tbuckley/cabot-search huggingface dataset:
Adherent cell depletion promotes the expansion of renal cell carcinoma infiltrating T cells with optimal characteristics for adoptive transfer
Authors: Mitchell W Braun, Haitham Abdelhakim, Meizhang Li, Stephen Hyter, Ziyan Pessetto, Devin C Koestler, Harsh B Pathak, Neil Dunavin, Andrew K Godwin
Journal: Journal for ImmunoTherapy of Cancer (2020)

Tumor-infiltrating lymphocyte (TIL) therapy is a personalized cancer treatment which involves generating ex vivo cultures of tumor-reactive T cells from surgically resected tumors and administering the expanded TILs as a therapeutic infusion. Phase 1 of many TIL production protocols use aldesleukin (IL-2) alone to establish TIL cultures (termed "PreREP" (Pre-Rapid Expansion Protocol)); however, this fails to consistently produce TIL cultures from renal cell carcinoma (RCC) in a timely manner. Adding mitogenic stimulation via anti-CD3/anti-CD28 beads along with IL-2 to the fresh tumor digest (FTD) during TIL generation (termed "FTD+ beads") increases successful TIL culture rates; however, T cells produced by this method may be suboptimal for adoptive transfer. We hypothesize that adherent cell depletion (ACD) before TIL expansion will produce a superior TIL product by removing the immunosuppressive signals originating from adherent tumor and stromal cells. Here we investigate if "panning," a technique for ACD prior to TIL expansion, will impact the phenotype, functionality and/or clonality of ex vivo expanded RCC TILs.Tumor specimens from 55 patients who underwent radical or partial nephrectomy at the University of Kansas Medical Center (KUMC) were used to develop the panning method and an additional 19 specimens were used to validate the protocol. Next-generation sequencing, immunohistochemistry/immunocytochemistry and flow cytometry were used during method development. The phenotype, functionality and clonality of autologous TILs generated in parallel by panning, PreREP, and FTD+ beads were assessed by flow cytometry, in vitro co-culture assays, and TCRB CDR3 sequencing.TIL cultures were successfully generated using the panning protocol from 15/16 clear cell, 0/1 chromophobe, and 0/2 papillary RCC samples. Significantly fewer regulatory (CD4+/CD25+/FOXP3+) (p=0.049, p=0.005), tissue-resident memory (CD8+/CD103+) (p=0.027, p=0.009), PD-1+/TIM-3+ double-positive (p=0.009, p=0.011) and TIGIT+ T cells (p=0.049, p=0.026) are generated by panning relative to PreREP and FTD+ beads respectively. Critically, a subset of TILs generated by panning were able to degranulate and/or produce interferon gamma in response to autologous tumor cells and the average tumor-reactive TIL yield was greatest when using the panning protocol.Removing immunosuppressive adherent cells within an RCC digest prior to TIL expansion allow for the rapid production of tumor-reactive T cells with optimal characteristics for adoptive transfer.
Learning Retention Mechanisms and Evolutionary Parameters of Duplicate Genes from Their Expression Data
Authors: Michael DeGiorgio, Raquel Assis
Journal: Molecular Biology and Evolution (2020)

Abstract Learning about the roles that duplicate genes play in the origins of novel phenotypes requires an understanding of how their functions evolve. A previous method for achieving this goal, CDROM, employs gene expression distances as proxies for functional divergence and then classifies the evolutionary mechanisms retaining duplicate genes from comparisons of these distances in a decision tree framework. However, CDROM does not account for stochastic shifts in gene expression or leverage advances in contemporary statistical learning for performing classification, nor is it capable of predicting the parameters driving duplicate gene evolution. Thus, here we develop CLOUD, a multi-layer neural network built on a model of gene expression evolution that can both classify duplicate gene retention mechanisms and predict their underlying evolutionary parameters. We show that not only is the CLOUD classifier substantially more powerful and accurate than CDROM, but that it also yields accurate parameter predictions, enabling a better understanding of the specific forces driving the evolution and long-term retention of duplicate genes. Further, application of the CLOUD classifier and predictor to empirical data from Drosophila recapitulates many previous findings about gene duplication in this lineage, showing that new functions often emerge rapidly and asymmetrically in younger duplicate gene copies, and that functional divergence is driven by strong natural selection. Hence, CLOUD represents a major advancement in classifying retention mechanisms and predicting evolutionary parameters of duplicate genes, thereby highlighting the utility of incorporating sophisticated statistical learning techniques to address long-standing questions about evolution after gene duplication.
Efficacy of Dapagliflozin on Renal Function and Outcomes in Patients With Heart Failure With Reduced Ejection Fraction
Authors: Pardeep S. Jhund, Scott D. Solomon, Kieran F. Docherty, Hiddo J.L. Heerspink, Inder S. Anand, Michael Böhm, Vijay Chopra, Rudolf A. de Boer, Akshay S. Desai, Junbo Ge, Masafumi Kitakaze, Bela Merkley, Eileen O'Meara, Morten Shou, Sergey Tereshchenko, Subodh Verma, Pham Nguyen Vinh, Silvio E. Inzucchi, Lars Køber, Mikhail N. Kosiborod, Felipe A. Martinez, Piotr Ponikowski, Marc S. Sabatine, Olof Bengtsson, Anna Maria Langkilde, Mikaela Sjöstrand, John J.V. McMurray
Journal: Circulation (2020)

Many patients with heart failure and reduced ejection fraction (HFrEF) have chronic kidney disease that complicates pharmacological management and is associated with worse outcomes. We assessed the safety and efficacy of dapagliflozin in patients with HFrEF, according to baseline kidney function, in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure). We also examined the effect of dapagliflozin on kidney function after randomization. Patients who have HFrEF with or without type 2 diabetes and an estimated glomerular filtration rate (eGFR) ≥30 mL·min-1·1.73 m-2 were enrolled in DAPA-HF. We calculated the incidence of the primary outcome (cardiovascular death or worsening heart failure) according to eGFR category at baseline (<60 and ≥60 mL·min-1·1.73 m-2) and used eGFR at baseline as a continuous measure, as well. Secondary cardiovascular outcomes and a prespecified composite renal outcome (≥50% sustained decline eGFR, end-stage renal disease, or renal death) were also examined, along with a decline in eGFR over time. Of 4742 patients with a baseline eGFR, 1926 (41%) had eGFR <60 mL·min-1·1.73 m-2. The effect of dapagliflozin on the primary and secondary outcomes did not differ by eGFR category or examining eGFR as a continuous measurement. The hazard ratio (95% CI) for the primary end point in patients with chronic kidney disease was 0.71 (0.59-0.86) versus 0.77 (0.64-0.93) in those with an eGFR ≥60 mL·min-1·1.73 m-2 (interaction P=0.54). The composite renal outcome was not reduced by dapagliflozin (hazard ratio=0.71 [95% CI, 0.44-1.16]; P=0.17) but the rate of decline in eGFR between day 14 and 720 was less with dapagliflozin, -1.09 (-1.40 to -0.77) versus placebo -2.85 (-3.17 to -2.53) mL·min-1·1.73 m-2 per year (P<0.001). This was observed in those with and without type 2 diabetes (P for interaction=0.92). Baseline kidney function did not modify the benefits of dapagliflozin on morbidity and mortality in HFrEF, and dapagliflozin slowed the rate of decline in eGFR, including in patients without diabetes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
Factors Associated With Hypoglycemia Among Neonates Born to Mothers With Gestational Diabetes Mellitus
Authors: Martha B. Kole, Nina K. Ayala, Melissa A. Clark, Phinnara Has, Mathew Esposito, Erika F. Werner
Journal: Diabetes Care (2020)

Among women with gestational diabetes mellitus (GDM), hyperinsulinemic hypoglycemia of the neonate is a common complication because the hyperglycemic intrauterine environment leads to a relative increase in fetal insulin secretion (1). After delivery, persistent insulin elevation results in neonatal hypoglycemia that can be identified by clinical symptoms or routine screening. Exposure to GDM and hyperinsulinemic hypoglycemia have been associated with neurological sequelae and poor neurodevelopmental outcomes (1) as well as long-term metabolic abnormalities including type 2 diabetes and childhood obesity (2). Despite the morbidity associated with neonatal hypoglycemia, there is a paucity of data on predictors of the condition. The goal of this secondary analysis was to evaluate pregnancy characteristics among neonates who developed hypoglycemia within the first 24 h of life compared with those who did not.

The prospective cohort study was performed at a single academic medical center between January 2016 and June 2018. Women included were ≥18 years old, diagnosed with GDM during their pregnancy, and enrolled during their postpartum hospitalization. Following enrollment, demographic, obstetric, and neonatal data were obtained from the electronic medical record.

Included in this analysis were 597 pregnancies among which 234 neonates (39%) had hypoglycemia and 363 neonates (61%) did …
The murine Microenvironment Cell Population counter method to estimate abundance of tissue-infiltrating immune and stromal cell populations in murine samples using gene expression
Authors: Florent Petitprez, Sacha Levy, Cheng-Ming Sun, Maxime Meylan, Christophe Linhard, Etienne Becht, Nabila Elarouci, David Tavel, Lubka T. Roumenina, Mira Ayadi, Catherine Sautès-Fridman, Wolf H. Fridman, Aurélien de Reyniès
Journal: Genome Medicine (2020)

Quantifying tissue-infiltrating immune and stromal cells provides clinically relevant information for various diseases. While numerous methods can quantify immune or stromal cells in human tissue samples from transcriptomic data, few are available for mouse studies. We introduce murine Microenvironment Cell Population counter (mMCP-counter), a method based on highly specific transcriptomic markers that accurately quantify 16 immune and stromal murine cell populations. We validated mMCP-counter with flow cytometry data and showed that mMCP-counter outperforms existing methods. We showed that mMCP-counter scores are predictive of response to immune checkpoint blockade in cancer mouse models and identify early immune impacts of Alzheimer's disease.
Support by peers in the clinical team in oncology: Perception of the contribution of patient advisors to improve the patient experience.
Authors: Marie-Pascale Pomey, Israël Fortin, Marie-Andrée Côté, Mado Desforges, Karine Bouchard, Cécile Vialaron, Monica Iliescu-Nelea, Louise Normandin
Journal: Journal of Clinical Oncology (2020)

57 Background: Since 2018, three establishments in Quebec have introduced patient advisors (PA) in their healthcare team in order to improve cancer patients’ experience. These PA, who have had a cancer experience, meet patients undergoing radiotherapy treatments or in oncogenetics for breast cancer on the healthcare site. They conduct consultations to complete the offer of services by bringing emotional, informational, and educational support. Methods: A longitudinal study of multiple cases was completed from January to June 2020. After each accompaniment, the PA filled out a logbook to document the main themes covered and the accompanied patient fill out a survey to evaluate their experience one week after the intervention. A qualitative analysis of the logbook content and descriptive statistics were conducted. The REDCAP platform was used for monitoring the process of data collection and to administer the surveys online. Results: In total, 67 patients were accompanied by 4 PA. 71 logbooks were completed by the PA. The logbooks show that 70.3% of accompaniments took place right before radiotherapy and 63.6% following the results of the genetic test in oncogenetics. 50% of meetings took place in person in the establishment (in a space dedicated to the PA or not) and 45.8% were by phone. The meetings lasted approximately 37 minutes (min: 15 minutes and max: 90 minutes). The majority only met once (93.1 %). The most common themes discussed are: the role of the PA (94.1%), returning to day life (57.6%) and dealing with stress and anxiety (52.2%). 96% of PA felt that they did not encounter any difficulties during the accompaniment. For the accompanied women, the partnership was most beneficial for their experience with the illness (sharing experiences of side-effects, on the impact of the illness on every day life, with their social circle). 79% of patients found that the accompaniment met their needs. 90% of patients estimate that these meetings are complimentary to the healthcare professionals’ interventions. Finally, 89.5% of accompanied patients think that it would be very important to develop these types of meetings on a larger scale. Concerning the adaptation of spaces for the meetings, 26.3% are very satisfied and 26.3% are rather satisfied (probably an area for improvement). Conclusions: Overall, the partnerships seem to answer the needs of the accompanied patients and the PA can share their experience inside the clinical team.
An effectiveness-implementation hybrid trial for informatics-based cancer symptom management.
Authors: Justin D. Smith, Sofia F. Garcia, Frank J. Penedo, Denise M. Scholtens, Betina Yanez, Sheetal Mehta Kircher, David Cella
Journal: Journal of Clinical Oncology (2020)

236 Background: Oncology outpatients can facesignificant cancer- and treatment-related symptoms that compromise health related quality of life and quality health care. Although the burden of symptoms on patients’ lives are well-known, most health care systems are not ideally set up to relieve them. Patients are not typically drawn into meaningful engagement with the health care team in ways that enable symptom self-management. As a result, opportunities for early identification and treatment are lost, causing avoidable human suffering and cost. The Northwestern University IMPACT (NU IMPACT) project aims to evaluate the effectiveness and implementation of an informatics-driven symptom monitoring and web-based self-management intervention. The project uses PROMIS measures, integrated into the EHR, to trigger response and intervention. This presentation describes the effectiveness-implementation hybrid trial design and measurement of implementation. Methods: NU IMPACT will test the effectiveness and implementation of a system-wide symptom management intervention, across six adult hematology/oncology and gynecologic oncology outpatient clinics at Northwestern Memorial HealthCare, using a cluster randomized pragmatic roll-out implementation trial with an embedded individual-level randomized clinical trial. This unique design allows for a fully-powered randomized trial to establish the efficacy of the intervention, as well as a randomized test of implementation. We are enrolling approximately 6,000 patients in pre-implementation and 6,000 in post-implementation, with half of the latter group randomly assigned to enhanced symptom management, and the other half to usual care. Results: Implementation process is guided by the Exploration, Preparation, Implementation, and Sustainment (EPIS) model with evaluation following the RE-AIM framework. Particular focus is paid to adoption at the clinic and provider levels, the extent to which the intervention achieves meaningful reach to cancer patients, and the potential for sustainment. Additionally, we are testing and validating a newly developed method for tracking and reporting dynamic changes to implementation strategies. Conclusions: Achieving the aims of the NU IMPACT project is a critical step in the advancement of informatics-driven symptom management interventions for cancer patients. The innovative implementation trial design and measurement approach will aid in the rapid translation of findings to other healthcare systems. Clinical trial information: NCT03988543 .
Breast cancer management duringCOVID-19 outbreak: Learned lessons
Authors: J. M. B. Sanchez, A. L. Picado, J. A. G. Saenz, M. E. O. Crespo, R. M. De La Plata Merlo, M. H. De La Muela
Journal: Clinical Cancer Research (2020)

Purpose: From the first case of COVID-19 infection in Wuhan (China), the infection spread westward around all theworld, causing a pandemic  Madrid has been one of the more impacted cities worldwide due to this infection  BC(breast cancer) remains a major public health problem due to its high incidence, prevalence, and mortality  Surgicaltreatmentss were cancelled and postponed within the worse weeks of the pandemic in our BC Unit, located insideSan Carlos Clinical Hospital in Madrid  We aimed to ensure the safety while maintaining the highest health carequality assisting our BC patients during the COVID-19 outbreak  Patients and Methods: All consecutive patients newly diagnosed with BC, patients undergoing neoadjuvanttherapy approaching to definitive for surgery, and patients whose surgical treatments were canceled, since March15th to April 21st, were included in our analysis  Our multidisciplinary team triaged these BC patients and patienttreatments were rescheduled including primary genomic platforms and harmonizing the antitumor systemictreatment  Telemedicine was used to evaluate the eventual side effects and to avoid unnecessary hospital visits, minimizing the exposure to COVID-19 risk infection  Results: Surgical treatment was delayed in seven diagnosed cases of CDIS (ductal carcinoma in situ)  Six patients with invasive triple-negative BC stage I-III underwent docetaxel plus CBDCA neoadjuvant systemic treatment  Twoadditional CBDCA-monotherapy cycles were scheduled in two patients in this TNBC group because the surgery hadto be postponed  Both patients achieved a pCR  Ten patients with HER+ 2+ BC either ER+ or ER- early (stages I-III)BC received antiHER2-based neoadjuvant chemotherapy (taxanes plus trastuzumab and pertuzumab)  Doubleneoadjuvant antiHER2 moAB followed beyond the 12-18 weeks until a safer time to perform surgery was obtained Eight out of 13 luminal breast cancer patients underwent the 21 gene recurrence score (RS) assay at the time of thediagnosis  High RS (>25) was found in 2 patients, so they received taxane-based neoadjuvant chemotherapy Patients with low RS (<25) received neoadjuvant endocrine therapy (w/o LH/RH analogs if needed)  The full cohortof our patients agreed on the perceived quality of care  Conclusion: Our patients received oncology primary treatments according to the molecular tumor subtypes until thesurgery was safe  The role of interdisciplinary committee and the molecular platforms in neoadjuvant scenarioallowed us to ensure safety and quality of care during the COVID outbreak  These strategies could be useful if asecond viral wave appears
Cost-effectiveness of Pembrolizumab Plus Axitinib Vs Nivolumab Plus Ipilimumab as First-Line Treatment of Advanced Renal Cell Carcinoma in the US
Authors: Tina R. Watson, Xin Gao, Kerry L. Reynolds, Chung Yin Kong
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Checkpoint inhibitor combination therapy represents a major advance in the first-line treatment of advanced renal cell carcinoma. Pembrolizumab-axitinib and nivolumab-ipilimumab have become standard of care options after demonstrating clinical efficacy against sunitinib in separate phase 3 trials. The cost-effectiveness of these regimens is unknown. <h3>Objective</h3> To evaluate the cost-effectiveness of pembrolizumab-axitinib and nivolumab- ipilimumab in the first-line treatment of advanced renal cell carcinoma. <h3>Design, Setting, and Participants</h3> For this economic evaluation, a primary microsimulation model was developed and run between August and December 2019. Separate analyses were conducted for an intermediate- and poor-risk patient population (base case) and a favorable-risk population (exploratory analysis) because prognosis is known to differ between risk groups; 100 000 patients with advanced renal cell carcinoma were simulated in each treatment arm. Survival, treatment regimens, and other relevant conditions were based on data from the phase 3 KEYNOTE-426 and CheckMate214 clinical trials. The study perspective was the US health care sector. <h3>Main Outcomes and Measures</h3> An incremental cost-effectiveness ratio was calculated for each of the 2 analyses and compared with a willingness-to-pay threshold of $100 000 per quality-adjusted life-year (QALY). <h3>Results</h3> Pembrolizumab-axitinib was estimated to add 0.60 QALYs compared with nivolumab-ipilimumab in the base case analysis (3.66 vs 3.05 QALYs) and 0.25 QALYs compared with nivolumab-ipilimumab in the exploratory analysis (4.55 vs 4.30 QALYs), and was more costly (base case analysis: $562 927 vs $458 961; exploratory analysis: $589 035 vs $470 403). The incremental cost-effectiveness ratio was $172 532 per QALY in the base case analysis and $468 682 per QALY in the exploratory analysis. One-way sensitivity analyses revealed that the base case model was most sensitive to first-line drug prices (incremental cost-effectiveness ratio at upper limit of nivolumab price and lower limits of axitinib and pembrolizumab prices: $89 983, $102 287, and $114 943 per QALY, respectively). The exploratory analysis model was most sensitive to overall survival rates (incremental cost-effectiveness ratio at lower limit of pembrolizumab-axitinib rate and upper limit of nivolumab-ipilimumab rate: $278 644 and $285 684 per QALY, respectively). <h3>Conclusions and Relevance</h3> The findings suggest that pembrolizumab-axitinib treatment is associated with greater QALYs compared with nivolumab/ipilimumab treatment in patients with advanced renal cell carcinoma but may not be cost-effective. Price reductions may make the cost of pembrolizumab-axitinib proportional to its clinical value and less financially burdensome to the US health care system.
Bimodal neuromodulation combining sound and tongue stimulation reduces tinnitus symptoms in a large randomized clinical study
Authors: Brendan Conlon, Berthold Langguth, Caroline Hamilton, Stephen Hughes, Emma Meade, Ciara O Connor, Martin Schecklmann, Deborah A. Hall, Sven Vanneste, Sook Ling Leong, Thavakumar Subramaniam, Shona D’Arcy, Hubert H. Lim
Journal: Science Translational Medicine (2020)

Tinnitus is a phantom auditory perception coded in the brain that can be bothersome or debilitating, affecting 10 to 15% of the population. Currently, there is no clinically recommended drug or device treatment for this major health condition. Animal research has revealed that sound paired with electrical somatosensory stimulation can drive extensive plasticity within the brain for tinnitus treatment. To investigate this bimodal neuromodulation approach in humans, we evaluated a noninvasive device that delivers sound to the ears and electrical stimulation to the tongue in a randomized, double-blinded, exploratory study that enrolled 326 adults with chronic subjective tinnitus. Participants were randomized into three parallel arms with different stimulation settings. Clinical outcomes were evaluated over a 12-week treatment period and a 12-month posttreatment phase. For the primary endpoints, participants achieved a statistically significant reduction in tinnitus symptom severity at the end of treatment based on two commonly used outcome measures, Tinnitus Handicap Inventory (Cohen's d effect size: -0.87 to -0.92 across arms; P < 0.001) and Tinnitus Functional Index (-0.77 to -0.87; P < 0.001). Therapeutic improvements continued for 12 months after treatment for specific bimodal stimulation settings, which had not previously been demonstrated in a large cohort for a tinnitus intervention. The treatment also achieved high compliance and satisfaction rates with no treatment-related serious adverse events. These positive therapeutic and long-term results motivate further clinical trials toward establishing bimodal neuromodulation as a clinically recommended device treatment for tinnitus.