tbuckley/cabot-search huggingface dataset:
Potentiation of trastuzumab emtansine (T-DM1)-driven antitumor activity by pertuzumab in a HER2-positive gastric cancer model.
Authors: Yoriko Yamashita-Kashima, Sei Shu, Naoki Harada, Kaori Fujimoto-Ouchi
Journal: Journal of Clinical Oncology (2012)

e13502 Background: The efficacy and safety of T-DM1 combined with pertuzumab in HER2-positive breast cancer is currently being investigated in a phase III clinical trial (MARIANNE). Anti-HER2 therapy with T-DM1 combined with pertuzumab in HER2-positive gastric cancer is of great interest. In a previous study in a HER2-positive gastric cancer xenograft model, T-DM1 in combination with pertuzumab demonstrated enhanced antitumor activity compared with each agent alone, and potentiated ADCC and apoptosis activity (AACR, 2011). In this study, we investigated the mechanisms underlying the enhanced activity observed with these two drugs. Methods: The binding of T-DM1 to cell surface HER2 was measured in a HER2-positive human gastric cancer cell line (NCI-N87) by flow cytometry using Alexa Fluor 647-labeled T-DM1. The phosphorylation status of HER signaling molecules was assessed by Western blot, and cellular localization of T-DM1 was determined by fluorescence microscopy using labeled T-DM1 in the presence/absence of pertuzumab. Results: Binding of T-DM1 to cell surface HER2 was significantly increased in the presence of pertuzumab. Concomitant treatment with T-DM1 and pertuzumab led to a reduction of phosphorylated (p)EGFR or pHER3 in EGF or heregulin-stimulated cells, respectively, resulting in suppression of downstream pERK or pAkt pathways. Fluorescence microscopy revealed that pertuzumab facilitated the internalization of HER2-bound T-DM1 from the cell surface into the cytoplasm. Conclusions: Results suggest that the enhanced antitumor activity observed with the combination of T-DM1 and pertuzumab may be attributed to 1) increased binding of T-DM1 to HER2, which could potentially augment ADCC and diminish downstream HER2-signaling, and 2) increased T-DM1 internalization into the cytoplasm, which may potentiate tumor cell death caused by DM1. These results suggest that T-DM1 in combination with pertuzumab may provide clinical benefit for patients with HER2-positive gastric cancer.
<sup>18</sup>F-FDG PET/CT Radiomic Analysis with Machine Learning for Identifying Bone Marrow Involvement in the Patients with Suspected Relapsed Acute Leukemia
Authors: Hebei Li, Chongrui Xu, Bowen Xin, Chaojie Zheng, Yunyun Zhao, Keji Hao, Qian Wang, Richard L. Wahl, Xiuying Wang, Yun Zhou
Journal: Theranostics (2019)

18 F-FDG PET / CT is used clinically for the detection of extramedullary lesions in patients with relapsed acute leukemia (AL).However, the visual analysis of 18 F-FDG diffuse bone marrow uptake in detecting bone marrow involvement (BMI) in routine clinical practice is still challenging.This study aims to improve the diagnostic performance of 18 F-FDG PET/CT in detecting BMI for patients with suspected relapsed AL.Methods: Forty-one patients (35 in training group and 6 in independent validation group) with suspected relapsed AL were retrospectively included in this study.All patients underwent both bone marrow biopsy (BMB) and 18 F-FDG PET/CT within one week.The BMB results were used as the gold standard or real "truth" for BMI.The bone marrow 18 F-FDG uptake was visually diagnosed as positive and negative by three nuclear medicine physicians.The skeletal volumes of interest were manually drawn on PET/CT images.A total of 781 PET and 1045 CT radiomic features were automatically extracted to provide a more comprehensive understanding of the embedded pattern.To select the most important and predictive features, an unsupervised consensus clustering method was first performed to analyze the feature correlations and then used to guide a random forest supervised machine learning model for feature importance analysis.Cross-validation and independent validation were conducted to justify the performance of our model. Results:The training group involved 16 BMB positive and 19 BMB negative patients.Based on the visual analysis of 18 F-FDG PET, 3 patients had focal uptake, 8 patients had normal uptake, and 24 patients had diffuse uptake.The sensitivity, specificity, and accuracy of visual analysis for BMI diagnosis were 62.5%, 73.7%, and 68.6%, respectively.With the cross-validation on the training group, the machine learning model correctly predicted 31 patients in BMI.The sensitivity, specificity, and accuracy of the machine learning model in BMI detection were 87.5%, 89.5%, and 88.6%, respectively, significantly higher than the ones in visual analysis (P < 0.05).The evaluation on the independent validation group showed that the machine learning model could achieve 83.3% accuracy.Conclusions: 18 F-FDG PET/CT radiomic analysis with machine learning model provided a quantitative, objective and efficient mechanism for identifying BMI in the patients with suspected relapsed AL.It is suggested in particular for the diagnosis of BMI in the patients with 18 F-FDG diffuse uptake patterns.
Spontaneous evolution of human skin fibroblasts into wound-healing keratinocyte-like cells
Authors: Fang Zhang, Dandan Zhang, Kai Cheng, Zaixin Zhou, Shupeng Liu, Liang Chen, Yijun Hu, Chuanbin Mao, Shanrong Liu
Journal: Theranostics (2019)

Producing keratinocyte cells (KCs) in large scale is difficult due to their slow proliferation, disabling their use as seed cells for skin regeneration and wound healing.Cell reprogramming is a promising inducer-based approach to KC production but only reaches very low cellular conversion.Here we reported a unique cellular conversion phenomenon, where human skin fibroblasts (FBs) were spontaneously converted into keratinocyte-like cells (KLCs) over the time without using any inducers.Methods: FBs were routinely cultured for more than 120 days in regular culture medium.Characteristics of KLCs were checked at the molecular and cellular level.Then the functionality and safety of the KLCs were verified by wound healing and tumorigenicity assay, respectively.To identify the mechanism of the cell conversion phenomenon, high-throughput RNA sequencing was also performed. Results:The global conversion started on day 90 and reached 90% on day 110.The KLCs were as functional and effective as KCs in wound healing without causing oncogenicity.The conversion was regulated via a PI3K-AKT signaling pathway mediated by a long non-coding RNA, LINC00672.Modulating the pathway could shorten the conversion time to 14 days. Conclusion:The discovered FBs-KLCs conversion in the study might open a new avenue to the scalable production of cell sources needed for regenerating skins and healing large-area wounds.
Epigenetically Upregulated MicroRNA-602 Is Involved in a Negative Feedback Loop with FOXK2 in Esophageal Squamous Cell Carcinoma
Authors: Meiyue Liu, Jiarui Yu, Dan Wang, Yi Niu, Siyuan Chen, Peng Gao, Zhao Yang, Huan Wang, Jie Zhang, Chao Zhang, Yue Zhao, Wanning Hu, Guogui Sun
Journal: Molecular Therapy (2019)

MicroRNA is an endogenous, small RNA controlling multiple target genes and playing roles in various tumorigenesis processes. In this study, our results revealed that miR-602 expression levels in tumor tissues and preoperative serum from esophageal squamous cell carcinoma (ESCC) patients were higher than those in non-tumorous tissues and healthy volunteers. miR-602 overexpression was closely related to lymph node metastasis and TNM stages and correlated short overall, and it acted as an independent prognostic marker of ESCC. The methylation status of the miR-602 gene indicated more frequent hypomethylation of the CpG sites located upstream of the miR-602 gene in the ESCC tissues than in the adjacent normal tissues, and the methylation status of miR-602 correlated inversely with its expression levels. Subsequently, miR-602 overexpression promoted ESCC proliferation and metastasis and regulated cell cycles in vitro and in vivo. Mechanistically, a dual-luciferase experiment validated that Fork head box (FOX)K2 (FOXK2) was a direct target of miR-602. More importantly, systemic delivery of formulated miR-602 antagomir could reduce tumor growth and increased FOXK2 protein expression in nude mice. This work provides novel insight into the molecular pathogenesis of ESCC. MicroRNA is an endogenous, small RNA controlling multiple target genes and playing roles in various tumorigenesis processes. In this study, our results revealed that miR-602 expression levels in tumor tissues and preoperative serum from esophageal squamous cell carcinoma (ESCC) patients were higher than those in non-tumorous tissues and healthy volunteers. miR-602 overexpression was closely related to lymph node metastasis and TNM stages and correlated short overall, and it acted as an independent prognostic marker of ESCC. The methylation status of the miR-602 gene indicated more frequent hypomethylation of the CpG sites located upstream of the miR-602 gene in the ESCC tissues than in the adjacent normal tissues, and the methylation status of miR-602 correlated inversely with its expression levels. Subsequently, miR-602 overexpression promoted ESCC proliferation and metastasis and regulated cell cycles in vitro and in vivo. Mechanistically, a dual-luciferase experiment validated that Fork head box (FOX)K2 (FOXK2) was a direct target of miR-602. More importantly, systemic delivery of formulated miR-602 antagomir could reduce tumor growth and increased FOXK2 protein expression in nude mice. This work provides novel insight into the molecular pathogenesis of ESCC.
NCCN Guidelines Insights: Survivorship, Version 2.2019
Authors: Tara Sanft, Crystal S. Denlinger, Saro Armenian, K. Scott Baker, Gregory Broderick, Wendy Demark-Wahnefried, Debra L. Friedman, Mindy Goldman, Melissa Hudson, Nazanin Khakpour, Divya Koura, Robin M. Lally, Terry S. Langbaum, Allison L. McDonough, Michelle Melisko, Kathi Mooney, Halle C.F. Moore, Javid J. Moslehi, Tracey O’Connor, Linda Overholser, Electra D. Paskett, Lindsay Peterson, William Pirl, M. Alma Rodriguez, Kathryn J. Ruddy, Sophia Smith, Karen L. Syrjala, Amye Tevaarwerk, Susan G. Urba, Phyllis Zee, Nicole R. McMillian, Deborah A. Freedman-Cass
Journal: Journal of the National Comprehensive Cancer Network (2019)

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for consequences of cancer and cancer treatment to aid healthcare professionals who work with survivors of adult-onset cancer. Guidance is also provided to help promote physical activity, weight management, and proper immunizations in survivors and to facilitate care coordination to ensure that all needs are addressed. These NCCN Insights summarize some of the topics discussed by the NCCN Survivorship Panel during the 2019 update of the guidelines, including the survivorship population addressed, ways to improve care coordination, and pain management.
Empty peptide-receptive MHC class I molecules for efficient detection of antigen-specific T cells
Authors: Sunil Kumar Saini, Tripti Tamhane, Raghavendra Anjanappa, Ankur Saikia, Sofie Ramskov, Marco Donia, Inge Marie Svane, Søren Nyboe Jakobsen, Maria Garcia-Alai, Martin Zacharias, Rob Meijers, Sebastian Springer, Sine Reker Hadrup
Journal: Science Immunology (2019)

Disulfide-stabilized MHC class I are empty peptide-receptive molecules that rapidly load peptide and improve T cell detection. See the related Research Article by Moritz et al . in this issue.
Characteristics, Treatments, and Outcomes of Patients with Lymphomatoid Granulomatosis—MD Anderson Cancer Center Experience
Authors: Preetesh Jain, Rashmi Kanagal-Shamanna, Ahmad Ghorab, Loretta Nastoupil, Luis E. Fayad, Jeffrey Medeiros, Shimin Hu, Sattva S. Neelapu, Jason R. Westin, Yasuhiro Oki, Michael Wang, Nathan H. Fowler
Journal: Blood (2017)
Mounting Evidence and Netflix’s Decision to Pull a Controversial Suicide Scene
Authors: Rebecca Voelker
Journal: JAMA (2019)

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Phase I trial of cancer vaccine with multiple peptides derived from novel onco-antigen and anti-angiogenic antigens for patients with advanced non-small cell lung cancer (NSCLC).
Authors: Hiroyuki Suzuki, Takeo Hasegawa, Jun Ohsugi, Mika Hoshino, Mitsunori Higuchi, Yutaka Shio, Koji Yoshida, Takuya Tsunoda, Yusuke Nakamura, Mitsukazu Gotoh
Journal: Journal of Clinical Oncology (2012)

e13015 Background: Two phase I clinical trials were conducted on patients with advanced or recurrent NSCLC to evaluate the safety, immunogenicity and clinical response of a multiple peptide vaccine that incorporates four epitope peptides. This vaccine is comprised of novel HLA-A24-restricted oncoantigens, including two of the following three peptides; up-regulated lung cancer 10 (URLC10), TTK protein kinase (TTK) and cell division associated 1 (CDCA1), in addition to peptides derived from vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2). Methods: Peptides derived from URLC10, TTK, VEGFR1 and VEGFR2 were tested in Trial 1, while peptides derived from URLC10, CDCA1, VEGFR1 and VEGFR2 were tested in Trial 2. Fifteen HLA-24-positive patients with NSCLC who had not responded to standard therapy were enrolled in this classic 3 patient per dose per cohort phase I trial, designed with varying dosages (Trial 1; 0.5mg, 1mg and 3mg, Trial 2; 1mg, 3mg). Vaccines were administered weekly by subcutaneous injection into patients’ axillary region with Montanide ISA-51 incomplete Freund’s adjuvant until progressive disease occurred and/or patients refused further treatment. Immunological responses were evaluated by INF-gamma ELiSPOT assays. Results: Vaccinations were well-tolerated withno severe treatment-associated adverse events. Specific T cell responses were induced in all patients against at least one epitope peptide. However, weak immunological responses were found in the 0.5mg group compared with the 1mg and 3mg groups in Trial 1, therefore the 0.5mg group was excluded in Trial 2. In terms of clinical responses, no complete and partial responses were found, however 9 of 15 patients (60 %) were categorized with stable disease. The median overall survival time was 13.2 months, while 1- and 2-year survival rates were 52.5% and 32.8% respectively. Conclusions: Multiple peptide vaccination therapy using four novel peptides was safe, and could possibly be effective in extending the patients’ survival. These encouraging immunological and clinical responses could provide a case for further stages of clinical trials.
Patients find GP online services “cumbersome,” survey finds
Authors: Ingrid Torjesen
Journal: BMJ (2019)

Patients are deterred from using online services offered by general practices, such as booking appointments online, because they find the registration process “a pain” and the range of services offered too narrow and inflexible, a survey has found.1

The 2014 NHS Five Year Forward View pledged to “harness technology and innovation” to improve patients’ access to health services through the greater use of apps, video consultations, and email and to reduce pressure on general practices. But little research has looked at how patients use existing technology, so between August and September 2018 Healthwatch Enfield gathered the views of 1071 local people through surveys and face-to-face sessions

The survey found that three quarters of patients were aware it was possible to book GP appointments and order repeat prescriptions through their practice online and that 39% had used this facility. Use increased with age, …
Novel and emerging therapies for B cell lymphoma
Authors: Sabarish Ayyappan, Kami Maddocks
Journal: Journal of Hematology & Oncology (2019)

Abstract Lymphomas are a heterogeneous group of lymphoproliferative disorders, with unique clinical and biological characteristics that exhibit variable response to therapy. Advances in chemo-immunotherapy have improved outcomes in a number of lymphoma subtypes; however, the prognosis for many patients with relapsed and refractory disease remains poor. Novel therapies including several small molecule inhibitors and chimeric antigen receptor T cells have been approved for the treatment of different lymphoma subtypes at relapse, changing the therapy landscape and further improving survival in many of these diseases. This has led to a focus on the development of new cellular therapy, antibody-based therapy, and small molecule inhibitors for relapsed and refractory disease that offer an alternative approach to cytotoxic chemotherapy. We will review these promising novel therapies and discuss their safety and efficacy in first in human studies.
Phase II trial of nanoparticle albumin-bound paclitaxel (ABX) + capecitabine (XEL) in first line treatment of metastatic breast cancer (MBC)
Authors: D. Mintzer, L. S. Schwartzberg, P. Cobb, D. Henry, A. Epperson, B. V. Fortner
Journal: Journal of Clinical Oncology (2006)

10731 Background: ABX and XEL both have substantial single agent activity in MBC. Taxane and anti-metabolic doublets improve response rate and TTP compared to singlet therapy. ABX given weekly has excellent safety and efficacy profile with maintenance of dose intensity. We designed this study to test the safety and efficacy of ABX + XEL given in a novel combination schedule. Methods: This phase II, multicenter open label study utilized ABX 125 mg/m 2 IV on day 1, 8 and with no premeds and Xeloda 825 mg/m 2 PO days 1–14 every three weeks. Entry criteria include measurable MBC by RECIST, no prior chemo for metastatic disease, &gt; 6 months since adjuvant fluoropyrimidine and paclitaxel. A total of 50 patients (pts) are scheduled to be enrolled. Primary endpoint is objective response rate. Results: To date, 14 patients have entered on study. Safety analysis prespecified by the protocol is completed in the 1 st six patients. No unique, unexpected or grade 4 toxicities have occurred. Two patients have grade 3 hand-foot syndrome, one had grade 3 neutropenia and one had grade 3 fatigue. Enrollment is continuing without change in dose/schedule. Response data is available in the first two cycles of therapy in 8 patients. At this point, two pts have achieved PR, four have stable disease and two have progressive disease. Conclusions: The combination of weekly ABX plus daily XEL orally at clinically effective doses is safe and shows preliminary evidence of efficacy. Complete enrollment of this trial is expected by May 2006 and updated results will be presented. [Table: see text]
STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade
Authors: Hannah Yang, Won Suk Lee, So Jung Kong, Chang Gon Kim, Joo Hoon Kim, Sei Kyung Chang, Sewha Kim, Gwangil Kim, Hong Jae Chon, Chan Kim
Journal: Journal of Clinical Investigation (2019)

The stimulator of IFN genes (STING) signaling pathway is a critical link between innate and adaptive immunity and induces antitumor immune responses. STING is expressed in vasculatures, but its role in tumor angiogenesis has not been elucidated. Here, we investigated STING-induced tumor vascular remodeling and the potential of STING-based combination immunotherapy. Endothelial STING expression was correlated with enhanced T cell infiltration and prolonged survival in human colon and breast cancer. Intratumoral STING activation with STING agonists (cGAMP or RR-CDA) normalized tumor vasculatures in implanted and spontaneous cancers, but not in STING-deficient mice. These were mediated by upregulation of type I/II IFN genes and vascular stabilizing genes (e.g., Angpt1, Pdgfrb, and Col4a). STING in nonhematopoietic cells is as important as STING in hematopoietic cells for inducing a maximal therapeutic efficacy of exogenous STING agonists. Vascular normalizing effects of STING agonists were dependent on type I IFN signaling and CD8+ T cells. Notably, STING-based immunotherapy was maximally effective when combined with VEGFR2 blockade and/or immune-checkpoint blockade (αPD-1 or αCTLA-4), leading to complete regression of immunotherapy-resistant tumors. Our data show that intratumoral STING activation can normalize tumor vasculature and the tumor microenvironment, providing a rationale for combining STING-based immunotherapy and antiangiogenic therapy.
Building machines that learn and think like people
Authors: Brenden M Lake, Tomer D Ullman, Joshua B Tenenbaum, Samuel J Gershman
Journal: Behavioral and Brain Sciences (2016)

Recent progress in artificial intelligence has renewed interest in building systems that learn and think like people. Many advances have come from using deep neural networks trained end-to-end in tasks such as object recognition, video games, and board games, achieving performance that equals or even beats that of humans in some respects. Despite their biological inspiration and performance achievements, these systems differ from human intelligence in crucial ways. We review progress in cognitive science suggesting that truly human-like learning and thinking machines will have to reach beyond current engineering trends in both what they learn and how they learn it. Specifically, we argue that these machines should (1) build causal models of the world that support explanation and understanding, rather than merely solving pattern recognition problems; (2) ground learning in intuitive theories of physics and psychology to support and enrich the knowledge that is learned; and (3) harness compositionality and learning-to-learn to rapidly acquire and generalize knowledge to new tasks and situations. We suggest concrete challenges and promising routes toward these goals that can combine the strengths of recent neural network advances with more structured cognitive models.
Surgical Management of Ciliated Hepatic Foregut Cyst
Authors: Ioannis A. Ziogas, Dirk J. van der Windt, Gregory C. Wilson, Alessandro Furlan, Michael A. Nalesnik, Samer Tohme, David A. Geller
Journal: Hepatology (2019)

Ziogas, Ioannis A.; van der Windt, Dirk J.; Wilson, Gregory C.; Furlan, Alessandro; Nalesnik, Michael A.; Tohme, Samer; Geller, David A. Author Information