tbuckley/cabot-search huggingface dataset:
Abstract CT114: Pharmacokinetic analysis of navitoclax in combination with sorafenib in patients with relapsed or refractory solid organ tumors
Authors: Emily J. Koubek, Brian A. Costello, Jun Yin, Renee M. McGovern, Sarah A. Buhrow, Renee A. Schoon, Carrie A. Strand, Yixing Jiang, Mitesh J. Borad, Naoko Takebe, Scott H. Kaufmann, Alex A. Adjei, Joel M. Reid
Journal: Cancer Research (2020)

Abstract Prior in vitro work in the human hepatoma cell lines Huh7 and HEP3B indicated that combination treatment of the BH3 mimetic, navitoclax, and the multi-kinase inhibitor, sorafenib, was more effective at inducing apoptosis than either compound alone. This current study was part of a phase I clinical trial to determine the maximum tolerated dose of concurrent navitoclax and sorafenib treatment in patients with relapsed or refractory solid organ tumors and sought to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of both agents in combination. Cleavage of cytokeratin 18 by caspase 3 was used as a biomarker for therapy-induced activation of apoptosis to determine if combination treatment results in an increase in apoptosis as previously observed in in vitro work. PK were assessed in 26 patients (ages 32 - 80) enrolled in a phase I clinical trial (NCT02143401). 150 mg of oral navitoclax was administered once daily for a seven day run-in (beginning Day -7) prior to 150 mg (Dose level 1) or 200 mg (Dose level 2) navitoclax concomitant treatment with 400 mg of twice daily oral sorafenib (Day 1). Samples for pharmacokinetic analysis were obtained on Day -7 and Day 1 prior to dosing and at 1, 2, 4, 8-12, and 24 hours post dosing. PK parameters were estimated by noncompartmental analysis using Phoenix® WinNonlin® Version 6.4. To examine the PD of both agents in combination, cytokeratin 18 cleavage was quantified by ELISA after the 7-day navitoclax run-in and on Day 2 or 4 and Day 8 of navitoclax and sorafenib combination treatment. PK estimates of maximum concentration, exposure, volume of distribution, and clearance for navitoclax on Day -7 and Day 1 were not significantly different, indicating a lack of navitoclax accumulation. Finally, no correlation was found between navitoclax exposure and apoptosis as indicated by cytokeratin-18 cleavage. This work was supported by the NCI Cancer Center Support Grant P30 CA15083 and NCI Experimental Therapeutics Phase I Grant UM1 CA186686. Citation Format: Emily J. Koubek, Brian A. Costello, Jun Yin, Renee M. McGovern, Sarah A. Buhrow, Renee A. Schoon, Carrie A. Strand, Yixing Jiang, Mitesh J. Borad, Naoko Takebe, Scott H. Kaufmann, Alex A. Adjei, Joel M. Reid. Pharmacokinetic analysis of navitoclax in combination with sorafenib in patients with relapsed or refractory solid organ tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT114.
OP0136 DIAGNOSTIC VALUE OF ULTRASOUND IN CALCIUM PYROPHOSPHATE DEPOSITION DISEASE OF THE KNEE JOINT
Authors: Kyung Ann Lee, Sang-Heon Lee, Hae-Rim Kim
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The Outcome Measures in Rheumatology (OMERACT) US subtask force published a new definition for calcium pyrophosphate deposition (CPPD) at the knee level. <h3>Objectives</h3> To assess the diagnostic performance of ultrasound (US) for CPPD at the level of menisci, hyaline cartilage (HC), tendons, and synovial fluid (SF) of the knee, and to examine inter- and intra-observer reliability. <h3>Methods</h3> We consecutively included patients with knee effusion over a 2-year period (43 patients with CPPD and 131 controls). All patients underwent SF analysis, conventional radiography (CR), and US examination using the Outcome Measures in Rheumatology (OMERACT) definition of the US characteristics of CPPD. Two independent operators performed the US, and inter-observer agreement was calculated. Intra-observer agreement was examined with static images obtained for all enrolled patients. <h3>Results</h3> US revealed calcium pyrophosphate (CPP) deposits in menisci, HC, and tendon more frequently in patients with CPPD than in control patients. The presence of US CPP deposits in SF was not significantly different between the two groups. Combined US evaluation of the 3 components (menisci, HC, and tendon) showed the best diagnostic performance. The sensitivity and specificity for US evaluation of the three components were 74.4% and 77.1%, respectively, while for CR evaluation, the sensitivity and specificity were 44.2% and 96.9%, respectively. Inter- and intra-observer agreement were excellent for medial (κ=0.930, 0.972) and lateral menisci (κ=0.905, 0.942), HC (κ=0.844, 0.957), and SF (κ=0.817, 0.925). Tendon showed fair inter-observer (κ=0.532) and good intra-observer reliability (κ=0.788). <h3>Conclusion</h3> Based on the OMERACT definition, US demonstrated better diagnostic capacity than CR to diagnose CPPD, with excellent reliability. Combined evaluation of menisci, HC, and tendon showed the best diagnostic accuracy. <h3>Reference</h3> [1] Filippou G, Scire CA, Damjanov N, Adinolfi A, Carrara G, Picerno V, et al. Definition and Reliability Assessment of Elementary Ultrasonographic Findings in Calcium Pyrophosphate Deposition Disease: A Study by the OMERACT Calcium Pyrophosphate Deposition Disease Ultrasound Subtask Force. J Rheumatol2017; 44: 1744-1749. <h3>Acknowledgement</h3> This research was supported by the Basic Science Research Programs through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (2015R1D1A1A01056763 and 2015R1D1A1A09058510). The funders had no role in study design, data collection, data analysis, data interpretation, writing or decision to submit the manuscript. <h3>Disclosure of Interests</h3> None declared
Female Surgical Trainees and Departmental Awards
Authors: Allison N. Martin, Sharon L. Stein
Journal: JAMA Surgery (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Increasing Access for the Treatment of Eating Disorders Among College Students
Authors: Jess P. Shatkin
Journal: JAMA Network Open (2020)

Ellen E. Fitzsimmons-Craft, PhD; C. Barr Taylor, MD; Andrea K. Graham, PhD; Shiri Sadeh-Sharvit, PhD; Katherine N. Balantekin, PhD, RD; Dawn M. Eichen, PhD; Grace E. Monterubio, MA; Neha J. Goel, MS; Rachael E. Flatt, MA; Anna M. Karam, PhD; Marie-Laure Firebaugh, LMSW; Corinna Jacobi, PhD; Booil Jo, PhD; Mickey T. Trockel, MD, PhD; Denise E. Wilfley, PhD
Targeted Natural Killer Cell–Based Adoptive Immunotherapy for the Treatment of Patients with NSCLC after Radiochemotherapy: A Randomized Phase II Clinical Trial
Authors: Gabriele Multhoff, Sophie Seier, Stefan Stangl, Wolfgang Sievert, Maxim Shevtsov, Caroline Werner, A. Graham Pockley, Christiane Blankenstein, Martin Hildebrandt, Robert Offner, Norbert Ahrens, Konrad Kokowski, Matthias Hautmann, Claus Rödel, Rainer Fietkau, Dorota Lubgan, Rudolf Huber, Hubert Hautmann, Thomas Duell, Michael Molls, Hanno Specht, Bernhard Haller, Michal Devecka, Andreas Sauter, Stephanie E. Combs
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Non–small cell lung cancer (NSCLC) is a fatal disease with poor prognosis. A membrane-bound form of Hsp70 (mHsp70) which is selectively expressed on high-risk tumors serves as a target for mHsp70-targeting natural killer (NK) cells. Patients with advanced mHsp70-positive NSCLC may therefore benefit from a therapeutic intervention involving mHsp70-targeting NK cells. The randomized phase II clinical trial (EudraCT2008-002130-30) explores tolerability and efficacy of ex vivo–activated NK cells in patients with NSCLC after radiochemotherapy (RCT). Patients and Methods: Patients with unresectable, mHsp70-positive NSCLC (stage IIIa/b) received 4 cycles of autologous NK cells activated ex vivo with TKD/IL2 [interventional arm (INT)] after RCT (60–70 Gy, platinum-based chemotherapy) or RCT alone [control arm (CTRL)]. The primary objective was progression-free survival (PFS), and secondary objectives were the assessment of quality of life (QoL, QLQ-LC13), toxicity, and immunobiological responses. Results: The NK-cell therapy after RCT was well tolerated, and no differences in QoL parameters between the two study arms were detected. Estimated 1-year probabilities for PFS were 67% [95% confidence interval (CI), 19%–90%] for the INT arm and 33% (95% CI, 5%–68%) for the CTRL arm (P = 0.36, 1-sided log-rank test). Clinical responses in the INT group were associated with an increase in the prevalence of activated NK cells in their peripheral blood. Conclusions: Ex vivo TKD/IL2-activated, autologous NK cells are well tolerated and deliver positive clinical responses in patients with advanced NSCLC after RCT.
Uché Blackstock: dismantling structural racism in health care
Authors: Aarathi Prasad
Journal: The Lancet (2020)

Uché Blackstock's father, a Jamaican immigrant, arrived in New York State, USA, aged just 17 years. "Like many young immigrant men, he had a variety of jobs", she recalls, "he was a mechanic, a refrigerator repair person, [and] he finally went to a Brooklyn college, where he met our mom." Her mother, Dale Blackstock, was a physician who went to Harvard Medical School and practised in Brooklyn, but had to fight her way to college. "She grew up in poverty here in Brooklyn, where I was born, and where I live.
ALPPL2 Is a Highly Specific and Targetable Tumor Cell Surface Antigen
Authors: Yang Su, Xin Zhang, Scott Bidlingmaier, Christopher R. Behrens, Nam-Kyung Lee, Bin Liu
Journal: Cancer Research (2020)

Identification of tumor-specific cell surface antigens has proven challenging, as the vast majority of tumor-associated antigens are also expressed in normal tissues. In mesothelioma, we identified a highly specific tumor cell surface antigen that can be targeted for therapy development. Mesothelioma is caused by malignant transformation of the mesothelium, is incurable, and can be categorized into three histologic subtypes: epithelioid, biphasic, and sarcomatoid. To identity novel mesothelioma cell surface antigens with broad subtype coverage and high tissue specificity, we have previously selected phage antibody display libraries on live mesothelioma cells and tissues following counterselection on normal cells and identified a panel of human antibodies that bind all subtypes of mesothelioma, but not normal mesothelium. One of the antibodies, M25, showed high specificity against an antigen we identify here as ALPPL2. IHC on normal human tissues found that ALPPL2 is expressed only on placental trophoblasts, but not on any other normal tissues. This significant tissue specificity and broad tumor type coverage suggest that ALPPL2 could be an excellent cell surface target for therapeutic development against mesothelioma. To evaluate therapeutic potential of ALPPL2 targeting, an ALPPL2-targeted antibody-drug conjugate was developed and demonstrated potent and specific tumor killing
Diffusion Limited Cryopreservation of Tissue with Radiofrequency Heated Metal Forms
Authors: Zonghu Han, Anirudh Sharma, Zhe Gao, Timothy W. Carlson, M. Gerard O'Sullivan, Erik B. Finger, John C. Bischof
Journal: Advanced Healthcare Materials (2020)

Cryopreserved tissues are increasingly needed in biomedical applications. However, successful cryopreservation is generally only reported for thin tissues (≤1 mm). This work presents several innovations to reduce cryoprotectant (CPA) toxicity and improve tissue cryopreservation, including 1) improved tissue warming rates through radiofrequency metal form and field optimization and 2) an experimentally verified predictive model to optimize CPA loading and rewarming to reduce toxicity. CPA loading is studied by microcomputed tomography (µCT) imaging, rewarming by thermal measurements, and modeling, and viability is measured after loading and/or cryopreservation by alamarBlue and histology. Loading conditions for three common CPA cocktails (6, 8.4, and 9.3 m) are designed, and then fast cooling and metal forms rewarming (up to 2000 °C min-1 ) achieve ≥90% viability in cryopreserved 1-2 mm arteries with various CPAs. Despite high viability by alamarBlue, histology shows subtle changes after cryopreservation suggesting some degree of cell damage especially in the central portions of thicker arteries up to 2 mm. While further studies are needed, these results show careful CPA loading and higher metal forms warming rates can help reduce CPA loading toxicity and improve outcomes from cryopreservation in tissues while also offering new protocols to preserve larger tissues ≥1 mm in thickness.
KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden
Authors: D. Marinelli, M. Mazzotta, S. Scalera, I. Terrenato, F. Sperati, L. D'Ambrosio, M. Pallocca, G. Corleone, E. Krasniqi, L. Pizzuti, M. Barba, S. Carpano, P. Vici, M. Filetti, R. Giusti, A. Vecchione, M. Occhipinti, A. Gelibter, A. Botticelli, F. De Nicola, L. Ciuffreda, F. Goeman, E. Gallo, P. Visca, E. Pescarmona, M. Fanciulli, R. De Maria, P. Marchetti, G. Ciliberto, M. Maugeri-Saccà
Journal: Annals of Oncology (2020)
Abstract 4309: A novel immune prognostic index for the stratification of high-risk patients with early breast cancer
Authors: Hannah Lee, Mi Jeong Kwon, Beom-Mo Koo, Jinil Han, Young Kee Shin
Journal: Cancer Research (2020)

Abstract The prognostic or predictive value of current commercial multigene assays for breast cancer are limited to hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer. Despite the prognostic or predictive significance of immune response-related genes in breast cancer, immune gene signatures have not been incorporated into most current assays. Here, we developed a novel immune gene based-prognostic model to predict the risk of recurrence in high-risk women with early breast cancer. Using public gene expression microarray datasets for breast cancer, we classified breast cancer patients into three risk groups according to clinical risk and proliferation risk, and identified the most significant five immune response-related genes (TRAT1, IL2RB, CTLA4, IGHM and IL21R) associated with clinical outcome in the clinical and proliferation high-risk (CPH) subgroup. Immune prognostic index based on the combination of the expression of five immune response-related genes and lymph node status was developed to predict the risk of recurrence in high-risk breast cancer patients and its prognostic significance was validated in independent validation datasets. Disease-free survival (DFS) or distant metastasis-free survival (DMFS) of patients classified as high risk according to the immune prognostic index was significantly lower than those of patients classified as intermediate and low risk in the CPH group. Multivariate analysis demonstrated that the immune prognostic index is an independent prognostic factor for DFS or DMFS. Moreover, c-index showed that the immune prognostic index is superior to clinicopathological variables in predicting the prognosis. Our immune index was also prognostic in independent validation datasets. Our immune prognostic index identified low-risk patients among patients classified as CPH group in all molecular subtypes of breast cancer and may be used to overcome the limitations of the current multigene assay. Citation Format: Hannah Lee, Mi Jeong Kwon, Beom-Mo Koo, Jinil Han, Young Kee Shin. A novel immune prognostic index for the stratification of high-risk patients with early breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4309.
Inhibition of Pendrin by a small molecule reduces Lipopolysaccharide-induced acute Lung Injury
Authors: Eun Hye Lee, Mi Hwa Shin, Mia Gi, Jinhong Park, Doona Song, Young-Min Hyun, Ji-Hwan Ryu, Je Kyung Seong, Yoon Jeon, Gyoonhee Han, Wan Namkung, Moo Suk Park, Jae Young Choi
Journal: Theranostics (2020)

Rationale: Pendrin is encoded by SLC26A4 and its mutation leads to congenital hearing loss. Additionally, pendrin is up-regulated in inflammatory airway diseases such as chronic obstructive pulmonary disease, allergic rhinitis, and asthma. In this study, the effects of a novel pendrin inhibitor, YS-01, were investigated in an LPS-induced acute lung injury (ALI) mice model, and the mechanism underlying the effect of YS-01 was examined. Methods: Lipopolysaccharide (LPS, 10 mg/kg) was intranasally instilled in wild type (WT) and pendrin-null mice. YS-01 (10 mg/kg) was administered intra-peritoneally before or after LPS inhalation. Lung injury parameters were assessed in the lung tissue and bronchoalveolar lavage fluid (BALF). Pendrin levels in the BALF of 41 patients with acute respiratory distress syndrome (ARDS) due to pneumonia and 25 control (solitary pulmonary nodule) patients were also measured. Results: LPS instillation induced lung injury in WT mice but not in pendrin-null mice. Pendrin expression was increased by LPS stimulation both in vitro and in vivo. YS-01 treatment dramatically attenuated lung injury and reduced BALF cell counts and protein concentration after LPS instillation in WT mice. Proinflammatory cytokines and NF-κB activation were suppressed by YS-01 treatment in LPS-induced ALI mice. In BALF of patients whose ARDS was caused by pneumonia, pendrin expression was up-regulated compared to that in controls (mean, 24.86 vs. 6.83 ng/mL, P < 0.001). Conclusions: A novel pendrin inhibitor, YS-01, suppressed lung injury in LPS-induced ALI mice and our data provide a new strategy for the treatment of inflammatory airway diseases including sepsis-induced ALI.
Abstract 12283: Outcomes of Pediatric Patients Treated With Extracorporeal Membrane Oxygenation (ECMO) for Intractable Supraventricular Arrhythmias - a Report From the Extracorporeal Life Support Organization (ELSO) Registry
Authors: Stephanie Ghaleb, Ravi Thiagarajan, Richard Czosek, David S Cooper
Journal: Circulation (2018)

Background: ECMO is increasingly utilized to support refractory cardio-respiratory failure. ECMO can be used in post-operative patients with congenital heart disease (CHD) but also in otherwise hea...
Abstract 6216: Therapeutic potential of IAP inhibitor APG-1387 in combination with PARP- or MEK-targeted therapy, or chemotherapy in pancreatic cancer
Authors: Qiang Li, Douglas D. Fang, Shoulai Gu, Dajun Yang, Yifan Zhai
Journal: Cancer Research (2020)

Abstract APG-1387 is a small molecule antagonist of the inhibitor of apoptosis proteins (IAPs) which blocks the activity of IAPs family proteins (XIAP, cIAP-1, cIAP-2, and ML-IAP) and consequently induces apoptosis. It is currently in phase I clinical development in patients with solid tumors, including pancreatic cancer. Targeting IAPs has been reported to effectively inhibit tumor growth in the preclinical models of pancreatic cancer. Currently, PARP and MEK inhibitors are also in clinical development for pancreatic cancer with BRCA1/2 or KRAS mutations. To further explore the therapeutic potential of APG-1387 in combination with PARP or MEK inhibitors, a genomic biomarker guided avatar mouse trial (n=2) using pancreatic cancer patient-derived xenografts (PDX) was conducted to evaluate antitumor activity of APG-1387 in combination with (i) the PARP inhibitor, olaparib, in PDXs carrying BRCA1/2 mutations, and (ii) the MEK inhibitor, trametinib, in PDXs carrying KRAS mutations. The results revealed that APG-1387 improved the antitumor activity of olaparib in 4 out of 6 (67%) BRCA1/2 mutant PDXs with a 44% reduction of T/C (%) value (T, treatment group, C, vehicle control), including one partial tumor regression (PR). In combination with trametinib, the antitumor activity was improved in 4 out of 9 (44%) KRAS mutant PDXs, showing a 34% reduction in the T/C value. Furthermore, synergy of the combinations of APG-1387 with PARP or MEK inhibitor was confirmed in a follow-up efficacy study (n=5) using a PDX model carrying both BRCA2 and KRAS mutations. The molecular mechanisms underlying the synergy are currently being investigated. In summary, our results suggest that APG-1387 is a potential agent for pancreatic cancer treatment, ascribing to its potential synergistic antitumor effect by combining with either PARP inhibitors in BRCA1/2 mutant or MEK inhibitors in KRAS mutant pancreatic cancers. Overall, our data provide the scientific rationale for the future clinical development of these combinations in pancreatic cancer patients with distinct genomic alterations. Citation Format: Qiang Li, Douglas D. Fang, Shoulai Gu, Dajun Yang, Yifan Zhai. Therapeutic potential of IAP inhibitor APG-1387 in combination with PARP- or MEK-targeted therapy, or chemotherapy in pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6216.