tbuckley/cabot-search huggingface dataset:
Beyond Steroids: Immunosuppressants in Steroid-Refractory or Resistant Immune-Related Adverse Events
Authors: Jia Luo, Jason A. Beattie, Paige Fuentes, Hira Rizvi, Jacklynn V. Egger, Jeffrey A. Kern, Donald Y.M. Leung, Mario E. Lacouture, Mark G. Kris, Maya Gambarin, Bianca D. Santomasso, David M. Faleck, Matthew D. Hellmann
Journal: Journal of Thoracic Oncology (2021)

IntroductionThe optimal management for immune-related adverse events (irAEs) in patients who do not respond or become intolerant to steroids is unclear. Guidelines suggest additional immunosuppressants on the basis of case reports and expert opinion.MethodsWe evaluated patients with lung cancers at Memorial Sloan Kettering Cancer Center treated with immune checkpoint blockade from 2011 to 2020. Pharmacy records were queried to identify patients who received systemic steroids and an additional immunosuppressant (e.g., tumor necrosis factor-α inhibitor, mycophenolate mofetil). Patient records were manually reviewed to evaluate baseline characteristics, management, and outcomes.ResultsAmong 2750 patients with lung cancers treated with immune checkpoint blockade, 51 (2%) received both steroids and an additional immunosuppressant for a severe irAE (tumor necrosis factor-α inhibitor (73%), mycophenolate mofetil (20%)). The most common events were colitis (53%), pneumonitis (20%), hepatitis (12%), and neuromuscular (10%). At 90 days after the start of an additional immunosuppressant, 57% were improved from their irAE, 18% were unchanged, and 25% were deceased. Improvement was more common in hepatitis (five of six) and colitis (18 of 27) but less common in neuromuscular (one of five) and pneumonitis (3 of 10). Of the patients who died, 8 of 13 were attributable directly to the irAE and 4 of 13 were related to toxicity from immunosuppression (three infection-related deaths, one drug-induced liver injury leading to acute liver failure).ConclusionsSteroid-refractory or resistant irAEs events are rare. Although existing treatments help patients with hepatitis and colitis, many patients with other irAEs remain refractory or experience toxicities from immunosuppression. A more precise understanding of the pathophysiology of specific irAEs is needed to guide biologically-informed treatments for severe irAEs.
Abstract 875: Associations of aspirin and other anti-inflammatory medications with breast cancer risk by the status of COX2 receptor
Authors: Lusine Na Yaghjyan, Heather Eliassen, Graham Colditz, Bernard Rosner, Akemi Wijayabahu, Rulla Tamimi
Journal: Cancer Research (2021)

Abstract Purpose: We investigated the associations of aspirin and other non-steroid anti-inflammatory drugs (NSAIDs) with breast cancer risk by the status of COX2 receptor expression. Methods: This study included 421 cases and 3,166 controls from a nested case-control study within the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII) cohorts. Information on medication use was first collected in 1980 (NHS) and 1989 (NHSII) and was updated biennially. Medication use was defined as none, past or current; average cumulative dose and frequency were calculated for all past or current users using data collected from all bi-annual questionnaires preceding the reference date. Immunochemistry for COX2 expression was performed using commercial antibody (Cayman Chemical and Thermo Fisher Scientific). We used polychotomous logistic regression to quantify associations of aspirin and NSAIDs with the risk of COX2+ and COX2- breast cancer tumors, while adjusting for known breast cancer risk factors. All tests of statistical significance were two-sided. Results: In multivariate analysis, heterogeneity tests indicated statistically significant differences in associations of most of the aspirin exposures and regular use of NSAIDs with breast cancer risk by COX2 receptor status. However, we observed no distinct differences in the patterns of associations between COX2+ and COX2- tumors for any of the exposure variables. Significant associations of these medications with breast cancer risk were observed for dosage of aspirin among current users in COX2- tumors (OR for &amp;gt;5 tablets per week vs. none 1.71, 95% CI 1.01-2.88, p-trend 0.04) Regular aspirin use was marginally associated with the risk of COX2- tumors (p-trend=0.06) only (p-heterogeneity&amp;lt;0.0001). Conclusions: Our findings suggested no differences in associations of aspirin and other NSAIDs with COX2+ and COX2- tumors. Citation Format: Lusine Na Yaghjyan, Heather Eliassen, Graham Colditz, Bernard Rosner, Akemi Wijayabahu, Rulla Tamimi. Associations of aspirin and other anti-inflammatory medications with breast cancer risk by the status of COX2 receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 875.
Expression patterns and prognostic potential of circular RNAs in mantle cell lymphoma: a study of younger patients from the MCL2 and MCL3 clinical trials
Authors: Mette Dahl, Simon Husby, Christian W. Eskelund, Søren Besenbacher, Søren Fjelstrup, Christophe Côme, Sara Ek, Arne Kolstad, Riikka Räty, Mats Jerkeman, Christian H. Geisler, Jørgen Kjems, Lasse S. Kristensen, Kirsten Grønbæk
Journal: Leukemia (2021)
Abstract 3090: Targeting WNT and retinoid signaling pathways to promote differentiation of cancer stem cells along the neuroendocrine lineage in CRC
Authors: Caroline O. Facey, Victoria O. Hunsu, Brian T. Osmond, Lynn M. Opdenaker, Bruce M. Boman
Journal: Cancer Research (2021)

Abstract Since APC mutations lead to overpopulation of ALDH+ stem cells (SCs) in colorectal cancers (CRCs) and that ALDH is a key component of the retinoic acid (RA) signaling pathway, the hypothesis was developed that human CRC evolves due to an imbalance between WNT and RA signaling. Indeed, we previously discovered that progressive overpopulation of ALDH+ SCs occurs in normal, mutant, adenomatous, and malignant colon crypt tissues, which coincided with the change in the APC mutation zygosity state in familial adenomatous polyposis (FAP) patients. Therefore, the SC overpopulation that drives development of CRC appears to result from dysregulated WNT signaling, of which APC is a negative regulator. Normal colonic SC differentiation is feedback regulated by neuroendocrine cells (NECs) that reside adjacent to SCs in the bottom of the colon crypt. Our goal was to determine if APC mutation and subsequent dysregulated WNT signaling contributes to the inability of SCs to differentiate into NECs, leading to overpopulation of cancer SCs (CSCs) during tumor development. Although RA signaling is altered in CRC, we still found that all- trans-retinoic acid (ATRA) could reduce the number of ALDH+ CSCs in several CRC cell lines. We also found that administering ATRA promotes differentiation of CSCs along the neuroendocrine lineage. Moreover, induction of wild-type (wt)-APC expression in HT29 CRC cells led to increased expression of several NEC markers including CGA, GLP2R, NSE, SSTR1; and decreased WNT/β-catenin signaling when tested via TCF reporter assay. Inducing wt-APC also led to reduced β-catenin and change in protein expression of several proteins known to be targeted by WNT signaling including c-MYC, c-JUN, MET, and CD44. Our preliminary results also show that inducing wt-APC expression increases the number of GLPR2+ NECs. Thus, a link between WNT and RA signaling provides a possible mechanism that might explain how mutant APC leads to decreased maturation of ALDH+ SCs along the NEC lineage and an increased the number of ALDH+ SCs. Therefore, discovering ways to increase differentiation of SCs along the NEC lineage in vivo might lead to new more effective treatment strategies for CRC patients. Citation Format: Caroline O. Facey, Victoria O. Hunsu, Brian T. Osmond, Lynn M. Opdenaker, Bruce M. Boman. Targeting WNT and retinoid signaling pathways to promote differentiation of cancer stem cells along the neuroendocrine lineage in CRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3090.
Isolation from human calcium oxalate renal stones of nephrocalcin, a glycoprotein inhibitor of calcium oxalate crystal growth. Evidence that nephrocalcin from patients with calcium oxalate nephrolithiasis is deficient in gamma-carboxyglutamic acid.
Authors: Y Nakagawa, M Ahmed, S L Hall, S Deganello, F L Coe
Journal: Journal of Clinical Investigation (1987)

We have determined that the organic matrix of calcium oxalate kidney stones contains a glycoprotein inhibitor of calcium oxalate crystal growth (nephrocalcin) that resembles nephrocalcin present in the urine of patients with calcium oxalate stones and differs from nephrocalcin from the urine of normal people. Pulverized calcium oxalate renal stones were extracted with 0.05 M EDTA, pH 8.0; nephrocalcin eluted in five peaks using DEAE-cellulose column chromatography, and each peak was further resolved by Sephacryl S-200 column chromatography. Four of the five DEAE peaks corresponded to those usually found in nephrocalcin from urine; the fifth eluted at a lower ionic strength than any found in urine. Amino acid compositions and surface properties of nephrocalcins isolated from kidney stones closely resembled those of nephrocalcins isolated from urine of stone-forming patients: they differed from normal in lacking gamma-carboxyglutamic acid residues, and in forming air-water interfacial films that were less stable than those formed by nephrocalcin from normal urine.
Pause in immunosuppressive treatment results in improved immune response to SARS-CoV-2 vaccine in autoimmune patient: a case report
Authors: Basil Golding, Youri Lee, Hana Golding, Surender Khurana
Journal: Annals of the Rheumatic Diseases (2021)

<h3>Background</h3> Patients with high blood pressure (hypertension) in the community frequently fail to meet treatment goals: a condition labelled as ‘uncontrolled’ hypertension. The optimal way to organise and deliver care to hypertensive patients has not been clearly identified. <h3>Aim</h3> To determine the effectiveness of interventions to improve control of blood pressure in patients with hypertension. <h3>Design of study</h3> Systematic review of randomised controlled trials. <h3>Setting</h3> Primary and ambulatory care. <h3>Method</h3> Interventions were categorised as following: self-monitoring; educational interventions directed to the patient; educational interventions directed to the health professional; health professional- (nurse or pharmacist) led care; organisational interventions that aimed to improve the delivery of care; and appointment reminder systems. Outcomes assessed were mean systolic and diastolic blood pressure, control of blood pressure and proportion of patients followed up at clinic. <h3>Results</h3> Seventy-two RCTs met the inclusion criteria. The trials showed a wide variety of methodological quality. Self-monitoring was associated with net reductions in systolic blood pressure (weighted mean difference [WMD] −2.5mmHg, 95%CI = −3.7 to −1.3 mmHg) and diastolic blood pressure (WMD −1.8mmHg, 95%CI = −2.4 to −1.2 mmHg). An organised system of regular review allied to vigorous antihypertensive drug therapy was shown to reduce blood pressure and all-cause mortality in a single large randomised controlled trial. <h3>Conclusion</h3> Antihypertensive drug therapy should be implemented by means of a vigorous stepped care approach when patients do not reach target blood pressure levels. Self-monitoring is a useful adjunct to care while reminder systems and nurse/pharmacist -led care require further evaluation.
The Effect of Dapagliflozin on Albuminuria in DECLARE-TIMI 58
Authors: Ofri Mosenzon, Stephen D. Wiviott, Hiddo J.L. Heerspink, Jamie P. Dwyer, Avivit Cahn, Erica L. Goodrich, Aliza Rozenberg, Meir Schechter, Ilan Yanuv, Sabina A. Murphy, Thomas A. Zelniker, Ingrid A.M. Gause-Nilsson, Anna Maria Langkilde, Martin Fredriksson, Peter A. Johansson, Deepak L. Bhatt, Lawrence A. Leiter, Darren K. McGuire, John P.H. Wilding, Marc S. Sabatine, Itamar Raz
Journal: Diabetes Care (2021)

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations with lower cardiorenal risk.DECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes, creatinine clearance >60 mL/min, and either atherosclerotic cardiovascular disease (CVD; 40.6%) or risk-factors for CVD (59.4%) to dapagliflozin or placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 months, and yearly thereafter. The change in UACR over time was measured as a continuous and categorical variable (≤15, >15 to <30, ≥30 to ≤300, and >300 mg/g) by treatment arm. The composite cardiorenal outcome was a ≥40% sustained decline in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and cardiovascular or renal death; specific renal outcome included all except cardiovascular death.Baseline UACR was available for 16,843 (98.15%) participants: 9,067 (53.83%) with ≤15 mg/g, 2,577 (15.30%) with >15 to <30 mg/g, 4,030 (23.93%) with 30-300 mg/g, and 1,169 (6.94%) with >300 mg/g. Measured as a continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared with placebo, across all UACR and eGFR categories (all P < 0.0001). Sustained confirmed ≥1 category improvement in UACR was more common in dapagliflozin versus placebo (hazard ratio 1.45 [95% CI 1.35-1.56], P < 0.0001). Cardiorenal outcome was reduced with dapagliflozin for subgroups of UACR ≥30 mg/g (P < 0.0125, Pinteraction = 0.033), and the renal-specific outcome was reduced for all UACR subgroups (P < 0.05, Pinteraction = 0.480).In DECLARE-TIMI 58, dapagliflozin demonstrated a favorable effect on UACR and renal-specific outcome across baseline UACR categories, including patients with normal albumin excretion. The results suggest a role for SGLT2i also in the primary prevention of diabetic kidney disease.
Abstract 2738: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediates tumor immune evasion in cholangiocarcinoma
Authors: Emilien Loeuillard, Jingchun Yang, Haidong Dong, Gregory J. Gores, Sumera Ilyas
Journal: Cancer Research (2021)

Abstract Background and Aims: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor superfamily, is predominantly expressed on immune cells. Although TRAIL biology has garnered considerable interest as a potential anti-cancer strategy, TR agonists have had very limited anti-cancer activity in humans. TRAIL signaling in T cells may also potentially provide an immune checkpoint function as it can inhibit T cell activation and proliferation by interfering with T cell receptor signaling. However, this potential immune checkpoint function of TRAIL has not been examined in cancer biology. Cholangiocarcinoma (CCA), a malignancy of the bile ducts, provides a model to examine the potential immune checkpoint function of TRAIL. Methods: Using a syngeneic, orthotopic murine model of CCA (PMID: 29464042), murine CCA cells (SB cells) that express both TRAIL and TRAIL receptor (TR) were implanted into livers of WT C57BL/6J and Tr−/− mice. Hence, in this model the host immune cells express TRAIL but not the receptor; they would be capable of inducing TRAIL-mediated apoptosis in CCA cells but would be resistant to potential TRAIL-mediated immunosuppression. After 4 weeks of tumor growth, mice were sacrificed and tumor and immune characterization (via flow cytometry) was conducted. Results: Implantation of SB cells into Tr−/− mice result in a significant reduction in tumor volumes compared to WT mice. Tumor-bearing Tr−/− mice had a significant infiltration of cytotoxic T lymphocytes (CTLs) (CD45+CD3+CD8+CD11a+) and enhanced CTL effector function. Moreover, Tr−/− mice tumors had a significant decrease in granulocytic and monocytic myeloid-derived suppressor cell (MDSCs) as well as tumor-associated macrophages (TAMs) (CD45+F4/80+CD11b+CD206+) compared to WT mice tumors. Conclusion: Using a unique syngeneic orthotopic implantation model of murine CCA, we demonstrate that CCA cells expressing TRAIL in a mouse genetically deficient for TR exhibit reduced tumor volumes enhanced CTL infiltration and function, and reduced MDSC and TAM infiltration into the tumors. These data suggest that TRAIL has a potential immune checkpoint function, and targeting TRAIL signaling with consequent augmentation of CTL function maybe a promising therapeutic approach in human cancers. Citation Format: Emilien Loeuillard, Jingchun Yang, Haidong Dong, Gregory J. Gores, Sumera Ilyas. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediates tumor immune evasion in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2738.
Functional Mitral Regurgitation Outcome and Grading in Heart Failure With Reduced Ejection Fraction
Authors: Giovanni Benfari, Clémence Antoine, Benjamin Essayagh, Roberta Batista, Joseph Maalouf, Andrea Rossi, Francesco Grigioni, Prabin Thapa, Hector I. Michelena, Maurice Enriquez-Sarano
Journal: JACC. Cardiovascular imaging (2021)
Abstract LB009: Dynamic changes in the compositions of cancer associated-fibroblasts correlate with clinical outcome in breast cancer
Authors: Gil Friedman, Oshrat Levi-Galibov, Eyal David, Chamutal Bornstein, Amir Giladi, Maya Dadiani, Avi Mayo, Coral Halperin, Meirav Pevsner-Fischer, Hagar Lavon, Shimrit Mayer, Reinat Nevo, Yaniv Stein, Nora Balint-Lahat, Iris Barshack, H. Raza Ali, Carlos Caldas, Einav Nili Gal-Yam, Uri Alon, Ido Amit, Ruth Scherz-Shouval
Journal: Cancer Research (2021)

Abstract Cancer associated fibroblasts (CAFs) are prevalent in carcinomas. CAFs are also heterogeneous and perform various tumor-promoting tasks. Understanding whether distinct CAF-subsets exert specific functions, and how the composition of CAFs changes as tumors evolve could improve the accuracy of cancer treatment. Here, we analyzed thousands of CAFs by single-cell RNA-sequencing and index-sorting at several timepoints along breast tumor progression in mice, revealing distinct CAF-subsets. We discovered that the transcriptional programs of these subsets change over time, shifting from an immune-regulatory program at earlier timepoints to wound-healing and antigen-presenting programs at later timepoints, indicating that the composition and functions of CAFs are dynamic. We also found the two main CAF subsets in human breast tumors, wherein their ratio was associated with disease outcome. This association was particularly correlated with BRCA mutations in triple-negative breast cancer. Our findings indicate that the diverse composition of CAFs in breast cancer changes over time as tumors progress, and that these changes are linked to disease outcome. Citation Format: Gil Friedman, Oshrat Levi-Galibov, Eyal David, Chamutal Bornstein, Amir Giladi, Maya Dadiani, Avi Mayo, Coral Halperin, Meirav Pevsner-Fischer, Hagar Lavon, Shimrit Mayer, Reinat Nevo, Yaniv Stein, Nora Balint-Lahat, Iris Barshack, H. Raza Ali, Carlos Caldas, Einav Nili Gal-Yam, Uri Alon, Ido Amit, Ruth Scherz-Shouval. Dynamic changes in the compositions of cancer associated-fibroblasts correlate with clinical outcome in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB009.
Does quality assured eLearning provide adequate preparation for robotic surgical skills; A prospective, randomized and multi-center study
Authors: S. Puliatti, M. Amato, R. Farinha, A. Paludo, G. Rosiello, R. De Groote, A. Mari, L. Bianchi, P. Piazza, B. Van Cleynenbreugel, E. Mazzone, F. Migliorini, S. Forte, C. Bravi, B. Rocco, P. Kiely, A. Mottrie, A. Gallagher
Journal: European Urology (2021)
Abstract 971: Chaperone-mediated protein degradation (CHAMP): A novel technology for tumor-targeted protein degradation
Authors: Kevin P. Foley, Long Ye, Mingkai Wang, Chenghao Ying, Wei Yin, Lingjie Zhang, Weiwen Ying
Journal: Cancer Research (2021)

Abstract The HSP90 chaperone mediates folding of many important client proteins and mutated oncoproteins, but can also direct its substrates towards degradation by the ubiquitin-proteasome system. Further, in tumor tissues, HSP90 complexes are in a highly activated state relative to normal tissues, which results in HSP90-binding small molecule compounds displaying unique tumor-selective pharmacokinetics. In order to take advantage of these attributes of HSP90 to degrade the transcription factor BRD4 in a tumor-selective fashion, hetero-bifunctional small molecule compounds were synthesized, termed chaperone-mediated protein degraders (CHAMPs), that chemically induced proximity between BRD4 and HSP90. In vitro, treatment of MV-4-11 leukemia cells with a BRD4-CHAMP compound resulted in formation of a BRD4:CHAMP:HSP90 ternary complex and subsequent proteasome-dependent BRD4 degradation and inhibition of cell proliferation. CHAMPs were identified that induced selective degradation of BRD4 and displayed only minimal effects on other HSP90-regulated client proteins. While BRD4 is a known HSP90 client protein, non-HSP90 clients such as mutated KRAS could also be degraded using this approach. In vivo, in the MV-4-11 mouse xenograft model, a selective BRD4-CHAMP compound displayed prolonged pharmacokinetics in tumors relative to plasma and normal tissues, with its tumor concentration remaining above the in vitro cytotoxicity EC50 value for at least 7 days following a single dose. This resulted in greater than 90% and prolonged degradation of BRD4 in tumors, as well as decreased expression of the BRD4-regulated MYC gene. Treatment with BRD4-CHAMP at its MTD resulted in dramatic tumor regressions after a single dose and the majority of tumors were undetectable following 3 weekly doses. In contrast, daily dosing of a clinical stage pan-BET inhibitor at its MTD resulted in stable to progressive disease, indicating that BRD4-CHAMP has a greatly improved therapeutic index in this model. CHAMP technology has a number of advantages relative to other targeted protein degradation approaches, such as PROTAC, including an improved safety margin due to selective accumulation in tumor tissues. Citation Format: Kevin P. Foley, Long Ye, Mingkai Wang, Chenghao Ying, Wei Yin, Lingjie Zhang, Weiwen Ying. Chaperone-mediated protein degradation (CHAMP): A novel technology for tumor-targeted protein degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 971.