tbuckley/cabot-search huggingface dataset:
Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia
Authors: Disha Malani, Ashwini Kumar, Oscar Brück, Mika Kontro, Bhagwan Yadav, Monica Hellesøy, Heikki Kuusanmäki, Olli Dufva, Matti Kankainen, Samuli Eldfors, Swapnil Potdar, Jani Saarela, Laura Turunen, Alun Parsons, Imre Västrik, Katja Kivinen, Janna Saarela, Riikka Räty, Minna Lehto, Maija Wolf, Bjorn Tore Gjertsen, Satu Mustjoki, Tero Aittokallio, Krister Wennerberg, Caroline A. Heckman, Olli Kallioniemi, Kimmo Porkka
Journal: Cancer Discovery (2021)

Abstract We generated ex vivo drug-response and multiomics profiling data for a prospective series of 252 samples from 186 patients with acute myeloid leukemia (AML). A functional precision medicine tumor board (FPMTB) integrated clinical, molecular, and functional data for application in clinical treatment decisions. Actionable drugs were found for 97% of patients with AML, and the recommendations were clinically implemented in 37 relapsed or refractory patients. We report a 59% objective response rate for the individually tailored therapies, including 13 complete responses, as well as bridging five patients with AML to allogeneic hematopoietic stem cell transplantation. Data integration across all cases enabled the identification of drug response biomarkers, such as the association of IL15 overexpression with resistance to FLT3 inhibitors. Integration of molecular profiling and large-scale drug response data across many patients will enable continuous improvement of the FPMTB recommendations, providing a paradigm for individualized implementation of functional precision cancer medicine. Significance: Oncogenomics data can guide clinical treatment decisions, but often such data are neither actionable nor predictive. Functional ex vivo drug testing contributes significant additional, clinically actionable therapeutic insights for individual patients with AML. Such data can be generated in four days, enabling rapid translation through FPMTB. See related commentary by Letai, p. 290. This article is highlighted in the In This Issue feature, p. 275
Abstract PO-127: A uPA/uPAR axis in both the tumor cell and stromal compartment drives PDAC disease progression
Authors: Yi Yang, Sara R. Abrahams, Aditi Kothari, Harshi Matada, Keely Davey, Alisa S. Wolberg, Matthew J. Flick
Journal: Cancer Research (2021)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal solid tumor malignancy with a 5-year survival rate of 9%. In both patients and animal models of disease, PDAC is associated with robust coagulation system activity. Intriguingly, in addition to being a rich source of procoagulant factors, PDAC tumors highly express fibrinolytic system components. Supporting this concept, urokinase plasminogen activator (uPA) and uPA receptor (uPAR) expression positively correlates with reduced overall patient survival. Here, we tested the hypothesis that the expression and activity of plasminogen activation (PA) system components are functionally linked to PDAC tumor growth and disease progression. We generated C57Bl/6-derived KPC (i.e., KRasG12D, TRP53R172H) PDAC cell lines in which uPA and uPAR were knocked out using CRISPR-Cas9. We then analyzed orthotopic tumor growth and experimental metastasis in mice carrying null or functional mutations in uPA, uPAR, or plasminogen to evaluate the interplay of PA components derived from tumor cells and/or stromal cells in mediating PDAC progression. Although both KPC cell CRISPR variants retained procoagulant function, elimination of tumor cell uPA or uPAR yielded significantly smaller tumors when compared to Cas9 control tumor cells in wildtype mice. Similarly, the growth of WT KPC tumor cells in C57Bl/6 background uPA-KO or uPAR-KO mice also resulted in reduced tumor growth. To our surprise, the metastasis potential of WT KPC tumor cells in uPA-KO or uPAR-KO mice did not change when compared to wildtype mice. Regarding to the uPA/uPAR axis downstream effector plasminogen, the growth of WT KPC tumors in plasminogen-KO mice was also significantly reduced, but not to the same extent as when eliminating uPA or uPAR. In addition, eliminating plasminogen drastically reduced WT KPC tumor cells metastasis potential. In conclusion, our data suggest a mechanism whereby uPA functions through uPAR in both the tumor cell and stromal cell compartments to promote PDAC progression through plasminogen-dependent and -independent mechanisms. Citation Format: Yi Yang, Sara R. Abrahams, Aditi Kothari, Harshi Matada, Keely Davey, Alisa S. Wolberg, Matthew J. Flick. A uPA/uPAR axis in both the tumor cell and stromal compartment drives PDAC disease progression [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-127.
Runx2 Deficiency in Osteoblasts Promotes Myeloma Resistance to Bortezomib By Increasing TSP-1-Dependent TGF-β1 Activation in Bone Marrow
Authors: Chao Zhang, Xiaoxuan Xu, Timothy Trotter, Amjad Javed, Joanne E. Murphy-Ullrich, Juan Li, Yang Yang
Journal: Blood (2021)
Abstract 9408: Serum and Urine Osmolality as Predictors of Adequate Diuresis in Acute Decompensated Heart Failure: A Prospective Cohort Study
Authors: Grace Salacup, Kevin Lo, Jerald Pelayo, Prapaipan Putthapiban, Ricardo Torres, Mario Naranjo, Janani Rangaswami
Journal: Circulation (2021)

Introduction: The utility of serum and urine osmolality in evaluating decongestion and outcomes in heart failure (HF) remain understudied. Methods: This is a prospective cohort single center study of patients with acute HF on intravenous diuretics &gt; 18 years old, with BNP &gt; 100 pg/mL or echocardiographic finding of reduced ejection fraction or diastolic dysfunction, and at least 1 symptom of volume overload. Patients with eGFR≤45mL/minute or on dialysis, and with exposure to contrast dye or nephrotoxins were excluded. Serum and urine osmolality were obtained daily for 5 days or until discharge. Wilcoxon signed-rank test was used to check for differences in serum and urine osmolality on admission and on discharge. Mann Whitney U test compared osmolality values between those with and without readmissions. ROC curve and Youden’s index were used to analyze the optimal cut-offs for the osmolality values in the prediction of readmissions. Results: A total of 100 hospitalized patients were included. Majority were males (62%) and African American (59%). The mean age was 64.41±12.53 with co-morbidities of hypertension (86%), diabetes (43%), coronary artery disease (39%), and heart failure with preserved ejection fraction (34%). The inpatient mortality rate was 3%, with 6% and 16% 30-day and 60-day readmission rates respectively. Patients with 30-day readmission had higher serum osmolality on admission (305 [299-310] vs 298 [294-303] p=0.044) and had higher drop in serum osmolality between admission and discharge (-7.5 [-9.0 - -1.25] vs -1.0 [-4.0 - 4.0]) [p=0.044]. Serum osmolality on admission of &gt;299 mOsm/kg (sensitivity: 83%, specificity: 61%) and drop in serum osmolality between admission and discharge of &gt;2 mOsm/kg (sensitivity: 83%, specificity: 65%) was associated with 30-day readmissions. Conclusions: Measurement of serum osmolality and urine osmolality may have some utility in the management of acute heart failure.
Counting the neurological cost of COVID-19
Authors: Abdul Mannan Baig
Journal: Nature Reviews Neurology (2021)

The neurological deficits caused by COVID-19, which were first reported in the early months of 2020, continue to intrigue neurologists and health-care professionals worldwide. As two new studies highlight, these manifestations are frequent and are expected to increase the burden of morbidity and mortality in the acute and chronic phases of COVID-19.
<i>Long-Term Quality of Life after Hematopoietic Cell Transplantation for Sickle Cell Disease: A Preliminary Report from the Sickle Cell Transplant Evaluation of Long Term and Late Effects Registry (STELLAR)</i>
Authors: Staci D. Arnold, Nitya Bakshi, Zhao Chang, Diana Ross, Allistair Abraham, Monica Bhatia, Gregory M.T. Guilcher, Ann Haight, Matthew Hsieh, Kimberly A. Kasow, Peter A. Lane, Lillian Meacham, Festus Olusola Olowoselu, Lakshmanan Krishnamurti
Journal: Blood (2021)
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Entospletinib in Combination with Intensive Induction and Consolidation Chemotherapy in Adults with Newly Diagnosed <i>N</i> <i>ucleophosmin 1-</i>mutated Acute Myeloid Leukemia
Authors: John C. Byrd, Jorge E. Cortes, Mark D. Minden, Thomas Oellerich, Eytan M. Stein, Jenna Elder, Pavan Kumar, Gordon Bray, Jorge DiMartino, Wendy Stock
Journal: Blood (2021)
Farah Jameel elected as chair of BMA’s England GP committee
Authors: Gareth Iacobucci
Journal: BMJ (2021)

The BMA’s England GP committee has elected Farah Jameel as its new chair.

Jameel, who succeeds outgoing chair Richard Vautrey, was elected following a vote at the committee’s meeting on 18 November. She was one of two candidates nominated for the post, along with Stoke-on-Trent GP Chandra Kanneganti.

Jameel, a GP based in …
Non-Invasive Genetic Profiling and Monitoring in Myelodysplastic Syndromes
Authors: Nieves Garcia-Gisbert, Brayan Merchan, Sara Garcia-Avila, Marta Salido, Concepción Fernández-Rodríguez, Joan Gibert, Lierni Fernández-Ibarrondo, Laura Camacho, Marta Lafuente, Raquel Longarón, Blanca Espinet, Patricia Vélez, Marcio M Andrade-Campos, Ramon M. Pujol, Leonor Arenillas, Xavier Calvo, Carles Besses, Antonio Salar, Beatriz Bellosillo
Journal: Blood (2021)
Optimizing Myeloablative Fractionated Busulfan, Fludarabine and Thiotepa Regimen: Results of Two Parallel Cohorts in a Phase 2 Prospective Clinical Trial
Authors: Uday R. Popat, Rohtesh S. Mehta, Roland Bassett, Amin M. Alousi, Gheath Alatrash, Qaiser Bashir, Chitra Hosing, Jin S. Im, Partow Kebriaei, Jitesh D. Kawedia, Issa F. Khouri, David Marin, Yago Nieto, Amanda L. Olson, Betul Oran, Jeremy L. Ramdial, Neeraj Saini, Samer A. Srour, Katayoun Rezvani, Muzaffar H. Qazilbash, Elizabeth J. Shpall, Borje S. Andersson, Richard E. Champlin
Journal: Blood (2021)
5hmC Gene Signature Predicts the Treatment Response to Azacitidine with High-Dose Cytarabine and Mitoxantrone in AML
Authors: Kirk Cahill, Linchen Wang, Guanghao Liang, Qiancheng You, Chuanyuan Chen, Wei Zhang, Noreen Fulton, Wendy Stock, Olatoyosi Odenike, Chuan He, Dali Han
Journal: Blood (2021)
Abstract 10047: Ethnic-Specific Trends in Long-Term Post-Stroke Recurrence and Mortality Over 13 Years
Authors: Chen Chen, Kevin He, Xu Shi, Fatema Shafie-Khorassani, Lewis B Morgenstern, Lynda D Lisabeth
Journal: Circulation (2021)

Introduction: Estimating trends in long-term outcomes after stroke is important for long-term planning of health resources. Data on trends in long-term post-stroke outcomes are not available among Hispanics. Whether race-ethnic disparities exist and how trends in these outcomes have changed over time comparing non-Hispanic Whites (NHWs) with Mexican Americans (MAs) are also unknown. Thus, we aimed to estimate ethnic-specific trends in risk of 5-year all-cause mortality and recurrence after initial stroke in MAs and NHWs. Methods: We included 3308 patients who had first-ever ischemic stroke ascertained between January 1, 2000 and December 31, 2012 from the Brain Attack Surveillance in Corpus Christi (BASIC) project in Texas. Data on recurrent stroke and death were available through December 31, 2017. Fine-Gray subdistribution hazard models including covariates and an interaction term between calendar year and ethnicity were used to calculate 5-year cumulative incidence of recurrence and death in both ethnic groups in each year. Results: Among the 3308 index stroke patients, 402 (12.15%) recurrences and 1420 (37.61%) deaths were observed during the 5-year follow-up. Adjusted 5-year cumulative incidence of recurrence among MAs declined from 15.76% to 11.28%. Among NHWs, a slight decline from 12.49% to 10.46% was observed. An ethnic disparity in 5-year recurrence was not apparent in 2000 (risk difference 3.27%, [95% CI, -10.41, 9.10]) or during the study duration (Figure). The greatest ethnic disparity in 5-year mortality risk was observed in 2000 but disappeared in 2012, which was driven by the increasing trend in MAs from 23.11% in 2000 to 24.28% in 2012 and the decreasing trend in NHWs from 31.09% to 27.19% accordingly. Conclusions: No apparent ethnic disparity in long-term stroke recurrence was found and long-term survival advantage in MAs presented early in the study gradually disappeared over the 13 years.
Abstract 9449: Extracorporeal Membrane Oxygenation versus Impella in Patients with Cardiogenic Shock from Inferior Wall Myocardial Infarction: Analysis from the National Inpatient Sample
Authors: Jashan Gill, Ram Chandra Khatri Chhetri
Journal: Circulation (2021)

Introduction: Since the IABP-SHOCK II trial, extracorporeal membrane oxygenation (ECMO), and the percutaneous ventricular assist device, Impella have emerged as the preferred mechanical circulatory assist devices for cardiogenic shock (CS). Studies have shown similar clinical outcomes with Impella and ECMO in patients with CS from unspecified myocardial infarction (MI) locations; however, data in patients with inferior wall MI is lacking. Hypothesis: ECMO is associated with an increased likelihood of adverse inpatient complications and medical costs compared to Impella in patients with CS from an inferior wall MI. Methods: We queried the National Inpatient Sample (NIS) from 2016-2018 to identify patients 18 years and older with a discharge diagnosis of CS from inferior wall MI who underwent ECMO or Impella placement. To mitigate selection bias, 8-to-1 propensity scoring was used to select matched samples between patients with ECMO and patients with Impella. The scoring was based on a multivariate logistic regression model accounting for age, gender, race, hospital type, income, and medical comorbidities. Results: We identified 638 patients with inferior wall MI resulting in CS, 15% (n=96) underwent ECMO and 85% (n=542) received Impella. ECMO was not associated with increased inpatient mortality (52% vs 50.7%; p=0.86) or cardiac arrest (24% vs 15%, p=0.09) when compared to Impella. After applying the multivariate logistic regression model, ECMO was not associated with an increased risk for acute kidney injury (OR 0.67; 95% CI 0.28-1.6, p=0.36), cerebrovascular events (OR 1.06; 95% CI 0.33-3.36, p=0.92), cardiac tamponade (OR 6.85; 95% CI 0.89-52.83, p=0.06) or CPR (OR 1.89; 95% CI 0.9-3.98; p=0.09). However, ECMO was associated with increased blood transfusions (OR 3.56; 95% CI 0.26-10.06, p=0.02), increased length of hospitalization (13.2 days vs 9.4 days; p&lt;0.0001), and medical costs ($501,435 vs 403,120, p&lt;0.0001). Conclusions: Our study demonstrates that ECMO is not associated with increased mortality in patients with CS from inferior wall MI compared to Impella, although Impella remains the more cost-effective choice in these patients. Future randomized studies are warranted comparing these circulatory assist devices in patients with CS.
Clinical Significance of Clonal Hematopoiesis in the Setting of Autologous Stem Cell Transplantation for Lymphoma
Authors: Sharon Ben Barouch, Tracy Lackraj, Jessie Medeiros, Mehran Bakhtiari, Jesse Joynt, Kit Tong, Andrea Arruda, Mark D. Minden, Mileidys Alvarez, John Kuruvilla, Sita Bhella, Vishal Kukreti, Michael Crump, Anca Prica, Christine I. Chen, Armand Keating, John E. Dick, Sagi Abelson, Robert Kridel
Journal: Blood (2021)
Effect of Loss-of-Function Genetic Variants in <i>PCSK9</i> on Glycemic Traits, Neurocognitive Impairment, and Hepatobiliary Function
Authors: Jonas Ghouse, Gustav Ahlberg, Henning Bundgaard, Morten S. Olesen
Journal: Diabetes Care (2021)

OBJECTIVE To evaluate the association between PCSK9 predicted loss-of-function (pLoF) variants and glycemic traits, hepatobiliary function, and neurocognitive traits. RESEARCH DESIGN AND METHODS We identified carriers of PCSK9 pLoF variants in UK Biobank exome sequencing data. We assessed the aggregate effects of these variants on lipid and lipoprotein traits, which served as a positive control. Association of PCSK9 pLoF carrier status and glycemic traits, hepatobiliary function, and neurocognitive traits was then evaluated as a measure for adverse effects. RESULTS We identified 374 individuals carrying one of 41 unique PCSK9 pLoF variants. As expected, we found that PCSK9 pLoF carriers had significantly lower LDL cholesterol C levels (P = 7.4 × 10−55) and apolipoprotein B levels (P = 7.6 × 10−50) than did noncarriers. However, we found no significant associations between pLoF carrier status and glycemic traits, hepatobiliary function, and neurocognitive traits (P &amp;gt; 0.05). CONCLUSIONS Our results do not support adverse effects of PCSK9 pLoF variants on glycemic traits, hepatobiliary function, or neurocognitive traits.
Tubular epithelial cell-to-macrophage communication forms a negative feedback loop via extracellular vesicle transfer to promote renal inflammation and apoptosis in diabetic nephropathy
Authors: Wen-juan Jiang, Chuan-ting Xu, Chang-lin Du, Jia-hui Dong, Song-bing Xu, Bing-feng Hu, Rui Feng, Dan-dan Zang, Xiao-ming Meng, Cheng Huang, Jun Li, Tao-tao Ma
Journal: Theranostics (2021)

Background: Macrophage infiltration around lipotoxic tubular epithelial cells (TECs) is a hallmark of diabetic nephropathy (DN).However, how these two types of cells communicate remains obscure.We previously demonstrated that LRG1 was elevated in the process of kidney injury.Here, we demonstrated that macrophage-derived, LRG1-enriched extracellular vesicles (EVs) exacerbated DN.Methods: We induced an experimental T2DM mouse model with a HFD diet for four months.Renal primary epithelial cells and macrophage-derived EVs were isolated from T2D mice by differential ultracentrifugation.To investigate whether lipotoxic TEC-derived EV (EVe) activate macrophages, mouse bone marrow-derived macrophages (BMDMs) were incubated with EVe.To investigate whether activated macrophage-derived EVs (EVm) induce lipotoxic TEC apoptosis, EVm were cocultured with primary renal tubular epithelial cells.Subsequently, we evaluated the effect of LRG1 in EVe by investigating the apoptosis mechanism.Results: We demonstrated that incubation of primary TECs of DN or HK-2 mTECs with lysophosphatidyl choline (LPC) increased the release of EVe.Interestingly, TEC-derived EVe activated an inflammatory phenotype in macrophages and induced the release of macrophage-derived EVm.Furthermore, EVm could induce apoptosis in TECs injured by LPC.Importantly, we found that leucine-rich α-2-glycoprotein 1 (LRG1)-enriched EVe activated macrophages via a TGFβR1-dependent process and that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-enriched EVm induced apoptosis in injured TECs via a death receptor 5 (DR5)-dependent process.Conclusion: Our findings indicated a novel cell communication mechanism between tubular epithelial cells and macrophages in DN, which could be a potential therapeutic target.
Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans
Authors: Kevin S. Chen, Krystal Menezes, Jarlath B. Rodgers, Darren M. O’Hara, Nhat Tran, Kazuko Fujisawa, Seiya Ishikura, Shahin Khodaei, Hien Chau, Anna Cranston, Minesh Kapadia, Grishma Pawar, Susan Ping, Aldis Krizus, Alix Lacoste, Scott Spangler, Naomi P. Visanji, Connie Marras, Nour K. Majbour, Omar M. A. El-Agnaf, Andres M. Lozano, Joseph Culotti, Satoshi Suo, William S. Ryu, Suneil K. Kalia, Lorraine V. Kalia
Journal: Molecular Neurodegeneration (2021)

Parkinson's disease is a disabling neurodegenerative movement disorder characterized by dopaminergic neuron loss induced by α-synuclein oligomers. There is an urgent need for disease-modifying therapies for Parkinson's disease, but drug discovery is challenged by lack of in vivo models that recapitulate early stages of neurodegeneration. Invertebrate organisms, such as the nematode worm Caenorhabditis elegans, provide in vivo models of human disease processes that can be instrumental for initial pharmacological studies.To identify early motor impairment of animals expressing α-synuclein in dopaminergic neurons, we first used a custom-built tracking microscope that captures locomotion of single C. elegans with high spatial and temporal resolution. Next, we devised a method for semi-automated and blinded quantification of motor impairment for a population of simultaneously recorded animals with multi-worm tracking and custom image processing. We then used genetic and pharmacological methods to define the features of early motor dysfunction of α-synuclein-expressing C. elegans. Finally, we applied the C. elegans model to a drug repurposing screen by combining it with an artificial intelligence platform and cell culture system to identify small molecules that inhibit α-synuclein oligomers. Screen hits were validated using in vitro and in vivo mammalian models.We found a previously undescribed motor phenotype in transgenic α-synuclein C. elegans that correlates with mutant or wild-type α-synuclein protein levels and results from dopaminergic neuron dysfunction, but precedes neuronal loss. Together with artificial intelligence-driven in silico and in vitro screening, this C. elegans model identified five compounds that reduced motor dysfunction induced by α-synuclein. Three of these compounds also decreased α-synuclein oligomers in mammalian neurons, including rifabutin which has not been previously investigated for Parkinson's disease. We found that treatment with rifabutin reduced nigrostriatal dopaminergic neurodegeneration due to α-synuclein in a rat model.We identified a C. elegans locomotor abnormality due to dopaminergic neuron dysfunction that models early α-synuclein-mediated neurodegeneration. Our innovative approach applying this in vivo model to a multi-step drug repurposing screen, with artificial intelligence-driven in silico and in vitro methods, resulted in the discovery of at least one drug that may be repurposed as a disease-modifying therapy for Parkinson's disease.
Platelet-Rich Plasma Injection vs Sham Injection and Tendon Dysfunction in Patients With Chronic Midportion Achilles Tendinopathy
Authors: Kuan-Kai Tung, James Cheng-Chung Wei
Journal: JAMA (2021)

To the Editor The authors of a recent JAMA article1 concluded that a single injection of intratendinous PRP was not superior to subcutaneous dry-needle insertion. Although this study provided valuable results, we believe some methodological concerns should be considered.