tbuckley/cabot-search huggingface dataset:
Biomimetic inorganic-organic hybrid nanoparticles from magnesium-substituted amorphous calcium phosphate clusters and polyacrylic acid molecules
Authors: Na Li, Wei Cui, Peifang Cong, Jie Tang, Yong Guan, Caihao Huang, Yunen Liu, Chengzhong Yu, Rui Yang, Xing Zhang
Journal: Bioactive Materials (2021)

Amorphous calcium phosphate (ACP) has been widely found during bone and tooth biomineralization, but the meta-stability and labile nature limit further biomedical applications. The present study found that the chelation of polyacrylic acid (PAA) molecules with Ca2+ ions in Mg-ACP clusters (~2.1 ± 0.5 nm) using a biomineralization strategy produced inorganic-organic Mg-ACP/PAA hybrid nanoparticles with better thermal stability. Mg-ACP/PAA hybrid nanoparticles (~24.0 ± 4.8 nm) were pH-responsive and could be efficiently digested under weak acidic conditions (pH 5.0-5.5). The internalization of assembled Mg-ACP/PAA nanoparticles by MC3T3-E1 cells occurred through endocytosis, indicated by laser scanning confocal microscopy and cryo-soft X-ray tomography. Our results showed that cellular lipid membranes remained intact without pore formation after Mg-ACP/PAA particle penetration. The assembled Mg-ACP/PAA particles could be digested in cell lysosomes within 24 h under weak acidic conditions, thereby indicating the potential to efficiently deliver encapsulated functional molecules. Both the in vitro and in vivo results preliminarily demonstrated good biosafety of the inorganic-organic Mg-ACP/PAA hybrid nanoparticles, which may have potential for biomedical applications.
Endpoints in clinical trials for liver cancer and their value in evidence-based clinical decision making: An unresolved Gordian knot
Authors: Jordi Bruix
Journal: Journal of Hepatology (2021)

The design and execution of clinical trials relies on strict definitions and criteria to avoid heterogeneous decisions by investigators at different sites. Ideally, definitions and decision making in clinical practice should mimic those implemented in trials, but this is not the case. Target populations are narrowly defined in trials, with the goal of evaluating activity and toxicity, and ultimately, demonstrating a survival benefit. In real-world practice, patients may not fit into the stringent inclusion/exclusion criteria of clinical trials. The evaluation of activity may also differ and the common policy to stop therapy upon progression may not be followed if progression is minor. Indeed, registration of progression may not reflect treatment failure or resistance. Parameters such as response according to RECIST criteria, time to progression and progression-free survival are not fully informative and cannot be assumed as a definitive surrogate for survival, which is the hardest endpoint in therapeutic cancer studies. This difference is because of the varying methods used to evaluate drug activity and tumour evolution, which ultimately dictates patient outcome. This expert opinion exposes the current discrepancies between research trials and clinical practice. Understanding the origin and limitations of such a conundrum should be the first step in refining the criteria that define drug activity, toxicity and treatment failure. Otherwise, evidence-based clinical practice and precision oncology will be an unattainable reality.
ELOVL5 Is a Critical and Targetable Fatty Acid Elongase in Prostate Cancer
Authors: Margaret M. Centenera, Julia S. Scott, Jelle Machiels, Zeyad D. Nassar, Deanna C. Miller, Irene Zinonos, Jonas Dehairs, Ingrid J.G. Burvenich, Giorgia Zadra, Paolo M. Chetta, Clyde Bango, Emma Evergren, Natalie K. Ryan, Joanna L. Gillis, Chui Yan Mah, Terence Tieu, Adrienne R. Hanson, Ryan Carelli, Katarzyna Bloch, Vasilios Panagopoulos, Etienne Waelkens, Rita Derua, Elizabeth D. Williams, Andreas Evdokiou, Anna Cifuentes-Rius, Nicolas H. Voelcker, Ian G. Mills, Wayne D. Tilley, Andrew M. Scott, Massimo Loda, Luke A. Selth, Johannes V. Swinnen, Lisa M. Butler
Journal: Cancer Research (2021)

The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes to more effectively target the AR dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, yet the relationship between AR and the lipidome remains undefined. Using mass spectrometry-based lipidomics, this study reveals increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgen-regulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL fatty acid elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts, and clinical tumors. Assessment of mRNA and protein in large-scale data sets revealed ELOVL5 as the predominant ELOVL expressed and upregulated in prostate cancer compared with nonmalignant prostate. ELOVL5 depletion markedly altered mitochondrial morphology and function, leading to excess generation of reactive oxygen species and resulting in suppression of prostate cancer cell proliferation, 3D growth, and in vivo tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell proliferation and migration effects of ELOVL5 knockdown. Collectively, these results identify lipid elongation as a protumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5. SIGNIFICANCE: This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis.
Contribution of PET imaging to radiotherapy planning and monitoring in glioma patients - a report of the PET/RANO group
Authors: Norbert Galldiks, Maximilian Niyazi, Anca L Grosu, Martin Kocher, Karl-Josef Langen, Ian Law, Giuseppe Minniti, Michelle M Kim, Christina Tsien, Frederic Dhermain, Riccardo Soffietti, Minesh P Mehta, Michael Weller, Jörg-Christian Tonn
Journal: Neuro-Oncology (2021)

The management of patients with glioma usually requires multimodality treatment including surgery, radiotherapy, and systemic therapy. Accurate neuroimaging plays a central role for radiotherapy planning and follow-up after radiotherapy completion. In order to maximize the radiation dose to the tumor and to minimize toxic effects on the surrounding brain parenchyma, reliable identification of tumor extent and target volume delineation is crucial. The use of positron emission tomography (PET) for radiotherapy planning and monitoring in gliomas has gained considerable interest over the last several years, but Class I data are not yet available. Furthermore, PET has been used after radiotherapy for response assessment and to distinguish tumor progression from pseudoprogression or radiation necrosis. Here, the Response Assessment in Neuro-Oncology (RANO) working group provides a summary of the literature and recommendations for the use of PET imaging for radiotherapy of patients with glioma based on published studies, constituting levels 1-3 evidence according to the Oxford Centre for Evidence-based Medicine.
Vitamin E analog, α-TEA, induces apoptosis in cisplatin sensitive and resistant human ovarian cancer cells and sensitizes resistant cells to cisplatin induced apoptosis: mechanistic study of signaling pathways
Authors: Weiping Yu, Kristen Anderson, Bob G. Sanders, Kimberly Kline
Journal: Cancer Research (2005)

5359  Cisplatin resistance is a major cause for treatment failure in ovarian cancer; 90% patients die with metastatic disease, highlighting the urgent need of more effective strategies for overcoming drug resistance either by direct killing of tumors or sensitizing the cancer cells to first line drug treatments. α-TEA, an analog of RRR-α-tocopherol (RRR-α-tocopherol ether-linked acetic acid) induces both cisplatin (CDDP) sensitive A2780 and resistant A2780/cp70 human ovarian cancer cells to undergo apoptosis in a dose dependent manner; whereas, CDDP induces apoptosis only in the A2780 cells. Treatment of A2780/cp70 cells with α-TEA + CDDP produces high levels of apoptosis significantly greater than separate treatments. Combination treatments with α-TEA + CDDP significantly reduced tumor burden, visible lung metastases, and microscopic lung metastases of A2780/cp70-GFP (green fluorescent protein) CDDP-resistant ovarian cancer cells transplanted into immunodeficient mice when compared to control or either treatment alone. α-TEA-induced apoptosis in human ovarian cancer cells is mediated via restoration of pro-apoptotic Fas/ Fas-ligand signaling pathway, induction of increased intensity and prolonged activation of the pro-apoptotic MAPK c-Jun N-terminal kinase (JNK) and its down-stream target, c-Jun transcription factor, and suppression of constitutively activated pro-survival Akt and MAPK extracellular regulated kinase (ERK1/2). These events trigger a caspase 8 and JNK-involved mitochondria-dependent apoptotic cascade; namely, Fas/FADD/caspase 8/Bid/Bax/cytochrome c/caspase 9/caspase 3/apoptosis and Fas/Daxx/JNK/Bax/cytochrome c/caspase 9/caspase 3/apoptosis, and a caspase 8-mediated mitochondria-independent apoptotic pathway; Fas/FADD/caspase 8/caspase 3/apoptosis. We speculate that α-TEA-induced suppression of constitutively activated pro-survival Akt and MAPK extracellular regulated kinase (ERK1/2) may be one of the mechanisms whereby α-TEA sensitizes A2780/cp70 ovarian cancer cells to CDDP-induced apoptosis. In summary, α-TEA is a potential therapeutic agent for CDDP sensitive ovarian cancer, and mediator to sensitize CDDP treatment for CDDP resistant ovarian cancer. Supported by CA59730, ES07784, and the Foundation for Research.
Gene Expression–Based Prediction of Neoadjuvant Chemotherapy Response in Early Breast Cancer: Results of the Prospective Multicenter EXPRESSION Trial
Authors: Karolina Edlund, Katrin Madjar, Antje Lebrecht, Bahriye Aktas, Henryk Pilch, Gerald Hoffmann, Manfred Hofmann, Hans-Christian Kolberg, Daniel Boehm, Marco Battista, Martina Seehase, Kathrin Stewen, Susanne Gebhard, Cristina Cadenas, Rosemarie Marchan, Walburgis Brenner, Annette Hasenburg, Heinz Koelbl, Christine Solbach, Mathias Gehrmann, Berno Tanner, Karsten E. Weber, Sibylle Loibl, Agapios Sachinidis, Jörg Rahnenführer, Marcus Schmidt, Jan G. Hengstler
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Expression-based classifiers to predict pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) are not routinely used in the clinic. We aimed to build and validate a classifier for pCR after NACT. Patients and Methods: We performed a prospective multicenter study (EXPRESSION) including 114 patients treated with anthracycline/taxane-based NACT. Pretreatment core needle biopsies from 91 patients were used for gene expression analysis and classifier construction, followed by validation in five external cohorts (n = 619). Results: A 20-gene classifier established in the EXPRESSION cohort using a Youden index–based cut-off point predicted pCR in the validation cohorts with an accuracy, AUC, negative predictive value (NPV), positive predictive value, sensitivity, and specificity of 0.811, 0.768, 0.829, 0.587, 0.216, and 0.962, respectively. Alternatively, aiming for a high NPV by defining the cut-off point for classification based on the complete responder with the lowest predicted probability of pCR in the EXPRESSION cohort led to an NPV of 0.960 upon external validation. With this extreme-low cut-off point, a recommendation to not treat with anthracycline/taxane-based NACT would be possible for 121 of 619 unselected patients (19.5%) and 112 of 322 patients with luminal breast cancer (34.8%). The analysis of the molecular subtypes showed that the identification of patients who do not achieve a pCR by the 20-gene classifier was particularly relevant in luminal breast cancer. Conclusions: The novel 20-gene classifier reliably identifies patients who do not achieve a pCR in about one third of luminal breast cancers in both the EXPRESSION and combined validation cohorts.
Chromosomal translocations as a mechanism of BRAF activation in two cases of large congenital melanocytic nevi.
Authors: B. Dessars, Linda De Raeve, H. El Housni, C. Debouck, P Sidon, R. Morandini, Diane Roseeuw, G.e. Ghanem, Gilbert Vassart, P. Heimann
Journal: Journal of the American Academy of Dermatology (2007)
Immunotherapy for sarcomas: new frontiers and unveiled opportunities
Authors: Harsimrat Kaur Birdi, Anna Jirovec, Serena Cortés-Kaplan, Joel Werier, Carolyn Nessim, Jean-Simon Diallo, Michele Ardolino
Journal: Journal for ImmunoTherapy of Cancer (2021)

Sarcomas are a rare malignancy of mesenchymal tissues, comprizing a plethora of unique subtypes, with more than 60 types. The sheer heterogeneity of disease phenotype makes this a particularly difficult cancer to treat. Radiotherapy, chemotherapy and surgery have been employed for over three decades and, although effective in early disease (stages I–II), in later stages, where metastatic tumors are present, these treatments are less effective. Given the spectacular results obtained by cancer immunotherapy in a variety of solid cancers and leukemias, there is now a great interest in appliying this new realm of therapy for sarcomas. The widespread use of immunotherapy for sarcoma relies on immuno-profiling of subtypes, immunomonitoring for prognosis, preclinical studies and insight into the safety profile of these novel therapies. Herein, we discuss preclinical and clinical data highlighting how immunotherapy is being used in soft tissue sarcoma and bone sarcomas.
RUNX-1 haploinsufficiency causes a marked deficiency of megakaryocyte-biased hematopoietic progenitor cells
Authors: Brian Estevez, Sara Borst, Danuta Jarocha, Varun Sudunagunta, Michael Gonzalez, James Garifallou, Hakon Hakonarson, Peng Gao, Kai Tan, Paul Liu, Sumedha Bagga, Nicholas Holdreith, Wei Tong, Nancy Speck, Deborah L. French, Paul Gadue, Mortimer Poncz
Journal: Blood (2021)
Pan-cancer detection of driver genes at the single-patient resolution
Authors: Joel Nulsen, Hrvoje Misetic, Christopher Yau, Francesca D. Ciccarelli
Journal: Genome Medicine (2021)

Abstract Background Identifying the complete repertoire of genes that drive cancer in individual patients is crucial for precision oncology. Most established methods identify driver genes that are recurrently altered across patient cohorts. However, mapping these genes back to patients leaves a sizeable fraction with few or no drivers, hindering our understanding of cancer mechanisms and limiting the choice of therapeutic interventions. Results We present sysSVM2, a machine learning software that integrates cancer genetic alterations with gene systems-level properties to predict drivers in individual patients. Using simulated pan-cancer data, we optimise sysSVM2 for application to any cancer type. We benchmark its performance on real cancer data and validate its applicability to a rare cancer type with few known driver genes. We show that drivers predicted by sysSVM2 have a low false-positive rate, are stable and disrupt well-known cancer-related pathways. Conclusions sysSVM2 can be used to identify driver alterations in patients lacking sufficient canonical drivers or belonging to rare cancer types for which assembling a large enough cohort is challenging, furthering the goals of precision oncology. As resources for the community, we provide the code to implement sysSVM2 and the pre-trained models in all TCGA cancer types ( https://github.com/ciccalab/sysSVM2 ).
Abstract PR004: Multi-dimensional biomarker analyses identify pembrolizumab responders in advanced stage, high grade endometrial cancer
Authors: Katherine Fuh, Elena Lomonosova, Russell Pachynski, Olga Malkova, Stephen Oh, Andrea Hagemann, Carolyn McCourt, Matthew Powell, Wendy Fantl, Premal Thaker
Journal: Clinical Cancer Research (2021)

Abstract Objectives: The recent FDA approval of pembrolizumab for the treatment of recurrent, tissue agnostic cancers with Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) has led to the treatment of a selected cohort of endometrial cancer (EC) patients. Methods: We designed a study to ascertain tumor immune modulatory effects of pembrolizumab in the front-line setting for advanced stage III/IV surgically-resectable endometrial cancers regardless of MSI-H or dMMR status. The primary objectives were to determine the safety of treatment with pembrolizumab by radiographic imaging and to determine progression-free survival at 6 months. Exploratory objective was to compare the immune response before and after treatment. In an open label, single-arm Phase I trial, 8 EC patients were treated with 2 doses of preoperative pembrolizumab IV prior to surgery followed by carboplatin and paclitaxel and 4 doses of pembrolizumab 200mg/kg q3 weeks IV. Peripheral blood was collected from EC patients at baseline level before treatment and post 2 doses of pembrolizumab treatment. Blood from healthy controls (HC) was also collected. Both were processed for high-dimensional single-cell mass cytometry (CyTOF) using an optimized lymphoid and myeloid panel. Results: Patients who responded to therapy showed lower frequency of circulating CD8+ naïve T cells but higher frequency of CD8+ effector T cells after the treatment than the poor responders. We observed post-therapy expansion of populations of CD8+ and CD4+ T cells expressing co-stimulatory receptor ICOS in responders but not in poor responders. Granzyme+CD8+ and Granzyme+CD4+ T cell populations were expanded after pembrolizumab treatment in responders but were decreased in poor responders. Higher frequency of CD27+Fas- CD4+ T cells at baseline and increased frequency of CD27-Fas+CD4+ T cells post-treatment were observed in responders but not in the poor responders. Furthermore, we identified that circulating MDSCs were reduced after pembrolizumab treatment in responders. Conclusions: Our results suggest that peripheral blood analysis may provide valuable insights into responses to anti-PD-1-targeted therapies in patients with endometrial cancers. Citation Format: Katherine Fuh, Elena Lomonosova, Russell Pachynski, Olga Malkova, Stephen Oh, Andrea Hagemann, Carolyn McCourt, Matthew Powell, Wendy Fantl, Premal Thaker. Multi-dimensional biomarker analyses identify pembrolizumab responders in advanced stage, high grade endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PR004.
Simultaneously targeting cancer-associated fibroblasts and angiogenic vessel as a treatment for TNBC
Authors: Malvika Sharma, Ravi Chakra Turaga, Yi Yuan, Ganesh Satyanarayana, Falguni Mishra, Zhen Bian, Wei Liu, Li Sun, Jenny Yang, Zhi-Ren Liu
Journal: The Journal of Experimental Medicine (2021)

Fibrotic tumor stroma plays an important role in facilitating triple-negative breast cancer (TNBC) progression and chemotherapeutic resistance. We previously reported a rationally designed protein (ProAgio) that targets integrin αvβ3 at a novel site. ProAgio induces apoptosis via the integrin. Cancer-associated fibroblasts (CAFs) and angiogenic endothelial cells (aECs) in TNBC tumor express high levels of integrin αvβ3. ProAgio effectively induces apoptosis in CAFs and aECs. The depletion of CAFs by ProAgio reduces intratumoral collagen and decreases growth factors released from CAFs in the tumor, resulting in decreased cancer cell proliferation and apoptotic resistance. ProAgio also eliminates leaky tumor angiogenic vessels, which consequently reduces tumor hypoxia and improves drug delivery. The depletion of CAFs and reduction in hypoxia by ProAgio decreases lysyl oxidase (LOX) secretion, which may play a role in the reduction of metastasis. ProAgio stand-alone or in combination with a chemotherapeutic agent provides survival benefit in TNBC murine models, highlighting the therapeutic potential of ProAgio as a treatment strategy.
Efficient endothelial and smooth muscle cell differentiation from human pluripotent stem cells through a simplified insulin-free culture system
Authors: Fengzhi Zhang, Yonglin Zhu, Jing Chen, Wenhua Kuang, Rujin Huang, Fuyu Duan, Yaqian Li, Lin Wang, Hui Qiu, Xia Chen, Jia Ming, Peng Liu, Yanan Du, Sophia Chia-Ning Chang, Ligong Chen, Jie Na
Journal: Biomaterials (2021)
A Presynaptic Protein Is a Net Gain for Pancreatic Tumor Progression
Authors: Mara H. Sherman
Journal: Cancer Discovery (2021)

Abstract Summary: Cancer-associated fibroblasts conduct an aberrant wound-healing response, including mechanisms that restrain and others that support tumor progression. In this issue of Cancer Discovery, Francescone and colleagues demonstrate expression of presynaptic protein NetG1 on fibroblasts in pancreatic ductal adenocarcinoma and characterize tumor-supportive functions of NetG1 in this context, including metabolic and immune-modulatory mechanisms. See related article by Francescone et al., p. 446.
Covid-19: Travellers to UK from “red list” countries will pay £1750 for 10 day hotel quarantine
Authors: Abi Rimmer
Journal: BMJ (2021)

The UK government has introduced new quarantine measures for international travellers in a bid to prevent the spread of covid-19, with heavy penalties for those who do not comply.

From 15 February, any UK residents returning to the UK having visited a country on the travel ban “red list”1 in the previous 10 days will be required to purchase a quarantine package.

Bookings will be made through a dedicated online portal and will include assigned government transportation, food and drinks, accommodation in a government approved facility, security, welfare, and testing. The charge for a single adult will be less than £1750 (€2000; $2420). The government has so far contracted 16 hotels with …
Understanding Reproductive Outcomes Among Women With Disabilities
Authors: Elizabeth Wall-Wieler
Journal: JAMA Network Open (2021)

Hilary K. Brown, PhD; Joel G. Ray, MD, MSc; Simon Chen, MPH; Astrid Guttmann, MDCM, MSc; Susan M. Havercamp, PhD; Susan Parish, PhD; Simone N. Vigod, MD, MSc; Lesley A. Tarasoff, PhD; Yona Lunsky, PhD