tbuckley/cabot-search huggingface dataset:
Transcriptome analysis of low-risk and high-risk non-muscular invasive bladder cancer patients to reveal disease progression related genes.
Authors: Zhichao Fu, Shenghua Liu, Jianfei Wang, Yiqun Zhang, Yadong Yang, Tianyuan Xu, Shrestha Anil, Yang Yan, Cheng Li, Zongtai Zheng, Xin Li, Xudong Yao
Journal: Journal of Clinical Oncology (2021)

483 Background: According to the EAU prognostic risk classes, non-muscle invasive bladder cancer (NMIBC) is divided into low, medium, and high risk. Patients with high-risk NMIBC (T1/Tis, with high grade/G3, or CIS) represent a challenging group as they are at greater risk of recurrence and progression.Our specific aim was to investigate the biomarkers associated with progression and recurrence in NMIBC. Methods: Tumor tissue were collected from 70 patients with bladder cancer, including high-risk NMIBC (n = 44),low-risk NMIBC (n = 10) and (n = 16) MIBC. mRNA sequenced using the ABclonal Whole RNA-seq Lib Prep kit.The differentially expressed genes were identified using DESeq2 and the analysis of the association between genes expression and patient survival with NMIBC cohorts data(Jakob et al., 2016). RNAseq data of human bladder cancer cell lines were achieved from the Cell Model Passports website (https://cellmodelpassports.sanger.ac.uk/). Results:A total of 456 genes are significantly high expressed in high-risk NMIBC group compared with the low-risk NMIBC group. Combined with MIBC expression data,we found 16 genes with consistently increasing expression from the low-risk NMIBC group to high-risk NMIBC group and MIBC group using a fold change of at least 2, and a false discovery rate (FDR) of 0.05.Among these genes,14 genes were also highly expressed in human bladder cancer cell lines. Survival analysis by Kaplan-Meier,we finally identified 13 high-expressed genes, including KRT6A、SPHK1、S100A9、SLC16A1、CDC25B、NELL2、PREX1、C15orf48、AKR1B10、CERCAM、PKMYT1、UCHL1、SLC16A1, were significantly associated with poor progression-free survival(p&lt;0.05). Conclusions: We identified a set of 13 genes that may predict the progression of NMIBC and may serve as molecular targets for NMIBC therapy. these study results need to be confirmed in larger research studies.
Abstract PR005: The dynamic tumor microenvironment: Oncostreams are self-organizing structures that modulate glioma progression and treatment
Authors: Andrea Comba, Sebastien Motsch, Patrick Dunn, Todd Hollon, Daniel Zamler, Anna Argento, Alon Kahana, Phillip Kish, Maria Castro, Pedro Lowenstein
Journal: Cancer Research (2021)

Abstract Intratumoral heterogeneity is a hallmark of high grade gliomas. However, whether heterogeneity is static or dynamic remains unknown. Here we demonstrate that gliomas’ core and border regions display areas of self-organized collective motion, which we have termed oncostreams. Histologically oncostreams appear as multicellular fascicles of elongated and aligned glioma cells with mesenchymal-like morphology, and their density correlates positively with tumor malignant behavior. Using time lapse confocal imaging of organotypic brain slices of experimental glioma we discovered oncostream dynamics, namely, as two self-organizing patterns of collective motion: streams (bidirectional motion) and flocks (unidirectional motion). Oncostreams were also present in human glioblastoma multiforme, and could also be detected using objective artificial indigent approaches. They were present in 47% of TCGA-GBM grade IV tumor tissues, in 8.6 % of TCGA-LGG grade III, and were absent in TCGA-LGG grade II. Oncostreams are heterogeneous, contain GFAP+ cells, Iba1+ microglia/macrophages cells, and ACTA2+ mesenchymal cells aligned along Sox2+ tumor cells. We propose that oncostreams function as highways possibly stimulating the spread of slower-moving glioma cells and/or non-tumor cells throughout the tumor mass, reinforcing a potential role of oncostreams in determining spatial heterogeneity and remodeling of the tumor microenvironment. To analyze the molecular landscape of oncostreams we used laser capture microdissection coupled to RNA-Seq and bioinformatics analysis: we detected the existence of genetic networks specific to oncostreams. Oncostreams were aligned along highly expressed extracellular matrix proteins, among them Col1a1 was the most differentially expressed. Genetic inhibition of Col1a1 dissembled oncostreams, decreased glioma heterogeneity and improved animal survival. We propose that oncostreams dynamics will be a promising avenue to understand glioma behavior, and treat these malignant tumors. Citation Format: Andrea Comba, Sebastien Motsch, Patrick Dunn, Todd Hollon, Daniel Zamler, Anna Argento, Alon Kahana, Phillip Kish, Maria Castro, Pedro Lowenstein. The dynamic tumor microenvironment: Oncostreams are self-organizing structures that modulate glioma progression and treatment [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 PR005.
Binding and Neutralization Antibody Titers After a Single Vaccine Dose in Health Care Workers Previously Infected With SARS-CoV-2
Authors: Saman Saadat, Zahra Rikhtegaran Tehrani, James Logue, Michelle Newman, Matthew B. Frieman, Anthony D. Harris, Mohammad M. Sajadi
Journal: JAMA (2021)

Venkata Viswanadh Edara, PhD; William H. Hudson, PhD; Xuping Xie, PhD; Rafi Ahmed, PhD; Mehul S. Suthar, PhD
Correspondence on ‘MRI lesions in the sacroiliac joints of patients with spondyloarthritis: an update of definitions and validation by the ASAS MRI working group’
Authors: Zaid Jibri, Ummugulsum Gazel, Dilek Solmaz, Gizem Ayan, Jacob Karsh, Sibel Zehra Aydin, Marcos Sampaio
Journal: Annals of the Rheumatic Diseases (2021)

The use of MRI in the evaluation of axial spondyloarthritis (axSpA) has become more established particularly over the past decade. The Assessment in SpondyloArthritis International Society (ASAS) has previously developed criteria for axSpA that incorporated clinical and imaging aspects including the use of MRI in the detection of active sacroiliitis.1 2 In addition to active inflammation represented by bone marrow oedema (BMO), MRI can demonstrate several structural changes that reflect chronic inflammation accumulated during the natural history of axSpA. Although the presence of structural sacroiliac joint (SIJ) changes on their own is not sufficient to meet the ASAS definition for a positive MRI, these features can influence the diagnosis when it is unclear whether the BMO lesion(s) meet the ASAS criterion.2

We read with great interest the article by Maksymowych et al , which provided an update on the ASAS …
Multimeric antibodies from antigen-specific human IgM+ memory B cells restrict <i>Plasmodium</i> parasites
Authors: Christopher D. Thouvenel, Mary F. Fontana, Jason Netland, Akshay T. Krishnamurty, Kennidy K. Takehara, Yu Chen, Suruchi Singh, Kazutoyo Miura, Gladys J. Keitany, Eric M. Lynch, Silvia Portugal, Marcos C. Miranda, Neil P. King, Justin M. Kollman, Peter D. Crompton, Carole A. Long, Marie Pancera, David J. Rawlings, Marion Pepper
Journal: The Journal of Experimental Medicine (2021)

Multimeric immunoglobulin-like molecules arose early in vertebrate evolution, yet the unique contributions of multimeric IgM antibodies to infection control are not well understood. This is partially due to the difficulty of distinguishing low-affinity IgM, secreted rapidly by plasmablasts, from high-affinity antibodies derived from later-arising memory cells. We developed a pipeline to express B cell receptors (BCRs) from Plasmodium falciparum–specific IgM+ and IgG+ human memory B cells (MBCs) as both IgM and IgG molecules. BCRs from both subsets were somatically hypermutated and exhibited comparable monomeric affinity. Crystallization of one IgM+ MBC-derived antibody complexed with antigen defined a linear epitope within a conserved Plasmodium protein. In its physiological multimeric state, this antibody displayed exponentially higher antigen binding than a clonally identical IgG monomer, and more effectively inhibited P. falciparum invasion. Forced multimerization of this IgG significantly improved both antigen binding and parasite restriction, underscoring how avidity can alter antibody function. This work demonstrates the potential of high-avidity IgM in both therapeutics and vaccines.
How does hormone transition in transgender women change body composition, muscle strength and haemoglobin? Systematic review with a focus on the implications for sport participation
Authors: Joanna Harper, Emma O'Donnell, Behzad Sorouri Khorashad, Hilary McDermott, Gemma L Witcomb
Journal: British Journal of Sports Medicine (2021)

Objectives We systemically reviewed the literature to assess how long-term testosterone suppressing gender-affirming hormone therapy influenced lean body mass (LBM), muscular area, muscular strength and haemoglobin (Hgb)/haematocrit (HCT). Design Systematic review. Data sources Four databases (BioMed Central, PubMed, Scopus and Web of Science) were searched in April 2020 for papers from 1999 to 2020. Eligibility criteria for selecting studies Eligible studies were those that measured at least one of the variables of interest, included transwomen and were written in English. Results Twenty-four studies were identified and reviewed. Transwomen experienced significant decreases in all parameters measured, with different time courses noted. After 4 months of hormone therapy, transwomen have Hgb/HCT levels equivalent to those of cisgender women. After 12 months of hormone therapy, significant decreases in measures of strength, LBM and muscle area are observed. The effects of longer duration therapy (36 months) in eliciting further decrements in these measures are unclear due to paucity of data. Notwithstanding, values for strength, LBM and muscle area in transwomen remain above those of cisgender women, even after 36 months of hormone therapy. Conclusion In transwomen, hormone therapy rapidly reduces Hgb to levels seen in cisgender women. In contrast, hormone therapy decreases strength, LBM and muscle area, yet values remain above that observed in cisgender women, even after 36 months. These findings suggest that strength may be well preserved in transwomen during the first 3 years of hormone therapy.
<i>Plasmodium falciparum</i>–specific IgM B cells dominate in children, expand with malaria, and produce functional IgM
Authors: Christine S. Hopp, Padmapriya Sekar, Ababacar Diouf, Kazutoyo Miura, Kristin Boswell, Jeff Skinner, Christopher M. Tipton, Mary E. Peterson, Michael J. Chambers, Sarah Andrews, Jinghua Lu, Joshua Tan, Shanping Li, Safiatou Doumbo, Kassoum Kayentao, Aissata Ongoiba, Boubacar Traore, Silvia Portugal, Peter D. Sun, Carole Long, Richard A. Koup, Eric O. Long, Adrian B. McDermott, Peter D. Crompton
Journal: The Journal of Experimental Medicine (2021)

IgG antibodies play a role in malaria immunity, but whether and how IgM protects from malaria and the biology of Plasmodium falciparum (Pf)–specific IgM B cells is unclear. In a Mali cohort spanning infants to adults, we conducted longitudinal analyses of Pf- and influenza-specific B cells. We found that Pf-specific memory B cells (MBCs) are disproportionally IgM+ and only gradually shift to IgG+ with age, in contrast to influenza-specific MBCs that are predominantly IgG+ from infancy to adulthood. B cell receptor analysis showed Pf-specific IgM MBCs are somatically hypermutated at levels comparable to influenza-specific IgG B cells. During acute malaria, Pf-specific IgM B cells expand and upregulate activation/costimulatory markers. Finally, plasma IgM was comparable to IgG in inhibiting Pf growth and enhancing phagocytosis of Pf by monocytes in vitro. Thus, somatically hypermutated Pf-specific IgM MBCs dominate in children, expand and activate during malaria, and produce IgM that inhibits Pf through neutralization and opsonic phagocytosis.
Rescue Protocol to Improve the Image Quality of 18F-FDG PET/CT Myocardial Metabolic Imaging
Authors: Xiao-Xin Sun, Shuheng Li, Yawen Wang, Wei Li, Hongxing Wei, Zuo-Xiang He
Journal: Clinical Nuclear Medicine (2021)

Purpose 18 F-FDG PET myocardial metabolic imaging is used to estimate myocardial viability. However, poor image quality can affect the accurate quantification of viable myocardium. We assessed the feasibility of a rescue protocol that reinjected low-dose 18 F-FDG with simultaneous 1 to 2 U of insulin injection and oral administration of 10 g of glucose to improve the image quality of 18 F-FDG PET myocardial metabolic imaging. Patients and Methods Fifty-one consecutive patients with poor quality to uninterpretable 18 F-FDG PET/CT myocardial metabolic images received the rescue protocol immediately after the initial image acquisition. The postrescue image acquisition was performed 1 hour later. The rescue image quality was compared with the initial image. The qualitative visual estimation of the images was graded as follows: grade 0, homogeneous, minimal uptake; grade 1, predominantly minimal or mild uptake; grade 2, moderate uptake; and grade 3, good uptake. The myocardium–to–blood pool activity ratio (M/B) was measured to assess the image quality quantitatively. Results The grades of 0 to 3 were observed in 24 (47%), 27 (53%), 0 (0%), and 0 (0%) patients, respectively, for the initial imaging, and in 0 (0%), 3 (5.9%), 4 (7.8%), and 44 (86.3%) patients for the rescue imaging ( P &lt; 0.001). The rescue M/B was significantly higher than the initial M/B (3.4 ± 1.4 vs 1.6 ± 0.6, respectively; P &lt; 0.001). Conclusions The rescue protocol successfully and rapidly improved the quality of myocardial 18 F-FDG metabolic imaging.
MR-guided focused ultrasound liquid biopsy enriches circulating biomarkers in patients with brain tumors
Authors: Ying Meng, Christopher B Pople, Suganth Suppiah, Maheleth Llinas, Yuexi Huang, Arjun Sahgal, James Perry, Julia Keith, Benjamin Davidson, Clement Hamani, Yutaka Amemiya, Arun Seth, Hon Leong, Chinthaka C Heyn, Isabelle Aubert, Kullervo Hynynen, Nir Lipsman
Journal: Neuro-Oncology (2021)

Abstract Background Liquid biopsy is promising for early detection, monitoring of response, and recurrence of cancer. The blood-brain barrier (BBB) limits the shedding of biomarker, such as cell-free DNA (cfDNA), into the blood from brain tumors, and their detection by conventional assays. Transcranial MR-guided focused ultrasound (MRgFUS) can safely and transiently open the BBB, providing an opportunity for less-invasive access to brain pathology. We hypothesized that MRgFUS can enrich the signal of circulating brain-derived biomarkers to aid in liquid biopsy. Methods Nine patients were treated in a prospective single-arm, open-label trial to investigate serial MRgFUS and adjuvant temozolomide combination in patients with glioblastoma (NCT03616860). Blood samples were collected as an exploratory measure within the hours before and after sonication, with control samples from non-brain tumor patients undergoing BBB opening (BBBO) alone (NCT03739905). Results Brain regions averaging 7.8 ± 6.0 cm3 (range 0.8-23.1 cm3) were successfully treated within 111 ± 39 minutes without any serious adverse events. We found MRgFUS acutely enhanced plasma cfDNA (2.6 ± 1.2-fold, P &amp;lt; .01, Wilcoxon signed-rank test), neuron-derived extracellular vesicles (3.2 ± 1.9-fold, P &amp;lt; .01), and brain-specific protein S100b (1.4 ± 0.2-fold, P &amp;lt; .01). Further comparison of the cfDNA methylation profiles suggests a signature that is disease- and post-BBBO-specific, in keeping with our hypothesis. We also found cfDNA-mutant copies of isocitrate dehydrogenase 1 (IDH1) increased, although this was in only one patient known to harbor the tumor mutation. Conclusions This first-in-human proof-of-concept study shows MRgFUS enriches the signal of circulating brain-derived biomarkers, demonstrating the potential of the technology to support liquid biopsy for the brain.
The road from Rous sarcoma virus to precision medicine
Authors: Olivier Elemento
Journal: The Journal of Experimental Medicine (2021)

In 1911, more than a century ago, Peyton Rous described a curious observation, later explained by a virus named for him that led to the discovery of oncogenes, the modern era of cancer research, and the emergent field of precision medicine (1911. J. Exp. Med. https://doi.org/10.1084/jem.13.4.397).
Unsuspected Bladder Diverticulum Resulted in False-Positive 68Ga-DOTATATE Uptake
Authors: Ying Deng, Yan Deng, Limeng He, Wei Zhang
Journal: Clinical Nuclear Medicine (2021)

Abstract A 67-year-old woman with medullary thyroid cancer was referred for a 68 Ga-DOTATATE PET/CT scan for staging. The images showed abnormal activity in the left thyroid gland and the left cervical lymph nodes. Surprisingly, increased activity was also noted in the posterolateral aspect of the urinary bladder without corresponding anatomical abnormality. This activity disappeared after urination, suggesting false-positive uptake due to bladder diverticulum.
Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake
Authors: Estifanos N. Habtemichael, Don T. Li, João Paulo Camporez, Xavier O. Westergaard, Chloe I. Sales, Xinran Liu, Francesc López-Giráldez, Stephen G. DeVries, Hanbing Li, Diana M. Ruiz, Kenny Y. Wang, Bhavesh S. Sayal, Sofia González Zapata, Pamela Dann, Stacey N. Brown, Sandro Hirabara, Daniel F. Vatner, Leigh Goedeke, William Philbrick, Gerald I. Shulman, Jonathan S. Bogan
Journal: Nature Metabolism (2021)
177Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel: Updated results including progression-free survival (PFS) and patient-reported outcomes (PROs) (TheraP ANZUP 1603).
Authors: Michael S Hofman, Louise Emmett, Shahneen Kaur Sandhu, Amir Iravani, Anthony M. Joshua, Jeffrey C. Goh, David A. Pattison, Thean Hsiang Tan, Ian D. Kirkwood, Siobhan Ng, Roslyn J. Francis, Craig Gedye, Natalie K. Rutherford, Alison Yan Zhang, Margaret Mary McJannett, Martin R. Stockler, John A. Violet, Scott Williams, Andrew James Martin, Ian D. Davis
Journal: Journal of Clinical Oncology (2021)

6 Background: TheraP is a randomized phase 2 trial that showed LuPSMA significantly improved the primary endpoint of PSA≥50% reduction (66% vs. 37%) compared to cabazitaxel in men with docetaxel-treated mCRPC. We now report results on other clinical endpoints and PROs reached the pre-specified target of 170 PFS events. Methods: 200 men with mCRPC (median age 72 y, prior enza/abi 91%) and high PSMA-expression by 68Ga-PSMA-11 and no sites of FDG-positive/PSMA-negative disease, were randomly assigned (1:1) to LuPSMA (6-8.5GBq q6wk up to 6 cycles; N = 99) or cabazitaxel (20mg/m2 q3wk up to 10 cycles; N = 101). Secondary endpoints include PSA/radiologic PFS (PCWG3), pain response (≥2 point reduction on McGill-Melzack Present Pain Intensity scale, objective response rate (ORR) (RECIST 1.1), adverse events (CTCAE), PROs (EORTC QLQ-C30) and overall survival (OS). Cut-off date for analysis of 20JUL20. Results: At a median follow-up of 18.4 months, PFS was significantly longer in those assigned Lu-PSMA rather than cabazitaxel (rates at 1y 19% [95%CI 12-27%] vs 3% [1-9%], hazard ratio (HR) 0.63, 95%CI 0.46-0.86; p = 0.003; 173 events). Similar benefit was seen for rPFS (HR 0.64, 95%CI 0.46-0.88; p = 0.007; 160 events) and PSA-PFS (HR 0.60 95%CI 0.44-0.83; p = 0.002; 172 events). ORR in 78 men with measurable disease was significantly greater in the LuPSMA arm (49% vs 24%, RR 2.1, 95%CI 1.1-4.1; p = 0.019). In 90 men with pain at baseline, pain responses occurred in 60% in the Lu-PSMA arm vs 43% for cabazitaxel (RR 1.42, 95%CI 0.84-4.48; p = 0.10). Patient-reported global health status was similar (LuPSMA 64 [95%CI 61-67] vs cabazitaxel 60 [57-64]) with significantly better outcomes reported for fatigue (34 [95%CI 31-37] vs 40 [36-43]), social functioning (79 [76-82] vs 73 [69-77]), insomnia (24 [20-27] vs 29 [25-33]) and diarrhoea (8.3 [5.6-11.0] vs 15.6 [12.6-18.6]) domains. No PRO domains were superior for cabazitaxel. G3-4 AEs were similar to previously reported (33% vs 53%). OS data remains immature (90 deaths). Conclusions: In men with docetaxel-treated mCRPC, LuPSMA is a promising alternative to cabazitaxel with significantly higher activity (PSA≥50%, PFS, ORR), fewer G3-4 AEs, similar effects on global health status, and improvements in some PRO domains. Clinical trial information: NCT03392428.
Conducting Real-world Evidence Studies on the Clinical Outcomes of Diabetes Treatments
Authors: Sebastian Schneeweiss, Elisabetta Patorno
Journal: Endocrine Reviews (2021)

Real-world evidence (RWE), the understanding of treatment effectiveness in clinical practice generated from longitudinal patient-level data from the routine operation of the healthcare system, is thought to complement evidence on the efficacy of medications from randomized controlled trials (RCTs). RWE studies follow a structured approach. (1) A design layer decides on the study design, which is driven by the study question and refined by a medically informed target population, patient-informed outcomes, and biologically informed effect windows. Imagining the randomized trial we would ideally perform before designing an RWE study in its likeness reduces bias; the new-user active comparator cohort design has proven useful in many RWE studies of diabetes treatments. (2) A measurement layer transforms the longitudinal patient-level data stream into variables that identify the study population, the pre-exposure patient characteristics, the treatment, and the treatment-emergent outcomes. Working with secondary data increases the measurement complexity compared to primary data collection that we find in most RCTs. (3) An analysis layer focuses on the causal treatment effect estimation. Propensity score analyses have gained in popularity to minimize confounding in healthcare database analyses. Well-understood investigator errors, like immortal time bias, adjustment for causal intermediates, or reverse causation, should be avoided. To increase reproducibility of RWE findings, studies require full implementation transparency. This article integrates state-of-the-art knowledge on how to conduct and review RWE studies on diabetes treatments to maximize study validity and ultimately increased confidence in RWE-based decision making.