tbuckley/cabot-search huggingface dataset:
A willow sex chromosome reveals convergent evolution of complex palindromic repeats
Authors: Ran Zhou, David Macaya-Sanz, Craig H. Carlson, Jeremy Schmutz, Jerry W. Jenkins, David Kudrna, Aditi Sharma, Laura Sandor, Shengqiang Shu, Kerrie Barry, Gerald A. Tuskan, Tao Ma, Jianquan Liu, Matthew Olson, Lawrence B. Smart, Stephen P. DiFazio
Journal: Genome biology (2020)

Sex chromosomes have arisen independently in a wide variety of species, yet they share common characteristics, including the presence of suppressed recombination surrounding sex determination loci. Mammalian sex chromosomes contain multiple palindromic repeats across the non-recombining region that show sequence conservation through gene conversion and contain genes that are crucial for sexual reproduction. In plants, it is not clear if palindromic repeats play a role in maintaining sequence conservation in the absence of homologous recombination.Here we present the first evidence of large palindromic structures in a plant sex chromosome, based on a highly contiguous assembly of the W chromosome of the dioecious shrub Salix purpurea. The W chromosome has an expanded number of genes due to transpositions from autosomes. It also contains two consecutive palindromes that span a region of 200 kb, with conspicuous 20-kb stretches of highly conserved sequences among the four arms that show evidence of gene conversion. Four genes in the palindrome are homologous to genes in the sex determination regions of the closely related genus Populus, which is located on a different chromosome. These genes show distinct, floral-biased expression patterns compared to paralogous copies on autosomes.The presence of palindromes in sex chromosomes of mammals and plants highlights the intrinsic importance of these features in adaptive evolution in the absence of recombination. Convergent evolution is driving both the independent establishment of sex chromosomes as well as their fine-scale sequence structure.
Photovoltaic Restoration of Central Vision in Atrophic Age-Related Macular Degeneration
Authors: Daniel Palanker, Yannick Le Mer, Saddek Mohand-Said, Mahiul Muqit, Jose A. Sahel
Journal: Ophthalmology (2020)

Loss of photoreceptors in atrophic age-related macular degeneration results in severe visual impairment, although some peripheral vision is retained. To restore central vision without compromising the residual peripheral field, we developed a wireless photovoltaic retinal implant (PRIMA; Pixium Vision, Paris, France) in which pixels convert images projected from video glasses using near-infrared light into electric current to stimulate the nearby inner retinal neurons.We carried out a first-in-human clinical trial to test the safety and efficacy of the prosthesis in patients with geographic atrophy (ClinicalTrials.gov identifier, NCT03333954).Five patients with geographic atrophy zone of at least 3 optic disc diameters, no foveal light perception, and best-corrected visual acuity of 20/400 to 20/1000 in the worse-seeing study eye.The 2-mm wide, 30-μm thick chip, containing 378 pixels (each 100 μm in diameter), was implanted subretinally in the area of atrophy (absolute scotoma).Anatomic outcomes were assessed with fundus photography and OCT for up to 12 months of follow-up. Prosthetic vision was assessed by mapping light perception, bar orientation, letter recognition, and Landolt C acuity.In all patients, the prosthesis was implanted successfully under the macula, although in 2 patients, it was implanted in unintended locations: within the choroid and off center by 2 mm. All 5 patients could perceive white-yellow prosthetic visual patterns with adjustable brightness in the previous scotomata. The 3 with optimal placement of the implant demonstrated prosthetic acuity of 20/460 to 20/550, and the patient with the off-center implant demonstrated 20/800 acuity. Residual natural acuity did not decrease after implantation in any patient.Implantation of the PRIMA did not decrease the residual natural acuity, and it restored visual sensitivity in the former scotoma in each of the 5 patients. In 3 patients with the proper placement of the chip, prosthetic visual acuity was only 10% to 30% less than the level expected from the pixel pitch (20/420). Therefore, the use of optical or electronic magnification in the glasses as well as smaller pixels in future implants may improve visual acuity even further.
Clinical correlation of circulating tumor cell (CTC) PD-L1 and HLA I expression in metastatic renal cell carcinoma (mRCC) using exclusion-based sample preparation technology.
Authors: Hamid Emamekhoo, Jennifer L. Schehr, Rory M. Bade, Xiao X. Wei, Rana R. McKay, Toni K. Choueiri, Joshua Michael Lang
Journal: Journal of Clinical Oncology (2020)

721 Background: Despite therapeutic advancement in Vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) for mRCC treatment, there is currently no reliable predictive biomarkers of response or resistance. Single site biopsies provide limited information given the heterogenous nature of mRCC. Liquid biopsies may overcome these limitations; however, prior CTC capture platforms lacked sufficient sensitivity and specificity to achieve clinically useful detection rates. Methods: Given the prevalence of VEGF dependency, and its reliance on hypoxia, we aimed to increase sensitivity and specificity of capturing and identifying mRCC CTCs using carbonic anhydrase IX (CA IX) and CA XII. In addition, traditional markers for cell capture and identification with epithelial cellular adhesion molecule (EpCAM) and cytokeratin (CK) were included. Exclusion-based Sample Preparation technology was used to maximize cell yield. CD45/34/66b positive blood cells were excluded to ensure high specificity in evaluation of PD-L1 and HLA I expression on CTCs. Results: In a preliminary cohort of 21 mRCC pts (treatment: TKI=12, ICI=5, TKI+ICI=2, baseline=2), we identified heterogeneous populations of CTCs with differential expression of CA XII and CK. We detected CK+ CTCs in 20/21 pts (mean= 5/mL; range 0-53), CAXII+ CTCs in 21/21 pts (mean= 1/mL; range 1-9), and CK+/CAXII+ CTCs in 19/21 pts (mean=7/mL; range 0-102). In pts with multiple CTC samples on treatment, there was a high correlation between the number of CK+ CTCs and treatment response (ROC AUC 0.88). PD-L1 expression in CAXII+ CTCs correlated with response to ICI (ROC AUC 0.77) and TKI (ROC AUC 0.73). HLA I expression in CAXII+ CTCs correlated with response to TKI (ROC AUC 0.73) better than ICI (ROC AUC 0.59). Conclusions: Assessment of CTC heterogeneity may provide valuable molecular insights and diversify tools for early detection of therapeutic response and resistance that may guide treatment decision making. This assay is being tested in ongoing Phase II clinical trials.
Sequencing chemotherapy and surgery in upper tract urothelial cancers.
Authors: Saurabh Parasramka, Alex Cook, Zin Myint, Ding Xue, Jianrong Wu, Peng Wang
Journal: Journal of Clinical Oncology (2020)

521 Background: Prognosis for high grade, non-metastatic upper tract urothelial carcinoma (UTUC) (renal pelvis or ureter) has not improved in past two decades. Given improvements in disease-free survival in phase III POUT study, adjuvant chemotherapy (AC) has been the preferred approach. Neoadjuvant chemotherapy (NAC) is favored based on median survival (OS) benefit seen in urothelial bladder cancer. We studied National Cancer Database (NCDB) to answer this question. Methods: We identified adults &gt; 18 years with non-metastatic, high grade, UTUC. All patients received surgery of the primary site and chemotherapy in the neoadjuvant or adjuvant setting. Patient’s receiving radiation therapy or who died within 90 days of surgery were not included. Descriptive statistics, log-rank tests and cox-regression tests were performed. Patients achieving complete pathological response (pCR) defined as (pTis, pT0, pTa and N0) were assessed for OS. Results: 1191 patients with complete data were identified; 225 (19%) received NAC and 966 (81%) received AC. 60% were males, median age was 68 and 73% had Charlson score (CS) of ‘0’. Median follow-up time for alive patients was 30.4 and 36.7 months in the NAC and AC groups respectively. Renal pelvis was the primary in 760 cases (63%) and ureter in 441 (37%). On univariate analysis receiving NAC, age &lt; 75 years and CS score ‘0’ was associated with significant survival benefit (p &lt; 0.05). Similarly on multivariate analysis receiving NAC and having CS of ‘0’ had significantly better survival with HR 0.75 (CI 0.58-0.96) and 0.8 (CI 0.65-0.96) respectively. Age &gt; 75 years had worse survival HR 1.34 (CI 1.08-1.66). Thirty-seven patients (17%) in the NAC group achieved pCR with OS &gt; 71.6 months which was significantly better than AC group and non-responders in the NAC group (p &lt; 0.05). There was a trend towards more benefit with NAC compared to AC in Stage 1 and 2 UTUC than in Stage 3 and 4. Conclusions: Our study indicates that subset of early stage UTUC benefit more from NAC comparing to AC. However, randomized prospective study is warranted to further explore the role of NAC in UTUC.
Histaminergic angioedema: similarities and differences between isolated angioedema and chronic urticaria with angioedema
Authors: Marta Ferrer, Marina Sabaté Brescó, Nuria Rodriguez-Garijo, Gorka Alkorta-Aranburu, Maria Baeza, Mar Guilarte, Valeria Herrera-Lasso Regás, Moises Labrador-Horrillo, Beatriz Veleiro, María Pilar Gil Sanchez
Journal: Journal of Allergy and Clinical Immunology (2020)
Hypomethylation-Linked Activation of PLCE1 Impedes Autophagy and Promotes Tumorigenesis through MDM2-Mediated Ubiquitination and Destabilization of p53
Authors: Yunzhao Chen, Huahua Xin, Hao Peng, Qi Shi, Menglu Li, Jie Yu, Yanxia Tian, Xueping Han, Xi Chen, Yi Zheng, Jun Li, Zhihao Yang, Lan Yang, Jianming Hu, Xuan Huang, Zheng Liu, Xiaoxi Huang, Hong Zhou, Xiaobin Cui, Feng Li
Journal: Cancer Research (2020)

Abstract Esophageal squamous cell carcinoma (ESCC) is one of the deadliest malignant diseases. Multiple studies with large clinic-based cohorts have revealed that variations of phospholipase C epsilon 1 (PLCE1) correlate with esophageal cancer susceptibility. However, the causative role of PLCE1 in ESCC has remained elusive. Here, we observed that hypomethylation-mediated upregulation of PLCE1 expression was implicated in esophageal carcinogenesis and poor prognosis in ESCC cohorts. PLCE1 inhibited cell autophagy and suppressed the protein expression of p53 and various p53-targeted genes in ESCC. Moreover, PLCE1 decreased the half-life of p53 and promoted p53 ubiquitination, whereas it increased the half-life of mouse double minute 2 homolog (MDM2) and inhibited its ubiquitination, leading to MDM2 stabilization. Mechanistically, the function of PLCE1 correlated with its direct binding to both p53 and MDM2, which promoted MDM2-dependent ubiquitination of p53 and subsequent degradation in vitro. Consequently, knockdown of PLCE1 combined with transfection of a recombinant adenoviral vector encoding wild-type p53 resulted in significantly increased levels of autophagy and apoptosis of esophageal cancer in vivo. Clinically, the upregulation of PLCE1 and mutant p53 protein predicted poor overall survival of patients with ESCC, and PLCE1 was positively correlated with p53 in ESCC cohorts. Collectively, this work identified an essential role for PLCE1- and MDM2-mediated ubiquitination and degradation of p53 in inhibiting ESCC autophagy and indicates that targeting the PLCE1–MDM2–p53 axis may provide a novel therapeutic approach for ESCC. Significance: These findings identify hypomethylation-mediated activation of PLCE1 as a potential oncogene that blocks cellular autophagy of esophageal carcinoma by facilitating the MDM2-dependent ubiquitination of p53 and subsequent degradation.
The effect of docetaxel, enzalutamide, abiraterone, and radium-223 on cognitive function in older men with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Shabbir M.H. Alibhai, Henriette Breunis, Narhari Timilshina, Aaron Richard Hansen, Anthony M. Joshua, Padraig Richard Warde, Richard William Gregg, Neil Eric Fleshner, George Tomlinson, Sebastien J. Hotte, Urban Emmenegger
Journal: Journal of Clinical Oncology (2020)

73 Background: Older adults are at greater risk of cognitive decline with various oncologic therapies. Emerging data suggest cognitive effects of various therapies for mCRPC but study populations are highly selected and published data are limited and focus mostly on self-reported cognitive function. We evaluated the effects of treatment with docetaxel chemotherapy (CHEMO), abiraterone (ABI), enzalutamide (ENZA), and radium 223 (Ra223) on cognitive function in older men with mCRPC. Methods: Men age 65+ with mCRPC starting any of the 4 treatments for mCRPC were enrolled in this multicenter prospective cohort study. Three short yet reliable and sensitive measures in older adults were administered at baseline and final visit (6 months with CHEMO and Ra223, mean 14-16 months with ENZA and ABI) using the Montreal Cognitive Assessment (MoCA), Trails A, and Trails B to assess global cognition, attention, and executive function, respectively. Absolute changes in cognitive scores over time were analyzed using multivariable linear regression, and the percentage of individuals with a decline of 1.5 SD in each domain were calculated. Higher scores on MoCA are better but worse for Trails A/B. Results: A total of 51, 26, 49, and 21 men starting CHEMO, ABI, ENZA, and Ra223 with complete data were included. Mean age, education, and baseline cognition were similar between groups (Table). Most patients demonstrated stable cognition or slight reductions. Executive function was the most sensitive of the 3 cognitive domains, and declined by at least 1.5 SD in about one-fifth of each cohort. Although ABI had numerically smaller declines than ENZA, differences were generally small and clinically unimportant. Conclusions: Most older men do not experience significant cognitive decline while on treatment for mCRPC regardless of treatment used.[Table: see text]
Alternative Lengthening of Telomeres and Differential Expression of Endocrine Transcription Factors Distinguish Metastatic and Non-metastatic Insulinomas
Authors: Wenzel M. Hackeng, Willemien Schelhaas, Folkert H. M. Morsink, Charlotte M. Heidsma, Susanne van Eeden, Gerlof D. Valk, Menno R. Vriens, Christopher M. Heaphy, Els J. M. Nieveen van Dijkum, G. Johan A. Offerhaus, Koen M. A. Dreijerink, Lodewijk A. A. Brosens
Journal: Endocrine Pathology (2020)

Abstract Insulin-producing pancreatic neuroendocrine tumors (PanNETs)/insulinomas are generally considered to be indolent tumors with an excellent prognosis after complete resection. However, some insulinomas have a poor prognosis due to relapses and metastatic disease. Recently, studies in non-functional PanNETs indicated that behavior can be stratified according to alpha- and beta-cell differentiation, as defined by expression of the transcription factors ARX and PDX1, respectively. It is unknown whether similar mechanisms play a role in insulinomas. Therefore, we determined ARX and PDX1 expression in a cohort of 35 sporadic primary insulinomas and two liver metastases of inoperable primary insulinomas. In addition, WHO grade and loss of ATRX or DAXX were determined by immunohistochemistry, and alternative lengthening of telomeres (ALT) and CDKN2A status by fluorescence in situ hybridization. These findings were correlated with tumor characteristics and clinical follow-up data. In total, five out of 37 insulinoma patients developed metastatic disease. Metastatic insulinomas were all larger than 3 cm, whereas the indolent insulinomas were smaller ( p value &lt; 0.05). All three primary insulinomas that metastasized showed ARX expression, 2/3 showed ALT, and 1/3 had a homozygous deletion of CDKN2A as opposed to absence of ARX expression, ALT, or CDKN2A deletions in the 32 non-metastatic cases. The two liver metastases also showed ARX expression and ALT (2/2). The presence of ARX expression, which is usually absent in beta-cells, and genetic alterations not seen in indolent insulinomas strongly suggest a distinct tumorigenic mechanism in malignant insulinomas, with similarities to non-functional PanNETs. These observations may inform future follow-up strategies after insulinoma surgery.
Epimedin Officinalis Inhibits NFkB, ERK and JNK Signaling and Enhances Nuclear Translocation of the Glucocorticoid Receptor: Implications for Reversing Steroid-Resistance
Authors: Ke Li, Hang Li, Kamal Srivastava, Changda Liu, Junxiong Li, Xiaohong Liu, Xiumin Li
Journal: Journal of Allergy and Clinical Immunology (2020)
Dual targeting of TGF-β and PD-L1 via a bifunctional anti-PD-L1/TGF-βRII agent: status of preclinical and clinical advances
Authors: Hanne Lind, Sofia R Gameiro, Caroline Jochems, Renee N. Donahue, Julius Strauss, James L Gulley, Claudia Palena, Jeffrey Schlom
Journal: Journal for ImmunoTherapy of Cancer (2020)

Immunosuppressive entities in the tumor microenvironment (TME) remain a major impediment to immunotherapeutic approaches for a majority of patients with cancer. While the immunosuppressive role of transforming growth factor-β (TGF-β) in the TME is well known, clinical studies to date with anti-TGF-β agents have led to limited success. The bifunctional agent bintrafusp alfa (previously designated M7824) has been developed in an attempt to address this issue. Bintrafusp alfa consists of an IgG 1 targeting programmed death ligand 1 (PD-L1) moiety fused via peptide linkers to the extracellular domain of two TGF-β receptor II molecules designed to ‘trap’ TGF-β in the TME. This agent is able to bring the TGF-β trap to the TME via its anti-PD-L1 component, thus simultaneously attacking both the immunosuppressive PD-L1 and TGF-β entities. A number of preclinical studies have shown bintrafusp alfa capable of (1) preventing or reverting TGF-β-induced epithelial-mesenchymal transition in human carcinoma cells; this alteration in tumor cell plasticity was shown to render human tumor cells more susceptible to immune-mediated attack as well as to several chemotherapeutic agents; (2) altering the phenotype of natural killer and T cells, thus enhancing their cytolytic ability against tumor cells; (3) mediating enhanced lysis of human tumor cells via the antibody-dependent cell-mediated cytotoxicity mechanism; (4) reducing the suppressive activity of T reg cells; (5) mediating antitumor activity in numerous preclinical models and (6) enhancing antitumor activity in combination with radiation, chemotherapy and several other immunotherapeutic agents. A phase I clinical trial demonstrated a safety profile similar to other programmed cell death protein 1 (PD-1)/PD-L1 checkpoint inhibitors, with objective and durable clinical responses. We summarize here preclinical and emerging clinical data in the use of this bispecific and potentially multifunctional agent.
Increasing the Clinical Psychiatric Knowledge Base About Pathogenic Copy Number Variation
Authors: Patrick F. Sullivan, Michael J. Owen
Journal: American Journal of Psychiatry (2020)

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Prenatal Egg Consumption and Infant Egg Sensitization in the CHILD Cohort
Authors: Keely Loewen, Theo Moraes, Stuart Turvey, Piush Mandhane, Malcolm Sears, Padmaja Subbarao, Allan Becker, Meghan Azad, Elinor Simons
Journal: Journal of Allergy and Clinical Immunology (2020)
Origin of somatic transformation in germ cell tumor of testis (TGCT): Role of differentiation versus dedifferentiation in a mature teratoma.
Authors: Eric Umbreit, Aron Joon, Mary E. Westerman, Shikhar Gautam Vyas, Tapati Maity, Joma Uthup, Wayne Lewis Hofstetter, John Francis Ward, Jose A. Karam, Miao Zhang, Louis L. Pisters, Christopher G. Wood, Shi-Ming Tu
Journal: Journal of Clinical Oncology (2020)

410 Background: TGCT is a prototype stem-cell malignancy recapitulating the ontogeny of solid tumors. We studied the roles of differentiation versus dedifferentiation in a bona fide well-differentiated tumor, namely mature teratomas, associated with or without somatic transformation. Methods: Between 2001 and 2013, we identified 7 out of 13 cases in which teratoma and somatic transformation were present within the same residual tumor after chemotherapy and resected at our institution with sufficient quantity and quality for DNA and RNA analysis. We performed primary cell culture, flow cytometry, and xenografts to evaluate stem-ness biomarkers and tumor phenotypes of freshly resected mature teratomas. Results: We detected very few mutations within a preselected gene pool (T200) in all tumor samples. The "within patient mutation agreement" from a mutation matrix of 57 genes, in which at least one mutation occurred between teratoma and somatic transformation, was 86.2 to 94.8%. There was disparity in gene expression, including miR7-3HG, ARHGEF35, and DLX6, between the 7 matched tumor pairs (log 2 fold change of about 2). Prospective primary cell culture studies using cell surface stem-ness markers (SSEA3, TRA1-60, Cripto-1, CD90, CD133, CD44) indicate presence of stem cells embedded within residual mature teratomas (n = 3) after chemotherapy. Conclusions: Molecular profiling confirms a common clonal origin between teratoma and somatic transformation but refutes the idea of dedifferentiation of teratoma to somatic transformation. Presence of stem cells embedded within mature teratomas and capable of differentiation into separate ontogenetic lineages could account for the origin of somatic transformation in TGCT.[Table: see text]
New patient-derived models of castrate-sensitive and castrate-resistant prostate cancer.
Authors: Mitchell Lawrence, David Clouston, Mark Frydenberg, Declan G. Murphy, Carmel Jo Pezaro, David William Pook, Heather Thorne, Shahneen Kaur Sandhu, Roxanne Toivanen, Renea Taylor, Gail Risbridger
Journal: Journal of Clinical Oncology (2020)

151 Background: There are fewer preclinical models of prostate cancer compared to other common tumours. New models that represent the diverse features of castrate-sensitive and castration-resistant prostate cancer (CRPC) are required for thorough preclinical testing of novel treatments. Therefore, the goal of the Melbourne Urological Research Alliance (MURAL) is to develop patient-derived xenografts (PDXs) spanning the clinical trajectory of prostate cancer. Methods: We grafted &gt;200 surgery, biopsy or rapid autopsy samples into testosterone-supplemented or castrated male NSG mice. Actively growing tumours were serially transplanted or grown as explants or organoids. PDXs were analysed using RNAseq, targeted genomic sequencing and histopathology review. Results: We previously reported 4 serially transplantable PDXs (Lawrence, et al., 2018, European Urology). Now we have established ~30 additional models spanning treatment naïve primary disease to CRPC. PDXs of CRPC were often from soft tissue metastases of patients who had failed docetaxel, cabazitaxel, enzalutamide, abiraterone and other contemporary treatments. Accordingly, they had diverse mechanisms of resistance, including AR mutations, genomic structural rearrangements, gene amplifications and expression of AR variants. In addition, several PDXs had AR-null phenotypes, including small cell prostate cancer. All PDXs closely reflected the genomic, transcriptomic and histopathological characteristics of the original patient tumours. As renewable sources of tissue, the PDXs could also be grown as ex vivo slice cultures and in vitro organoids, providing complementary models with different timescales and endpoints. Conclusions: We have developed a new collection of castrate-sensitive and castrate-resistant PDXs of prostate cancer, providing diverse tumours for preclinical testing of candidate treatments.