tbuckley/cabot-search huggingface dataset:
Pregnancy After Breast Cancer in Patients With Germline <i>BRCA</i> Mutations
Authors: Matteo Lambertini, Lieveke Ameye, Anne-Sophie Hamy, Anna Zingarello, Philip D. Poorvu, Estela Carrasco, Albert Grinshpun, Sileny Han, Christine Rousset-Jablonski, Alberta Ferrari, Shani Paluch-Shimon, Laura Cortesi, Claire Senechal, Gianmaria Miolo, Katarzyna Pogoda, Jose Alejandro Pérez-Fidalgo, Laura De Marchis, Riccardo Ponzone, Luca Livraghi, Maria Del Pilar Estevez-Diz, Cynthia Villarreal-Garza, Maria Vittoria Dieci, Florian Clatot, Martine Berlière, Rossella Graffeo, Luis Teixeira, Octavi Córdoba, Amir Sonnenblick, Helena Luna Pais, Michail Ignatiadis, Marianne Paesmans, Ann H. Partridge, Olivier Caron, Claire Saule, Lucia Del Mastro, Fedro A. Peccatori, Hatem A. Azim
Journal: Journal of Clinical Oncology (2020)

Young women with germline BRCA mutations have unique reproductive challenges. Pregnancy after breast cancer does not increase the risk of recurrence; however, very limited data are available in patients with BRCA mutations. This study investigated the impact of pregnancy on breast cancer outcomes in patients with germline BRCA mutations.This is an international, multicenter, hospital-based, retrospective cohort study. Eligible patients were diagnosed between January 2000 and December 2012 with invasive early breast cancer at age ≤ 40 years and harbored deleterious germline BRCA mutations. Primary end points were pregnancy rate, and disease-free survival (DFS) between patients with and without a pregnancy after breast cancer. Pregnancy outcomes and overall survival (OS) were secondary end points. Survival analyses were adjusted for guarantee-time bias controlling for known prognostic factors.Of 1,252 patients with germline BRCA mutations (BRCA1, 811 patients; BRCA2, 430 patients; BRCA1/2, 11 patients) included, 195 had at least 1 pregnancy after breast cancer (pregnancy rate at 10 years, 19%; 95% CI, 17% to 22%). Induced abortions and miscarriages occurred in 16 (8.2%) and 20 (10.3%) patients, respectively. Among the 150 patients who gave birth (76.9%; 170 babies), pregnancy complications and congenital anomalies occurred in 13 (11.6%) and 2 (1.8%) cases, respectively. Median follow-up from breast cancer diagnosis was 8.3 years. No differences in DFS (adjusted hazard ratio [HR], 0.87; 95% CI, 0.61 to 1.23; P = .41) or OS (adjusted HR, 0.88; 95% CI, 0.50 to 1.56; P = .66) were observed between the pregnancy and nonpregnancy cohorts.Pregnancy after breast cancer in patients with germline BRCA mutations is safe without apparent worsening of maternal prognosis and is associated with favorable fetal outcomes. These results provide reassurance to patients with BRCA-mutated breast cancer interested in future fertility.
Impact of total body irradiation‐ vs chemotherapy‐based myeloablative conditioning on outcomes of haploidentical hematopoietic cell transplantation for acute myelogenous leukemia
Authors: Bhagirathbhai Dholaria, Myriam Labopin, Emanuele Angelucci, Fabio Ciceri, Jose L. Diez‐Martin, Benedetto Bruno, Simona Sica, Yener Koc, Zafer Gülbas, Christoph Schmid, Didier Blaise, Angelo Michele Carella, Guiseppe Visani, Bipin N. Savani, Arnon Nagler, Mohamad Mohty
Journal: American Journal of Hematology (2020)

Abstract The optimal myeloablative conditioning (MAC) for patients undergoing haploidentical hematopoietic cell transplantation (haplo‐HCT) is unknown. We studied the outcomes of total body irradiation (TBI) vs chemotherapy (CT) based MAC regimens in acute myeloid leukemia (AML) patients. The study included 1008 patients who underwent first haplo‐HCT with post‐transplant cyclophosphamide, following TBI (N = 89, 9%) or CT (n = 919, 91%) based MAC. Patients in the TBI cohort were younger (median age, 38 vs 47 years, P &lt; .01) and more likely to receive BM graft (57% vs 43%, P = .01). Two‐year overall chronic GVHD (cGVHD) incidence was 42% vs 27% ( P &lt; .01) and extensive cGVHD incidence was 9% vs 12% ( P = .33) in TBI and CT cohorts, respectively. Graft failure was reported in two (2%) TBI‐ and 65 (7%) CT‐MAC recipients ( P = .08). Death from veno‐occlusive disease was reported in one (3%) TBI and 11 (3%) CT patients who died during the study period. In the multivariate analysis, TBI was associated with increased risk for overall cGVHD (hazard ratio = 1.95, 95% confidence interval:1.2‐3.1, P &lt; .01) compared to CT‐based MAC. The choice of conditioning regimen did not impact relapse incidence, leukemia‐free survival, non‐relapse mortality, overall survival or GVHD‐relapse‐free survival in multivariate analysis. In conclusion, major transplant outcomes were not statistically different between TBI‐based MAC and CT‐based MAC in patients with AML after haplo‐HCT/PTCy.
Long-term Trace of Radiation Pneumonitis With 18F-Fluoroestradiol
Authors: Agnès Morel, Bruno Maucherat, Sophie Chiavassa, Françoise Kraeber-Bodéré, Caroline Rousseau
Journal: Clinical Nuclear Medicine (2020)

Abstract Radiation pneumonitis (RP) can be an adverse complication of radiotherapy and usually occurs as an acute reaction from 6 to 12 weeks after radiotherapy. FDG PET is described as an early and adequate barometer for RP diagnosis. Only 1 case of fluoroestradiol uptake contemporary of metabolic FDG changes attributed to RP is reported. We report a case of a breast cancer patient with asymptomatic RP, who at 1 year later, at sequelar stage on CT, showed long-term memory of RP by 18 F-fluoroestradiol PET imaging with nonmetabolic FDG PET.
Agarose-based biomaterials for advanced drug delivery
Authors: Mohsen Khodadadi Yazdi, Ali Taghizadeh, Mohsen Taghizadeh, Florian J. Stadler, Mehdi Farokhi, Fatemeh Mottaghitalab, Payam Zarrintaj, Joshua D. Ramsey, Farzad Seidi, Mohammad Reza Saeb, Masoud Mozafari
Journal: Journal of Controlled Release (2020)
The Molecular Machinery of Gametogenesis in<i>Geodia</i>Demosponges (Porifera): Evolutionary Origins of a Conserved Toolkit across Animals
Authors: Vasiliki Koutsouveli, Paco Cárdenas, Nadiezhda Santodomingo, Anabel Marina, Esperanza Morato, Hans Tore Rapp, Ana Riesgo
Journal: Molecular Biology and Evolution (2020)

All animals are capable of undergoing gametogenesis. The ability of forming haploid cells from diploid cells through meiosis and recombination appeared early in eukaryotes, whereas further gamete differentiation is mostly a metazoan signature. Morphologically, the gametogenic process presents many similarities across animal taxa, but little is known about its conservation at the molecular level. Porifera are the earliest divergent animals and therefore are an ideal phylum to understand evolution of the gametogenic toolkits. Although sponge gametogenesis is well known at the histological level, the molecular toolkits for gamete production are largely unknown. Our goal was to identify the genes and their expression levels which regulate oogenesis and spermatogenesis in five gonochoristic and oviparous species of the genus Geodia, using both RNAseq and proteomic analyses. In the early stages of both female and male gametogenesis, genes involved in germ cell fate and cell-renewal were upregulated. Then, molecular signals involved in retinoic acid pathway could trigger the meiotic processes. During later stages of oogenesis, female sponges expressed genes involved in cell growth, vitellogenesis, and extracellular matrix reassembly, which are conserved elements of oocyte maturation in Metazoa. Likewise, in spermatogenesis, genes regulating the whole meiotic cycle, chromatin compaction, and flagellum axoneme formation, that are common across Metazoa were overexpressed in the sponges. Finally, molecular signals possibly related to sperm capacitation were identified during late stages of spermatogenesis for the first time in Porifera. In conclusion, the activated molecular toolkit during gametogenesis in sponges was remarkably similar to that deployed during gametogenesis in vertebrates.
Well-Being, Burnout, and Depression Among North American Psychiatrists: The State of Our Profession
Authors: Richard F. Summers, Tristan Gorrindo, Seungyoung Hwang, Rashi Aggarwal, Constance Guille
Journal: American Journal of Psychiatry (2020)

Objective: The authors examined the prevalence of burnout and depressive symptoms among North American psychiatrists, determined demographic and practice characteristics that increase the risk for these symptoms, and assessed the correlation between burnout and depression. Methods: A total of 2,084 North American psychiatrists participated in an online survey, completed the Oldenburg Burnout Inventory (OLBI) and the Patient Health Questionnaire–9 (PHQ-9), and provided demographic data and practice information. Linear regression analysis was used to determine factors associated with higher burnout and depression scores. Results: Participants’ mean OLBI score was 40.4 (SD=7.9) and mean PHQ-9 score was 5.1 (SD=4.9). A total of 78% (N=1,625) of participants had an OLBI score ≥35, suggestive of high levels of burnout, and 16.1% (N=336) of participants had PHQ-9 scores ≥10, suggesting a diagnosis of major depression. Presence of depressive symptoms, female gender, inability to control one’s schedule, and work setting were significantly associated with higher OLBI scores. Burnout, female gender, resident or early-career stage, and nonacademic setting practice were significantly associated with higher PHQ-9 scores. A total of 98% of psychiatrists who had PHQ-9 scores ≥10 also had OLBI scores >35. Suicidal ideation was not significantly associated with burnout in a partially adjusted linear regression model. Conclusions: Psychiatrists experience burnout and depression at a substantial rate. This study advances the understanding of factors that increase the risk for burnout and depression among psychiatrists and has implications for the development of targeted interventions to reduce the high rates of burnout and depression among psychiatrists. These findings have significance for future work aimed at workforce retention and improving quality of care for psychiatric patients.
Single-cell lineage analysis reveals genetic and epigenetic interplay in glioblastoma drug resistance
Authors: Christine E. Eyler, Hironori Matsunaga, Volker Hovestadt, Samantha J. Vantine, Peter van Galen, Bradley E. Bernstein
Journal: Genome biology (2020)

Abstract Background Tumors can evolve and adapt to therapeutic pressure by acquiring genetic and epigenetic alterations that may be transient or stable. A precise understanding of how such events contribute to intratumoral heterogeneity, dynamic subpopulations, and overall tumor fitness will require experimental approaches to prospectively label, track, and characterize resistant or otherwise adaptive populations at the single-cell level. In glioblastoma, poor efficacy of receptor tyrosine kinase (RTK) therapies has been alternatively ascribed to genetic heterogeneity or to epigenetic transitions that circumvent signaling blockade. Results We combine cell lineage barcoding and single-cell transcriptomics to trace the emergence of drug resistance in stem-like glioblastoma cells treated with RTK inhibitors. Whereas a broad variety of barcoded lineages adopt a Notch-dependent persister phenotype that sustains them through early drug exposure, rare subclones acquire genetic changes that enable their rapid outgrowth over time. Single-cell analyses reveal that these genetic subclones gain copy number amplifications of the insulin receptor substrate-1 and substrate-2 (IRS1 or IRS2) loci, which activate insulin and AKT signaling programs. Persister-like cells and genomic amplifications of IRS2 and other loci are evident in primary glioblastomas and may underlie the inefficacy of targeted therapies in this disease. Conclusions A method for combined lineage tracing and scRNA-seq reveals the interplay between complementary genetic and epigenetic mechanisms of resistance in a heterogeneous glioblastoma tumor model.
In situ vaccination at a peripheral tumor site augments response against melanoma brain metastases
Authors: Paul A Clark, Raghava N Sriramaneni, Won Jong Jin, Justin C Jagodinsky, Amber M Bates, Abigail A Jaquish, Bryce R Anderson, Trang Le, Jonathan A Lubin, Ishan Chakravarty, Ian S Arthur, Clinton M Heinze, Emily I Guy, Jasdeep Kler, Kelsey A Klar, Peter M Carlson, Kyung Mann Kim, John S Kuo, Zachary S Morris
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immune checkpoint inhibition (ICI) alone is not efficacious for a large number of patients with melanoma brain metastases. We previously established an in situ vaccination (ISV) regimen combining radiation and immunocytokine to enhance response to ICIs. Here, we tested whether ISV inhibits the development of brain metastases in a murine melanoma model. Methods B78 (GD2 + ) melanoma ‘primary’ tumors were engrafted on the right flank of C57BL/6 mice. After 3–4 weeks, primary tumors were treated with ISV (radiation (12 Gy, day 1), α-GD2 immunocytokine (hu14.18-IL2, days 6–10)) and ICI (α-CTLA-4, days 3, 6, 9). Complete response (CR) was defined as no residual tumor observed at treatment day 90. Mice with CR were tested for immune memory by re-engraftment with B78 in the left flank and then the brain. To test ISV efficacy against metastases, tumors were also engrafted in the left flank and brain of previously untreated mice. Tumors were analyzed by quantitative reverse transcription-PCR, immunohistochemistry, flow cytometry and multiplex cytokine assay. Results ISV+α-CTLA-4 resulted in immune memory and rejection of B78 engraftment in the brain in 11 of 12 mice. When B78 was engrafted in brain prior to treatment, ISV+α-CTLA-4 increased survival compared with ICI alone. ISV+α-CTLA-4 eradicated left flank tumors but did not elicit CR at brain sites when tumor cells were engrafted in brain prior to ISV. ISV+α-CTLA-4 increased CD8 + and CD4 + T cells in flank and brain tumors compared with untreated mice. Among ISV + α-CTLA-4 treated mice, left flank tumors showed increased CD8 + infiltration and CD8 + :FOXP3 + ratio compared with brain tumors. Flank and brain tumors showed minimal differences in expression of immune checkpoint receptors/ligands or Mhc-1 . Cytokine productions were similar in left flank and brain tumors in untreated mice. Following ISV+α-CTLA-4, production of immune-stimulatory cytokines was greater in left flank compared with brain tumor grafts. Conclusion ISV augmented response to ICIs in murine melanoma at brain and extracranial tumor sites. Although baseline tumor-immune microenvironments were similar at brain and extracranial tumor sites, response to ISV+α-CTLA-4 was divergent with reduced infiltration and activation of immune cells in brain tumors. Additional therapies may be needed for effective antitumor immune response against melanoma brain metastases.
Earlier diagnosis of lung cancer in a randomised trial of an autoantibody blood test followed by imaging
Authors: Frank M. Sullivan, Frances S. Mair, William Anderson, Pauline Armory, Andrew Briggs, Cindy Chew, Alistair Dorward, John Haughney, Fiona Hogarth, Denise Kendrick, Roberta Littleford, Alex McConnachie, Colin McCowan, Nicola Mcmeekin, Manish Patel, Petra Rauchhaus, Lewis Ritchie, Chris Robertson, John Robertson, Jose Robles-Zurita, Joseph Sarvesvaran, Herbert Sewell, Michael Sproule, Thomas Taylor, Agnes Tello, Shaun Treweek, Kavita Vedhara, Stuart Schembri
Journal: European Respiratory Journal (2020)

The EarlyCDT-Lung test is a high specificity blood-based autoantibody biomarker that could contribute to predicting lung cancer risk. Here we report on the results of a phase IV biomarker evaluation of whether using the EarlyCDT-Lung test and any subsequent CT scanning to identify those at high risk of lung cancer reduces the incidence of patients with stage III/IV/Unspecified lung cancer at diagnosis, compared with the standard clinical practice at the time the study began. ECLS was a randomised controlled trial of 12 208 participants at risk of developing lung cancer in Scotland. The intervention arm received the EarlyCDT-Lung test and, if test positive, low-dose CT scanning six-monthly for up to 2 years. EarlyCDT-Lung test negative and control arm participants received standard clinical care. Outcomes were assessed at 2 years post-randomisation using validated data on cancer occurrence, cancer staging, mortality and comorbidities. At 2 years, 127 lung cancers were detected in the study population (1.0%). In the intervention arm, 33/56 (58.9%) lung cancers were diagnosed at stage III/IV compared to 52/71 (73.2%) in the control arm. The hazard ratio for stage III/IV presentation was 0.64 (95% confidence interval 0.41, 0.99). There were non-significant differences in lung cancer and all-cause mortality after 2 years. ECLS compared EarlyCDT-Lung plus CT screening to standard clinical care (symptomatic presentation), and was not designed to assess the incremental contribution of the EarlyCDT-Lung test. The observation of a stage-shift towards earlier-stage lung cancer diagnosis merits further investigations to evaluate whether the EarlyCDT-Lung test adds anything to the emerging standard of LDCT.
Point of Care Nucleic Acid Testing for SARS-CoV-2 in Hospitalized Patients: A Clinical Validation Trial and Implementation Study
Authors: Dami A. Collier, Sonny M. Assennato, Ben Warne, Nyarie Sithole, Katherine Sharrocks, Allyson Ritchie, Pooja Ravji, Matthew Routledge, Dominic Sparkes, Jordan Skittrall, Anna Smielewska, Isobel Ramsey, Neha Goel, Martin Curran, David Enoch, Rhys Tassell, Michelle Lineham, Devan Vaghela, Clare Leong, Hoi Ping Mok, John Bradley, Kenneth G.C. Smith, Vivienne Mendoza, Nikos Demiris, Martin Besser, Gordon Dougan, Paul J. Lehner, Mark J. Siedner, Hongyi Zhang, Claire S. Waddington, Helen Lee, Ravindra K. Gupta, Stephen Baker, John Bradley, Gordon Dougan, Ian Goodfellow, Ravindra K. Gupta, Paul J. Lehner, Paul Lyons, Nicholas J. Matheson, Kenneth G.C. Smith, Mark Toshner, Michael P. Weekes, Nick Brown, Martin Curran, Surendra Palmar, Hongyi Zhang, David Enoch, Daniel Chapman, Ashley Shaw, Vivien Mendoza, Sherly Jose, Areti Bermperi, Julie Ann Zerrudo, Evgenia Kourampa, Caroline Saunders, Ranalie de Jesus, Jason Domingo, Ciro Pasquale, Bensi Vergese, Phoebe Vargas, Marivic Fabiculana, Marlyn Perales, Richard Skells, Lee Mynott, Elizabeth Blake, Amy Bates, Anne-laure Vallier, Alexandra Williams, David Phillips, Edmund Chiu, Alex Overhill, Nicola Ramenante, Jamal Sipple, Steven Frost, Helena Knock, Richard Hardy, Emily Foster, Fiona Davidson, Viona Rundell, Purity Bundi, Richmond Abeseabe, Sarah Clark, Isabel Vicente
Journal: Cell Reports Medicine (2020)

There is an urgent need for rapid SARS-CoV-2 testing in hospitals to limit nosocomial spread. We report an evaluation of point of care (POC) nucleic acid amplification testing (NAAT) in 149 participants with parallel combined nasal and throat swabbing for POC versus standard lab RT-PCR testing. Median time to result is 2.6 (IQR 2.3–4.8) versus 26.4 h (IQR 21.4–31.4, p < 0.001), with 32 (21.5%) positive and 117 (78.5%) negative. Cohen's κ correlation between tests is 0.96 (95% CI 0.91–1.00). When comparing nearly 1,000 tests pre- and post-implementation, the median time to definitive bed placement from admission is 23.4 (8.6-41.9) versus 17.1 h (9.0–28.8), p = 0.02. Mean length of stay on COVID-19 "holding" wards is 58.5 versus 29.9 h (p < 0.001). POC testing increases isolation room availability, avoids bed closures, allows discharge to care homes, and expedites access to hospital procedures. POC testing could mitigate the impact of COVID-19 on hospital systems.
Abstract B62: The need to improve exercise prescriptions to support care in pediatric oncology
Authors: Maxime Caru, Kateryna Petrykey, Mariia Samoilenko, Simon Drouin, Valérie Lemay, Laurence Kern, Lucia Romo, Patrick Beaulieu, Pascal St-Onge, Laurence Bertout, Geneviéve Lefebvre, Gregor Andelfinger, Maja Krajinovic, Caroline Laverdière, Daniel Sinnett, Daniel Curnier
Journal: Cancer Research (2020)

Abstract Purpose: Cancer survivors’ exposure to chemotherapeutic agents leads to multiple long-term side effects with a decrease in their cardiorespiratory fitness. The first aim was to determine whether cardiorespiratory fitness and physical activity levels were lower among survivors than healthy Canadians, while the second aim was to report associations between genetic variants and cardiorespiratory fitness in survivors. Methods: Cardiorespiratory fitness (VO2peak) and moderate to vigorous physical activity (MVPA) were compared between childhood ALL survivors (N=221) and healthy Canadians (N=825). We performed whole-exome sequencing in survivors. Germline variants (both common and rare) in a selected set of trainability genes were analyzed for an association with cardiorespiratory fitness. Results: Survivors’ VO2 peak was found to be 22% lower than healthy Canadians. The cardiorespiratory fitness level was different between survivors and healthy Canadians despite a clinically equivalent level of MVPA. Positive associations between the cardiorespiratory fitness level and trainability genes (TTN, LEPR, IGFBPI, and ENO3 genes) were reported, especially in female survivors with a low cardiorespiratory fitness level. Conclusion: The cardiorespiratory fitness was significantly lower in survivors, which can be associated with variants in genes related to subjects’ trainability. At this time, it appears that more physical activity would be beneficial to survivors to achieve the same benefits as the healthy population. However, the optimal amount of physical activity needed to reach these benefits is not yet clear. The survivors’ responder or nonresponder status several years after the end of the treatments is unknown. This study has important implications for the field of exercise in oncology. Citation Format: Maxime Caru, Kateryna Petrykey, Mariia Samoilenko, Simon Drouin, Valérie Lemay, Laurence Kern, Lucia Romo, Patrick Beaulieu, Pascal St-Onge, Laurence Bertout, Geneviéve Lefebvre, Gregor Andelfinger, Maja Krajinovic, Caroline Laverdière, Daniel Sinnett, Daniel Curnier. The need to improve exercise prescriptions to support care in pediatric oncology [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B62.