tbuckley/cabot-search huggingface dataset:
Transcatheter Aortic Valve Replacement in Bicuspid Aortic Valve Stenosis
Authors: Flavien Vincent, Julien Ternacle, Tom Denimal, Mylène Shen, Bjorn Redfors, Cédric Delhaye, Matheus Simonato, Nicolas Debry, Basile Verdier, Bahira Shahim, Thibault Pamart, Hugues Spillemaeker, Guillaume Schurtz, François Pontana, Vinod H. Thourani, Philippe Pibarot, Eric Van Belle
Journal: Circulation (2021)

After 15 years of successive randomized, controlled trials, indications for transcatheter aortic valve replacement (TAVR) are rapidly expanding. In the coming years, this procedure could become the first line treatment for patients with a symptomatic severe aortic stenosis and a tricuspid aortic valve anatomy. However, randomized, controlled trials have excluded bicuspid aortic valve (BAV), which is the most frequent congenital heart disease occurring in 1% to 2% of the total population and representing at least 25% of patients 80 years of age or older referred for aortic valve replacement. The use of a less invasive transcatheter therapy in this elderly population became rapidly attractive, and approximately 10% of patients currently undergoing TAVR have a BAV. The U.S. Food and Drug Administration and the "European Conformity" have approved TAVR for low-risk patients regardless of the aortic valve anatomy whereas international guidelines recommend surgical replacement in BAV populations. Given this progressive expansion of TAVR toward younger and lower-risk patients, heart teams are encountering BAV patients more frequently, while the ability of this therapy to treat such a challenging anatomy remains uncertain. This review will address the singularity of BAV anatomy and associated technical challenges for the TAVR procedure. We will examine and summarize available clinical evidence and highlight critical knowledge gaps regarding TAVR utilization in BAV patients. We will provide a comprehensive overview of the role of computed tomography scans in the diagnosis, and classification of BAV and TAVR procedure planning. Overall, we will offer an integrated framework for understanding the current role of TAVR in the treatment of bicuspid aortic stenosis and for guiding physicians in clinical decision-making.
Comparative analysis of sarcopenia induced by long-term abiraterone (A) versus enzalutamide (E) therapy in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Mahdi Farzad Naimi, Maira Khan, Juan Rodrigo Briones Carvajal, Urban Emmenegger
Journal: Journal of Clinical Oncology (2021)

69 Background: Androgen deprivation therapy induces osteosarcopenia, which in turn is associated with prostate cancer related morbidity, mortality and health expenditures. Although bone and skeletal muscle health are interconnected at multiple levels, clinical guidelines focus on the prevention and management of osteoporosis while largely ignoring skeletal muscle health. Due to the paucity of studies investigating the impact of A or E therapy on skeletal muscle loss, we decided to compare the effects of the two agents on sarcopenia development among men with mCRPC. Methods: In this retrospective single-centre study we identified a total of 58 mCRPC patients (pts) who (i) had received treatment with A (n = 29) or E (n = 29) for &gt; 1.5 years, (ii) had an available routine abdominopelvic CT scan at baseline, and (iii) had at least one follow-up CT scan 12 and/or 24 months after treatment initiation. Using the contour tool of the eUnity imaging platform, we obtained the total contour area of the left and right psoas muscle at the inferior endplate of L3 in order to calculate the Psoas Muscle Index (PMI; defined as the total contour area divided by patients’ height in meters) as a measure of sarcopenia. Results: The median age of men undergoing A or E therapy was 75 (range 70-79) versus 69 (67-75) years (p = 0.09), with A use for first line mCRPC therapy in 65.5% of pts, and of E in 69.0% of pts. The median time on A was 30.3 (95%CI 27.2-46.0) months, compared to 42.8 (27.4-49.9) months for men on E (p = 0.96). Using a PMI cut-off for sarcopenia of &lt; 5.7, the rate of sarcopenia increased from 34.5% at baseline to 39.3% at 24 months in pts undergoing A therapy (p = 0.71); the median PMI of A pts at baseline was 6.79 (95%CI 5.48-7.22) and steadily decreased to 5.86 (5.46-6.42) at 24 months (p = 0.0002). As for E, the rate of sarcopenia increased from 24.1% to 39.3% after 24 months of treatment (p = 0.21), with a concurrent PMI decrease from 6.73 (95%CI 5.87-7.64) to 6.32 (5.25-6.90; p = 0.001). There were no significant PMI differences between the A and E cohorts at baseline, month 12, or month 24. Furthermore, the presence versus absence of baseline sarcopenia was not significantly associated with the time on A or E therapy (p = 0.15 and p = 0.54, respectively). Conclusions: A sizeable number of men with mCRPC are sarcopenic at start of A or E therapy. In addition, the use of both agents is associated with an increase in the rate of sarcopenia, and with significant PMI decreases over time. The sarcopenia-inducing potential of A and E is comparable, while baseline sarcopenia seems not to predict time on A or E.
Bispecific antibodies targeting mutant<i>RAS</i>neoantigens
Authors: Jacqueline Douglass, Emily Han-Chung Hsiue, Brian J. Mog, Michael S. Hwang, Sarah R. DiNapoli, Alexander H. Pearlman, Michelle S. Miller, Katharine M. Wright, P. Aitana Azurmendi, Qing Wang, Suman Paul, Annika Schaefer, Andrew D. Skora, Marco Dal Molin, Maximilian F. Konig, Qiang Liu, Evangeline Watson, Yana Li, Michael B. Murphy, Drew M. Pardoll, Chetan Bettegowda, Nickolas Papadopoulos, Sandra B. Gabelli, Kenneth W. Kinzler, Bert Vogelstein, Shibin Zhou
Journal: Science Immunology (2021)

Bispecific T cell–engaging antibodies capable of specifically killing cancer cells expressing mutant RAS neoantigens were generated.
Adiposity and response to androgen signaling inhibition (ASI) in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Andrew Warren Hahn, Rebecca Tidwell, Devaki Shilpa Surasi, Patrick Glen Pilie, Daniel Frigo, Sumit Kumar Subudhi, Eleni Efstathiou, Amado J. Zurita, Shi-Ming Tu, Brian Francis Chapin, David R. Fogelman, Michael W Starbuck, Paul G. Corn, Ana Aparicio, Jennifer Leigh McQuade, Christopher Logothetis
Journal: Journal of Clinical Oncology (2021)

72 Background: Improved understanding of how host factors influence the efficacy and toxicity of ASI could improve outcomes. Adiposity increases the risk for recurrence and lethal disease in men with localized prostate cancer. Few studies have evaluated the influence of adiposity in metastatic prostate cancer, and in these studies, adiposity was associated with improved outcomes, a potential “obesity paradox”. Herein, we assess whether adiposity is associated with response to maximal ASI in mCRPC and assess how individual body composition measurements interact to influence outcomes. Methods: Men with mCRPC uniformly treated on a prospective clinical trial with abiraterone acetate plus apalutamide were included in this post-hoc analysis (NCT02703623). Responders were defined as those with a decrease in PSA of &gt; 50% after 8 weeks of therapy. Body composition was assessed at the level of L3 on baseline CT scan at trial registration using Slice-O-Matic version 5.0. Body composition indices were normalized for height (m 2 ). Non-parametric Kruskal-Wallis test was used to evaluate associations between continuous baseline measures. A multivariable CART model was used to determine if baseline measures could divide patients into distinct risk groups. Results: In 186 men with mCRPC, responders to maximal ASI (n = 128) had higher subcutaneous adiposity (SATi, 79.3 vs. 67.6, p = 0.02), visceral adiposity (VATi, 76.4 vs. 61.5, p = 0.03), and body mass index (BMI, 30.3 vs. 29.2, p = 0.04). There was a strong correlation between BMI and SAT (r = 0.81). In exploratory multivariable modeling, BMI and VATi had the strongest associations with response to ASI. Specifically, men with a BMI ≥ 26.73 had a higher response rate (75% vs. 46%). For men with a BMI &lt; 26.73, a VATi ≥ 24.7 enriched for response to therapy (86% vs. 26%). Conclusions: Elevated subcutaneous and visceral adiposity is associated with improved response to maximal ASI in men with mCRPC. In hypothesis-generating models, visceral adiposity had the strongest association with response to ASI in men with lower BMI. Further studies need to assess how and when adiposity becomes favorable for outcomes in advanced prostate cancer.
LIBRETTO-431: Selpercatinib in treatment (Tx)-naive patients with RET fusion-positive (RET plus ) non-small cell lung cancer (NSCLC)
Authors: Hhf Loong, K Goto, YY Elamin, B Solomon, FC Santini, V Soldatenkova, A Sashegyi, A Bence Lin, BK Lin, J Wolf, GR Oxnard, C Zhou, A Drilon, K Park
Journal: Annals of Oncology (2020)
Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapy
Authors: Pascale Hubert, Patrick Roncarati, Stephanie Demoulin, Charlotte Pilard, Marie Ancion, Celia Reynders, Thomas Lerho, Diane Bruyere, Alizee Lebeau, Coraline Radermecker, Margot Meunier, Marie-Julie Nokin, Elodie Hendrick, Olivier Peulen, Philippe Delvenne, Michael Herfs
Journal: Journal for ImmunoTherapy of Cancer (2021)

High-mobility group box 1 (HMGB1) is a multifunctional redox-sensitive protein involved in various intracellular (eg, chromatin remodeling, transcription, autophagy) and extracellular (inflammation, autoimmunity) processes. Regarding its role in cancer development/progression, paradoxical results exist in the literature and it is still unclear whether HMGB1 mainly acts as an oncogene or a tumor suppressor.
HLA class I–associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children
Authors: Rebecca A. Porritt, Lisa Paschold, Magali Noval Rivas, Mary Hongying Cheng, Lael M. Yonker, Harsha Chandnani, Merrick Lopez, Donjete Simnica, Christoph Schultheiß, Chintda Santiskulvong, Jennifer Van Eyk, John K. McCormick, Alessio Fasano, Ivet Bahar, Mascha Binder, Moshe Arditi
Journal: Journal of Clinical Investigation (2021)

Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. Superantigen specificity for different Vβ chains results in Vβ skewing, whereby T cells with specific Vβ chains and diverse antigen specificity are overrepresented in the T cell receptor (TCR) repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCRβ variable gene 11-2 (TRBV11-2), with up to 24% of clonal T cell space occupied by TRBV11-2 T cells, which correlated with MIS-C severity and serum cytokine levels. Analysis of TRBJ gene usage and complementarity-determining region 3 (CDR3) length distribution of MIS-C expanded TRBV11-2 clones revealed extensive junctional diversity. Patients with TRBV11-2 expansion shared HLA class I alleles A02, B35, and C04, indicating what we believe is a novel mechanism for CDR3-independent T cell expansion. In silico modeling indicated that polyacidic residues in the Vβ chain encoded by TRBV11-2 (Vβ21.3) strongly interact with the superantigen-like motif of SARS-CoV-2 spike glycoprotein, suggesting that unprocessed SARS-CoV-2 spike may directly mediate TRBV11-2 expansion. Overall, our data indicate that a CDR3-independent interaction between SARS-CoV-2 spike and TCR leads to T cell expansion and possibly activation, which may account for the clinical presentation of MIS-C.
The Johnson &amp; Johnson Vaccine for COVID-19
Authors: Edward H. Livingston, Preeti N. Malani, C. Buddy Creech
Journal: JAMA (2021)

This JAMA Patient Page explains how the Johnson & Johnson COVID-19 vaccine, likely to be the third SARS-CoV-2 vaccine approved for widespread use, uses an adenovirus 26 vector to deliver coronavirus DNA to host cells to produce spike proteins and safely and effectively induce immunity.
Type I IFN Activating Type I Dendritic Cells for Antitumor Immunity
Authors: Yong Liang, Raquibul Hannan, Yang-Xin Fu
Journal: Clinical Cancer Research (2021)

Abstract Immune checkpoint inhibitors are successful immunotherapy modalities that enhance CD8+ T-cell responses. Although T cells are initially primed in draining lymph nodes, the mechanisms that underlie their reactivation inside the tumor microenvironment are less clear. Recent studies have found that not only is the cross-priming of conventional type 1 dendritic cells (cDC1) required to initiate CD8+ T-cell responses during tumor progression, but it also plays a central role in immunotherapy-mediated reactivation of tumor-specific CD8+ T cells for tumor regression. Moreover, many cancer treatment modalities trigger type I IFN responses, which play critical roles in boosting cDC1 cross-priming and CD8+ T-cell reactivation. Inducing type I IFNs within tumors can overcome innate immune resistance and activate antitumor adaptive immunity. Here, we review recent studies on how type I IFN-cDC1 cross-priming reactivates CD8+ T cells and contributes to tumor control by cancer immunotherapy.
Efficacy of enfortumab vedotin in advanced urothelial cancer: Retrospective analysis of the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) Study.
Authors: Vadim S Koshkin, Yilun Sun, Dory Freeman, Chelsea K. Osterman, Christopher Su, Divya Natesan, Ali Raza Khaki, Dimitrios Makrakis, Jayanshu Jain, Anders Olsen, Arnab Basu, Pedro C. Barata, Yousef Zakharia, Mehmet Asim Bilen, Hamid Emamekhoo, Nancy B. Davis, Matthew I. Milowsky, Deepak Kilari, Guru Sonpavde, Ajjai Shivaram Alva
Journal: Journal of Clinical Oncology (2021)

443 Background: Enfortumab vedotin (EV) is an antibody-drug conjugate targeting Nectin-4, which is FDA approved for patients (pts) with treatment-refractory advanced urothelial cancer (aUC). The activity of EV in pt subsets of interest such as those with distinct histological variants has not been well defined. Methods: A retrospective study of pts with aUC treated with ≥1 dose of EV as standard of care (SOC) or on a clinical trial (if trial results already reported) at 12 US sites was undertaken. Objective response rate (ORR) was investigator-assessed for pts with at least one post-baseline scan or clear evidence of clinical progression. ORR was compared across subsets of interest using proportion test. Results: A total of 184 patients with aUC were included; median age at diagnosis 70, 20% women and 60% with definitive surgery. Most common primary sites included bladder (70%) and upper tract (28%). Majority of pts (72%) had pure urothelial histology (UH) per local review, but 26% had at least a component of variant histology (VH), most commonly squamous (14%), micropapillary (8%) or plasmacytoid (3%). EV was given as monotherapy in 84% and as SOC in 58%; and 81% had ≥ 1 prior treatment in the metastatic (met) setting. ECOG PS was ≥2 in 15%; 37% had baseline neuropathy, 15% diabetes and 9% had GFR≤30. At median follow-up of 37.0 (IQR: 20.5-60.2) months from initial diagnosis, median time from met diagnosis to EV start was 11.7 (IQR: 4.3 – 20.5) months. Median duration of EV was 5.5 (IQR: 1.4 – 6.7) months, and 84% of pts were evaluable for response. ORR for evaluable pts was 53% (8% CR, 45% PR); 25% had SD and 21% PD. Median PFS and OS were not yet reached. At data cutoff in 9/2020, 55% had stopped EV (36% due to PD, 19% intolerance) and 65% were alive. Comparison of ORR in subgroups of interest for 127 evaluable pts treated with EV monotherapy is shown in the table below. Notably, among 31 pts with FGFR3 alterations, 26 were evaluable and ORR was 46%. Conclusions: In a large, retrospective, multi-institutional cohort, responses to EV were observed across a broad range of aUC pts, including pts with variant histology component, FGFR3 alterations and also in populations previously excluded from clinical trials such as pts with GFR&lt;30 and significant baseline comorbidities. No significant differences in ORR were demonstrated for patient subsets of interest. [Table: see text]
Dynamic Changes in the Nasal Microbiome Associated With Disease Activity in Patients With Granulomatosis With Polyangiitis
Authors: Rennie L. Rhee, Jiarui Lu, Kyle Bittinger, Jung‐Jin Lee, Lisa M. Mattei, Antoine G. Sreih, Sherry Chou, Jonathan J. Miner, Noam A. Cohen, Brendan J. Kelly, Hongzhe Lee, Peter C. Grayson, Ronald G. Collman, Peter A. Merkel
Journal: Arthritis & Rheumatology (2021)

Little is known about temporal changes in nasal bacteria in granulomatosis with polyangiitis (GPA). This study was undertaken to examine longitudinal changes in the nasal microbiome in association with relapse in GPA patients.Bacterial 16S ribosomal RNA gene sequencing was performed on nasal swabs from 19 patients with GPA who were followed up longitudinally for a total of 78 visits, including 9 patients who experienced a relapse and 10 patients who remained in remission. Relative abundance of bacteria and ratios between bacteria were examined. Generalized estimating equation models were used to evaluate the association between bacterial composition and 1) disease activity and 2) levels of antineutrophil cytoplasmic antibody (ANCA) with specificity for proteinase 3 (PR3), adjusted for medication.Corynebacterium and Staphylococcus were the most abundant bacterial genera across all nasal samples. Patients with quiescent disease maintained a stable ratio of Corynebacterium to Staphylococcus across visits. In contrast, in patients who experienced a relapse, a significantly lower ratio was observed at the visit prior to relapse, followed by a higher ratio at the time of relapse (adjusted P < 0.01). Species-level analysis identified an association between a higher abundance of nasal Corynebacterium tuberculostearicum and 1) relapse (adjusted P = 0.04) and 2) higher PR3-ANCA levels (adjusted P = 0.02).In GPA, significant changes occur in the nasal microbiome over time and are associated with disease activity. The occurrence of these changes months prior to the onset of relapse supports a pathogenic role of nasal bacteria in GPA. Our results uphold existing hypotheses implicating Staphylococcus as an instigator of disease and have generated a novel finding involving Corynebacterium as a potential mediator of disease in GPA.
Abstract 14024: The Effectiveness of Right Ventricular Septal Pacing in Elderly Patients
Authors: Kensaku Higashi, Yoshimasa Baba, Yusuke Ishikawa, Kiyohisa Hiramine, Hideki Tanaka, Norihito Nuruki, Masahiro Sonoda
Journal: Circulation (2017)

Introduction: It is unknown whether the right ventricular septal pacing (RVSP) is effective for a long time in elderly patients. We investigated the prognosis of patents implanted permanent pacemak...
Abstract 15747: The Sarcoplasmic Reticulum Calcium ATPase Pump Modulates Whole-body Glucose Homeostasis Through a Protein Disulfide Isomerase-dependent Pathway
Authors: Matthew Rochowski, Zahra Maria, Allison Campolo, Shanell Shoop, Steven D Hartson, Gary D Lopaschuk, Véronique A Lacombe
Journal: Circulation (2020)

Introduction: The heart is a very active metabolic organ which exerts endocrine effects by secreting cardiokines. However, its role in regulating whole-body metabolism has received scarce attention. Hypothesis: We hypothesized that cardiac-specific overexpression of the sarcoplasmic reticulum calcium ATPase (SERCA) pump, which tightly regulates cytosolic calcium, modulates whole-body glucose homeostasis by secreting cardiokines during healthy and diabetic states. Methods: Diabetes was induced by streptozotocin in wild type (WT) and transgenic (TG) mice overexpressing the SERCA pump in the heart (n=6-10/group). Translocation of glucose transporters (GLUTs) to the cell surface was measured via a photolabeling biotinylation assay. Glucose and palmitate oxidation rates, cardiac work and ATP production were quantified in isolated working hearts. Results: Blood glucose levels were lower in diabetic TG mice compared to diabetic WT mice (P=0.023). Diabetes induced a downregulation of cell surface GLUT4 protein content in cardiac and skeletal muscle (by 56% and 79%, respectively, P&lt;0.05), as well as in white and brown adipose tissue of WT mice (by 68% and 74%, respectively, P&lt;0.05), which was rescued in TG diabetic mice. WT diabetic hearts had decreased cardiac glucose oxidation rates and cardiac efficiency, and increased palmitate oxidation rates (P&lt;0.05), which were restored in TG diabetic hearts. Using quantitative mass spectrometry, we found protein disulfide isomerase (PDI) upregulated in the heart of TG mice (by 1822%, P&lt;0.0001), which was confirmed in the serum of TG mice via an ELISA assay (by 243%, P=0.03). Inoculation with exogenous PDI reduced blood glucose in WT healthy mice and partially rescued hyperglycemia in WT diabetic mice compared to untreated counterparts (P=0.009 and P=0.044, respectively). Conclusions: These data suggest that cardiac-specific SERCA overexpression rescues hyperglycemia by improving glucose transport in striated muscle and adipose tissue of diabetic TG mice. Identification of the pathways by which the SERCA pump and cardiac secreted proteins (i.e. PDI) are involved in the regulation of whole-body glucose homeostasis could lead to the identification of novel pharmacological targets in diabetic patients.
NHS pensions: what do changes to the lifetime allowance mean?
Authors: Abi Rimmer
Journal: BMJ (2021)

Nothing has happened to NHS pensions specifically. But like all pensions they will be affected by an announcement, made by the UK chancellor Rishi Sunak in the budget on 3 March,1 that the lifetime allowance will remain at its current level of £1 073 100 until April 2026.

The lifetime allowance is a limit on the amount of pension benefit that can be taken without triggering an extra tax charge. All pension benefits, except the state pension and certain exempt smaller pensions, count towards the lifetime allowance.2

In the simplest terms it means that, over time, high earners are now more likely to exceed the limit and pay tax on their pension. The rate of tax payable on any excess over and above the lifetime allowance depends on how your pension benefits are paid.

For members of the NHS pension scheme this money will normally be paid as part of your annual pension “income.” This means that you will be taxed at a rate of 25% on anything over the £1 073 100 limit. NHS Pensions will deduct this tax charge from your pension before it’s paid to you. So, as Rachael Hall, principal partner at Sandringham …