tbuckley/cabot-search huggingface dataset:
Feasibility and Therapeutic Potential of 177Lu–Fibroblast Activation Protein Inhibitor–46 for Patients With Relapsed or Refractory Cancers
Authors: Majid Assadi, Seyed Javad Rekabpour, Esmail Jafari, GhasemAli Divband, Babak Nikkholgh, Hamidreza Amini, Hassan Kamali, Sakineh Ebrahimi, Nader Shakibazad, Narges Jokar, Iraj Nabipour, Hojjat Ahmadzadehfar
Journal: Clinical Nuclear Medicine (2021)

Fibroblast activation protein (FAP) is a member of the serine protease family and has a high expression in the stroma of approximately 90% of epithelial malignancies. The present investigation aimed to assess the feasibility, safety, and dosimetry data of 177Lu-FAPI-46 in diverse malignancies.Patients with advanced cancers with nonoperable tumors, or tumors refractory to conventional therapies, were enrolled. Treatment included escalating doses of 177Lu-FAPI-46 (1.85-4.44 GBq) per cycle using a combination of clinical and statistical expertise design, and intervals of 4 to 6 weeks were considered between the cycles. Biodistribution and dosimetry were examined by whole-body scans. We applied the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 to measure peptide-targeted radionuclide therapy (PTRT)-associated toxicity.A total of 21 patients (11 females and 10 males) with a median age of 50 years (range, 6-79 years) were investigated. Of 21 participants, 18 cases were selected for PTRT. Overall, 36 PTRT cycles were performed. The median number of PTRT cycles and the median injected amount of activity in each cycle were 2 and 3.7 GBq, respectively. The dosimetric analysis revealed median absorbed doses of 0.026, 0.136, 0.886, and 0.02 with ranges of 0.023-0.034, 0.001-0.2, 0.076-1.39, and 0.002-0.2 mGy/MBq for the whole body, liver, kidneys, and spleen, respectively. The therapy was well tolerated in almost all patients.The findings of this preliminary investigation might indicate the potential feasibility and safety of PTRT using 177Lu-FAPI-46 for different aggressive tumors. Moreover, the current study could be beneficial in determining the suitable amount of activity for a phase 2 study.
Abstract 411: New estimators for mediation effects in complex sampling schemes: A comparison with applications
Authors: Yujiao Mai, Deo Kumar Srivastava
Journal: Cancer Research (2021)

Abstract Mediation analysis examines the indirect effects via a third variable on the pathway between exposures and outcomes. For the finite-population surveys, that often use stratified cluster sampling, the conventional methods assuming simple random sampling are not appropriate. The point estimation of the effect can be corrected using sampling weights, but the standard error needs further improvement. Recent studies have integrated mediation analysis with balanced repeated replication for standard error estimation. Alternative estimators include Jackknife repeated replication (JRR), bootstrap, and Taylor series linear approximation (TSE). This study proposes new standard error estimators by incorporating the classic linear mediation analysis with JRR, bootstrap, and TSE for complex surveys and compares them using Monte Carlo simulations. The preliminary results show that replication methods have lower Type-I error rates and higher confidence-interval coverage rates than conventional methods. The proposed methods are applied to National Health Interview Surveys to explore the mediation effects on the pathway between cancer survivors' health status and employment status. Citation Format: Yujiao Mai, Deo Kumar Srivastava. New estimators for mediation effects in complex sampling schemes: A comparison with applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 411.
Abstract 2717: Glioma immune microenvironment change during tumor recurrence
Authors: Tathiane Maistro Malta, Indrani Datta, Thais Sabedot, Ruicong She, AnaValeria Castro, Antonio Iavarone, Laila M. Poisson, Houtan Noushmehr
Journal: Cancer Research (2021)

Abstract Background: Gliomas are the most common malignant brain tumor, have a very aggressive behavior, and invariably relapse and progress. Despite the recent advances, only a few drugs are approved and they present limited success. Currently, there are numerous clinical trials evaluating the efficacy of immunotherapy for gliomas, which are not completed yet. Deciphering the composition of the tumor microenvironment (TME) can have an important and immediate impact on therapeutic interventions and on the development of prognostic and predictive biomarkers for gliomas immunotherapy. To investigate the molecular dynamics over time and in response to therapeutic pressures, the Glioma Longitudinal AnalySiS (GLASS) Consortium, a multinational collaboration, is investigating epigenome-wide molecular data from primary and recurrent matched pairs. Objective: Our aim is to evaluate glioma TME using the deconvolution method methylCIBERSORT applied to DNA methylation data from GLASS. Methods: We generated and validated a customized reference signature defining 10 cell types to predict the relative proportions of immune cell type in the TME of 370 glioma specimens, including 132 longitudinal pairs (initial and recurrent tumors) in association with clinical features (recurrence, survival etc). Results: We found that the TME differs across gliomas of different subtypes. In general, IDHmut subtypes (Codel, GCIMP-high, and GCIMP-low) presented less immune infiltration than IDHwt (Classic-like, Mesenchymal-like, and PA-like). The most abundant estimated infiltrated cell types in IDHmut and IDHwt gliomas were TCD4 cells and macrophages, respectively. Post-treatment (chemo+radiotherapy), we found a decrease of TCD4 and an increase of TCD8 cells in recurrent Codel and G-CIMP-high subtypes; and an increase of macrophages in classic recurrent tumors. High frequency of macrophages and TCD8 cells were associated with poorer overall survival in the IDHwt patients (log-rank p=0.040, hazard ratio (HR) = 1.38; log-rank p=0.046, HR = 2.37, respectively). Conclusions: Using a DNA methylation-based deconvolution approach, we have described the TME of longitudinal gliomas. We found a TME diversity across glioma molecular subtypes and an association with IDH mutation and overall survival. Our findings indicate that the epigenomic deconvolution of TME has a potential therapeutic and prognostic implication to guide the management of patients with gliomas. Citation Format: Tathiane Maistro Malta, Indrani Datta, Thais Sabedot, Ruicong She, AnaValeria Castro, GLASS Consortium GLASS Consortium, Antonio Iavarone, Laila M. Poisson, Houtan Noushmehr. Glioma immune microenvironment change during tumor recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2717.
The Use of Augmented Reality to Guide the Intraoperative Frozen Section During Robot-assisted Radical Prostatectomy
Authors: Lorenzo Bianchi, Francesco Chessa, Andrea Angiolini, Laura Cercenelli, Simone Lodi, Barbara Bortolani, Enrico Molinaroli, Carlo Casablanca, Matteo Droghetti, Caterina Gaudiano, Angelo Mottaran, Angelo Porreca, Rita Golfieri, Daniele Romagnoli, Francesca Giunchi, Michelangelo Fiorentino, Pietro Piazza, Stefano Puliatti, Stefano Diciotti, Emanuela Marcelli, Alexandre Mottrie, Riccardo Schiavina
Journal: European Urology (2021)
InSync Model808およびAttain Model218(InSync)にて心臓再同期療法を施行した2症例
Authors: やな瀬正伸, 田中美穂, 村田欣洋, 河合秀樹, 子安正純, 堀部秀樹, 野本茂, 加藤倫子, 室原豊明
Journal: Circulation (2004)
Abstract 1599: SMARCA4 regulates tumor resistance to anti-tumor immune response
Authors: Apoorvi Chaudhri, Yunfei Wang, Leilei Shi, Kunal Rai, Patrick Hwu
Journal: Cancer Research (2021)

Abstract Chromatin remodelers regulate chromatin accessibility and translocation of the nucleosome to expose the underlying DNA sequence. SWI/SNF is a conserved chromatin remodeling complex required for transcriptional activation or repression. In fact, SWI/SNF is the most frequently mutated chromatin regulator in cancer. Though the general understanding is that subunits of the SWI/SNF complex mainly act as tumor suppressors, studies have shown that they can have a context-dependent oncogenic role. Moreover, the PBAF subunits of the complex, PBRM1 and ARID2 impart immunoresistance in B16 melanoma tumors. We perform a TCGA analysis of the subunits based on expression and see that high PBRM1 or SMARCA4 expression in SKCM melanoma correlates with lower survival. Interestingly, SMARCA4 is the conserved catalytic subunit of the complex, and is essential to hydrolyze the energy of the ATP to execute the remodeling function of the complex. On performing a knockdown of SMARCA4 in an in vitro model of B16 cells, a co-culture with antigen specific T cells shows an increase in T cell cytotoxicity. Furthermore, RNA sequencing reveals that knockdown of SMARCA4 upregulates the genes associated with interferon response and downregulates MYC targets. We show that SMARCA4 may mediate immunoresistance such that a knockdown of SMARCA4 in the tumor will sensitize it to anti-tumor immunity. We will next take an in vivo approach to examine if SMARCA4 knockdown will enhance the tumor immune response via an interferon related mechanism. Citation Format: Apoorvi Chaudhri, Yunfei Wang, Leilei Shi, Kunal Rai, Patrick Hwu. SMARCA4 regulates tumor resistance to anti-tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1599.
Rapid spread of the SARS-CoV-2 Delta variant in some French regions, June 2021
Authors: Samuel Alizon, Stéphanie Haim-Boukobza, Vincent Foulongne, Laura Verdurme, Sabine Trombert-Paolantoni, Emmanuel Lecorche, Bénédicte Roquebert, Mircea T. Sofonea
Journal: Eurosurveillance (2021)

We analysed 9,030 variant-specific RT-PCR tests performed on SARS-CoV-2-positive samples collected in France between 31 May and 21 June 2021. This analysis revealed rapid growth of the Delta variant in three of the 13 metropolitan French regions and estimated a +79% (95% confidence interval: 52–110%) transmission advantage compared with the Alpha variant. The next weeks will prove decisive and the magnitude of the estimated transmission advantages of the Delta variant could represent a major challenge for public health authorities.
Abstract 2161: A transcriptomic signature for measuring YAP1 activity in patient samples and tumor models
Authors: Emmanuel Spanakis, Loreley Calvet, Odette Dos Santos, Colette Dib, Sukhvinder Sidhu, Jurgen Moll, Laurent Debussche, Jack Pollard, Iris Valtingojer
Journal: Cancer Research (2021)

Abstract Over the past years, the HIPPO tumor suppressor pathway and its downstream effector Yes1-associated transcriptional regulator (YAP1) present increasing interest in cancer research. The YAP1-TEAD complex regulates transcription for cell proliferation, survival, plasticity, and migration. Aberrant activation of YAP1 has been reported for multiple different cancer types. To estimate the proportion of cases where YAP1/TEAD-dependent transcription may be responsible for tumor development or evolution and evaluate the pharmacodynamics of novel TEAD-inhibitors, we have identified a transcriptional signature of YAP1 activity. The signature comprises 500 genes, positive and negative downstream effectors at about equal proportions, selected by differential expression analyses from 10 published datasets reporting, in total, 19 YAP1-activation and 18 YAP1-inhibition experiments. YAP1/TEAD-dependent transcription was scored in single samples as the difference Rp - Rn, where Rp is the mean fractional rank of the positive YAP1-effectors, and Rn, that of the negative effectors. We so scored, and called, YAP1 activation in normal tissues (GTEx collection; N~9000), in primary, recurrent, or metastatic tumors (TCGA; N~10000), and in cell lines (CCLE; N~1000) for the selection of models. We further applied the signature to follow the degree of YAP1 inhibition in cell and tumor models either after genetic knockdown of HIPPO-YAP1 pathway components or by pharmacologic inhibition using small-molecule TEAD-inhibitors. Our data confirm the robustness of the YAP1-transcription signature as a biomarker for both, tumor indication selection and pharmacodynamics of YAP1-TEAD activity. Citation Format: Emmanuel Spanakis, Loreley Calvet, Odette Dos Santos, Colette Dib, Sukhvinder Sidhu, Jurgen Moll, Laurent Debussche, Jack Pollard, Iris Valtingojer. A transcriptomic signature for measuring YAP1 activity in patient samples and tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2161.
Abstract PL04-02: Targeting regulatory T cells in cancer: From mechanisms to new therapies
Authors: Sergio Quezada
Journal: Cancer Research (2021)

Abstract Regulatory T cells have a critical role in the maintenance of immune homeostasis in mice and man. However, despite their role in maintaining host integrity, their function is known to be hijacked in the context of cancer. The murine and human tumour microenvironment actively recruits regulatory T cells bearing features of activation such as upregulation of the high affinity IL2Ra (CD25) and the immune-regulatory receptor CTLA-4. In mice, anti-CTLA-4 antibodies are able to promote depletion of Tregs and enhanced tumour control whilst in humans this remains less clear. That said, in human cancers, the number of tumour infiltrating regulatory T cells and their spatial distribution with regards to effector T cells has been negatively associated to patient outcomes, underscoring their negative role in anti-tumour immunity and the need for tools that tamper with their function and number. In this talk I will discuss the role of regulatory T cells in the context of cancer, as well as old and new strategies to target this compartment including the development of a new CD25-targeting Treg depleting antibody for mice and man. Citation Format: Sergio Quezada. Targeting regulatory T cells in cancer: From mechanisms to new therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr PL04-02.
p53 convergently activates Dux/DUX4 in embryonic stem cells and in facioscapulohumeral muscular dystrophy cell models
Authors: Edward J. Grow, Bradley D. Weaver, Christina M. Smith, Jingtao Guo, Paula Stein, Sean C. Shadle, Peter G. Hendrickson, Nicholas E. Johnson, Russell J. Butterfield, Roberta Menafra, Susan L. Kloet, Silvère M. van der Maarel, Carmen J. Williams, Bradley R. Cairns
Journal: Nature Genetics (2021)
Predicted dominance of variant Delta of SARS-CoV-2 before Tokyo Olympic Games, Japan, July 2021
Authors: Kimihito Ito, Chayada Piantham, Hiroshi Nishiura
Journal: Eurosurveillance (2021)

Using numbers of SARS-CoV-2 variants detected in Japan as at 13 June 2021, relative instantaneous reproduction numbers (R RI ) of the R.1, Alpha, and Delta variants with respect to other strains circulating in Japan were estimated at 1.25, 1.44, and 1.95. Depending on the assumed serial interval distributions, R RI varies from 1.20–1.32 for R.1, 1.34–1.58 for Alpha, and 1.70–2.30 for Delta. The frequency of Delta is expected to take over Alpha in Japan before 23 July 2021.
Abstract 2406: The essential role of ATP binding to the mitochondrial protein ATAD3A in driving oncogenesis of head and neck squamous cell carcinoma
Authors: Liwei Lang, Tiffany Lam, Alex Chen, Chole Shay, Yong Teng
Journal: Cancer Research (2021)

Abstract Head and neck squamous cell carcinoma (HNSCC) represents only 4% of all cancers in the US, but the adverse impact of this disease on health quality is dramatic. There has been little improvement in HNSCC treatment outcomes in decades, and a better understanding of the molecular biology of HNSCC is urgently needed to facilitate the design of anti-HNSCC therapies. The mitochondrial ATPase family AAA-domain containing protein 3A (ATAD3A) has been demonstrated as an oncogene in breast and lung cancer. However, nothing has been reported regarding its role in HNSCC. We report here that loss of ATAD3A expression inhibits HNSCC cell growth as evidenced by reduced cell proliferation and decreased the ability of colony formation and anchorage-independent growth in soft agar, whereas gain of ATAD3A expression counteracts the observed effects. Overexpression of a Walker A dead mutant of ATAD3A (ATAD3AK358) leads to a suppression in HNSCC cell growth and lipids synthesis, suggesting a potent dominant-negative effect of defective ATP-binding of ATAD3A. In line with the in vitro data, overexpression of ATAD3A facilities tumor growth in an orthotopic mouse model of HNSCC. In contrast, inhibition of ATAD3A function by knockout of ATAD3A or expression of ATAD3AK358 induces significant repression of tumor growth. These findings indicate that the mitochondrial protein ATAD3A plays an oncogenic role in HNSCC, and abrogating its ATP-binding ability may represent a promising regimen for better treatment of patients with HNSCC. Citation Format: Liwei Lang, Tiffany Lam, Alex Chen, Chole Shay, Yong Teng. The essential role of ATP binding to the mitochondrial protein ATAD3A in driving oncogenesis of head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2406.
The genetic architecture of temperature adaptation is shaped by population ancestry and not by selection regime
Authors: Kathrin A. Otte, Viola Nolte, François Mallard, Christian Schlötterer
Journal: Genome biology (2021)

Abstract Background Understanding the genetic architecture of temperature adaptation is key for characterizing and predicting the effect of climate change on natural populations. One particularly promising approach is Evolve and Resequence, which combines advantages of experimental evolution such as time series, replicate populations, and controlled environmental conditions, with whole genome sequencing. Recent analysis of replicate populations from two different Drosophila simulans founder populations, which were adapting to the same novel hot environment, uncovered very different architectures—either many selection targets with large heterogeneity among replicates or fewer selection targets with a consistent response among replicates. Results Here, we expose the founder population from Portugal to a cold temperature regime. Although almost no selection targets are shared between the hot and cold selection regime, the adaptive architecture was similar. We identify a moderate number of targets under strong selection (19 selection targets, mean selection coefficient = 0.072) and parallel responses in the cold evolved replicates. This similarity across different environments indicates that the adaptive architecture depends more on the ancestry of the founder population than the specific selection regime. Conclusions These observations will have broad implications for the correct interpretation of the genomic responses to a changing climate in natural populations.
Minocycline-Induced Hyperpigmentation
Authors: Patrick Wang, James P. Farmer, Jacob Rullo
Journal: JAMA Dermatology (2021)

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Genome Analysis Traces Regional Dispersal of Rice in Taiwan and Southeast Asia
Authors: Ornob Alam, Rafal M Gutaker, Cheng-Chieh Wu, Karen A Hicks, Kyle Bocinsky, Cristina Cobo Castillo, Stephen Acabado, Dorian Fuller, Jade A d’Alpoim Guedes, Yue-Ie Hsing, Michael D Purugganan
Journal: Molecular Biology and Evolution (2021)

The dispersal of rice (Oryza sativa) following domestication influenced massive social and cultural changes across South, East, and Southeast (SE) Asia. The history of dispersal across islands of SE Asia, and the role of Taiwan and the Austronesian expansion in this process remain largely unresolved. Here, we reconstructed the routes of dispersal of O. sativa ssp. japonica rice to Taiwan and the northern Philippines using whole-genome resequencing of indigenous rice landraces coupled with archaeological and paleoclimate data. Our results indicate that japonica rice found in the northern Philippines diverged from Indonesian landraces as early as 3,500 years before present (BP). In contrast, rice cultivated by the indigenous peoples of the Taiwanese mountains has complex origins. It comprises two distinct populations, each best explained as a result of admixture between temperate japonica that presumably came from northeast Asia, and tropical japonica from the northern Philippines and mainland SE Asia, respectively. We find that the temperate japonica component of these indigenous Taiwan populations diverged from northeast Asia subpopulations at about 2,600 BP, whereas gene flow from the northern Philippines had begun before ∼1,300 BP. This coincides with a period of intensified trade established across the South China Sea. Finally, we find evidence for positive selection acting on distinct genomic regions in different rice subpopulations, indicating local adaptation associated with the spread of japonica rice.