tbuckley/cabot-search huggingface dataset:
Real-world prevalence of homologous recombination repair gene (<i>BRCA1/2</i> and <i>ATM</i>) mutations (HRRm) in patients (pts) with advanced prostate cancer (aPC) as detected by comprehensive genomic profiling (CGP) of circulating cell-free DNA (cfDNA).
Authors: Nicolas Sayegh, Umang Swami, Pedro C. Barata, Michael B. Lilly, Roberto Nussenzveig, Chuck Hensel, Alan Haruo Bryce, Mehmet Asim Bilen, Elisabeth I. Heath, Lakshminarayanan Nandagopal, Rohan Garje, Philip James Saylor, Hani M. Babiker, Daniel A. Vaena, Manish Kohli, Sumanta K. Pal, A. Oliver Sartor, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2021)

256 Background: PARP inhibitors, olaparib and rucaparib recently improved survival outcomes (in the Profound and Triton-2 trials) in pts with aPC harboring HRRm. Notably, ~35% of pts screened for the PROfound trial did not meet eligibility solely due to the lack of adequate quality/quantity of tumor tissue required for CGP (De Bono, NEJM, 2020). cfDNA analysis non-invasively assesses tumor-derived genomic alterations. We evaluated the prevalence of HRRm in a real-world aPC population, who had commercially available cfDNA assay results available. Methods: cfDNA based CGP (using a clinically-validated 73- to 74-gene panel i.e. Guardant360 or G360) from consecutive aPC pts between 11/2016–8/2020 were used for detection of HRRm. Frameshift and nonsense mutations were included as pathogenic. Variants of unknown significance were excluded. In this unmatched study, the prevalence of each HRRm was compared with those reported in literature using the chi square test. Results: cfDNA CGP from 7701 aPC pts were available for interrogation of BRCA1/BRCA2 mutations, &amp; from 4671 aPC pts for ATM mutations. Prevalence of BRCA1 and 2 as detected by cfDNA was similar to historical CGP of primary tissue. Prevalence of BRCA1 was higher than historical CGP of metastatic tissue. Prevalence of ATM in cfDNA was higher than historic tumor tissue CGP but similar to prior reports from cfDNA testing (Table). Conclusions: In this large real-world population of pts with aPC undergoing routine cfDNA CGP by a CLIA certified lab, prevalence of HRRm was similar (or higher for BRCA1 and ATM) to what has been previously reported from the tumor tissue. These data provide the rationale for utilizing cfDNA CGP as a routine test for detection of HRRm in men with aPC to identify men who are candidates for PARPi. [Table: see text]
A potent neutralizing nanobody against SARS‐CoV‐2 with inhaled delivery potential
Authors: Junwei Gai, Linlin Ma, Guanghui Li, Min Zhu, Peng Qiao, Xiaofei Li, Haiwei Zhang, Yanmin Zhang, Yadong Chen, Weiwei Ji, Hao Zhang, Huanhuan Cao, Xionghui Li, Rui Gong, Yakun Wan
Journal: MedComm (2021)

Abstract The coronavirus disease 2019 (COVID‐19) pandemic has become a serious burden on global public health. Although therapeutic drugs against COVID‐19 have been used in many countries, their efficacy is still limited. We here reported nanobody (Nb) phage display libraries derived from four camels immunized with the SARS‐CoV‐2 spike receptor‐binding domain (RBD), from which 381 Nbs were identified to recognize SARS‐CoV‐2‐RBD. Furthermore, seven Nbs were shown to block interaction of human angiotensin‐converting enzyme 2 (ACE2) with SARS‐CoV‐2‐RBD variants and two Nbs blocked the interaction of human ACE2 with bat‐SL‐CoV‐WIV1‐RBD and SARS‐CoV‐1‐RBD. Among these candidates, Nb11‐59 exhibited the highest activity against authentic SARS‐CoV‐2 with 50% neutralizing dose (ND 50 ) of 0.55 μg/ml. Nb11‐59 can be produced on large scale in Pichia pastoris , with 20 g/L titer and 99.36% purity. It also showed good stability profile, and nebulization did not impact its stability. Overall, Nb11‐59 might be a promising prophylactic and therapeutic molecule against COVID‐19, especially through inhalation delivery.
Abstract IA-23: Multi-scale modeling of cancer patients
Authors: Olivier Gevaert
Journal: Clinical Cancer Research (2021)

Abstract Recently biomedical analysis in both imaging and non-imaging data has advanced rapidly aided by the modeling power of deep learning networks. Complex diseases such as cancer may reveal different aspects of disease characteristics in different data modalities, and thus integrating imaging with non-imaging biomarkers and clinical data has the potential to discover information that is not obvious in any single data modality. We are developing methods for integrating image, genomic and clinical data to improve precision medicine applications for cancer patients. Our results suggest that the integration strategies achieve improved prediction results than using each single data modality alone. We further show that information is transferrable across age groups or tumor subtypes under the data fusion framework. Citation Format: Olivier Gevaert. Multi-scale modeling of cancer patients [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr IA-23.
Abstract PO-007: Deep learning-based computational pathology predicts origins for cancers of unknown primary
Authors: Ming Yang Lu, Tiffany Y. Chen, Drew D.W. Williamson, Melissa Zhao, Maha Shady, Jana Lipkova, Faisal Mahmood
Journal: Clinical Cancer Research (2021)

Abstract Cancer of unknown primary (CUP) is an enigmatic group of diagnoses where the primary anatomical site of tumor origin is undetermined. This poses a significant challenge to effective patient care as modern therapeutics are often specific to the primary tumor. Patients with a CUP diagnosis routinely undergo an extensive diagnostic work-up to determine the primary origin, which is resource-intensive, might significantly delay the administration of suitable treatment, and is not always successful. While previous works have demonstrated the feasibility of predicting the primary origin based on molecular information, we present a deep learning-based algorithm that can provide a differential diagnosis for CUP using routine histology slides. We used 22,833 gigapixel whole slide images with known primaries spread over 18 common origins to train a multi-task deep model to identify the tumor as primary or metastatic and predict its site of origin. We tested our model on a set of 6,499 cases with known primaries and achieved a top-1 accuracy of 0.83, a top-3 accuracy of 0.96 while on our external set of 682 cases from 202 different hospitals, it achieved a top-1 and top-3 accuracy of 0.80 and 0.93 respectively. Additionally, on 316 CUP cases assigned a differential diagnosis, our predictions resulted in concordance for 61% of cases (κ=0.52) and a top-3 agreement of 82%. Our approach can potentially be used as an assistive tool for pathologists and reduce the number of diagnostic IHCs required and improve the quality of diagnosis particularly in low-resource settings where pathology expertise is limited, and genomic testing may not be available. Citation Format: Ming Yang Lu, Tiffany Y. Chen, Drew D.W. Williamson, Melissa Zhao, Maha Shady, Jana Lipkova, Faisal Mahmood. Deep learning-based computational pathology predicts origins for cancers of unknown primary [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-007.
Abstract 14895: Bicuspid Aortic Valves Facilitate Significantly Increased 3-Dimensional Pressure Gradients, Circumferential Wall Shear Stress, and Viscous Energy Loss
Authors: Patrick Geeraert, Michael S Bristow, Xuexin Gao, Bobby Heydari, Carmen Lydell, Andrew G Howarth, Paul Fedak, Julio Garcia, James White
Journal: Circulation (2018)

Introduction: By investigating the concomitance of altered 3D pressure gradients (3D-PG), wall shear stress (WSS), and viscous energy loss (EL) in bicuspid aortic valve (BAV) patients, a more holis...
Incidence and cost of radical prostatectomy for NCCN low-risk prostate cancer in Utah.
Authors: David Michael Gill, Jessica Baumgartner, Jesse Gygi, Bridget Foy, Bryan Crawford, Zoya Sandhu, Jamie Brant, Brandon M. Barney, Jonathan David Tward
Journal: Journal of Clinical Oncology (2021)

232 Background: Guidelines Support active surveillance (AS) as the preferred treatment for men with NCCN low-risk prostate cancer (Gleason 3+3, prostate-specific antigen [PSA] &lt;10 ng/ml, ≤T2a). Recent work from Mahal BA et al. (JAMA 2019) reports AS rates are increasing, but only 42.1% of men with low-risk prostate cancer underwent AS in 2015. Low-risk prostate cancer accounted for 30.1% of diagnoses. The majority of Utah residents treated for prostate cancer receive therapy at either The Huntsman Cancer Institute or Intermountain Healthcare facilities. We modeled the costs associated with the presumptive overtreatment of men with low-risk disease treated in 2017-2019. Methods: Data from The Huntsman Cancer Institute and Intermountain Healthcare cancer databases from 2017 to 2019 were retrospectively analyzed. Men with available pathologic, laboratory and clinical data who had undergone prostatectomy were stratified by having NCCN low, intermediate, and high-risk disease. Rates of radical prostatectomy by year and institution were analyzed. The cost of prostatectomy compared to AS was estimated to be $14,453 from recent work by Trogdon JG et al. (JAMA Oncol 2019). Results: Data was available for 1,155 Utahn men (Table). Of the 1155 surgeries performed, 69 (6%) were in low-risk patients. The total costs of care that might have been avoided over these three years are estimated to be $1 million. Conclusions: Approximately 6% of prostatectomies performed in Utah are in men with NCCN low-risk prostate cancer. While these rates are lower than the national average, we estimate approximately $1 million in medical costs and toxicities could be deferred had these patients opted for AS. Work is ongoing to characterize clinical toxicity of treatment in these men, and a multi-institutional collaborative education outreach program to reduce overtreatment is in development. [Table: see text]
New international reporting guidelines for clinical trials evaluating effectiveness of artificial intelligence interventions in dermatology: strengthening the SPIRIT of robust trial reporting
Authors: M. Charalambides, C. Flohr, P. Bahadoran, R.N. Matin
Journal: British Journal of Dermatology (2021)

AI can refer to either machine learning or deep learning 1 The potential for AI and machine learning to improve the management of skin diseases is immense  Artificial intelligence (AI) can be defined simply as the ability of computers to simulate intelligent human behaviour  [Extracted from the article] Copyright of British Journal of Dermatology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission  However, users may print, download, or email articles for individual use  This abstract may be abridged  No warranty is given about the accuracy of the copy  Users should refer to the original published version of the material for the full abstract  (Copyright applies to all Abstracts )
Presynaptic store-operated Ca2+ entry drives excitatory spontaneous neurotransmission and augments endoplasmic reticulum stress
Authors: Natali L. Chanaday, Elena Nosyreva, Ok-Ho Shin, Hua Zhang, Iltan Aklan, Deniz Atasoy, Ilya Bezprozvanny, Ege T. Kavalali
Journal: Neuron (2021)
Ultrasensitive Chemodynamic Therapy: Bimetallic Peroxide Triggers High pH‐Activated, Synergistic Effect/H<sub>2</sub>O<sub>2</sub> Self‐Supply‐Mediated Cascade Fenton Chemistry
Authors: Hao Zhou, Xiaowei Li, Dechao Niu, Yongsheng Li, Xiaohang Liu, Chengfeng Li, Weimeng Si, Jun Cao, Yuanda Song, Guangwu Wen, Zhihui Niu, Lijuan Zhang
Journal: Advanced Healthcare Materials (2021)

Abstract Recently, nanoparticle‐triggered in situ catalytic Fenton/Fenton‐like reaction is widely explored for tumor‐specific chemodynamic therapy (CDT). However, despite the great potential of CDT in tumor treatment, insensitive response to the relatively high pH of the tumor sites and the insufficient intratumoral H 2 O 2 level leads to limited efficiency of most Fenton/Fenton‐like reactions, which greatly imped its clinical conversion. This paper reports the fabrication of Fenton‐type bimetallic peroxides for ultrasensitive chemodynamic therapy with high pH‐activated, synergistic effect/H 2 O 2 self‐supply‐mediated cascade Fenton chemistry for the first time. The observations reveal that these bimetallic peroxides exhibit an ultrasensitive acid‐activated decomposition‐mediated Fenton‐like reaction at the relatively high pH of 6.5–7.0, accompanied with highly increased •OH generation efficiency (especially, 40–60‐fold increase at pH 7.0) by the metal‐mediated synergistic effect‐enhanced Fenton chemistry as well as in situ self‐generated H 2 O 2 supplement. Moreover, the bimetallic peroxides exhibit high tumor accumulation which along with a high‐efficiency tumor catalytic‐therapeutic with negligible side effects in vivo. Developing these novel bimetallic peroxides, together with the already demonstrated capacity of the key metals (Fe, Mn, Cu, etc.) for magnetic resonance imaging or photodynamic/immune‐enhanced therapy, will propel interest in development of smart high‐efficiency nanoplatform for cancer theranostics.
Using progress feedback to improve outcomes and reduce drop-out, treatment duration, and deterioration: A multilevel meta-analysis
Authors: Kim de Jong, Judith M. Conijn, Roisin A.V. Gallagher, Alexandra S. Reshetnikova, Marya Heij, Miranda C. Lutz
Journal: Clinical Psychology Review (2021)

Progress feedback is an intervention aimed at enhancing patient outcomes in routine clinical practice. This study reports a comprehensive multilevel meta-analysis on the effectiveness of progress feedback in psychological treatments in curative care. The short- and long-term effects of feedback on symptom reduction were investigated using 58 (randomized and non-randomized) studies, analyzing 110 effect sizes in a total of 21,699 patients. Effects of feedback on dropout rate, percentage of deteriorated cases, and treatment duration were also examined. Moderation analyses were conducted for study and feedback characteristics. A small significant effect of progress feedback on symptom reduction (d = 0.15, 95% CI: [0.10, 0.20]) was found, compared to control groups. This was also true for not-on-track cases (d = 0.17, 95% CI: [0.11, 0.22]). In addition, feedback had a small favorable effect on dropout rates (OR = 1.19, 95% CI: [1.03, 1.38]). The moderation analyses identified several potentially interesting variables for further research, including feedback instrument, outcome instrument, type of feedback, feedback frequency, treatment intensity, and country in which the study was conducted. Future studies should report on these variables more consistently so that we can obtain a better understanding of when and why feedback improves outcomes.
Tracheal Agenesis with Bronchoesophageal Fistula
Authors: Sihem Darouich, Aida Masmoudi
Journal: New England Journal of Medicine (2021)

Respiratory distress developed in a neonate after delivery at 32 weeks of gestation. Endotracheal intubation was unsuccessful, and he died 4 hours after delivery. A postmortem esophagram obtained after the administration of barium showed tracheal agenesis and bronchoesophageal fistula.
Ticagrelor vs Clopidogrel for Patients With Acute Coronary Syndrome Undergoing Percutaneous Intervention
Authors: Hyun Kuk Kim, Jacek Kubica, Young-Hoon Jeong
Journal: JAMA (2021)

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Abstract LT003: Endothelin-1 drives invadopodia and cross-talk with submesothelial matrix invasion cell through ILK
Authors: Ilenia Masi, Valentina Caprara, Francesca Spadaro, Lidia Chellini, Rosanna Sestito, Andrea Zancla, Alberto Rainer, Anna Bagnato, Laura Rosanò
Journal: Cancer Research (2021)

Abstract During the metastatic progression, invading cells might achieve degradation and invasion into the extracellular matrix (ECM) using invadopodia, actin-based protrusions. Several growth factors, among other stimuli, might induce invadopodia, generating signaling cues implicated from the initial steps of anchoring and protein recruitment to the final steps of matrix degradation or structure dissembling. In this context, the endothelin A receptor (ETAR) a drives invadopodia in serous ovarian cancer (SOC) cells through the scaffolding function of β-arrestin1 (β-arr1), although the coordinated signaling network is not fully explored. Growing evidence demonstrated that integrins and associated proteins, such as integrin-linked kinase (ILK), operate in the same subcellular compartments to control invadopodium maturation and ECM degradation. Since endothelin-1 (ET-1) through ETAR regulated by ILK, in this study whether ET-1/β-arr1-driven ILK signaling could provide additional mean to enhance invadopodium activity in ovarian cancer progression. We found that β-arr1 functions as a linker for ILK/βPIX (Pax-interacting exchange factor beta) complex, required for activation of Rac3 GTPase, emerging at a crossroad between adhesion and proteolytic signaling, resulting to be overexpressed in tumour compared normal ovarian tissues. Rac3 operates the phosphorylation of PAK1 and cofilin, and regulates invadopodia-dependent ECM degradation and invasion. Moreover, ETAR/ILK/Rac3-dependent signaling supports the communication of SOC cells with mesothelial cells, favouring adhesion and transmigration to. In vivo, ambrisentan, an ETAR antagonist, inhibits the adhesion of HG-SOC cells to intraperitoneal organs, and their spreading, associated with a reduction of invadopodia markers. Finally, high ETAR/ILK expression positively correlates with poor prognosis, representing SOC prognostic factors. Our findings uncover a paradigm indicating where ET-1R/β-arr1/ILK pathway integrates adhesive and proteolytic signaling to invadopodia-mediated ECM degradation, favouring cancer-stroma interactions and SOC metastatic behaviour. Citation Format: Ilenia Masi, Valentina Caprara, Francesca Spadaro, Lidia Chellini, Rosanna Sestito, Andrea Zancla, Alberto Rainer, Anna Bagnato, Laura Rosanò. Endothelin-1 drives invadopodia and cross-talk with submesothelial matrix invasion cell through ILK [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT003.
Diuretic response and effects of diuretic omission in ambulatory heart failure patients on chronic low‐dose loop diuretic therapy
Authors: Jeroen Dauw, Pieter Martens, Gregorio Tersalvi, Joren Schouteden, Sébastien Deferm, Henri Gruwez, Bart De Moor, Petra Nijst, Matthias Dupont, Wilfried Mullens
Journal: European Journal of Heart Failure (2021)
Exosome-guided bone targeted delivery of Antagomir-188 as an anabolic therapy for bone loss
Authors: Yan Hu, Xiaoqun Li, Qin Zhang, Zhengrong Gu, Ying Luo, Jiawei Guo, Xiuhui Wang, Yingying Jing, Xiao Chen, Jiacan Su
Journal: Bioactive Materials (2021)

The differentiation shift from osteogenesis to adipogenesis of bone marrow mesenchymal stem cells (BMSCs) characterizes many pathological bone loss conditions. Stromal cell-derived factor-1 (SDF1) is highly enriched in the bone marrow for C-X-C motif chemokine receptor 4 (CXCR4)-positive hematopoietic stem cell (HSC) homing and tumor bone metastasis. In this study, we displayed CXCR4 on the surface of exosomes derived from genetically engineered NIH-3T3 cells. CXCR4+ exosomes selectively accumulated in the bone marrow. Then, we fused CXCR4+ exosomes with liposomes carrying antagomir-188 to produce hybrid nanoparticles (NPs). The hybrid NPs specifically gathered in the bone marrow and released antagomir-188, which promoted osteogenesis and inhibited adipogenesis of BMSCs and thereby reversed age-related trabecular bone loss and decreased cortical bone porosity in mice. Taken together, this study presents a novel way to obtain bone-targeted exosomes via surface display of CXCR4 and a promising anabolic therapeutic approach for age-related bone loss.
Comprehensive genomic profiling of matched primary prostate cancer tissue and cell-free DNA (cfDNA) to assess ontogeny of BRCA1/BRCA2 mutations.
Authors: Taylor Ryan McFarland, Roberto Nussenzveig, Umang Swami, Nicolas Sayegh, Adam Kessel, Prayushi Sharma, Haoran Li, Manish Kohli, Benjamin Louis Maughan, Sumanta K. Pal, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2021)

166 Background: Both olaparib and rucaparib have recently been approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) with BRCA1/2 mutations (BRCAm). In the PROFOUND trial, 36.9% of men had either no tissue or tissue that was inadequate for genomic profiling (PMID: 32343890). A recent report suggests BRCAm may be an early event in the evolution of prostate cancer (PMID: 29662167). This suggests comprehensive genomic profiling (CGP) of primary prostate tissue may suffice to guide treatment selection, even years after tissue collection. Herein, we investigate the ontogeny of BRCAm by comparing CGP of matched primary prostate cancer tissue to CGP of cfDNA. Methods: Eligibility criteria included men diagnosed with metastatic prostate cancer that had matched CGP of both primary prostate cancer tissue and cfDNA. Genomic profiling was performed by CLIA certified laboratories. Only somatic mutations detectable by both platforms were used for concordance analysis. Results: We identified 198 patients that had matched CGP of primary prostate tissue and cfDNA. Thirteen men had a pathogenic BRCAm in at least one test. Of these 13 positive test for BRCAm, 2 were rearrangements, 1 copy number loss, and 5 were germline mutations. Both platforms tend to filter out germline alterations therefore, they were not included in the estimation of concordance. Overall somatic BRCAm concordance between primary prostate tissue and cfDNA was 196/198 (98%). Notably, no new BRCAm were identified in cfDNA with a median difference of 23.62 (0.1 - 232.2) months between prostate cancer tissue and cfDNA collection. Conclusions: There were no BRCAm detected only in cfDNA, suggesting that BRCAm is an early event in the ontogeny of prostate cancer. Based on this, it is unlikely that delaying sequencing would benefit patients with advanced prostate cancer. In the event that tissue is unavailable or inadequate for CGP, profiling of cfDNA is a valuable alternative for detection of BRCAm.