tbuckley/cabot-search huggingface dataset:
Abstract 204: Identification of gene expression signatures as potential novel biomarkers in malignant melanoma
Authors: Stephanie Figueroa, Raj Tiwari, Jan Geliebter
Journal: Cancer Research (2021)

Abstract Melanoma accounts for the vast majority of skin cancer-related deaths due to its ability to metastasize and therapeutic resistance. We aimed to identify expression-based signatures associated with melanoma patient survival by analyzing The Cancer Genome Atlas (TCGA) database to identify potential, prognostic biomarkers of cutaneous melanoma. Genes overexpressed in melanoma, compared with normal skin, as well as genes associated with the survival of melanoma patients were found using the online bioinformatics platform GEPIA2 (Gene Expression Profiling Interactive Analysis). The Metascape bioinformatics tool was then used for clustering of the genes based on processes and Protein-Protein Interaction (PPI) Enrichment Analysis. The genes from the 6 most significantly enriched pathways were selected to create gene signatures, which were then subjected to Kaplan-Meier survival analysis. Melanoma patients from the TCGA database (458) were placed into two groups (229 patients each): a high and a low expression group. There were 139 statistically significantly upregulated genes in melanoma (p&amp;lt;0.01), while 500 genes had expression levels that were significantly associated with the survival of melanoma patients. Overexpressed genes were found to belong to pigment-related pathways (pigmentation, cellular pigmentation, and pigment cell differentiation), while survival-associated genes were found to function in immune system-related pathways (adaptive immune response, lymphocyte activation, and immune response-regulating signaling pathways). Kaplan-Meier survival analysis showed that the most overexpressed genes in melanoma correlated with poorer survival, while higher expression of the most-significantly survival associated gene signatures correlated with better survival. Together, these gene signatures may serve as predictors of survival in melanoma patients. Citation Format: Stephanie Figueroa, Raj Tiwari, Jan Geliebter. Identification of gene expression signatures as potential novel biomarkers in malignant melanoma [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 204.
Abstract 2692: CXCR4 as a therapeutic target in angiosarcoma
Authors: Anindita Ghosh, Robert E. Brown, Joan M. Bull, Shaimaa M. Elzamly, Jamie J. Buryanek
Journal: Cancer Research (2021)

Abstract Angiosarcomas account about 2-3% of adult soft tissue sarcomas. This is a rare form of malignancy with remarkable clinical heterogeneity in term of presentation and behavior and can occur in any location of the body. Although radiation and chemotherapy are the usual form of therapy, frequent recurrence and metastasis is observed. The prognosis of angiosarcoma is relatively poor, and the overall 5-year survival rate is approximately 35%. Previous studies have shown the SDF-1 (stromal derived factor-1)/CXCR4 pathway is involved in the progression and the metastasis of angiosarcoma. CXCR4 is a chemokine receptor involved in metastatic spread of malignant tumors and is upregulated by many factors, including hypoxia and the histone methyltransferase EZH2. CXCR4 in turn activates the JAK/STAT3 pathway, which regulates the immune environment by inducing an infiltrate of tumor associated macrophages (TAMs) of the M2 (immunosuppressive) phenotype. Sarcomas in general have increased TAMs of the M2 phenotype and accumulating evidence indicates that a high number of TAMs are associated with an unfavorable prognosis in a variety of malignancies including angiosarcoma. The monocyte chemokine CCL2 has already been documented previously in canine hemangiosarcoma as one of the primary chemoattractants for M2 macrophages. The SDF-1/CXCR4 pathway has also been documented in other malignancies as a regulator of M2 macrophage infiltration and the immunosuppressive environment. It has also been reported that blockade of CXCR4 selectively reduces M2-polarized macrophages. We studied the expression of EZH2, p-STAT3, CXCR4, and CD163 (M2 macrophage marker), in four known cases of angiosarcoma. Two cases involved right lower leg soft tissue and two cases involved tissues from aortic wall. In all of our four cases the tumor cells of angiosarcoma stained positive for EZH2, p-STAT3, CXCR4, and CD163. This supports our hypothesis that indeed in angiosarcoma the M2 macrophages has an association with CXCR4 and pSTAT3. Clinical implications of this are that plerixafor or other CXCR4 antagonists could be used to treat angiosarcoma. By blocking CXCR4, the progression and metastasis of angiosarcoma could be abrogated and the immunosuppressive environment can be normalized. Our study indicates that CXCR4 could be considered a therapeutic target in angiosarcoma and the CXCR4 antagonist plerixafor should be further investigated as a potential agent to improve patient outcomes. Citation Format: Anindita Ghosh, Robert E. Brown, Joan M. Bull, Shaimaa M. Elzamly, Jamie J. Buryanek. CXCR4 as a therapeutic target in angiosarcoma [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 2692.
Influence of bladder neck preservation and the urethro-urethroanastomosis implementation technique during retropubic radical prostatectomy on urinary continence
Authors: I. Belousov, M.B. Chibichyan, V.V. Mitusov, S.K. Tokhtamishyan, R.S. Ismailov, M.I. Kogan
Journal: European Urology (2021)
Abstract 350: Co-expression and predictive value of HER family members for the response to therapy with cetuximab in patients with metastatic colorectal cancer
Authors: Said A. Khelwatty, Soozana Puvanenthiran, Sharadah Essapen, Izhar Bagwan, Alan M. Seddon, Helmout Modjtahedi
Journal: Cancer Research (2021)

Abstract Background: Overexpression of the EGFR is common in patients with a wide range of cancers and the EGFR is an important target for therapy with monoclonal antibodies (mAbs) based drugs. Of these, cetuximab and panitumumab have been approved for the treatment of patients with metastatic colorectal cancer (mCRC). However, therapeutic benefits are seen in a subset of such patients and the duration of response can also be short. Indeed, there is currently no reliable predictive biomarkers for the selection of patients who benefit from therapy with the anti-EGFR antibodies. While KRAS mutation is currently used as an important negative predictive biomarker for the response to therapy with anti-EGFR mAbs, not all patients with wild type KRAS gain benefit from therapy with anti-EGFR mAbs and objective responses have been reported in mCRC patients with KRAS mutations. Aim: The aim of this study was to investigate the predictive value of EGFR and its dimerization partner (i.e. all other members of the HER family) for the response to treatment with cetuximab in patients with wild-type KRAS status mCRC. Methods: Using immunohistochemistry (IHC) we investigated the co-expression and predictive value of all four members of the HER family, for the response to cetuximab in 144 mCRC patients and in 21 paired primary tumours and their metastatic sites. Results: Co-expression of all four members of the HER family were found in 10% of the cases examined. The expression of wtEGFR was an indicator of poorer overall survival and the membranous expression of HER2 and HER3 3+ intensity was associated with a shorter progression free survival (PFS). In contrast, the cytoplasmic expression of HER2 was associated with better PFS. In 48% and 71% of the cases examined, there were discordance in the expression of EGFR or one or more HER family members in paired primary and related metastatic tumours, respectively. Conclusion: Our results implicate the importance of large prospective investigation of the expression level and predictive value of not only the therapeutic target (i.e. EGFR protein) but also its dimerization partners for the response to therapy with anti-EGFR mAbs and other forms of HER inhibitors in both the primary tumours and metastatic sites in colorectal cancer. Citation Format: Said A. Khelwatty, Soozana Puvanenthiran, Sharadah Essapen, Izhar Bagwan, Alan M. Seddon, Helmout Modjtahedi. Co-expression and predictive value of HER family members for the response to therapy with cetuximab in patients with metastatic colorectal 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 350.
Abstract 1348: Targeted degradation of PARP14 Using a heterobifunctional small molecule
Authors: Tim Wigle, Yue Ren, Jennifer Molina, Danielle Blackwell, Laurie Schenkel, Kerren Swinger, Anne Cheug, Ryan Abo, Elena Minissale, Alvin Lu, Christina Majer, William Church, Bryan Dorsey, Mario Niepel, Nicholas Perl, Kristy Kuplast-Barr, Kristen McEachern, Melissa Vasbinder, Heike Keilhack, Kevin Kuntz
Journal: Cancer Research (2021)

Abstract PARP14 is an interferon-stimulated gene that is overexpressed in multiple tumor types and has been shown to promote the pro-tumor M2 polarization of macrophages and support Th2/Th17 signaling in models of allergic airway disease. PARP14 is a large 203 kDa protein that possesses a catalytic domain responsible for the transfer of mono-ADP-ribose to its substrates, three macrodomains that bind mono-ADP-ribose, a WWE domain that serves as a binding module for poly-ADP-ribose, and an RNA recognition motif. We have previously shown that the potent and reversible enzymatic inhibitor, RBN012759 (IC50 &amp;lt; 0.003 μM, 300-fold selective over monoPARPs, &amp;gt; 1,000-fold selective over polyPARPs), links PARP14 catalytic inhibition with suppression of the antitumor immune response in human primary macrophages and human kidney cancer explants. While this catalytic inhibitor of PARP14 was able to suppress IL-4-driven pro-tumor gene expression in macrophages, it is unknown what roles the non-enzymatic biomolecular recognition motifs play in the biological function of PARP14. To further understand this, we describe a heterobifunctional small molecule, RBN012811, based on a catalytic inhibitor of PARP14 that binds in the enzyme's NAD+-binding site and recruits the E3 ligase cereblon to ubiquitinate PARP14 and selectively target it for degradation. RBN012811 has a IC50 of 0.01 μM against PARP14 in a biophysical assay and is at least 200-fold selective over all other PARPs. In KYSE-270 cancer cells, RBN012811 has a half-maximal degradation concentration (DC50) of 0.005 μM and it does not cause degradation of other PARP enzymes. In human primary macrophages PARP14 degradation by RBN012811 led to a dose-dependent decrease of IL-10 release induced by IL-4 stimulation. Our data demonstrates that RBN012811 is a useful tool to enable further exploration of the role of PARP14 in inflammation and cancer. Citation Format: Tim Wigle, Yue Ren, Jennifer Molina, Danielle Blackwell, Laurie Schenkel, Kerren Swinger, Anne Cheug, Ryan Abo, Elena Minissale, Alvin Lu, Christina Majer, William Church, Bryan Dorsey, Mario Niepel, Nicholas Perl, Kristy Kuplast-Barr, Kristen McEachern, Melissa Vasbinder, Heike Keilhack, Kevin Kuntz. Targeted degradation of PARP14 Using a heterobifunctional small molecule [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 1348.
Preliminary results from the PEDAL trial: A prospective single arm paired comparison of ability to diagnose and locate prostate cancer between multiparametric MRI and 18F-PSMA-PET/CT
Authors: V. Tran, T. Sutherland, K. Taubman, S.F. Lee, S. Schlicht, N. Corcoran, N. Lawrentschuk, L. Tarlinton, L.M. Wong
Journal: European Urology (2021)
Next-Generation Sequencing with a 54-Gene Panel Identifies Unique Mutational Profile and Prognostic Markers in Chinese Patients with Myelofibrosis
Authors: Harinder Gill, Ho-Wan Ip, Rita Yim, Tommy W.F. Tang, Herbert H Pang, Paul Lee, Garret Mk Leung, Jamilla Li, Karen Tang, Jason Chi Chiu So, Rock Y.Y. Leung, Jun Li, Gianni Panagioutou, Clarence C.K. Lam, Yok-Lam Kwong
Journal: Blood (2017)
Integrated Human and Murine Clinical Study Establishes Clinical Efficacy of Ruxolitinib in Chronic Myelomonocytic Leukemia
Authors: Anthony M. Hunter, Hannah Newman, Amy E. Dezern, David P. Steensma, Sandrine Niyongere, Gail J. Roboz, Qianxing Mo, Onyee Chan, Aaron Gerds, David A. Sallman, William Dominguez-Viqueira, Christopher Letson, Maria E. Balasis, Markus Ball, Traci Kruer, Hailing Zhang, Jeffrey E. Lancet, Alan F. List, Mikkael A. Sekeres, Rami S. Komrokji, Eric Padron
Journal: Clinical Cancer Research (2021)

Chronic myelomonocytic leukemia (CMML) is a rare leukemia characterized by peripheral monocytosis with no disease-modifying therapies. CMML cells are uniquely hypersensitive to granulocyte-macrophage colony-stimulating factor (GM-CSF) and robustly engraft in immunocompromised mice that secrete human cytokines. To leverage these unique biological features, we conducted an integrated human and murine study evaluating ruxolitinib, a JAK1/2 inhibitor that potently downregulates intracellular GM-CSF signaling.A total of 50 patients with WHO-defined CMML were enrolled in this open-label, multi-institution phase I/II clinical study, with a ruxolitinib dose of 20 mg twice daily studied in phase II. In parallel, 49 patient-derived xenografts (PDX) derived from 13 study participants were generated and randomized to receive ruxolitinib or vehicle control.The most common grade 3/4 treatment-related toxicities observed were anemia (10%) and thrombocytopenia (6%). The clinical overall response rate was 38% by Myelodysplastic Syndrome/Myeloproliferative Neoplasm (MDS/MPN) International Working Group (IWG) criteria and 43% of patients with baseline splenomegaly achieved a spleen response. Profiling of cytokine levels and somatic mutations at baseline failed to identify predictive biomarkers. PDX models derived from screening samples of study participants recapitulated responses seen in humans, particularly spleen responses, and corroborated ruxolitinib's clinical efficacy in a randomized murine study not feasible in human trials.Ruxolitinib demonstrated clinical efficacy and an acceptable adverse event profile in patients with CMML, identifying a potential novel therapeutic in this rare malignancy. Furthermore, this study demonstrates proof of concept that PDX modeling can recapitulate responses of patients treated on clinical trial and represents a novel correlative study that corroborates clinical efficacy seen in humans.See related commentary by Shastri and Adrianzen-Herrera, p. 6069.
Proteomics to improve phenotyping in obese patients with heart failure with preserved ejection fraction
Authors: Karl‐Patrik Kresoja, Karl‐Philipp Rommel, Rolf Wachter, Sylvia Henger, Christian Besler, Nora Klöting, Moritz Schnelle, Anne Hoffmann, Petra Büttner, Uta Ceglarek, Holger Thiele, Markus Scholz, Frank Edelmann, Matthias Blüher, Philipp Lurz
Journal: European Journal of Heart Failure (2021)

Abstract Aims Recent evidence points towards a distinct obese phenotype among patients with heart failure with preserved ejection fraction (HFpEF). We aimed to identify differentially expressed circulating biomarkers in obese HFpEF patients and link them to disease severity and outcomes. Methods and results From the LIFE‐Heart study, 999 patients with HFpEF and 999 patients without heart failure (no‐HF) were selected and 92 circulating serum biomarkers were measured using a proximity extension assay. Elevation of identified biomarkers was validated in 220 patients from the Aldo‐DHF trial with diagnosed HFpEF. HFpEF patients were older and had more comorbidities including coronary artery disease and type 2 diabetes as compared to no‐HF patients ( P &lt; 0.05 for all). After adjusting for covariates, adrenomedullin (ADM), galectin‐9 (Gal‐9), thrombospondin‐2 (THBS‐2), CD4, and tumour necrosis factor‐related apoptosis‐inducing ligand receptor 2 (TRAIL‐R2) were significantly higher in obese HFpEF patients [body mass index (BMI) ≥30 kg/m 2 , n = 464] as compared to lean HFpEF (BMI &lt;30 kg/m 2 , n = 535) and obese no‐HF patients (BMI ≥30 kg/m 2 , n = 387) ( P &lt; 0.001 for both); these findings were verified in the Aldo‐DHF validation cohort ( P &lt; 0.001). Except for CD4 these proteins were associated with increased estimates of left atrial pressure in a linear fashion. Importantly, ADM and CD4 were associated with increased mortality in obese HFpEF patients after adjusting for covariates. Conclusion Obese HFpEF patients exhibit higher circulating biomarkers of volume expansion (ADM), myocardial fibrosis (THBS‐2) and systemic inflammation (Gal‐9, CD4) compared to obese non‐HFpEF or lean HFpEF patients. These findings support the clinical definition of a distinct obese HFpEF phenotype and might merit further investigation.
Association of Mitral Annular Disjunction With Cardiovascular Outcomes Among Patients With Marfan Syndrome
Authors: Anthony Demolder, Frank Timmermans, Mattias Duytschaever, Laura Muiño-Mosquera, Julie De Backer
Journal: JAMA Cardiology (2021)

Mitral annular disjunction (MAD) has received particular interest in patients with mitral valve prolapse, ventricular tachycardia, and sudden cardiac death. The clinical significance of MAD for patients with Marfan syndrome (MFS) remains largely unexplored.To define the prevalence of MAD and examine its association with cardiovascular outcomes and arrhythmia among patients with MFS.This retrospective, single-center cohort study included 142 patients with a diagnosis of MFS based on the revised Ghent criteria and a confirmed (likely) pathogenic variant in the FBN1 gene who underwent regular follow-up between January 1, 2004, and December 31, 2019.The presence of MAD was assessed by echocardiography, and the extent of MAD was categorized in tertiles. Patients also underwent resting electrocardiography and 24-hour Holter monitoring. Outcomes included aortic events (aortic dissection or prophylactic aortic surgery), arrhythmic events (defined as sustained ventricular tachycardia or sudden cardiac death), and mitral valve surgery.A total of 142 patients (72 female patients [51%]; median age at first examination, 25 years [range, 2-64 years]) were evaluated. Forty-eight patients (34%) had MAD. Patients with MAD had larger aortic root z scores than patients without MAD (4.1 [interquartile range, 2.8-5.7] vs 3.0 [interquartile range, 1.8-4.0]; P < .001) and more often had mitral valve prolapse (34 of 48 [71%] vs 14 of 94 [15%]; P < .001), ventricular ectopy (14 of 33 [42%] vs 15 of 70 [21%]; P = .03), and nonsustained ventricular tachycardia (13 of 33 [39%] vs 12 of 70 [17%]; P = .01). During follow-up, aortic events occurred at similar rates among patients with vs without MAD (15 of 43 [35%] vs 21 of 84 [25%]; P = .24), but patients in the upper MAD tertile (>10 mm) showed a higher occurrence of aortic events compared with patients with MAD of 10 mm or smaller (9 of 15 [60%] vs 6 of 28 [21%]; P = .01). Patients with arrhythmic events (n = 5) and patients requiring mitral valve surgery (n = 7) were observed exclusively in the group displaying MAD.This study suggests that MAD among patients with MFS is associated with the occurrence of arrhythmic events, a higher need for mitral valve intervention, and, among patients with extensive MAD, more aortic events. Cardiac imaging for patients with MFS should consider the assessment of MAD as a potential marker for adverse outcomes.
Abstract 170: Anticancer potential of curcuma and target identification in hematologic malignancies: A focus on mismatch repair
Authors: Priyanjali Bhattacharya, Trupti N. Patel
Journal: Cancer Research (2021)

Abstract Introduction- Cancer, an heterogeneous condition, arises through mutations in the tumor suppressors and proto oncogenes which are otherwise involved in numerous cellular processes.These mutations rewire the signaling cascades to promote ‘malignant phenotype'. Under such circumstances the DNA repair system aids in rectifying the mutations and establishing normalcy.Plant derived products have shown promising success in treatment of cancer. In the present study, we make an attempt to screen various curcumin compounds to identify putative targets related to hematologic malignancies which in turn modulate the functionally altered mismatch repair system (MMR) using computational tools. Methods-A total of 536 curcumin compounds, retrieved from peer reviewed literature and black turmeric database, were analyzed for molecular characteristics, biological activities, ADME/Tox and, drug-like properties through Molinspiration and PreADMET. This was followed by prediction of site of metabolism via FAME3SOM tool. Simultaneously, COSMIC database was used for selection of proteins associated to haematologic malignancies. The database helped us to identify 9 proteins viz. abl1, max, myb, myc, pcna, p73, top3a, blm and vbp1; molecular aberrations of which are associated with malignant transformation in blood related cancers. Additionally, STRING identified these proteins having significant interaction with proteins of mismatch repair system. The crystal structures of the proteins were obtained from PDB and their domains and active sites were predicted using scanPROSITE, MOTIF Search, metaPOCKET2 and PrankWeb tools. Finally the proteins and ligands were energy minimized using YASARA and subjected to virtual screening and molecular docking using Autodock Vina and Autodock Tools respectively. Results-The overall results revealed six of the curcuma compounds (two monocarbonyl derivatives, one non-curcuminoid and three black turmeric natural compounds) may have the potential to modulate the identified targets and thus revive the MMR functionality; rescuing the genome from being unstable. Conclusion-With these analyses we predict that curcumin compounds can modulate therapeutic targets identified here and in turn rescue the function of MMR in hematologic malignancies. Citation Format: Priyanjali Bhattacharya, Trupti N. Patel. Anticancer potential of curcuma and target identification in hematologic malignancies: A focus on mismatch repair [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 170.