tbuckley/cabot-search huggingface dataset:
Impact of Graft Versus Host Disease on Outcome of Allogeneic Haematopoietic Stem Cell Transplantation for Thalassemia Major - Comparison of Bone Marrow Vs Peripheral Blood Stem Cell Grafts
Authors: Fouzia N., Uday Prakash Kulkarni, Anup Joseph Devasia, Anu Korula, Kavitha M Lakshmi, Aby Abraham, Biju George, Vikram Mathews, Alok Srivastava
Journal: Blood (2019)
Metformin Suppress Cellular and Molecular Processes Related to Maintenance and Proliferation of Myeloproliferative Neoplasm Stem Cell
Authors: Juan L Coelho-Silva, Thiago Mantello Bianco, Antonio Bruno Alves Silva, Diego Antonio Pereira-Martins, Natasha Peixoto Fonseca, Isabel Weinhäuser, Eduardo M Rego, Fernando Chahud, João Agostinho Machado-Neto, Lorena Lobo Figueiredo-Pontes, Fabiola Traina
Journal: Blood (2019)
Genetics of Type 1A Diabetes
Authors: Vincenzo Sepe, Andrea Loviselli, Gian Franco Bottazzo
Journal: New England Journal of Medicine (2009)

To the Editor: In their review article on the genetics of type 1A diabetes, Concannon et al. (April 16 issue),1 citing Aly et al.,2 state that the disorder develops in approximately 1 of 20 persons...
INNV-40. TARGETED NEXT GENERATION SEQUENCING OF PEDIATRIC HIGH-GRADE GLIOMA AND ITS THERAPEUTIC IMPLICATIONS, MD ANDERSON EXPERIENCE
Authors: David McCall, Agda Eterovic, Tyler Moss, Muhammed Baig, Greg Fuller, Jason Huse, David I Sandberg, Michael Rytting, Jonathan Gill, Joya Chandra, Soumen Khatua, Kenna Shaw, Funda Meric-Bernstam, Wafik Zaky
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION The new understanding of molecular pathways in cancer is paving the way towards personalized cancer medicine, especially in refractory disease. High-grade gliomas (HGG) are common pediatric brain tumors that tend to recur, with no available standard therapy upon recurrence. HGG are challenging tumors with illusive biology and poor outcome. We report here the molecular testing of 27 pediatric HGG patients. MATERIALS AND METHODS An analysis of pediatric patients with HGG treated at UT MD Anderson Cancer Center (MDACC) who underwent molecular genetic profiling using next generation sequencing with different genomic panels (AmpliSeq™Cancer Hotspot and Oncomine Panels – by Thermo Fisher Scientific). RESULTS 27 patients with HGG (median age 14 years, range 3–18 years old) underwent genomic profiling. Primary diagnoses were glioblastoma multiforme (n=22), anaplastic astrocytoma (n = 2), gliosarcoma (n= 1), anaplastic pleomorphic xanthoastrocytoma (n= 1) and anaplastic oligoastrocytoma (n= 1). There are 46 genes common to the panels used. The most common mutation was in TP53 (73%). Other mutations included PIK3CA (19%), IDH1 (11.5%), 7.7% for ATM, EGFR and PTEN, and 3.8% for BRAF, FGFR1 and FGFR2. 24 out of 27 patients were tested at initial diagnosis and 3 upon relapse/progression. Patients at initial diagnosis received standard of care therapy of radiation and temozolomide. Only 5 patients received targeted therapy upon progression/recurrence. Some challenges of genomically-matched therapy included lack of clinical trials accepting pediatric patients, unavailability of a liquid form of a drug, and insurance disapproval for off-label use. CONCLUSION The next generation of therapy for childhood cancers will be based upon in-depth molecular phenotyping that may facilitate the development of rational risk-adapted and target-based therapies. This cohort, though limited by sample size, highlights the opportunity to perform molecular testing and identification of alterations in actionable genes.
Chromosome Banding Analysis Versus Genomic Microarrays: A Comparison of Methods for Genomic Complexity Risk Stratification in Chronic Lymphocytic Leukemia Patients with Complex Karyotype
Authors: Silvia Ramos Campoy, Anna Puiggros, Silvia Bea, Sandrine Bougeon, Maria Jose Larrayoz, Guillem Clot, Dolors Costa, Gian Matteo Rigolin, Margarita Ortega, Laura Blanco, Rosa Collado, Rocio N Salgado, María-Dolores García-Malo, Andrea Campeny, Alberto Valiente, Ferran Nadeu, Julio Delgado, Tycho Baumann, Idoya Ancín, Marco Antonio Moro García, Eva Gimeno, Carol Moreno, Francesc Bosch, Ana Ferrer, Gonzalo Blanco, Maria Jose Calasanz, Antonio Cuneo, Claudia Haferlach, Jacqueline Schoumans, Blanca Espinet
Journal: Blood (2019)
ANGI-10. CHEMOTHERAPEUTIC STRESS INDUCES TRANSDIFFERENTIATION OF GLIOBLASTOMA CELLS TO PROMOTE VASCULAR MIMICRY
Authors: Shivani Baisiwala, Brenda Auffinger, Seamus Caragher, Jack Shireman, Riasat Ahsan, Cheol Park, Atique Ahmed
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor affecting adults, with a median survival of approximately 21 months after diagnosis. A key factor underlying the limited efficacy of current treatment modalities is the remarkable plasticity exhibited by GBM cells, which allows them to effectively adapt to changes induced by our current treatment strategies. In addition to their plasticity, GBM tumors are also highly vascularized with aberrant vessels that further promote its aggressiveness. Recent research has demonstrated that GBM cells have the ability to transdifferentiate into endothelial cells (ECs), which suggests that GBM cells may use their properties of plasticity and vascularity in concert, leading to the creation of tumor-derived blood vessels. The mechanism behind this transdifferentiation remains unclear. Here, we show that treatment with temozolamide (TMZ)-based chemotherapy (the current standard of care) induces time-dependent increases in expression of markers for glioma stem cells (GSCs) and immature and mature ECs over 8 days of treatment (p &lt; .001) in multiple patient-derived xenograft (PDX) lines. In addition, GBM tumors growing as orthotopic xenografts in nude mice showed significantly increased expression of GSC markers (CD15 and CD133) and EC markers (CD105 and CD144) after 8 days of TMZ treatment (p &lt; .01). Ex-vivo FACS analysis of these orthotopic xenografts showed the presence of immature and mature EC populations in addition to GSC populations. To assess the functionality of these increased EC populations, a tube forming assay was performed. Results showed that the tube forming capacity of PDX lines was significantly increased (p &lt; .01) after therapy. Furthermore, immunofluorescence analysis revealed increased tumor-derived vessels in TMZ-recurrent tumors. Overall, this study identifies chemotherapeutic stress as a new driver of transdifferentiation of tumor cells to endothelial cells and highlights cellular plasticity as a key player in therapeutic resistance and tumor recurrence.
Differential Alemtuzumab Dosage Effects in T-Cell Deplete Allogeneic Haematopoietic Stem Cell Transplants for Myeloid Malignancies- King's College Hospital London Experience
Authors: Varun Mehra, Daniele Avenoso, Ximena Cabrera Castellano, Adrian Choy, Stefani Widya, Mili Shah, Shafqat Inam, Shreyans Gandhi, Austin Kulasekararaj, Francesco Dazzi, Ghulam J. Mufti, Antonio Pagliuca, Hugues De Lavallade, Victoria Potter
Journal: Blood (2019)
TMOD-27. A NEURAL CREST CELL SUBPOPULATION UNDERLIES INTRATUMOR HETEROGENEITY IN MENINGIOMA
Authors: Stephen Magill, Harish Vasudevan, Kyounghee Seo, S John Liu, Stephanie Hilz, Javier Villanueva-Meyer, Abrar Choudhury, Benjamin Demaree, Daniel Lim, Steve Braunstein, Nancy Ann Oberheim-Bush, Erik Ullian, Manish Aghi, Philip Theodosopoulos, Patricia Sneed, Adam Abate, Mitchel Berger, Mike McDermott, Joseph Costello, David Raleigh
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Meningiomas are the most common primary intracranial tumor, and high grade meningiomas are resistant to most cancer therapies. Intratumor heterogeneity is a recognized source of resistance to treatment in numerous malignancies. Thus, we hypothesized that investigating molecular heterogeneity in meningiomas would elucidate biologic drivers and shed light on tumor evolution and mechanisms of resistance. METHODS We collected 86 spatially distinct samples at the time of resection from 13 meningiomas. Seven meningiomas were WHO grade I (46 samples), three were grade II (22 samples), and three were grade III (18 samples). Seven meningiomas were sampled at the time of salvage surgery (48 samples), and 6 were sampled at the time of initial diagnosis (38 samples). We performed multiplatform molecular profiling of these samples to identify drivers of intratumor heterogeneity, and validated our results using meningioma cells co-cultured with human cerebral organoids and RNA sequencing of paired primary and recurrent meningiomas. RESULTS Using bulk RNA sequencing, DNA methylation profiling and phylogenetic analysis of spatially distinct samples, we discovered significant transcriptomic, epigenomic and genomic heterogeneity in meningioma. In particular, we identified chromosomal structural alterations and differences in immune and neuronal signaling that underlie clonal evolution in high grade tumors. Using MRI-stratified bulk RNA sequencing, single nuclear RNA sequencing, RNA sequencing of paired primary and recurrent meningiomas, and live cell microscopy and single cell RNA sequencing of meningioma cells in co-culture with human cerebral organoids, we revealed a rare meningioma cell subpopulation with strong transcriptional concordance to the neural crest, a multipotent embryonic tissue that forms the meninges in development. CONCLUSIONS These data suggest that misactivation of a developmental cell population underlies intratumor heterogeneity in meningioma and that expression of neural crest and immediate early genes are an important step in meningeal oncogenesis.
A Double-Blind, Placebo-Controlled, Phase 3 Registration Trial to Evaluate the Efficacy of Uproleselan (GMI-1271) with Standard Salvage Chemotherapy in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia
Authors: Daniel J. DeAngelo, Harry P. Erba, Brian A Jonas, Michael E O'Dwyer, Paula Marlton, Gerwin Huls, Jane L. Liesveld, Brenda Cooper, Bhavana Bhatnagar, Geoffrey L. Uy, Gavin Cull, Michael B. Armstrong, William E. Fogler, Mary M Chen, John L. Magnani, Helen M Thackray, Eric J. Feldman, Anjali S. Advani, Pamela S. Becker
Journal: Blood (2019)
PDTM-21. MULTI-MODAL PROFILING OF PEDIATRIC HIGH-GRADE GLIOMA SINGLE CELLS USING PATCH-SEQ
Authors: Shawn Gillespie, Marlene Arzt, Pamelyn Woo, Michelle Monje
Journal: Neuro-Oncology (2019)

Abstract Pediatric and adult high-grade gliomas are characterized by extensive intra-tumoral transcriptional heterogeneity. When measured by single cell RNA sequencing, gliomas reveal themselves as continuums of stemness and differentiation programs with important implications for therapy, but to date this transcriptional information has not been directly linked to physiological behaviors of cells. Recent work from our group establishes the electrical integration of glioma cells into neural circuitry. One subpopulation of glioma cells participates in glutamatergic synaptic communication with neurons, and a distinct subpopulation of cells sense and respond to extracellular potassium flux of neuronal networks by an entirely distinct mechanism. Our data support a model in which both modes of electrical communication are critical to glioma growth, but current associations between the electrophysiological properties of a cell, its transcriptional profile and developmental state are correlational in nature. Patch-seq is needed to clarify the relationship between transcriptional profiles of quiescent/cycling stem-like cells and the observed electrophysiological behaviors. Put more simply, patch-seq will clarify where the synaptically-connected glioma cells exist along a developmental hierarchy. METHODS Here, we adapt a recently described technique called patch-seq to record the electrophysiological profiles of individual pediatric high-grade glioma cells by whole cell patch-clamp and subsequently isolate their mRNA for single cell sequencing by smart-seq2 and analysis using Seurat. In this way, we couple electrophysiological and transcriptomic profiles to unambiguously assign functional identities to cells with transcriptional profiles along a developmental hierarchy. RESULTS We report the successful adaptation of patch-seq for use with patient-derived diffuse intrinsic pontine glioma (DIPG) xenografts in acute brain slice preparations, enabling evaluation of single glioma cells integrated in intact neural circuitry. CONCLUSIONS Data synthesizing the electrophysiological and transcriptomic profiles of single glioma cells in the context of the developmental hierarchy will be presented.
Targeted Marrow Radiation (TMI) Improves Therapeutic Efficacy of STAT3 Decoy Molecules By Augmenting Its Delivery and Immune Modulation in an AML Mouse Model
Authors: Srideshikan Sargur Madabushi, Darren Zuro, Yu-Lin SU, Paresh Vishwasrao, Jamison Brooks, Liliana E Parra, James F Sanchez, Jeffrey Wong, Marcin Kortylewski, Susanta Hui
Journal: Blood (2019)
Evolutionary Action (EA) Score of TP53 Mutations Defines Prognostic Subsets within TP53 Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia
Authors: Rashmi Kanagal-Shamanna, Guillermo Montalban-Bravo, Caleb Class, Koji Sasaki, Christopher B. Benton, Kelly Soltysiak, Elias Jabbour, Tapan M. Kadia, Carlos E. Bueso-Ramos, Keyur P. Patel, Mark Routbort, Irene Ganan-Gomez, Yue Wei, Gautam M. Borthakur, Farhad Ravandi, Kim-Anh Do, L. Jeffrey Medeiros, Hagop M. Kantarjian, Guillermo Garcia-Manero
Journal: Blood (2019)
Aspacytarabine (BST-236) Is Safe and Efficacious As a Single-Agent, First-Line Therapy for Patients with Acute Myeloid Leukemia Unfit for Standard Chemotherapy. Integrated Results from a Phase 1/2a and an Ongoing Phase 2b
Authors: Jessica K. Altman, Tsila Zuckerman, Olga Frankfurt, Selina M. Luger, Dale L. Bixby, Vamsi Kota, Micah M. Burch, Ofir Wolach, Itai Levi, Anna Gourevitch, Ron Ram, Liat Flaishon, Shoshi Tessler, Stela Gengrinovitch, Ruth Ben Yakar, Jacob M. Rowe
Journal: Blood (2019)
Preliminary Phase 1 Data on the Safety and Efficacy of a Novel PET Radiotracer, 124I-p5+14, for Imaging Systemic Amyloidosis
Authors: Jonathan S. Wall, Alan Stuckey, Emily B. Martin, Tina Richey, Angela Williams, Daniel Craig Wooliver, Sallie Macy, James S. Foster, Bryan Whittle, Robin Geldrich, Mark Powell, Yitong Fu, Dustin Powell, Dustin Osborne, R. Eric Heidel, Barbara Marine, Myrwood Besozzi, Radhakrishnan Ramchandren, Ronald H. Lands, Stephen J. Kennel
Journal: Blood (2019)
Outcome of 673 Patients with Hematologic Malignancies Surviving at Least 8 YEARS Post- Allogeneic Transplants: Risk Factors and Quality of Life
Authors: Giuseppe Sapienza, Teresa Lamparelli, Alida Dominietto, Anna Maria Raiola, Carmen Di Grazia, Francesca Gualandi, Simona Sica, Elisabetta Metafuni, Emanuele Angelucci, Andrea Bacigalupo
Journal: Blood (2019)
Impact of Continuous and Maintenance Therapy on Survival Outcome in Patients with Newly Diagnosed Multiple Myeloma: A Multicenter Retrospective Collaborative Study of the Japanese Society of Myeloma
Authors: Shuji Ozaki, Hiroshi Handa, Takayuki Saitoh, Kazutaka Sunami, Tadao Ishida, Kenshi Suzuki, Tomoko Narita, Shinsuke Iida, Yuichi Nakamura, Kazuhito Suzuki, Noriko Nishimura, Hirokazu Murakami, Kazuyuki Shimizu
Journal: Blood (2019)
Highly Differentiated Anti-CD47 Antibody, AO-176, Potently Inhibits Hematologic Malignancies Alone and in Combination
Authors: John Richards, Myriam N Bouchlaka, Robyn J Puro, Ben J Capoccia, Ronald R Hiebsch, Michael J Donio, W. Casey Wilson, Prabir Chakraborty, Victoria Sung, Daniel S Pereira
Journal: Blood (2019)
EXTH-21. DIFFERENTIAL PROTEIN EXPRESSION LEVELS OF ABC AND SOLUTE CARRIER TRANSPORTERS AT THE BLOOD-BRAIN BARRIER OF HUMAN BRAIN AND GLIOBLASTOMA
Authors: Xun Bao, Jianmei Wu, Youming Xie, Seongho Kim, Sharon Michelhaugh, Jun Jiang, Sandeep Mittal, Nader Sanai, Jing Li
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Mechanistic understanding and quantitative prediction of drug penetration across the human blood-brain barrier (BBB) is critical to rational drug development and treatment for brain cancer especially glioblastoma. However, prediction of drug brain/tumor penetration has been significantly hindered mainly due to the lack of quantitation data on transporter protein expression levels at the human BBB. This study was to determine protein expression levels of major transporters and markers at the BBB of human brain and glioblastoma. METHOD The absolute protein expression levels of major transporters and markers were determined in isolated microvessels of human brain (N=30), glioblastoma (N=47), rat (N=10) and mouse brain (N=10), using liquid chromatography with tandem mass spectrometry (LC-MS/MS) based targeted proteomics. RESULTS In isolated microvessels of 30 human brain specimens, the median protein abundances for ABCB1, ABCG2, GLUT1, GLUT3, LAT1, MCT1, Na/K ATPase, and Claudin-5 were 3.38, 6.21, 54.51, 7.17, 3.42, 5.71, 32.14, and 1.15 fmol/µg protein, respectively. In glioblastoma microvessels, ABCB1, ABCG2, MCT1, GLUT1, Na/K ATPase, and Claudin-5 protein levels were significantly reduced, while LAT1 was increased and GLU1 remained the same. ABCC4, OATP1A2, OATP2B1, and OAT3 were undetectable in isolated microvessels of both human brain and glioblastoma. There was species difference in transporter protein expression levels in isolated microvessels of human, rat and mouse brain. Specifically, rodent BBB expressed significantly higher ABCB1 but similar ABCG2, as compared to human BBB. CONCLUSION The physical and biochemical barriers of the BBB in glioblastomas are largely disrupted, as indicated by the loss or significant reduction in protein expression of the tight junction marker (claudin-5), brain endothelial cell marker (GLUT1), and major efflux transporters (ABCB1 and ABCG2) as compared to normal human BBB. Differential BBB transporter protein expression levels provides mechanistic and quantitative basis for the prediction of heterogeneous drug penetration into human normal brain and glioblastoma.
HOUT-13. CLINICAL TRIALS IN GLIOBLASTOMA: LEARNING FROM PREVIOUS EXPERIENCES TOWARDS OPTIMAL DEVELOPMENT OF TRIAL DESIGN
Authors: Adithya Balasubramanian, Ashray Gunjur, Sagun Parakh, Lawrence Cher, Hui Gan
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION We undertook a literature review testing the hypothesis that inefficiencies in the Phase 2/3 transition contributes to most GBM Phase 3 trials (P3T’s) being negative. METHODS Studies between 2005–2019 inclusive were identified though MEDLINE(R) using keywords and MeSH terms, and manual bibliography searches. Clinical, statistical and sponsor characteristics were extracted by two reviewers (AB&amp;AG). For each P3T, Phase 2 trial (P2T) data was “optimally matched” where same drug was used in similar schedule and GBM population; “partially matched” where dis-similar schedule and/or treatment setting; and “lacking” in all other circumstances. Data were compared by Pearson Correlation, t-test or chi-square as appropriate. RESULTS 18 relevant P3T’s and 15 P2T’s were identified. Median values for median progression free survival (mPFS) and median overall survival (mOS) in P3T’s were 7.9 and 17.9 mths respectively for first line studies; 2.2 and 7.9 mths for recurrent studies. These were 11.8 and 20.4 mths for 1st line P2T’s, suggesting selection bias, and 3.3 and 7.5 mths for recurrent studies. 50% of P3T had optimally matched P2D, with high concordance for mPFS (r2= 0.90, p&lt; 0.01) and mOS (r2= 0.84, p&lt; 0.01) between corresponding P3T and P2T. The remain 50% of P3T had ‘partially matched’ (22.2%) or lacked P2T data (27.8%). ‘Partially matched’ trials also had a high concordance for mPFS (r2= 0.92, p&lt; 0.01) and mOS (r2= 0.83, p&lt; 0.01). However, 80% of P3T planned for HR didn’t meet expected benefit. All first-line P2T with mPFS&lt; 15 months and/or OS&lt; 22 months had negative P3T. All recurrent P2T with mPFS&lt; 5 months and mOS&lt; 12 months had negative P3T. Impact of sponsors and molecular subtypes will be presented. CONCLUSIONS This review identified issues (selection bias, lack of appropriate P2T and possible underpowered P3T’s) at the Phase 2/3 interface and provides data for future trial design.
Immune complexes exposed on mast cell‐derived nanovesicles amplify allergic inflammation
Authors: Rosa Molfetta, Mario Lecce, Linda Quatrini, Giulio Caracciolo, Luca Digiacomo, Laura Masuelli, Nadia Domenica Milito, Elisabetta Vulpis, Alessandra Zingoni, Ricciarda Galandrini, Angela Santoni, Rossella Paolini
Journal: Allergy (2019)

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The health of the nation
Authors: E J Brunner
Journal: BMJ (1991)

infant mortality, the denominator is also increased.The effect of this is to again render even quite large percentage changes in mortality over time liable to chance variation.For example, there was an apparent decrease of 12 1% in deaths from coronary heart disease from 1981 to 1989 for men aged 35-64 in Hull.However, the 95% confidence intervals for this change in mortality are wide (-2 7x 10 4 to 12x 10 3) and allow the possibility either of no change or of an increase in the true mortality for men of this age.Indeed, the same uncertainty is true of the district mortality trends for all the conditions suggested in The Health of the Nation.We suggest, therefore, that changes in death rates are a statistically inappropriate method of measuring variations over time in the health of a district population.This is a further argument for the need to develop measures of health that are not based on mortality for use at district level.
CSIG-28. ROLE OF ALTERNATIVE SPLICING IN CONFERRING SPATIAL HETEROGENEITY SIGNATURES IN GBM
Authors: Sadashib Ghosh, Marat S Pavlyukov, Soniya Bastola, Chaoxi Li, Shinobu Yamaguchi, Svetlana Komarova, Daisuke Yamashita, Ichiro Nakano
Journal: Neuro-Oncology (2019)

Abstract Therapeutic interventions induce cell stress to trigger apoptosis in tumor cells. Specific cellular stressors, including those initiated by radio-chemotherapy, activate distinct pro-death proteins through a multitude of mechanisms. Apoptosis consists of highly regulated pathways involving post-translational modifications and cleavage of proteins leading to sequential inactivation of the main cellular processes e.g. cell cycle progression. Recently, we demonstrated that apoptotic bodies/ApoEVs in GBM transfer spliceosomal machinery components to neighboring cells, which are subsequently internalized and confer survival advantage through changes in mRNA splicing. Following the validation of the role of RBM11, a spliceosomal component in the said intercellular communication, we extended our findings in the characterization of spatially distinct clonally derived sphere lines from tumor edge and core-located tissues from GBM patients. We analyzed the expression of spliceosomal genes in edge and core-derived clones and found spatially distinct splicing capabilities and that the genes that were affected by alternative splicing events in edge and core cells have different splicing of genes that are involved in ubiquitination and regulate cell cycle progression. Downstream analyses revealed that the most promising target is MDM2. Importantly, this gene regulates cell cycle via ubiquitination. Further, western blot revealed differential expression of both RBM11 and MDM2 in egde and core-derived clones.Collectively, the data so far provides motivation for the possibility of finding cellular vulnerabilities in the splicing machinery and thus actionable targets for intervention that accounts for the bearings of spatial heterogeneity.
Retired and retiring consultants: an unrecognised and undervalued resource
Authors: Rajendra Kumar Sinha
Journal: BMJ (2019)

Cuts in job advertisements and the lack of trainees have been blamed for the shortage of doctors in the NHS in the 2019 census report of the Royal Colleges of Physicians.1 Calls made for improving retention of consultants and increasing the number of trainees are not new. By the time these are achieved, it might be too …