tbuckley/cabot-search huggingface dataset:
Free circulating mitochondrial DNA in blood of melanoma patients
Authors: Hiroya Takeuchi, Akihide Fujimoto, Dave S. B. Hoon
Journal: Cancer Research (2004)

1904  Genetic changes in mitochondrial DNA (mtDNA) cause a variety of diseases including cancers. The mtDNA is particularly susceptible to mutations because of a high level of reactive oxygen species generation that produce mtDNA mutations in mitochondria and a low level of DNA repair system. Somatic mtDNA mutations are identified in various human carcinomas, and most mutations are found in the displacement loop (D-loop) region of mtDNA. We hypothesized that malignant melanoma frequently has genetic alterations in the D-loop region and mtDNA alterations detected in the blood are available as a circulating DNA melanoma marker. D-loop region from 20 melanoma cell lines, 12 melanoma specimens and corresponding lymphocytes and plasma samples were sequenced using CEQ 8000 XL Genetic Analysis System (Beckman Coulter). Subsequently, the D-loop region in paired lymphocytes and plasma obtained from 32 melanoma patients was sequenced. Nine of 20 (45%) melanoma cell lines and 5 of 12 (42%) melanoma specimens contained somatic mutations in the D-loop region of mtDNA. DNA alterations in the poly-cytosine tract (C-tract) of D-loop were detected in 6 of 20 (30%) cell lines and 2 of 12 (17%) specimens. Two of 5 paired plasma samples (40%) contained the same mutations as melanoma specimens. In comparison between lymphocytes and plasma, 9 of 44 paired plasma samples (20%) contained at least one mutation compared to corresponding lymphocytes. Somatic mutations in the D-loop region of tumor and paired plasma did not correlate with clinicopathological characteristics. However, circulating mtDNA alterations were more frequent in advanced disease (AJCC stage I, 0%; stage II, 0%; stage III, 18%; stage IV, 25%). Studies suggest that circulating mtDNA mutations in plasma in melanoma patients can be detected.
Abstract 2538: p53 activation induces cell cycle arrest by promoting DREAM and RB repression of cell cycle genes
Authors: Amy E. Schade, Martin Fischer, James A. DeCaprio
Journal: Cancer Research (2019)

Abstract p53 activation results cell cycle arrest at the G1/S checkpoint and the repression of early (G1/S) and late (G2/M) cell cycle gene expression in a p21 dependent manner. The mechanism how p53 and p21 repress cell cycle gene expression is unclear. p21 is known to repress CDK2 which is a key inhibitor of the pocket protein family members RB and p130. During a normal cell cycle, p130 as part of the DREAM complex (DP1, RB-like p130, E2F4, and MuvB) and RB cooperate to repress expression of early (G1/S) and late (G2/M) cell cycle gene expression. DREAM binds and represses late (G2/M) cell cycle promoters through MuvB binding and early (G1/S) cell cycle promoters though repressor E2F binding. RB is only able to bind and repress early (G1/S) cell cycle promoters through its interaction with activator E2Fs. The requirement for DREAM and RB for control of cell cycle gene expression after p53 activation was unknown. We hypothesized that DREAM and RB would cooperate to repress cell cycle gene expression after DNA damage. Using primary human foreskin fibroblast cells lacking RB and/or p130, we found repression of early and late cell cycle gene expression is differentially regulated after p53 activation. We found that while RB is required for repression of early (G1/S) cell cycle genes after p53 activation, DREAM is required for repression of expression of late (G2/M) cell cycle genes. Surprisingly, DREAM was unable to repress early cell cycle genes after p53 activation, suggesting that RB is the key regulator of G1/S gene expression during cellular stress like DNA damage. Further, the requirement for DREAM to repress late cell cycle gene expression underlies the importance of DREAM to prevent expression of mitosis inducing genes in a state like DNA damage when mitosis could result in propagation of mutated DNA. We found that p107, a protein reported be able to replace p130 in DREAM, does not potently repress early cell cycle genes in HFFs under contact arrest and serum starvation. However, we found that p107 strongly represses expression of late cell cycle genes during G0 in cells lacking p130 alone or in combination with RB. These data provide evidence for a specific role for p107-DREAM not previously appreciated. Together, our data show that control of cell cycle gene expression after p53 activation is split in two: RB represses early cell cycle genes while DREAM represses late cell cycle genes. Citation Format: Amy E. Schade, Martin Fischer, James A. DeCaprio. p53 activation induces cell cycle arrest by promoting DREAM and RB repression of cell cycle genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2538.
Abstract 3956: A novel compound screen for enhancing T-cell based immunotherapy identifies aurora kinases as a targetable mechanism for tumor immune escape in pancreatic ductal adenocarcinoma preclinical models
Authors: Emily L. Ashkin, Deborah Silverman, Simone Punt, Soraya Zorro Manrique, Leila Williams, Yunfei Wang, Patrick Hwu
Journal: Cancer Research (2019)

Abstract Harnessing a patient’s immune system by attenuating endogenous immune checkpoints on T-cells has led to dramatic, durable tumor rejection for multiple tumor types. Nonetheless, many cancers, including pancreatic ductal adenocarcinoma (PDAC), still do not respond to immunotherapy. PDAC remains largely resistant to all therapies, leading to its notoriety as one of the most lethal malignancies, with a 6% 5-year survival rate. We aimed to find novel, targetable mechanisms by which tumors escape the adaptive immune system and resist immunotherapy. We conducted a high throughput screen of 1280 compounds producing a synergistic effect with T-cell killing to assess differences and similarities among distinct pathways inclusive between PDAC and melanoma. These screens identified several aurora kinase inhibitors as synergistic with autologous T-cell killing of tumor target. Here we present results underlying the mechanism by which aurora kinase inhibition enhances autologous T-cell mediated killing and may improve T-cell-mediated cancer immunotherapy. These findings may contribute to the design of new therapeutic combination strategies for enhancing immunotherapy treatment of melanoma, PDAC, and other “immunologically cold” tumors. Note: This abstract was not presented at the meeting. Citation Format: Emily L. Ashkin, Deborah Silverman, Simone Punt, Soraya Zorro Manrique, Leila Williams, Yunfei Wang, Patrick Hwu. A novel compound screen for enhancing T-cell based immunotherapy identifies aurora kinases as a targetable mechanism for tumor immune escape in pancreatic ductal adenocarcinoma preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3956.
Improving Quality for All Patients With Aortic Stenosis
Authors: Patrick T. O’Gara, Ajay J. Kirtane, Robert O. Bonow
Journal: JAMA Cardiology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Local activator and T cell engager (LocATE) selectively blocks PD-L1 at the cytolytic synapse for deeper responses in multiple myeloma.
Authors: Christian Leisner, Leonardo Borras, Stephanie Jungmichel, Philipp Richle, Fabian Scheifele, Thomas Schleier
Journal: Journal of Clinical Oncology (2019)

8045 Background: The BCMA-targeting bispecific T-cell engager AMG420 emerged as the first bispecific that achieved responses similar to CAR-T therapies in patients with relapsed/refractory (RR) multiple myeloma (MM). Despite improved ORR, the median duration until relapse is currently limited to approximately 12 months. Persistent minimal residual disease drives relapse and is characterized by increased expression of PD-1/PD-L1. Efficacy with checkpoint inhibitors is compromised by 1) their activity not been targeted specifically to the immune synapse between T cells and cancer cells, and 2) dose-limiting broadly distributed immune-related adverse events, which has halted several clinical trials. This underscores the need for localized checkpoint inhibition within the cytolytic synapse. We developed a Local Activator and T cell Engager (LocATE) antibody that combines binding to CD3 and BCMA with selective blockade of PD-L1 at the immune synapse in just one scaffold. Selectivity is achieved via low afffinity for PD-L1 and high affinity for BCMA. Methods: Antibody mediated Cytotoxicity (LDH assay) and T cell activation (IL-2 release) was measured in vitro using MM cell lines together with isolated human CD3 + T cells. Human ex vivo T cell activity and redirection was evaluated on fresh bone marrow biopsies from MM patients with different disease stages by automated microscopy (pharmacoscopy) and image analysis. Results: The LocATE antibody showed a 5-fold increase in T cell activation and MM cell killing in vitro compared to a BCMAxCD3 BiTE. Furthermore, patient-derived MM cells showed up to a 19-fold increase in T cell activation as compared to a BCMAxCD3 BiTE or a combination of BiTE and PD-L1 inhibitor, while no activity was observed on healthy cells. Conclusions: These results suggest that T cell redirection with simultaneous checkpoint inhibition in the synapse is highly potent while minimizing off-tumor toxicity, therefore, has high therapeutic potential for patients with relapsed MM.
Abstract 3001: Isolation of large and diverse monoclonal antibody panels against difficult targets in oncology
Authors: Joseph Rucker
Journal: Cancer Research (2019)

Abstract Although monoclonal antibodies (MAbs) are a well-established treatment approach in oncology, multipass membrane proteins are largely inaccessible as targets for MAb discovery due to their poor expression, membrane-dependent structure, small extracellular regions, and high sequence conservation between humans and rodents. We have developed a platform, MPS Antibody Discovery, that specifically addresses these challenges. We will present case studies of our successful isolation of large and diverse panels of MAbs, including functional (agonist/antagonist) MAbs, against oncology targets, including claudins, GLUT4, CXCR5, CCR7, and other chemokine receptors. Several key features of our MPS platform enabled our ability to isolate MAb panels against these targets. Antigen engineering allowed us to increase the expression levels of the target protein. Immunizing divergent animal species with a combination of DNA and Lipoparticles (high-concentration membrane proteins) allowed us to obtain high-titer immune responses against the native form of the membrane protein. Performing phage display with Lipoparticles allowed us to isolate diverse panels of MAbs with a success rate &amp;gt;95%. Our technology offers the potential for discovering MAbs against difficult targets in cancer, including neoantigens. Citation Format: Joseph Rucker. Isolation of large and diverse monoclonal antibody panels against difficult targets in oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3001.
Outcomes of patients with light chain amyloidosis who had autologous stem cell transplantation with three or more organs involved.
Authors: Abdullah Al Saleh, M Hasib Sidiqi, Angela Dispenzieri, Eli Muchtar, Francis Buadi, David Dingli, Martha Lacy, Rahma M. Warsame, Wilson I. Gonsalves, Taxiarchis Kourelis, William J. Hogan, Suzanne R. Hayman, Prashant Kapoor, Shaji Kumar, Morie A. Gertz
Journal: Journal of Clinical Oncology (2019)

8011 Background: Literature suggests that three or more organ involvement is a contraindication for autologous stem cell transplant (ASCT) in light chain amyloidosis (AL). Most centers limit transplantation to patients who have no more than two organs significantly involved. Methods: We retrospectively reviewed all patients with AL Amyloidosis involving three or more organs and who had ASCT between 1996-2015 at Mayo clinic, Rochester, Minnesota. Results: Seventy five patients underwent ASCT with three or more organs involved. Median age at diagnosis was 54 years and 67% were males. The heart was involved in 95%, followed by kidneys (84%). Thirty eight patients (51%) had no induction treatment prior to ASCT. Full dose melphalan (200mg/m2) was given in 45%, and the remaining received a reduced dose (140mg/m2). Overall response rate (hematological) was 75%. The median progression-free (PFS) and overall survival (OS) were 16.3 and 68.9 months, respectively. The 100-day mortality was 16% and overall forty four patients (59%) died during the follow up period. The most common causes of death were cardiovascular events (32%) and progressive amyloidosis (25%). On multivariable analysis, predictors for PFS were Mayo stage III/IV (RR 3.3, P = 0.0012) and hematological response (≥VGPR, RR 0.4, P = 0.012). An NT-ProBNP level of ≥2000 pg/ml was an independent predictor for shorter PFS (RR 2.6, P = 0.013). Predictors for OS included any hematological response (RR 0.1, P &lt; 0.0001) and Mayo stage III/IV (RR 7, P &lt; 0.0001). When looking at the NT-ProBNP, a level ≥2000 was prognostic (RR 5.5, P = 0.001). Number of organs involved (3 vs. 4-5) was not significant in either PFS or OS. Conclusions: We conclude that the high prevalence of cardiac involvement is the main driver for the poor outcome in patients who have three or more organs involved. Using selection criteria defined for safe transplantation in cardiac amyloidosis should result in low therapy-related mortality independent of the number of organs involved. The concept of considering patients with three organs involved ineligible for stem cell transplantation should be abandoned.
Mutational profile of non-metastatic anal squamous cell carcinoma: a restrictive high impact genetic variants analysis
Authors: L. Trilla, I. Ghanem, A. Gámez, J. Maurel, À Campos-Barros, L. G-Pastrián, M. Mendiola, C. Peña, M. Cuatrecasas, P. García Alfonso, J. Fresno, J. Feliu
Journal: Annals of Oncology (2019)
Efficacy and safety of daratumumab, lenalidomide, and dexamethasone (D-Rd) in relapsed or refractory multiple myeloma (RRMM): Updated subgroup analysis of POLLUX based on cytogenetic risk.
Authors: Jonathan L. Kaufman, Meletios A. Dimopoulos, Merav Leiba, James Morton, P. Joy Ho, Kihyun Kim, Philippe Moreau, Heather J Sutherland, Shinsuke Iida, Jin Seok Kim, H. Miles Prince, Albert Oriol Rocafiguera, Nizar J. Bahlis, Ajai Chari, Herve Avet-Loiseau, Christopher Chiu, David Soong, Jon Ukropec, Ming Qi, Jesus San Miguel
Journal: Journal of Clinical Oncology (2019)

8038 Background: High-risk cytogenetic abnormalities confer poor outcomes in MM patients (pts). In POLLUX, D-Rd demonstrated significant clinical benefit, including prolonged progression-free survival (PFS) vs lenalidomide and dexamethasone (Rd), and tolerability in RRMM pts. We present a subgroup analysis of POLLUX, based on cytogenetic risk. Methods: Pts had ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of fluorescence in situ hybridization/karyotype testing and next-generation sequencing (NGS). High-risk pts had t(4;14), t(14;16), or del17p abnormalities; standard (std)-risk pts did not meet high-risk criteria. Minimal residual disease (MRD; 10 –5 ) was assessed via NGS using clonoSEQ ® assay V2.0. Results: In POLLUX (D-Rd, n = 286; Rd, n = 283), 17.1% of pts in the D-Rd group and 20.1% of pts in the Rd group had high-risk abnormalities. After 44.3 months (mo) of median follow up, D-Rd prolonged PFS vs Rd in pts with high- (median 26.8 vs 8.8 mo; HR, 0.54 [95% CI, 0.32-0.91]; P = 0.0175) or std-risk (median not reached [NR] vs 19.9 mo; HR, 0.41 [95% CI, 0.31-0.55]; P &lt;0.0001). Responses with D-Rd were deep, including higher rates of MRD negativity and sustained MRD negativity vs Rd (Table). D-Rd prolonged PFS in first relapse pts (high risk: median 46.0 vs 7.3 mo; HR, 0.26 [95% CI, 0.11-0.59]; P = 0.0005; std risk: median NR vs 20.6 mo; HR, 0.43 [95% CI, 0.28-0.66]; P &lt;0.0001) and prolonged PFS2 vs Rd in high- (median 38.3 vs 22.1 mo; HR, 0.53 [95% CI, 0.30-0.93]; P = 0.0249) or std-risk (median NR vs 33.8 mo; HR, 0.53 [95% CI, 0.39-0.72]; P &lt;0.0001) pts. Additional data will be presented. Conclusions: D-Rd demonstrates significant efficacy in high-risk RRMM. Among high-risk pts, MRD negativity was only achieved with D-Rd. Clinical trial information: NCT02076009. [Table: see text]
Abstract LB-295: Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma
Authors: Mingzhi Han, Shuai Wang, Xingang Li, Jian Wang, Rolf Bjerkvig
Journal: Cancer Research (2019)

Abstract BACKGROUND Tumor cells display higher cholesterol levels compared to normal cells and emerging evidence indicates a pivotal role of cholesterol content in tumor cell proliferation and growth mediated by a dysregulation of key regulators involved in cholesterol homeostasis has been implicated in various cancers. In this study, we assessed the dependency of glioblastoma (GBM) cells to extracellular cholesterol levels for growth. Through analysis of whole-transcriptome databases, we identified the cholesterol homeostasis-related genes whose expression are dysregulated in gliomas. One of the most dramatically down-regulated genes identified encodes cholesterol 24-hydroxylase (CYP46A1), a brain-specific enzyme responsible for elimination of cholesterol via conversion of cholesterol to 24(S)-hydroxycholesterol (24OHC). METHODS Molecular and clinical data was obtained from publicly genomic databases. Immunohistochemistry was applied to assess the protein level of CYP46A1 in tissue microarrays. Functionally, CYP46A1 overexpression was determined using lentiviral constructs in LN229 and a primary glioblastoma cell line (GBM#P3). Cells were characterized in vitro and implanted in vivo to generate orthotopic xenografts in order to assess their molecular status, cell survival, and self-renewal by western blotting, flow cytometry, and extreme limiting dilution assay (ELDA), respectively. RESULTS Down-regulation of CYP46A1 was found in malignant glioma samples compared to normal brain tissue. Importantly, reduced CYP46A1 expression was associated with aggressive clinicopathological features and poor prognosis of GBM patients. In functional assays, restoration of CYP46A1 suppressed cell proliferation and in vivo tumour growth by increasing 24OHC levels. Consistent, treatment of GBM cells with 24OHC inhibited tumour growth and induced apoptosis in a concentration dependent manner. RNA-seq data showed that 24OHC regulated LXR and sterol regulatory-element binding protein 1 (SREBP1) signalling activity. Intriguingly, efavirenz (EFV), a widespread used anti-HIV medication that effectively penetrates the blood–brain barrier, has recently been reported as a potent activator of the CYP46A1 enzyme. The therapeutic potential of EFV is currently being assessed in vivo and the data will be presented. CONCLUSIONS Collectively, our findings demonstrate that CYP46A1 is a critical cellular cholesterol regulator in GBM and that the CYP46A1/24OHC axis is a potential therapeutic target in GBM. Citation Format: Mingzhi Han, Shuai Wang, Xingang Li, Jian Wang, Rolf Bjerkvig. Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-295.
Abstract LB-068: Tomivosertib (eFT508), a potent and highly selective inhibitor of MNK1 and MNK2, enhances CAR T cell activity through modulating T cell differentiation
Authors: Vikas K. Goel, Rajesh K. Sharma, Jocelyn Staunton, Craig R. Stumpf, Nathan P. Young, Peggy A. Thompson, Gary G. Chiang, Kevin R. Webster
Journal: Cancer Research (2019)

Abstract Chimeric antigen receptor (CAR) T cells have shown great promise in treating hematopoietic malignancies, such as leukemia and non-Hodgkin’s lymphoma. The efficacy and durability of CAR T cell therapy have been correlated with higher levels of T stem cell memory (TSCM) and T central memory (TCM) populations. Accordingly, various strategies to enrich these CAR T cell populations are of intense interest. It is well-established that the PI3K/mTOR pathway plays an important role in T cell activation and differentiation, and perturbations in this pathway can enhance T cell memory populations. Work from our group has demonstrated that MNK modifies mTOR signaling and T cell differentiation. Here, we demonstrate that the MNK1/2 inhibitor tomivosertib can substantially increase TCM and TSCM populations in both primary murine and human T cells. Tomivosertib treatment of murine OT-I T cells biases T cell differentiation towards a TCM (CD8+ CD44+ CD62L+) population upon SIINFEKL peptide stimulation in vitro without adverse effects on T cell proliferation, interferon-γ production or cytotoxic function. Similar effects are seen in vivo, where tomivosertib treatment also enriches the TCM cell pool in a SIINFEKL vaccine-induced OT-I adoptive T cell transfer model, which results in increased persistence as demonstrated by a higher memory-recall T cell response upon re-challenge. Furthermore, addition of tomivosertib during production of human CAR (anti-CD19 scFv-4-1BB-CD3ζ) T cells leads to a significantly increased population of TSCM (CD8+ CD45RO CD45RA+ CD27+ CD95+) cells. Based on these data, the combination of tomivosertib with CD19-directed CAR T cells was assessed in the CD19+ Pfeiffer DLBCL model in vivo. Daily oral administration of tomivosertib in combination with CD19-directed CAR T cells results in improved efficacy in comparison to either monotherapy alone, consistent with tomivosertib promoting and maintaining TSCM populations in vivo. Tomivosertib is currently in multiple Phase II clinical trials as a monotherapy or in combination with checkpoint inhibitors. Citation Format: Vikas K. Goel, Rajesh K. Sharma, Jocelyn Staunton, Craig R. Stumpf, Nathan P. Young, Peggy A. Thompson, Gary G. Chiang, Kevin R. Webster. Tomivosertib (eFT508), a potent and highly selective inhibitor of MNK1 and MNK2, enhances CAR T cell activity through modulating T cell differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-068.