are less resource intense, and are amenable to high-throughput drug and RNA interference screening to test a myriad of promising drugs against novel targets. In this review, we introduce species-specific breeding strategies, highlight the advantages of modeling brain tumors in each non-mammalian species, and underscore the successes attributed to scientific investigation using these models. We conclude with an optimistic proposal that discoveries in the fields of cancer research, and in particular neuro-oncology, may be expedited using these powerful screening tools and strategies.
Metachronous Contralateral Testicular Cancer in the Cisplatin Era: A Population-Based Cohort Study
Authors: Ragnhild Hellesnes, Tor Åge Myklebust, Roy M. Bremnes, Ása Karlsdottir, Øivind Kvammen, Helene F. S. Negaard, Torgrim Tandstad, Tom Wilsgaard, Sophie D. Fosså, Hege S. Haugnes
Journal: Journal of Clinical Oncology (2020)

PURPOSE It is hypothesized that cisplatin-based chemotherapy (CBCT) reduces the occurrence of metachronous contralateral (second) germ cell testicular cancer (TC). However, studies including treatment details are lacking. The aim of this study was to assess the second TC risk, emphasizing the impact of previous TC treatment. PATIENTS AND METHODS Based on the Cancer Registry of Norway, 5,620 men were diagnosed with first TC between 1980 and 2009. Treatment data regarding TC were retrieved from medical records. Cumulative incidences of second TC were estimated, and standardized incidence ratios were calculated. The effect of treatment intensity was investigated using Cox proportional hazard regression. RESULTS Median follow-up was 18.0 years, during which 218 men were diagnosed with a second TC after median 6.2 years. Overall, the 20-year crude cumulative incidence was 4.0% (95% CI, 3.5 to 4.6), with lower incidence after chemotherapy (CT) (3.2%; 95% CI, 2.5 to 4.0) than after surgery only (5.4%; 95% CI, 4.2 to 6.8). The second TC incidence was also lower for those age ≥ 30 years (2.8%; 95% CI, 2.3 to 3.4) at first TC diagnosis than those age &lt; 30 years (6.0%; 95% CI, 5.0 to 7.1). Overall, the second TC risk was 13-fold higher compared with the risk of developing TC in the general male population (standardized incidence ratio, 13.1; 95% CI, 11.5 to 15.0). With surgery only as reference, treatment with CT significantly reduced the second TC risk (hazard ratio [HR], 0.55). For each additional CBCT cycle administered, the second TC risk decreased significantly after three, four, and more than four cycles (HRs, 0.53, 0.41, and 0.21, respectively). CONCLUSION Age at first TC diagnosis and treatment intensity influenced the second TC risk, with significantly reduced risks after more than two CBCT cycles.
Genome-wide profiling of chromosomal aberrations in renal cell carcinoma using high-density single nucleotide polymorphism arrays
Authors: Meng Chen, Yuanqing Ye, Hushan Yang, Surena Matin, Nizar Tannir, Christopher Wood, Jian Gu, Xifeng Wu
Journal: Cancer Research (2008)

1699  Renal cell carcinoma (RCC) is one of the top ten leading causes of cancer death in the United States. Clear cell RCC (ccRCC) accounts for about 80% of all RCC cases. The accumulation of genetic aberrations plays a pivotal role in the initiation and progression of ccRCC and most other cancers. The identification of genetic aberrations may help understand the mechanisms of tumorigenesis and have implications for diagnosis, prognosis and treatment. SNP-CGH is a newly developed powerful tool to detect both copy number variations and LOH events. In this study, we applied Illumina’s 317K high-density SNP-arrays to profile chromosomal aberrations in tumors from 81 histologically confirmed RCC patients. Of the 81 tumors, 73 exhibited chromosome abnormalities. The most common chromosome losses were 3p, with 67 tumors (82.7%) having loss of heterozygosity (LOH) at 3p, including 35 ( 43.2%) whole 3p arm loss, 31 (38.3%) large fragment LOH (mostly spanning 3p21-pter), and 1 interstitial LOH (spanning 3p12-14, 3p21-22, and 3p24, but not including VHL gene in 3p25), followed by chromosome losses at 14q (29.6%), 8p21-pter (25.9%), 6q23-25 (24.7%), 1p36 (18.5%), 9q32-qter (16.1%), 10q26 (16.1%), and 9p21-23 (14.8%). The most frequent chromosome gains were at 5q (29 cases, 35.8%), including 9 whole chromosome arm 5q amplification, 19 common amplifications in 5q32-ter, and 1 focal amplification in 5q35.3 with a length 0.65MB. Two other common chromosome gains were at 5p (12.4%) and 8q (11.1%). We then analyzed the association of LOH/amplification events at each chromosome arm with clinicopathological characteristics. LOH at 13q and 9q exhibited significant associations with larger tumor size (rank sum p = 0.025 and 0.047, respectively). Significant associations of LOH at 9p (p = 0.002), 18q (p = 0.002), 17p (p = 0.011), 14q (p = 0.023), 8q (p = 0.033), 4q and 9q (p = 0.041 for both) were observed with higher nuclear grade. The percentage of samples with LOH at 2p at higher stage (18.52%) was significantly more than that at lower stage (3.8%) (p = 0.04). We also observed significantly positive association between tumor stage and LOH at 2p and 14q (p = 0.04 for both). No significant association was detected between amplification and any of the clinicopathological parameters. This is the first study to use high-density SNP-array CGH to profile whole-genome chromosome aberrations in RCC. The identified regions may lead to the discovery of novel genes involved in RCC development and progression. Supported by NCI grant CA098897.
68Ga-FAPI PET/CT Versus 68Ga-DOTATATE PET/CT in the Evaluation of a Patient With Neuroendocrine Tumor
Authors: Halil Kömek, Cihan Gündoğan, Canan Can
Journal: Clinical Nuclear Medicine (2020)

68Ga-FAPI (fibroblast activation protein-specific inhibitor) PET/CT was performed in a 56-year-old man with multiple liver masses, which were confirmed grade 2 well-differentiated neuroendocrine tumors with liver Tru-Cut biopsy. With 68Ga-DOTATE PET/CT, primary tumor in the pancreas, multiple metastases in the liver and metastatic portocaval lymph node were detected. In 68Ga-FAPI PET/CT imaging performed for comparison, it was seen that metastatic lesions in the liver were distinguished much better because of low background activity, and the primary tumor and metastatic lymph node were clearly selected. This case suggested that FAPI-bounded radionuclides may be useful in the evaluation and targeted therapy of neuroendocrine tumors.
Repair of the Congenitally Bicuspid Regurgitant Aortic Valve: A Strategic Advance⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Jeffrey S. Borer, Leonard N. Girardi
Journal: Journal of the American College of Cardiology (2008)
Maintaining Safety with SARS-CoV-2 Vaccines
Authors: Mariana C Castells, Elizabeth J Phillips
Journal: New England Journal of Medicine (2020)

The following table lists substances, other than active ingredients (i.e., antigens), shown in the manufacturers' package insert (PI) as being contained in the final formulation of each vaccine.Substances used in the manufacture of a vaccine but not listed as contained in the final product (e.g., culture media) can be found in each PI, but are not shown on this table.Each PI, which can be found on the FDA's website (see below) contains a description of that vaccine's manufacturing process, including the amount and purpose of each substance.In most PIs, this information is found in Section 11: "Description." Please refer to the PI for a complete list of ingredients or excipients.
The Treatment of Femoropopliteal In-Stent Restenosis: Back to the Future⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: John R. Laird, Khung Keong Yeo
Journal: Journal of the American College of Cardiology (2012)
Liver-targeted polymeric prodrugs of 8-aminoquinolines for malaria radical cure
Authors: Selvi Srinivasan, Debashish Roy, Thomas E.J. Chavas, Vladimir Vlaskin, Duy-Khiet Ho, Ayumi Pottenger, Clare L.M. LeGuyader, Mahdi Maktabi, Pamela Strauch, Conner Jackson, Siobhan M. Flaherty, Hsiuling Lin, Jing Zhang, Brandon Pybus, Qigui Li, Hans E. Huber, Paul A. Burke, David Wesche, Rosemary Rochford, Patrick S. Stayton
Journal: Journal of Controlled Release (2020)
COVID-19 in CKD: Retrospective, Propensity Score-Matched Cohort Study
Authors: Ahmet B. Dirim, Erol Demir, Serap Yadigar, Seda Safak, Ergün Parmaksız, Nurana Guller, Alpay Medetalibeyoglu, Ozgur A. Oto, Kubra Aydin Bahat, Meric Oruc, Seniha Basaran, Günseli Orhun, Halil Yazici, Aydin Turkmen
Journal: Journal of the American Society of Nephrology (2020)

Background: The prognostic factors for COVID-19 in patients with chronic kidney disease (CKD) are uncertain  We conducted a propensity score-matched study to compare clinical and prognostic features between hospitalized COVID-19 patients with and without CKD  Methods: Patients with estimated creatinine clearance below 60 ml/min/1 73 m2 for more than three months, were included in the CKD group  Fifty-six patients and the propensity score-matched fifty-six control patients were followed-up at least 15 days or until death after diagnosis of COVID-19  All demographic data and diagnostic and therapeutic methods were evaluated  The endpoints were all-cause mortality and acute kidney injury (AKI)  Results: Patient and control groups were reviewed retrospectively over a median follow-up of 44 days (IQR, 36-52 days) after diagnosis of COVID-19  Patients in the CKD group had higher intensive care unit follow-up and mortality rates than the other group, but these results did not reach statistical significance (16 [28 6%] vs  19 [33 9%];p=0 54 and 11 [19 6%] vs  16 [28 6%], p=0 269, respectively)  The frequency of AKI was significantly higher in predialysis patients with CKD compared to the other group (8 [14 3%] vs  5 [45 5%];p<0 001), but there was no significant difference between the groups in terms of cytokine release syndrome and respiratory failure (13 [23 2%] vs  8 [14 2%];p=0 226, 25 [44 6%] vs  22 [39 3%], p=0 566, respectively)  Multivariate logistic regression analysis revealed that respiratory failure (39 283 [95% CI, 7 296 to 211 519;P<0 001] and AKI (10 961 [95% CI, 1 688 to 71 186;P=0 012] were independent risk factors for the mortality  Conclusions: The prognosis of COVID-19 in patients with CKD is worse than non-uremic patients  Also, AKI and respiratory failure are independent risk factors for mortality
COVID-19 Outbreak and Experience in a Dialysis Unit in the Philippines
Authors: Ma. Anna Angelica S. Cruzado, Filoteo Ferrer
Journal: Journal of the American Society of Nephrology (2020)

Journal of the American Society of Nephrology 31(10S):p 266, October 2020. | DOI: 10.1681/ASN.20203110S1266a
Maternally Orphaned Children and Intergenerational Concerns Associated With Breast Cancer Deaths Among Women in Sub-Saharan Africa
Authors: Moses Galukande, Joachim Schüz, Benjamin O. Anderson, Annelle Zietsman, Charles Adisa, Angelica Anele, Groesbeck Parham, Leeya F. Pinder, Songiso Mutumba, Dorothy Lombe, Anna Cabanes, Milena Foerster, Isabel dos-Santos-Silva, Valerie McCormack
Journal: JAMA Oncology (2020)

Low breast cancer survival in sub-Saharan Africa's young population increases the likelihood that breast cancer deaths result in maternal orphans, ie, children (<18 years) losing their mother.
Making, Cloning, and the Expression of Human Insulin Genes in Bacteria: The Path to Humulin
Authors: Arthur D Riggs
Journal: Endocrine Reviews (2020)

In the mid- to late 1970s, recombinant deoxyribonucleic acid methods for cloning and expressing genes in E. coli were under intense development. The important question had become: Can humans design and chemically synthesize novel genes that function in bacteria? This question was answered in 1978 and in 1979 with the successful expression in E. coli of 2 mammalian hormones, first somatostatin and then human insulin. The successful production of human insulin in bacteria provided, for the first time, a practical, scalable source of human insulin and resulted in the approval, in 1982, of human insulin for the treatment of diabetics. In this short review, I give my personal view of how the making, cloning, and expressing of human insulin genes was accomplished by a team of scientists led by Keiichi Itakura, Herbert W. Boyer, and myself.
Using Metrics of Kilograms (or Pounds) Overweight or Kilograms (or Pounds) Obese to Help Interpret and Communicate Magnitudes of Excess Body Mass Index
Authors: Thomas N. Robinson
Journal: JAMA Pediatrics (2020)

Body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) has become the standard metric for assessing excess weight in clinical, public health, and research contexts because of its high levels of accessibility, mea-
Potential Molecular Targets in the Setting of Chemoradiation for Esophageal Malignancies
Authors: Salma K Jabbour, Terence M Williams, Mutlay Sayan, Eric D Miller, Jaffer A Ajani, Andrew C Chang, Norman Coleman, Wael El-Rifai, Michael Haddock, David Ilson, Daniel Jamorabo, Charles Kunos, Steven Lin, Geoffrey Liu, Pataje G Prasanna, Anil K Rustgi, Rosemary Wong, Bhadrasain Vikram, Mansoor M Ahmed
Journal: JNCI Journal of the National Cancer Institute (2020)

Although the development of effective combined chemoradiation regimens for esophageal cancers has resulted in statistically significant survival benefits, the majority of patients treated with curative intent develop locoregional and/or distant relapse. Further improvements in disease control and survival will require the development of individualized therapy based on the knowledge of host and tumor genomics and potentially harnessing the host immune system. Although there are a number of gene targets that are amplified and proteins that are overexpressed in esophageal cancers, attempts to target several of these have not proven successful in unselected patients. Herein, we review our current state of knowledge regarding the molecular pathways implicated in esophageal carcinoma, and the available agents for targeting these pathways that may rationally be combined with standard chemoradiation, with the hope that this commentary will guide future efforts of novel combinations of therapy.
An Automated Organoid Platform with Inter-organoid Homogeneity and Inter-patient Heterogeneity
Authors: Shengwei Jiang, Haoran Zhao, Weijie Zhang, Jiaqi Wang, Yuhong Liu, Yuanxiong Cao, Honghui Zheng, Zhiwei Hu, Shubin Wang, Yu Zhu, Wei Wang, Shuzhong Cui, Peter E. Lobie, Laiqiang Huang, Shaohua Ma
Journal: Cell Reports Medicine (2020)

Current organoid technologies require intensive manual manipulation and lack uniformity in organoid size and cell composition. We present here an automated organoid platform that generates uniform organoid precursors in high-throughput. This is achieved by templating from monodisperse Matrigel droplets and sequentially delivering them into wells using a synchronized microfluidic droplet printer. Each droplet encapsulates a certain number of cells (e.g., 1,500 cells), which statistically represent the heterogeneous cell population in a tumor section. The system produces >400-μm organoids within 1 week with both inter-organoid homogeneity and inter-patient heterogeneity. This enables automated organoid printing to obtain one organoid per well. The organoids recapitulate 97% gene mutations in the parental tumor and reflect the patient-to-patient variation in drug response and sensitivity, from which we obtained more than 80% accuracy among the 21 patients investigated. This organoid platform is anticipated to fulfill the personalized medicine goal of 1-week high-throughput screening for cancer patients.
Human saphenous vein provides a unique source of anti-calcific pericytes for prosthetic cardiac valve engineering
Authors: Eva Jover Garcia, Marco Fagnano, William R Cathery, Sadie C Slater, Emanuela Pisanu, Yue Gu, Elisa Avolio, Vito Domenico Bruno, Daniel Baz Lopez, Ashton R M Faulkner, Michele Carrabba, Gianni D Angelini, Paolo R Madeddu
Journal: European Journal of Heart Failure (2020)
Determinants of Use of Biotherapeutics in sub-Saharan Africa
Authors: Rajiv Shah, Dzifa Dey, Thomas Pietzonka, Paul Obeng, Bisola Ashiru, Martin Schiestl, Andrew Cavey, Edwin Nkansah, Guerric Radiere, Jonathan Spector, Christiaan Scott
Journal: Trends in Pharmacological Sciences (2020)