tbuckley/cabot-search huggingface dataset:
The comparison of cytoreductive nephrectomy (CN) with tyrosine kinase inhibitor therapy alone in patients with primary metastatic renal cell carcinoma (mRCC).
Authors: Shingo Hatakeyama, Sei Naito, Kazuyuki Numakura, Renpei Kato, Tomoyuki Koguchi, Takahiro Kojima, Yoshihide Kawasaki, Kandori Kandori, Eiki Tsushima, Hiroyuki Nishiyama, Akihiro Ito, Yoshiyuki Kojima, Tomonori Habuchi, Wataru Obara, Norihiko Tsuchiya, Chikara Ohyama
Journal: Journal of Clinical Oncology (2021)

304 Background: We aimed to compare overall survival (OS) between patients with metastatic renal cell carcinoma (mRCC) treated by cytoreductive nephrectomy (CN) and those not treated by CN. Methods: We retrospectively evaluated 278 patients with mRCC treated with first-line tyrosine kinase inhibitors (TKIs) between January 2008 and November 2019. Patients were divided into two groups, CN group (immediate or deferred CN) and systemic TKI therapies alone without CN (Ctrl group). The OS was compared in all patients between the Ctrl and CN groups, between the Ctrl and immediate CN groups, between the Ctrl and deferred CN groups, and between the deferred CN and immediate CN groups. Analyses were weighted using the propensity score–based inverse probability of treatment weighting (IPTW) method to adjust for group imbalances. Results: The median age of the patients was 65 (range 59–73) years. Of the 278 patients, 132 and 146 were in the Ctrl and CN (immediate: 107 and deferred: 39) groups, respectively. A significant difference was noted between the Ctrl and CN groups in age, clinical stage, IMDC risk factors, and the number of metastatic sites. An IPTW-adjusted Cox regression analysis revealed a significant difference in OS between the Ctrl and CN groups and between the Ctrl and immediate or deferred CN groups. However, there was no significant difference in OS between immediate and deferred CN groups. Conclusions: The OS in CN group was significantly longer than that in Ctrl group even after the adjustment of potential selection biases.
Abstract 110: Statin Therapy Alters the Transcriptome of Ventricular Fibroblasts From Human Failing Heart
Authors: Gracious R Ross, Stacie Edwards, Farhan Rizvi, Paul Werner, A Jamil Tajik, Arshad Jahangir
Journal: Circulation Research (2017)

Introduction: The mechanical and electrical dysfunction in heart failure (HF) is associated with excessive cardiac fibrosis (CF). Activation of human ventricular fibroblasts (hVF) and transdifferentiation to myofibroblasts underlies the increased CF. We recently reported that statin therapy reduced differentiation of hVF in HF patients. However, the underlying mechanism is not known. Therefore, we studied the effect of statin therapy on the transcriptome of hVF from HF patients. Hypothesis: We tested the hypothesis that statin therapy alters the expression of differentiation-associated transcription factors (TF) in hVFs from HF patients. Methods: Primary cultures of hVF obtained from HF patients undergoing left ventricular assist device implantation either under statin therapy for at least 1 year (n=3) or not (n=3). The extent of transcriptomic changes induced by statin therapy in hVFs was studied from total RNA using RT 2 Profiler TM PCR array - human transcription factors (Qiagen, Catalog No: PAHS-075Z ) run on Roche LightCycler 96-well block. Fold change was calculated by 2 -ΔΔCt method. Data were analyzed by Student’s t test, and P value &lt;0.05 was considered significant. Results: Out of the 84 related genes profiled, statin therapy upregulated significantly (P&lt;0.05) at least two-fold the following genes: CREB1 (Cyclic AMP-responsive element-binding protein 1), SMAD1, TCF7L2 (transcription factor 7-like 2 ), MEF2A(myocyte enhancer factor-2), ATF1(activating transcription factor 1), and SP3. CREB1, SMAD1, TCFL2, and MEF2A are mainly involved in signaling pathways of G-protein coupled receptors, bone morphogenetic proteins, Wnt, and mitogen-activated protein kinases/extracellular signal-regulated kinases, respectively, while ATF1 and SP3 are involved in various signaling pathways. TFAP2A (transcription factor AP-2 alpha) tends to be downregulated by two-fold, however, did not reach statistical significance. Conclusion: Statin therapy mitigates differentiation of hVFs from human failing heart patients by associated changes in the transcriptome. Selective targeting of hVF transcription factor may be a potential therapeutic strategy to de-differentiate myofibroblasts and mitigate the progression of CF and HF.
Exploring the mental health experiences of young trans and gender diverse people during the Covid-19 pandemic
Authors: Bethany A. Jones, Mhairi Bowe, Niamh McNamara, Ella Guerin, Tim Carter
Journal: International Journal of Transgender Health (2021)

Both anxiety and depression have been identified as negative health outcomes associated with the distressing nature of the Covid-19 pandemic, especially among young people. Within this age demographic, trans and gender diverse people may be particularly vulnerable to pandemic-related mental health outcomes, such as anxiety and depression, due to the social challenges, gender dissonance, and poor mental health they experience. Furthermore, the social distancing measures impose several unique social and help-seeking challenges which may further contribute to the worsening of mental health. While there has been acknowledgment that vulnerable populations may be disproportionally affected by the pandemic, the experiences of trans and gender diverse youth have received very little empirical attention.To explore the mental health impact of Covid-19 on the lives of young trans and gender diverse people in the UK.In total, 243 people took part in an online survey between May and July in 2020. Eighty-two people were removed due to providing insufficient data. The analyzed dataset therefore comprised of 161 respondents ranging from 16 to 25 years (M = 20; SD = 2.68). Participants were asked how social distancing measures had impact on their social lives, mental health and access to health services. They were also asked to complete validated measures of anxiety and depression.This study found that those who experienced a greater impact of the Covid-19 outbreak and its associated social distancing measures, reported poorer mental health. Lack of social support, negative interpersonal interactions, unsupportive and non-affirming living environments and the inability to access mental health support and gender-affirming interventions were all factors that were associated with poor mental health.The findings provide specific direction for the tailoring of mental health service delivery to this population, noting the need for private, safe spaces in which young people can feel supported and have their gender identity affirmed.
QALYs, DALYs and Now PALYs: Strengthening the Argument for Prevention of CKD
Authors: Mark Canney, Adeera Levin
Journal: Journal of the American Society of Nephrology (2021)

In any healthcare system, financial and human resources are finite and the decision to invest in any therapy or strategy must be considered through that lens. Traditionally, we have used certain thresholds to establish whether a new intervention represents value for money, and the opportunity cost
Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial
Authors: Arvinder S Soin, Kuldeep Kumar, Narendra S Choudhary, Pooja Sharma, Yatin Mehta, Sushila Kataria, Deepak Govil, Vikas Deswal, Dhruva Chaudhry, Pawan Kumar Singh, Ashish Gupta, Vikas Agarwal, Suresh Kumar, Shashikala A Sangle, Rajesh Chawla, Suneetha Narreddy, Rahul Pandit, Vipul Mishra, Manoj Goel, Athimalaipet V Ramanan
Journal: The Lancet Respiratory Medicine (2021)

Global randomised controlled trials of the anti-IL-6 receptor antibody tocilizumab in patients admitted to hospital with COVID-19 have shown conflicting results but potential decreases in time to discharge and burden on intensive care. Tocilizumab reduced progression to mechanical ventilation and death in a trial population enriched for racial and ethnic minorities. We aimed to investigate whether tocilizumab treatment could prevent COVID-19 progression in the first multicentre randomised controlled trial of tocilizumab done entirely in a lower-middle-income country.
Cancer cachexia is associated with decreased responsiveness of immune cells to immunomodulatory cytokines
Authors: Gregory Lesinski, Gregory Young, Melanie Brasdovich, William Carson
Journal: Cancer Research (2008)

3792  Cachexia is characterized by loss of adipose tissue and skeletal muscle, occurs in half of all cancer patients and is associated with decreased survival. A number of cytokines including IL-6, IL-1b, IFN-g and TNF-a play a role in mediating cachexia, and are elevated in cancer patients with cachexia. We hypothesized that cytokines implicated in cachexia also function to suppress the host response to other endogenously produced or exogenously administered cytokines. The C26 adenocarcinoma model of cancer cachexia was used to study whether this syndrome is accompanied by a reduced responsiveness of immune cells to IFN-a and IFN-g. The IFNs modulate tumor immunosurveillance and are induced in response to or used as immune-based therapeutic agents. In the C26 model, cachexia develops ~20 days following subcutaneous tumor injection in immune competent mice. Twenty-five days following tumor injection, splenocytes were harvested from cachectic, C26-bearing mice or age-matched controls. C26-bearing mice displayed marked weight loss and significantly elevated plasma IL-6 (Mean = 256.6 pg/mL,; Range = 11.6 - 1263 pg/mL) as compared to controls (Mean = 2.2 pg/mL; Range = 0 - 6.3 pg/mL; n = 23 mice/group, p
A multicenter, retrospective study on impact of immunotherapy in urothelial carcinoma with bone metastases (Meet-Uro01 Study).
Authors: Patrizia Giannatempo, Laura Marandino, Daniele Raggi, Francesco Pierantoni, Marco Maruzzo, Helga Lipari, Giuseppe Luigi Banna, Ugo De Giorgi, Emanuele Naglieri, Sebastiano Buti, Marco Stellato, Francesca Vignani, Giandomenico Roviello, Antonello Veccia, Tania Losanno, Claudia Mucciarini, Sandro Pignata, Andrea Necchi, Massimo Di Maio
Journal: Journal of Clinical Oncology (2021)

401 Background: Considerable numbers of patients (pts) with metastatic urothelial carcinoma (mUC) (approximately 25-47%) develop bone metastases (BoM). Their impact on the efficacy of immunotherapy (IO) is not yet sufficiently investigated. We developed a national collaboration on this issue, with the aim to assess the effect of BoM on survival outcomes of immunotherapy-treated pts in a large retrospective cohort. Methods: Data on pts diagnosed with mUC and treated between 07/14 and 08/20 with single-agent immunotherapy (IO) after failure of at least 1 previous line of chemotherapy (CT) for advanced disease, or (neo-)adjuvant CT within 12 months were retrospectively collected across 14 centers. PFS and OS were analyzed using the Kaplan-Meier method. Cox regression analysis was performed evaluating potential prognostic factors for OS and PFS. Each factor was evaluated in univariable (UV) and multivariable (MVA) analysis. Results: A total of 208 evaluable pts treated with single-agent immunotherapy (anti PD-1 n=42; anti PD-L1 n=166) were identified, including 122 without BoM (59% BoM-) and 86 (41%) BoM+. 13% of pts had progressed within 12 months after (neo-)adjuvant CT and 79% after a previous line of platinum-based CT for advanced disease (cisplatin 42.8%; carboplatin 36.5%). The presence of BoM negatively affected performance status (PS) of patients at baseline (ECOG PS 0/1/2 in 58% / 37% / 5% in BoM- vs 38% / 52% / 9% in BoM+; p=0.017). Other baseline characteristics were comparable. BoM+ showed shorter PFS (median 2.0 vs 2.6 months, HR 1.76 [95%CI, 1.31-2.37], p&lt;0.001) and OS (median 3.9 vs 7.8 months, HR 1.59 [95%CI, 1.15-2.20], p=0.005) than BoM-. Probability of being alive was 62% vs 40% after 6 months, 38% vs 23% after 1 year and 24% vs 13% after 2 years, in BoM- and BoM+ respectively. Within each Bellmunt score, PFS and OS of BoM+ pts were shorter compared to BoM-. Both BoM and higher Bellmunt risk score were significantly associated with shorter PFS and OS in UV and MV analyses (Table). Conclusions: Patients with mUC treated with single-agent immunotherapy for BoM+ advanced disease have a dismal prognosis compared with BoM-. Further research is needed to understand the mechanism behind these clinical outcomes. [Table: see text]
Use of 18F-fluciclovine PET/CT (FluPET) for prostate cancer (PC): Initial results from a prospective registry at a tertiary academic center.
Authors: Risa Liang Wong, Heather H. Cheng, Sarah K Holt, Nathan Conrad, Hannah Loesch, Sara Fernandez, Rameen Sahoo, Zoya Bauer, Andrea Toulouse, Petros Grivas, Todd Yezefski, Kenneth J. Russell, Jonathan L. Wright, Michael Thomas Schweizer, Robert B. Montgomery, Jean H Lee, Delphine L. Chen, Jing Zeng, Daniel W. Lin, Evan Y. Yu
Journal: Journal of Clinical Oncology (2021)

29 Background: FluPET, a next-generation imaging modality approved in 2016 for suspected PC recurrence with elevated PSA after prior therapy, is becoming more widely available; however, practice patterns and impact on outcomes is unknown. We hypothesize FluPET is ordered for a variety of reasons, with findings often leading to changes in treatment plan. Methods: In this prospective registry, providers are surveyed before, 1-2 weeks after, and 1 year after FluPET to assess reasons for obtaining FluPET, projected treatment plan, changes in plan due to FluPET findings, and toxicity potentially attributable to change in treatment plan. Baseline patient characteristics, FluPET results, and longitudinal outcomes are collected. We report early descriptive findings with χ 2 and student’s t-test used for univariate analyses. Results: 50 patients enrolled 12/2018-08/2020 had baseline characteristics described in Table; 46 underwent FluPET. Rationale for ordering included initial staging prior to definitive local therapy (6.1%), guidance of salvage local therapy for 1st biochemical recurrence (BCR) (46.9%), guidance of additional salvage after ≥2 local therapies and 2nd BCR (36.7%), and confirmation of equivocal metastatic disease (10.2%). When queried on next steps, providers considered observation (67.3%), androgen deprivation therapy (ADT) (26.5%), ADT + docetaxel or novel anti-androgens (AA) (20.4%), and salvage therapy with surgery, radiation, or cryotherapy (26.5%), often selecting ≥1 option. FluPET found ≥1 PC lesion in 73.9% of cases, ≥1 indeterminate lesion in 8.7%, and no lesions in 17.4%. 45.5% of providers reported changing treatment plan based on FluPET results; 6.8% changed to observation, 20.5% to systemic therapy, 13.6% to local salvage therapy, and 4.5% to a combination of local and systemic therapies. Change in therapy was associated with positive FluPET (54.5% vs. 18.2%, p=0.044), and within those cases, with higher SUVMax (mean 7.7 vs. 5.2, p=0.021) but not number of lesions (p=0.804). Conclusions: FluPET is often obtained to guide salvage therapy after BCR but is also used for initial staging or resolving equivocal findings of metastases. Many providers changed intended treatment based on FluPET findings, especially if positive; de-escalation to observation was rare. [Table: see text]
Outcome of T‐cell acute lymphoblastic leukemia/lymphoma: Focus on <scp>near‐ETP</scp> phenotype and differential impact of nelarabine
Authors: Kiyomi Morita, Nitin Jain, Hagop Kantarjian, Koichi Takahashi, Hong Fang, Marina Konopleva, Siba El Hussein, Feng Wang, Nicholas J. Short, Abhishek Maiti, Koji Sasaki, Guillermo Garcia‐Manero, Sergej Konoplev, Farhad Ravandi, Joseph D. Khoury, Elias Jabbour
Journal: American Journal of Hematology (2021)

Abstract Early T‐cell precursor acute lymphoblastic leukemia/lymphoma (ETP‐ALL/LBL) is characterized by a distinct immunophenotype (CD1a‐negative, CD8‐negative, CD5‐negative or weak‐positive &lt;75%, myeloid/stem‐cell markers positive) and poor clinical outcomes. Near‐ETP ALL is transcriptionally similar to ETP‐ALL but CD5 expression level is not low enough to meet the criteria of ETP immunophenotype. Outcomes of near‐ETP ALL are not well characterized. We reviewed 171 patients with newly‐diagnosed T‐ALL/LBL. Patients were categorized into three groups; ETP ( N = 27), near‐ETP ( N = 24), and non‐ETP ALL/LBL ( N = 120). ETP‐ALL/LBL was associated with a significantly worse survival compared with non‐ETP ALL/LBL: 5‐year overall survival (OS) rates 32% versus 63% ( p &lt; .001). Outcome was similar between near‐ETP and non‐ETP ALL/LBL: 5‐year OS rates 56% versus 63% ( p = .543). Landmark analysis showed that allogeneic stem cell transplant (allo‐SCT) in first remission was beneficial in ETP‐ALL/LBL (5‐year event‐free survival rates 36% versus 18%, p = .030) but not in near‐ETP or non‐ETP ALL/LBL. Multivariate analysis selected the following as significant independent prognostic factors for OS: age ≥ 60 years (HR 3.11; p = .003); elevated WBC ≥100 × 10 9 /L (HR 2.60; p = .005); and ETP immunophenotype (HR 2.29; p = .010). A survival advantage with adding nelarabine to hyper‐CVAD was observed in non‐ETP ALL (5‐year OS rates 83% versus 38% with hyper‐CVAD plus neralabine versus hyper‐CVAD, p = .003). In conclusion, outcome of ETP‐ALL/LBL was poor and improved with allo‐SCT; outcome of near‐ETP ALL/LBL was similar to non‐ETP ALL/LBL; the addition of nelarabine to hyper‐CVAD improved the survival in non‐ETP ALL only.
Advanced Therapies for Ventricular Arrhythmias in Patients With Chagasic Cardiomyopathy
Authors: Jorge Romero, Alejandro Velasco, Cristiano F. Pisani, Isabella Alviz, David Briceno, Juan Carlos Díaz, Domenico Giovanni Della Rocca, Andrea Natale, Maria de Lourdes Higuchi, Mauricio Scanavacca, Luigi Di Biase
Journal: Journal of the American College of Cardiology (2021)
Abstract 10759: Sustained Effects of Apolipoprotein E Mimetic Peptides on Established Atherosclerotic Lesions in Apo E Null Mice
Authors: Dennis I Goldberg, Gaurav Nayyar, David W Garber, Shaila P Handattu, G. M Anatharamaiah
Journal: Circulation (2013)

Background: Apolipoprotein E (apoE) has been shown to have direct effects on the artery wall that promote regression of atherosclerosis and improve vascular function. The dual domain apoE mimetic p...
Inhibiting cardiac myeloperoxidase alleviates the relaxation defect in hypertrophic cardiomyocytes
Authors: Chrishan J A Ramachandra, Myu Mai Ja Kp, Jasper Chua, Sauri Hernandez-Resendiz, Elisa A Liehn, Ralph Knöll, Li-Ming Gan, Erik Michaëlsson, Malin K B Jonsson, Katarina Ryden-Markinhuhta, Ratan V Bhat, Regina Fritsche-Danielson, Ying-Hsi Lin, Sakthivel Sadayappan, Hak Chiaw Tang, Philip Wong, Winston Shim, Derek J Hausenloy
Journal: Cardiovascular Research (2021)

Abstract Aims Hypertrophic cardiomyopathy (HCM) is characterized by cardiomyocyte hypertrophy and disarray, and myocardial stiffness due to interstitial fibrosis, which result in impaired left ventricular filling and diastolic dysfunction. The latter manifests as exercise intolerance, angina, and dyspnoea. There is currently no specific treatment for improving diastolic function in HCM. Here, we investigated whether myeloperoxidase (MPO) is expressed in cardiomyocytes and provides a novel therapeutic target for alleviating diastolic dysfunction in HCM. Methods and results Human cardiomyocytes derived from control-induced pluripotent stem cells (iPSC-CMs) were shown to express MPO, with MPO levels being increased in iPSC-CMs generated from two HCM patients harbouring sarcomeric mutations in the MYBPC3 and MYH7 genes. The presence of cardiomyocyte MPO was associated with higher chlorination and peroxidation activity, increased levels of 3-chlorotyrosine-modified cardiac myosin binding protein-C (MYBPC3), attenuated phosphorylation of MYBPC3 at Ser-282, perturbed calcium signalling, and impaired cardiomyocyte relaxation. Interestingly, treatment with the MPO inhibitor, AZD5904, reduced 3-chlorotyrosine-modified MYBPC3 levels, restored MYBPC3 phosphorylation, and alleviated the calcium signalling and relaxation defects. Finally, we found that MPO protein was expressed in healthy adult murine and human cardiomyocytes, and MPO levels were increased in diseased hearts with left ventricular hypertrophy. Conclusion This study demonstrates that MPO inhibition alleviates the relaxation defect in hypertrophic iPSC-CMs through MYBPC3 phosphorylation. These findings highlight cardiomyocyte MPO as a novel therapeutic target for improving myocardial relaxation associated with HCM, a treatment strategy which can be readily investigated in the clinical setting, given that MPO inhibitors are already available for clinical testing.
Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity
Authors: John P. Murad, Dileshni Tilakawardane, Anthony K. Park, Lupita S. Lopez, Cari A. Young, Jackson Gibson, Yukiko Yamaguchi, Hee Jun Lee, Kelly T. Kennewick, Brenna J. Gittins, Wen-Chung Chang, Chau P. Tran, Catalina Martinez, Anna M. Wu, Robert E. Reiter, Tanya B. Dorff, Stephen J. Forman, Saul J. Priceman
Journal: Molecular Therapy (2021)

Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its effectiveness in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate and pancreas cancer, including those targeting prostate stem cell antigen (PSCA), are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human PSCA knockin (hPSCA-KI) immunocompetent mouse model, we evaluated the safety and therapeutic efficacy of PSCA-CAR T cells. We demonstrated that cyclophosphamide (Cy) pre-conditioning significantly modified the immunosuppressive TME and was required to uncover the efficacy of PSCA-CAR T cells in metastatic prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous expression of PSCA. This combination dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, as well as endogenous and adoptively transferred T cells, resulting in long-term anti-tumor immunity.
Subcutaneous Fat Necrosis During Nivolumab Therapy for Metastatic Melanoma
Authors: Jolanta Pach, Brianna Olamiju, Sarah Weiss, William Damsky, Jonathan Leventhal
Journal: JAMA Dermatology (2021)

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