tbuckley/cabot-search huggingface dataset:
Baseline pathogenic mutations in non-AR/non-TP53 genes and prediction of response to high-dose testosterone.
Authors: Ellen Jaeger, Sydney Caputo, Elisa Marie Ledet, Marcus W. Moses, Jodi Lyn Layton, Brian E. Lewis, Pedro C. Barata, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2021)

146 Background: The fact that high dose of testosterone (HDT) elicits positive responses in a subset of prostate cancer patients (pts) is surprising and puzzling. Genomics data differentiating responders (Rs) from non-responders (NRs) is sparse. Pts with mutations in DNA repair pathway genes may be particularly sensitive to HDT (see BA Teply et al. Eur Urol 71:499, 2017). Herein we perform exploratory analyses to better understand the role of pathogenic mutations (muts) in ctDNA as a predictive biomarker for patients treated with HDT. Methods: ctDNA essays were performed with the Guardant360 methodology pre-HDT. Point mutations were classified by cancervar (http://cancervar.wglab.org). Truncating mutations (frameshift and nonsense) were manually curated to assess for pathogenicity. All patients had CRPC and were pre-treated with abiraterone and/or enzalutamide. HDT was typically administered as 400 mg testosterone cypionate q 3-4 weeks. Rs were compared to NRs. All Rs had &gt;3 more cycles of HDT and a &gt;50% PSA decline (N = 17). Non-responders had &lt;3 cycles and no PSA decline (N = 23). Only muts with an allelic fraction of &gt;0.5% were analyzed given dubious importance of mutations with lower allelic fractions. Results: AR muts (4/17 vs 6/23 in Rs and NRs) and TP53 muts (10/17 vs 11/23 in Rs and NRs) were similar ( P= 0.85 and 0.49, respectively) but the number of pts with non-AR/non-TP53 muts was distinct (3/17 for Rs, and 12/23 for NRs; P= 0.026). The average number of non-AR/non-TP53 muts (Rs = 0.23 and NRs = 0.83) was higher in the NRs (P = 0.046). When analyzing DNA repair alterations, no differences were noted in those with BRCA1/BRCA2/ATM mutations in the Rs and NRs (1/17 vs 6/23 respectively; P= 0.09). Conclusions: AR and TP53 pathogenic mutations are common in both Rs and NRs but other pathogenic mutations are more common in non-responders. We hypothesize that genetic pathways outside of the AR/TP53 axis drive resistance to HDT. Additional studies are warranted to assess whether or not these pathways drive resistance to HDT. Limitations are acknowledged with regard to the Guardant assay gene selection for CRPC pts.
Digital public health surveillance: a systematic scoping review
Authors: Zahra Shakeri Hossein Abad, Adrienne Kline, Madeena Sultana, Mohammad Noaeen, Elvira Nurmambetova, Filipe Lucini, Majed Al-Jefri, Joon Lee
Journal: npj Digital Medicine (2021)

Abstract The ubiquitous and openly accessible information produced by the public on the Internet has sparked an increasing interest in developing digital public health surveillance (DPHS) systems. We conducted a systematic scoping review in accordance with the PRISMA extension for scoping reviews to consolidate and characterize the existing research on DPHS and identify areas for further research. We used Natural Language Processing and content analysis to define the search strings and searched Global Health, Web of Science, PubMed, and Google Scholar from 2005 to January 2020 for peer-reviewed articles on DPHS, with extensive hand searching. Seven hundred fifty-five articles were included in this review. The studies were from 54 countries and utilized 26 digital platforms to study 208 sub-categories of 49 categories associated with 16 public health surveillance (PHS) themes. Most studies were conducted by researchers from the United States (56%, 426) and dominated by communicable diseases-related topics (25%, 187), followed by behavioural risk factors (17%, 131). While this review discusses the potentials of using Internet-based data as an affordable and instantaneous resource for DPHS, it highlights the paucity of longitudinal studies and the methodological and inherent practical limitations underpinning the successful implementation of a DPHS system. Little work studied Internet users’ demographics when developing DPHS systems, and 39% (291) of studies did not stratify their results by geographic region. A clear methodology by which the results of DPHS can be linked to public health action has yet to be established, as only six (0.8%) studies deployed their system into a PHS context.
Genetic Profiling and Deep IDH1 Mutation Clearance to ≤0.04% in Ivosidenib (AG-120)-Treated Patients with Mutant IDH1 Relapsed or Refractory and Untreated AML
Authors: Richard M. Stone, Sung Choe, Vickie Zhang, Benoit Marteyn, Virginie Penard-Lacronique, Hongfang Wang, Courtney D. DiNardo, Eytan M. Stein, Amir T. Fathi, Martin S. Tallman, Hagop M. Kantarjian, Eyal C. Attar, Bin Wu, Stephane de Botton
Journal: Blood (2017)
Abstract PO-079: Fused LASSO application for gastric cancer image segmentation
Authors: Jiwon Jung, Jin Roh, Chan-Sik Park
Journal: Clinical Cancer Research (2021)

Abstract Despite recent advances in digital pathology, the development of a robust deep learning model for identifying tumor regions on digitalized slide images has been plagued by problems related to the patch-based approach attributable to the narrow and limited field-of-views. In this study, we explored the effect of the fused lasso technique on diagnostic performance using gastric cancer pathology images. Our goal is to develop a speedy tumor segmentation scheme that overcomes performance degradation arising from the limitations of the patch-based approach. We used 27 specimens with partial annotation from tissue-microarrays (TMAs) with gastric cancer from the Asan Medical Center. Our segmentation adjustment method was tested on multiple renowned deep learning model architectures to detect malignancy on tissue slides. In the fused lasso formulation, fusion and lasso penalty were adopted to penalize variables with L1-norms based on both the patchwise predictions and their pairwise differences between adjoining patches. To obtain well-structured boundaries and discard irrelevant observations, the best performing hyperparameters controlling the degree to be penalized were adaptively determined via cross-validation. We demonstrated that adoption of fused lasso penalties can produce segmentation close to that generated by experts without a significant increase in computing time. The average test performance in terms of IOU, dice, accuracy, precision, recall, and AUROC increased by a degree of 3.74%p, 3.27%p, 0.93%p, 5.32%p, 3.20%p, and 1.58%p, respectively. This study provides a use case of the application of fused lasso modeling for precisely identifying tumor area, which can alleviate the bottleneck in gastric cancer research. Citation Format: Jiwon Jung, Jin Roh, Chan-Sik Park. Fused LASSO application for gastric cancer image segmentation [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-079.
COVID‐19 Disease in Patients With Recurrent Pericarditis During Treatment With Anakinra: Comment on the Article by Navarro‐Millán et al
Authors: Enrica Negro, Lucia Trotta, Massimo Pancrazi, Emanuele Bizzi, Martino Brenna, Vartan Mardigyan, Massimo Imazio, Antonio Brucato
Journal: Arthritis & Rheumatology (2021)

To the Editor: We read with interest the article by Dr. Navarro-Millán and colleagues about the use of anakinra to prevent mechanical ventilation in patients with COVID-19 (1). However, it is also important to consider patients who develop COVID-19 while being treated with anakinra for their underlying condition (2). We describe 5 patients, median age 43 years, with recurrent pericarditis (post-pericardiotomy in 1 case; idiopathic pericarditis in 4 cases) who developed COVID-19 disease during treatment with anakinra. Median duration of recurrent pericarditis was 48 months. All patients were being treated with anakinra when COVID-19 disease occurred, after having initially received treatment with glucocorticoids and/or nonsteroidal antiinflammatory drugs (including colchicine) (Table 1). The patients developed COVID-19 disease between March 2020 and October 2020. Symptoms, usually mild, included fever, cough, ageusia, anosmia, headache, diarrhea, dyspnea, and chest pain (Table 1). SARS–CoV-2 was diagnosed by nasopharyngeal swab in 4 patients, and by serologic test in 1 patient, after symptoms began. Two patients went to the emergency room; in one case, chest radiograph showed a small lung infiltrate, but neither of the patients required hospitalization. Treatment with anakinra was continued unchanged, and 3 patients received additional therapies after the development of COVID-19 disease (Table 1). All patients recovered completely within 15 days and had no recurrence of pericarditis. Polytherapy is often necessary in patients with recurrent pericarditis and treatment with an interleukin-1 receptor antagonist may lead to resolution of symptoms (3); however, a concern may be raised that biologic therapy could aggravate the clinical course of COVID-19. Our small case series shows that anakinra therapy in patients with recurrent pericarditis may be associated with a benign clinical course. We propose that there is no reason to discontinue anakinra therapy if a patient with recurrent pericarditis develops COVID-19 disease (4-7). Our recommendation is consistent with the findings obtained in the study by Dr. Navarro-Millán et al (1). Dr. Brucato has received research support from Sobi and Acarpia. Dr. Imazio has received consulting fees or honoraria from Kiniksa and Sobi (less than $10,000 each).
Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer
Authors: Davide Melisi, Do-Youn Oh, Antoine Hollebecque, Emiliano Calvo, Anna Varghese, Erkut Borazanci, Teresa Macarulla, Valeria Merz, Camilla Zecchetto, Yumin Zhao, Ivelina Gueorguieva, Michael Man, Leena Gandhi, Shawn T Estrem, Karim A Benhadji, Mark C Lanasa, Emin Avsar, Susan C Guba, Rocio Garcia-Carbonero
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background We assessed the safety, efficacy, and pharmacokinetics of the transforming growth factor beta (TGFβ) receptor inhibitor galunisertib co-administered with the anti-programmed death-ligand 1 (PD-L1) antibody durvalumab in recurrent/refractory metastatic pancreatic cancer previously treated with ≤2 systemic regimens. Methods This was a two-part, single-arm, multinational, phase Ib study. In a dose-finding phase, escalating oral doses of galunisertib were co-administered on days 1–14 with fixed-dose intravenous durvalumab 1500 mg on day 1 every 4 weeks (Q4W), followed by an expansion cohort phase. Results The galunisertib recommended phase II dose (RP2D) when co-administered with durvalumab 1500 mg Q4W was 150 mg two times per day. No dose-limiting toxicities were recorded. Among 32 patients treated with galunisertib RP2D, 1 patient had partial response, 7 had stable disease, 15 had objective progressive disease, and 9 were not evaluable. Disease control rate was 25.0%. Median overall survival and progression-free survival were 5.72 months (95% CI: 4.01 to 8.38) and 1.87 months (95% CI: 1.58 to 3.09), respectively. Pharmacokinetic profiles for combination therapy were comparable to those published for each drug. There was no association between potential biomarkers and treatment outcomes. Conclusion Galunisertib 150 mg two times per day co-administered with durvalumab 1500 mg Q4W was tolerable. Clinical activity was limited. Studying this combination in patients in an earlier line of treatment or selected for predictive biomarkers of TGFβ inhibition might be a more suitable approach. Trial registration number ClinicalTrials.gov identifier: NCT02734160 .
Telomerase-specific replication-selective virotherapy for human cancer
Authors: Toshiyoshi Fujiwara, Takeshi Kawashima, Masaki Taki, Hiroyuki Kishimoto, Takanori Watanabe, Takuya Fukazawa, Satoru Kyo, Noriaki Tanaka
Journal: Cancer Research (2004)

1175  Replication-selective tumor-specific viruses present a novel approach for treating neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We investigated the antitumor effect of the hTERT-specific replication-competent adenovirus on human cancer cells. We constructed an adenovirus 5 vector (TRAD), in which the hTERT promoter element drives expression of E1A and E1B genes linked with an IRES, and examined the selective replication and the antitumor effect in human cancer cells in vitro and in vivo. TRAD induced selective E1A and E1B expression in human cancer cells, but not in normal cells such as human fibroblasts. TRAD replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human fibroblasts lacking telomerase activity. In nu/nu mice carrying subcutaneous human lung tumor xenografts, intratumoral injection of TRAD resulted in a significant inhibition of tumor growth. No evidence of TRAD was identified in tissues outside of the tumors despite the presence of TRAD in the circulation. Moreover, TRAD replication in the distant, un-injected tumors was demonstrated. Our results suggest that the hTERT promoter confers competence for selective replication of TRAD in human cancer cells, an outcome that has important implications for the treatment of human cancers.
Orofacial granulomatosis: Clinical and therapeutic features in an Italian cohort and review of the literature
Authors: Maria R. Galdiero, Filomena Maio, Francesco Arcoleo, Elisa Boni, Laura Bonzano, Luisa Brussino, Mauro Cancian, Luigi Cremonte, Stefano R. Del Giacco, Amato De Paulis, Aikaterini Detoraki, Davide Firinu, Donatella Lamacchia, Stefania Loffredo, Eustachio Nettis, Roberta Parente, Paola Parronchi, Giovanni Pellacani, Angelica Petraroli, Giovanni Rolla, Riccardo Senter, Massimo Triggiani, Gianfranco Vitiello, Giuseppe Spadaro, Maria Bova
Journal: Allergy (2021)

Abstract Background Orofacial granulomatosis (OFG) is characterized by granulomatous inflammation of the soft tissues of maxillofacial region. We explored OFG patients from 10 different Italian centers and summarized the most recent literature data. Methods A review of patients with OFG was carried out. An extensive online literature search was performed to identify studies reporting diagnosis and management of OFG. Results Thirty‐nine patients were recruited between January 2018 and February 2020. Most of them (97.4%) displayed involvement of the lips, and 28.2% suffered from Melkersson‐Rosenthal syndrome. Two patients received diagnosis of CD and one patient of sarcoidosis, suggesting secondary OFG. Oral aphthosis and cervical lymphadenopathy were also described. The mean diagnostic delay was 3.4 years. Histological evaluation was performed in 34/39 patients (87.2%); non‐caseating granulomas were found in 73.5% of them. Neurological symptoms (28.2%), gastrointestinal symptoms in absence of overt inflammatory bowel disease (IBD) (20.5%), and atopy (35.9%) were also identified. Therapeutic approaches varied among the centers. Steroids (51.3%) were used with good or partial results. Anti‐TNF‐α and anti‐IgE monoclonal antibodies were used in 6 (15.4%) and 1 (2.6%) patients, respectively, with variable results. Surgery was the choice for 2 patients with good response. Conclusions OFG is a rare and neglected disease showing multiple clinical phenotypes. While early diagnosis is crucial, management is difficult and highly dependent on the expertise of clinicians due to the lack of international guidelines. There is a need to establish registry databases and address challenges of long‐term management.
ステージIII結腸癌を切除したKRAS野生型(WT)患者(pts)におけるセツキシマブ(Cmab)の有無にかかわらずmFOLFOX6アジュバント治療:NCCTG群間第3相試験NO147の結果
Authors: S R Alberts, D J Sargent, T C Smyrk, A F Shields, E Chan, R M Goldberg, S Gill, M S Kahlenberg, S N Thibodeau, S Nair
Journal: Journal of Clinical Oncology (2010)
Identification of tumor antigens and immune subtypes of cholangiocarcinoma for mRNA vaccine development
Authors: Xing Huang, Tianyu Tang, Gang Zhang, Tingbo Liang
Journal: Molecular Cancer (2021)

The mRNA-based cancer vaccine has been considered a promising strategy and the next hotspot in cancer immunotherapy. However, its application on cholangiocarcinoma remains largely uncharacterized. This study aimed to identify potential antigens of cholangiocarcinoma for development of anti-cholangiocarcinoma mRNA vaccine, and determine immune subtypes of cholangiocarcinoma for selection of suitable patients from an extremely heterogeneous population.Gene expression profiles and corresponding clinical information were collected from GEO and TCGA, respectively. cBioPortal was used to visualize and compare genetic alterations. GEPIA2 was used to calculate the prognostic index of the selected antigens. TIMER was used to visualize the correlation between the infiltration of antigen-presenting cells and the expression of the identified antigens. Consensus clustering analysis was performed to identify the immune subtypes. Graph learning-based dimensionality reduction analysis was conducted to visualize the immune landscape of cholangiocarcinoma.Three tumor antigens, such as CD247, FCGR1A, and TRRAP, correlated with superior prognoses and infiltration of antigen-presenting cells were identified in cholangiocarcinoma. Cholangiocarcinoma patients were stratified into two immune subtypes characterized by differential molecular, cellular and clinical features. Patients with the IS1 tumor had immune "hot" and immunosuppressive phenotype, whereas those with the IS2 tumor had immune "cold" phenotype. Interestingly, patients with the IS2 tumor had a superior survival than those with the IS1 tumor. Furthermore, distinct expression of immune checkpoints and immunogenic cell death modulators was observed between different immune subtype tumors. Finally, the immune landscape of cholangiocarcinoma revealed immune cell components in individual patient.CD247, FCGR1A, and TRRAP are potential antigens for mRNA vaccine development against cholangiocarcinoma, specifically for patients with IS2 tumors. Therefore, this study provides a theoretical basis for the anti-cholangiocarcinoma mRNA vaccine and defines suitable patients for vaccination.
Gains from no real PAINS: Where ‘Fair Trial Strategy’ stands in the development of multi-target ligands
Authors: Jianbo Sun, Hui Zhong, Kun Wang, Na Li, Li Chen
Journal: Acta Pharmaceutica Sinica B (2021)

Compounds that selectively modulate multiple targets can provide clinical benefits and are an alternative to traditional highly selective agents for unique targets. High-throughput screening (HTS) for multitarget-directed ligands (MTDLs) using approved drugs, and fragment-based drug design has become a regular strategy to achieve an ideal multitarget combination. However, the unexpected presence of pan-assay interference compounds (PAINS) suspects in the development of MTDLs frequently results in nonspecific interactions or other undesirable effects leading to artefacts or false-positive data of biological assays. Publicly available filters can help to identify PAINS suspects; however, these filters cannot comprehensively conclude whether these suspects are "bad" or innocent. Additionally, these in silico approaches may inappropriately label a ligand as PAINS. More than 80% of the initial hits can be identified as PAINS by the filters if appropriate biochemical tests are not used resulting in false positive data that are unacceptable for medicinal chemists in manuscript peer review and future studies. Therefore, extensive offline experiments should be used after online filtering to discriminate "bad" PAINS and avoid incorrect evaluation of good scaffolds. We suggest that the use of "Fair Trial Strategy" to identify interesting molecules in PAINS suspects to provide certain structure‒function insight in MTDL development.
Giotto: a toolbox for integrative analysis and visualization of spatial expression data
Authors: Ruben Dries, Qian Zhu, Rui Dong, Chee-Huat Linus Eng, Huipeng Li, Kan Liu, Yuntian Fu, Tianxiao Zhao, Arpan Sarkar, Feng Bao, Rani E. George, Nico Pierson, Long Cai, Guo-Cheng Yuan
Journal: Genome biology (2021)

Abstract Spatial transcriptomic and proteomic technologies have provided new opportunities to investigate cells in their native microenvironment. Here we present Giotto, a comprehensive and open-source toolbox for spatial data analysis and visualization. The analysis module provides end-to-end analysis by implementing a wide range of algorithms for characterizing tissue composition, spatial expression patterns, and cellular interactions. Furthermore, single-cell RNAseq data can be integrated for spatial cell-type enrichment analysis. The visualization module allows users to interactively visualize analysis outputs and imaging features. To demonstrate its general applicability, we apply Giotto to a wide range of datasets encompassing diverse technologies and platforms.
Abstract 268: Evaluation of the Abdominal Aortic and Junctional Tourniquet as an Adjunct to Chest Compressions in a Swine Model of Out-Of-Hospital Cardiac Arrest
Authors: Jason Rall, Chris Hewitt, Matthew Pombo, Maria Castaneda, Perry Blough
Journal: Circulation (2019)

Introduction: Overall success in treating out-of-hospital cardiac arrest using traditional chest compressions is low. The abdominal aortic and junctional tourniquet (AAJT) is a device with a wedge-shaped air bladder that can be used to occlude the descending aorta at the level of bifurcation. In addition to shunting blood away from the lower extremities, this device may increase pleural pressures by inhibiting movement of the diaphragm during compressions. We have previously shown that the addition of an AAJT to mechanical chest compression leads to an increase in rate of survival in a model of traumatic cardiac arrest. Hypothesis: This study was designed to determine if application of the AAJT would lead to more effective chest compressions as measured by an increased rate of return of spontaneous circulation (ROSC) and hemodynamic parameters. Methods: Yorkshire swine (n=6 per group) underwent general anesthesia and instrumentation. Ventricular fibrillation was electrically induced using spinal needles placed in contact with the left ventricle. After eight minutes of arrest, chest compressions were initiated. Animals were then allocated into groups with or without the AAJT. Following a total of ten minutes of compressions, the animals entered into a ten-minute advanced cardiac life support phase. Results: A ROSC was not achieved in either group. No significant differences were observed with coronary perfusion pressure or end tidal CO 2 . However, the AAJT group had a significantly higher carotid diastolic pressure and higher blood flow in the carotid as compared with repeated-measures ANOVA (p = 0.016 and 0.028 respectively). Conclusion: The AAJT did not confer a survival advantage during chest compressions in our swine model of cardiac arrest. However, while the AAJT was in place, improvement was observed in some measures of CPR efficacy. Disclaimer: The views expressed are those of the authors and do not reflect the official views or policy of the Department of Defense or its Components. The experiments reported herein were conducted according to the principles set forth in the National Institute of Health Publication No. 80-23, Guide for the Care and Use of Laboratory Animals and the Animal Welfare Act of 1966, as amended.