bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A23: Effects of anti-CTLA-4 and anti-PD-1 on memory T-cell differentiation and resistance to tumor relapse
Authors: Mok Stephen , Duffy Colm R. , Anang Nana-Ama A. , Allison James P.
Published: June 2022

Both anti-CTLA-4 and anti-PD-1 mediate significant response rates in cancer patients. As a hallmark of successful immunotherapies, they also mediate durable responses that last for years. For example, anti-CTLA-4 mediates a 22% 10-year overall survival rate, while anti-PD-1 mediates a 34% 5-year overall survival rate. Because of the broader uses of immunotherapies, the number of patients who have tumor relapse also increases. About 25% of patients who initially responded to anti-PD-1 have tumor relapse within 24 months. However, the relationship between tumor relapse and long-term effect of immunotherapies is still not clear. The goal of this study is to understand the differential effect of anti-CTLA-4 and anti-PD-1 on memory T-cell differentiation in murine tumor models. By rechallenging mice with tumor cells that have had tumors previously eradicated by either treatment, our results have shown that anti-CTLA-4 induces a more durable memory antitumor response compared to that treated with anti-PD-1. By tracing the antigen-specific CD8 T-cells throughout the memory phase, anti-CTLA-4 increases the frequency and cytokine production of antigen-specific T cells compared with anti-PD-1. We have also found that anti-CTLA-4 induces the population of KLRG1+ effector CD8 T cells among the effectors compared with anti-PD-1 during rechallenge, despite the ratio between central memory and effectors remaining the same. Our studies enable us to identify the long-term effect of immunotherapies on immune system.

Citation Format: Stephen Mok, Colm R. Duffy, Nana-Ama A. Anang, James P. Allison. Effects of anti-CTLA-4 and anti-PD-1 on memory T-cell differentiation and resistance to tumor relapse [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A23.
Abstract A31: A novel melanoma-derived cyclic decapeptide dimer mediates restoration of contact inhibition of growth and reversal of the malignant phenotype
Authors: Rosenberg Martin , Bethard Jennifer R. , Aronoff Linda , Lipkin George
Published: June 2022

Knowledge of the molecular basis for contact inhibition of growth, an in vitro property differentiating benign from malignant cells and correlated with in vivo growth control, could provide new targets for reestablishing control of malignant cell proliferation. We previously reported a soluble Contact Inhibitory Factor (CIF) in culture medium from a revertant contact inhibited melanoma cell line that restored contact-, serum-, and anchorage-dependent growth control to melanoma cells, closely linked to reversal of multiple malignant properties and whose contact inhibitory effects extended to a wide spectrum of other cancers. We now report identification, purification, and synthesis of the molecule, CIF, responsible for restoring contact inhibition: a structurally novel cyclic decapeptide dimer. Its discovery has both clinical and theoretical implications. Availability of CIF should not only facilitate evaluation of its therapeutic potential but also may provide the key to its target and the sequence of molecular events linking contact inhibition to broad phenotypic reversal. CIF may be the ligand for a widely distributed contact inhibitory checkpoint, one that is defective in cancer cells but pharmacologically correctible by CIF, and controlling replication at a single locus, potentially simplifying treatment. CIF is the first cell-derived peptide that restores contact inhibition of growth to melanoma and a wide spectrum of other cancers, with an obligatory link in melanoma to reversal of multiple aspects of the malignant phenotype. It suggests the possibility of an alternative approach to treatment of intractable melanoma and other cancers: broad-spectrum, endogenous peptide-based control of malignancy through phenotypic reversal that tilts the biologic balance to favor host recapture of control over tumor.

Citation Format: Martin Rosenberg, Jennifer R. Bethard, Linda Aronoff, George Lipkin. A novel melanoma-derived cyclic decapeptide dimer mediates restoration of contact inhibition of growth and reversal of the malignant phenotype [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A31.
Abstract B01: Genome-scale shRNA screen provides insight into the role of CUL3 in adaptive mechanisms of resistance to mutant BRAF inhibition
Authors: Vanneste Marion , Zhu Eliot , Feddersen Charlotte , Varzavand Afshin , Foley Tyler , Zhao Lei , Piper Rob , Stipp Christopher , Dupuy Adam , Henry Michael
Published: June 2022

MAPK inhibition with targeted BRAF inhibitors has revolutionized the treatment of BRAF-mutant melanoma. However, in most cases, the effects of mutant BRAF inhibition are transient, owing to the acquisition of drug resistance. To resolve mechanisms that drive resistance to mutant BRAF inhibition, we performed a genome-scale shRNA screen capable of revealing genes whose loss of function confers resistance to vemurafenib (VEM). We validated ten of our top candidates with independent lentiviral shRNA constructs. We found that knockdown of NF1 and CUL3 confers resistance to VEM. This result is consistent with previous genome-scale loss-of-function screens that have also identified NF1 and CUL3 as drivers of resistance to mutant BRAF inhibition. NF1 encodes a protein that hydrolyzes Ras-GTP. Not surprisingly, it has been shown that loss of NF1 results in increased Ras-GTP levels that lead to reactivation of MAPK in the presence of VEM. However, little is known about the mechanistic changes that underlie CUL3-mediated resistance. Here, we show that unlike the classical reactivation of MAPK that is seen with the loss of NF1, loss of CUL3 results in increased signaling through a Rac1-dependent focal-adhesion-like process that is accompanied by sustained MAPK activity in the presence of VEM. Furthermore, we show that this mechanism of resistance can be abrogated by inhibiting the Src kinase family, a nine-member protein family that critically mediates integrin signaling. In relation to other known drivers of resistance to mutant BRAF inhibition, loss of NF1 reactivates MAPK in a manner much like RAS mutations or BRAF alterations/amplification. By contrast, loss of CUL3 leads to resistance reminiscent of a reversible therapy-resistant state that lacks the key genomic alterations in MAPK signaling proteins.

Citation Format: Marion Vanneste, Eliot Zhu, Charlotte Feddersen, Afshin Varzavand, Tyler Foley, Lei Zhao, Rob Piper, Christopher Stipp, Adam Dupuy, Michael Henry. Genome-scale shRNA screen provides insight into the role of CUL3 in adaptive mechanisms of resistance to mutant BRAF inhibition [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B01.
Abstract B07: Rho-mediated gene transcription promotes BRAFi resistance in de-differentiated melanoma cells
Authors: Misek Sean A. , Appleton Kate M. , Dexheimer Tom S. , Lisabeth Erika M. , Lo Roger S. , Larsen Scott D. , Gallo Kathleen A. , Neubig Richard R.
Published: June 2022

The goal of this study is to identify pharmacologically tractable resistance mechanisms, and ultimately to prevent or reverse drug resistance in melanoma. We demonstrate that a subset of BRAFi-resistant melanoma cell lines showed diminished expression of melanocyte differentiation markers (e.g., Sox10). The transcriptional signature of 15% of treatment-naïve TCGA SKCM (skin cutaneous melanoma) tumors is similar to that of de-differentiated BRAFi-resistant cell lines. This transcriptional signature in BRAFi-resistant melanoma cells and human tumors is associated with increased Rho activation and increased expression of a RhoA/C gene signature. Using a machine learning approach, we predict that these tumors have decreased sensitivity to multiple BRAF/MEK inhibitors, consistent with our observations in multiple cell line models. De-differentiated tumors are predicted to have increased sensitivity to multiple ROCK inhibitors, and this prediction was validated in multiple BRAFi-resistant cell line models. Since ROCK is one of the canonical Rho effector proteins, these data suggest that melanoma cells and tumors with low differentiation characteristics activate the Rho pathway and are sensitive to Rho pathway inhibition. As a consequence of the effect of Rho on the actin cytoskeleton, Rho regulates gene transcription through modulating transcriptional co-activators such as MRTFA and YAP1. Both MRTFA and YAP1 are activated in de-differentiated BRAFi-resistant cells and are predicted to be activated in human tumors with a similar transcriptomic profile. Consistent with our predictions, melanoma cells with MRTFA activation are sensitive to an MRTFA pathway inhibitor and those with high YAP1 activity are sensitive to indirect blockade of YAP1 activation. In total, these results demonstrate that over the course of drug resistance a subset of cells and tumors lose melanocyte lineage characteristics and gain Rho activation. In summary, our work has used bioinformatics/ML approaches to identify Rho-mediated gene transcription as an important, targetable mechanism of BRAFi resistance in de-differentiated melanomas. We experimentally demonstrate the efficacy of this approach in multiple BRAFi-resistant models, highlighting the potential of targeting Rho-mediated transcription for treating drug-resistant melanomas.

Citation Format: Sean A. Misek, Kate M. Appleton, Tom S. Dexheimer, Erika M. Lisabeth, Roger S. Lo, Scott D. Larsen, Kathleen A. Gallo, Richard R. Neubig. Rho-mediated gene transcription promotes BRAFi resistance in de-differentiated melanoma cells [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B07.
Abstract B21: Arylsulfatase B (ARSB) is reduced in melanoma metastases and decline in ARSB increases programmed death-ligand (PDL) 1
Authors: Tobacman Joanne K. , Bhattacharyya Sumit , Feferman Leo
Published: June 2022

Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) is the enzyme that removes 4-sulfate groups from chondroitin 4-sulfate (C4S) and dermatan sulfate. In previous work, we have shown decline in ARSB with increasing aggressiveness of melanoma cell lines. C4S increased as ARSB declined in the cultured melanoma cell lines. Decline in ARSB was associated with increased expression of chondroitin sulfate proteoglycan (CSPG) 4 and matrix metalloproteinase (MMP) 2. The increase in CSPG4 was attributed to reduced binding of galectin-3 with C4S, and the increase of MMP2 was attributed to inhibition of SHP2, the tyrosine-protein phosphatase nonreceptor type 11 (PTPN11), due to increased binding with C4S. The invasiveness of the cultured melanoma cells increased when ARSB was silenced by siRNA. To further address the role of ARSB in melanoma progression, metastatic melanoma tissue was obtained from the biorepository of the University of Illinois at Chicago. ARSB activity and expression were reduced in the metastatic tissues and ARSB promoter methylation was increased. ARSB promoter methylation was also increased in cultured metastatic melanoma cells compared to normal melanocytes and to radial growth phase melanoma cells. In the metastatic tissues from skin and liver, SHP2 activity declined, and mRNA expression of MMP2 and CSPG4 increased. When ARSB was silenced by siRNA in the cultured normal melanocytes, Programmed Death-Ligand (PD-L) 1 increased from 78 ± 7 pg/mg protein to 128 ± 11 pg/mg protein by ELISA (p<0.001). In a metastatic melanoma cell line, PD-L1 increased from baseline value of 407 ± 34 pg/mg to 462 ± 26 pg/mg when ARSB was silenced. These findings indicate that decline in ARSB contributes to the progression of metastatic melanoma and to the immune checkpoint responsiveness of the melanoma cells. Further studies are required to determine how ARSB leads to increased PD-L1 expression and how treatment with recombinant ARSB can retard the progression of melanoma.

Citation Format: Joanne K. Tobacman, Sumit Bhattacharyya, Leo Feferman. Arylsulfatase B (ARSB) is reduced in melanoma metastases and decline in ARSB increases programmed death-ligand (PDL) 1 [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B21.
Abstract B27: MT1-MMP targeting in melanoma brain metastasis
Authors: Escandon Julia , Thakur Varsha , Bedogni Barbara
Published: June 2022

Background: Melanoma brain metastases contribute to morbidity and mortality of melanoma, and the treatment is limited due to its accessibility for drugs and also for surgical approaches. Radiotherapy is a widely used approach for disseminated metastatic foci in the brain. However, there is a gap in therapeutics since there are few to no alternatives to melanoma brain metastasis after the radiotherapy dose has been maximized. MT1-MMP is a metalloproteinase that has shown a direct correlation with metastasis and whose inhibition slows down the occurrence of metastasis and tumor growth. By microarray analysis, it has been found that inhibition of MT1-MMP downregulates the expression of DNA-damage response genes.

Objective/Hypothesis: We hypothesize that the inhibition of MT1-MMP in combination with radiotherapy will enhance the tumor cell killing efficacy by means of preventing cells from responding to the DNA damage that is caused by radiation. Further, we hypothesize that the Integrin beta 1 pathway downstream of MT1-MMP is the mediator in the downregulation of DNA-damage response genes.

Methods: We utilized melanoma cell lines, A375, WM-266-4-Luciferase, and K457, in which we introduced shMT1-MMP lentivirus with control shGFP. Cell culture assays compared the response of shMT1-MMP cells and shGFP cells in the presence of radiotherapy and the assays included comet assay, foci of gammaH2AX staining, clonogenic assay, and evaluation of radiotherapy response by Western blot. Furthermore, a nude mouse model was utilized in which WM-266-4-luciferase shMT1-MMP and control shGFP cells were inoculated by stereotactic injection. In vivo imaging system (IVIS) was utilized to follow up the tumors.

Results: Ongoing experiments aim to look at the response of shMT1-MMP cells to radiotherapy compared to shGFP cells by DNA damage evaluation assays (Comet assay, gammaH2AX foci, DNA-damage response proteins by Western blot), downstream signaling of Integrin beta 1 pathway, and the survival of nude mice in shMT1-MMP inoculated tumors and their response to radiotherapy.

Impact: This project has the potential to advance the current treatment of melanoma brain metastasis and also has the potential of advancing the understanding of the DNA-damage response in melanoma.

Citation Format: Julia Escandon, Varsha Thakur, Barbara Bedogni. MT1-MMP targeting in melanoma brain metastasis [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B27.
Abstract B30: The histone demethylase PHF8 epigenetically regulates the TGFbeta pathway to promote melanoma metastasis
Authors: Moubarak Rana , De Pablos-Aragoneses Ana , Ortiz-Barahona Vanessa , Von Itter Richard , Gong Yixiao , Gowen Michael , Stefan Sebastian , Argibay Diana , De Miera-Vega Eleazar , Dolgalev Igor , Sokolova Elena , Darvishian Farbod , Tsirigos Aristotelis , Osman Iman , Hernando Eva
Published: June 2022

The specific contribution of epigenetic dysregulation to the metastatic process remains understudied. Through a meta-analysis of gene expression datasets followed by a functional mini-screen, we identified PHF8, a histone demethylase of the Jumonji C proteins family, as a novel prometastatic factor in melanoma. Loss- and gain-of-function approaches demonstrate that PHF8 promotes cell invasion without affecting proliferation in vitro, and increases dissemination but not tumor growth in vivo, thus strengthening its specific contribution to the acquisition of metastatic potential. PHF8 demethylase activity is required for its proinvasive role. Transcriptomic and epigenomic analyses revealed that PHF8 orchestrates molecular changes that directly control the TGFβ signaling pathway and, as a direct consequence, melanoma invasion.

Citation Format: Rana Moubarak, Ana De Pablos-Aragoneses, Vanessa Ortiz-Barahona, Richard Von Itter, Yixiao Gong, Michael Gowen, Sebastian Stefan, Diana Argibay, Eleazar De Miera-Vega, Igor Dolgalev, Elena Sokolova, Farbod Darvishian, Aristotelis Tsirigos, Iman Osman, Eva Hernando. The histone demethylase PHF8 epigenetically regulates the TGFbeta pathway to promote melanoma metastasis [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B30.
Abstract IA02: Next targets for immune checkpoint blockade in melanoma
Authors: Chauvin Joe-Marc , Ka Mignane , Pagliano Ornella , Foucade Julien , Menna Carmine , Davar Diwakar , Kirkwood John , Kuchroo Vijay , Anderson Ana , Korman Alan , Zarour Hassane
Published: June 2022

Multiple mechanisms of melanoma-induced immune escape contribute to the failure of T-cell responses to control tumor growth in humans. Many inhibitory pathways play a critical role in impeding T-cell responses to tumor antigens (TAs), including PD-1, the T-cell immunoglobulin and mucin-domain containing-protein 3 (Tim-3), and the T-cell immunoreceptor with Ig and ITIM domains (TIGIT). These inhibitory receptors (IRs) are upregulated by TA-specific CD8+T cells in the tumor microenvironment (TME) while their respective ligands are expressed by antigen-presenting cells (APCs) and tumor cells. Circulating TA-specific CD8+ T cells and CD8+ tumor-infiltrating lymphocytes (TILs) that coexpress PD-1, TIGIT and Tim-3 exhibit different levels of T-cell dysfunction. Dysfunctional/exhausted CD8+ TILs are not totally inert and can exhibit cytolytic functions but are likely kept in check by multiple inhibitory pathways that can be targeted by immune checkpoint blockade. TIGIT is an attractive target for the next-generation immune checkpoint blockade for several reasons. First, it is highly expressed by the majority of CD8+ TILs together with PD-1. Second, the TIGIT ligands, CD155/PVR, and CD112, are highly expressed in the TME by melanoma cells and APCs. Third, dual PD-1/TIGIT blockade augments the expansion and function of human TA-specific CD8+ T cells in vitro and promotes tumor rejection in animal models. Fourth, TIGIT also acts in Tregs and NK cells to regulate antitumor immune responses. CD8+ TILs in melanoma and other solid tumors downregulate the costimulatory molecule DNAM-1/CD226, which competes with TIGIT for binding to the same ligands CD155 and CD112. Therefore, in addition to the TIGIT-mediated T-cell intrinsic inhibitory effects, the downregulation of CD226 expression by CD8+TILs in the TME also contributes to impede T-cell responses to melanoma. Collectively, our findings provide the rationale for dual PD-1/TIGIT blockade together with therapeutic strategies to counteract CD226 downregulation in the TME to improve the clinical benefits of single PD-1 blockade in patients with melanoma and other solid tumors.

Citation Format: Joe-Marc Chauvin, Mignane Ka, Ornella Pagliano, Julien Foucade, Carmine Menna, Diwakar Davar, John Kirkwood, Vijay Kuchroo, Ana Anderson, Alan Korman, Hassane Zarour. Next targets for immune checkpoint blockade in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA02.
Abstract IA11: The War on Melanoma: Oregon’s early detection experiment
Authors: Leachman Sancy A. , Lapidus Jodi , Sonmez Kemal , Heath Michael , Detweiler-Bedell Brian , Detweiler-Bedell Jerusha , Berry Elizabeth G. , Stoos Elizabeth
Published: June 2022

Early detection of melanoma has several advantages over treatment of late-stage disease. Cure rates are higher, disfigurement is reduced, both short-term and long-term side effects from unnecessary systemic therapies are avoided, and most importantly, a large number of lives of individuals who would never have responded to these treatments in the first place are saved. Early detection is also likely to reduce the overall cost of care because early-stage treatments are far less expensive than those used in advanced disease. Despite the potential benefits of screening and early detection, relatively few prospective interventional studies have been performed to objectively demonstrate effectiveness or quantify the effects. However, multivariate data do show that a basic awareness of skin health and appearance (not requiring specialized knowledge of melanoma features) is associated with early detection of melanoma. The purpose of the War on Melanoma research study is to prospectively test whether a statewide early-detection campaign can improve melanoma outcomes. We will compare three objective metrics before and after the intervention (the education campaign): (1) melanoma knowledge in the general public by survey of a representative population sample; (2) state cancer registry data on stage, mortality, etc.; and (3) cost information from an all-claims, all-payers database. We hypothesize that there will be an increase in melanoma-specific knowledge in the general public, an improved prognosis at the time of diagnosis, and a decrease in melanoma mortality in Oregon compared to two control states (Utah and Washington). We will also quantify the difference in cost of care for melanoma before and after the campaign and will determine if these costs are associated with knowledge levels and/or prognostic/mortality data. These results will provide a model for future early-detection campaigns in other states or for other cancers, by providing evidence for the impact of public health education.

Citation Format: Sancy A. Leachman, Jodi Lapidus, Kemal Sonmez, Michael Heath, Brian Detweiler-Bedell, Jerusha Detweiler-Bedell, Elizabeth G. Berry, Elizabeth Stoos. The War on Melanoma: Oregon’s early detection experiment [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA11.
Abstract IA24: Are there nonimmune targets in the BRAFV600 WT melanoma patient?
Authors: Sosman Jeffrey A.
Published: June 2022

Molecular targeting of melanoma beyond the BRAFV600 mutation has been a frustrating and largely unsuccessful pursuit. The dominant driver in many of these cases is the gain of function NRAS mutations, while a smaller subset are in part driven by NF1 loss of function genetic alterations, and lastly a subset (WT) with a variety of mutations, most of which activate the MAPK pathway such as mutations in c-Kit, MEK, KRAS, HRAS, and alternate non-V600 BRAF mutations. This effort has concentrated on the inhibition of the activated MAPK pathway with MEK inhibitors and targeted NRAS tumors, which make at least 1/3 of the non-BRAF V600 mutant melanoma. As a single agent this approach has been disappointing, but preclinical data support the need for combination therapy, including MEK inhibition with inhibition of alternate pathways such as the PI3/Akt pathway, the cell cycle pathway with CDK4/6 inhibitors, or MDM2 inhibitors to restore functional p53 driven apoptosis. These approaches have been frequently plagued by significant toxicity. Many of these approaches continue to be pursued in the clinic in the hope that different schedules will be more effective and less toxic. An obvious target has been inhibition of downstream pERK which has shown some limited clinical activity. Attacking other pathways looks promising, including targeting mitotic kinases, such as PLK1 and Aurora kinase A. Either inhibiting autophagy or enhancing Bim-directed apoptosis is also under investigation. Finally, we now have a better understanding about the interaction between the targeted agent and the tumor microenvironment. Preclinical and clinical studies show that MEK inhibition can actually enhance the T-cell response at the site of the tumor by selectively eliminating naïve T cells; CDK4/6 inhibition can influence PD-L1 expression and induce retroviral sequences, which then induce an inflammatory (hot) tumor microenvironment. On the other hand, there is further evidence that the microenvironment may be critical for targeted therapy to be effective. This supports an approach combining targeted agents with immune checkpoint inhibitors even in BRAF WT melanoma. While immunotherapy approaches dominate treatment of BRAF WT melanoma, it is critical that we do not lose focus on defining targets, developing better agents, and learning to administer them by an optimal schedule.

Citation Format: Jeffrey A. Sosman. Are there nonimmune targets in the BRAFV600 WT melanoma patient? [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA24.
Abstract PR09: Pharmacologic targeting of Gq reveals new pathways in uveal melanoma
Authors: Onken Michael D. , Makepeace Carol M. , Kaltenbronn Kevin M. , Kanai Stanley M. , Todd Tyson D. , Wang Shiqi , Broekelmann Thomas J. , Rao Prabakar Kumar , Cooper John A. , Blumer Kendall J.
Published: June 2022

Constitutively activating mutations in GNAQ (Gαq) or GNA11 (Gα11) are the oncogenic drivers of uveal (eye) melanoma (UM), occurring in over 90% of tumors. We show that constitutively active Gαq in UM cells can be targeted by the cyclic depsipeptide FR900359 (FR). FR inhibits GDP/GTP exchange allosterically to trap constitutively active Gαq in inactive GDP-bound Gαβγ heterotrimers, and allosteric inhibition of other Gα subunits can be achieved by introduction of an FR binding site. In UM cells driven by constitutively active Gαq, FR inhibits second messenger signaling, arrests proliferation, and reinstates melanocytic differentiation. At higher doses, FR also induces apoptosis. FR has no effect on Gαq/11-wild-type UM cells. FR promotes UM cell differentiation by reactivating polycomb repressive complex 2 (PRC2)-mediated gene silencing, antagonized by a heretofore unrecognized effector system of constitutively active Gαq in UM. Constitutively active Gαq and PRC2 therefore provide important therapeutic targets for UM. Further, the development of FR analogs specific for other Gα subunit subtypes may provide novel therapeutic approaches for diseases driven by constitutively active Gα subunits or multiple G protein-coupled receptors where targeting a single receptor is ineffective.

This abstract is also being presented as Poster A10.

Citation Format: Michael D. Onken, Carol M. Makepeace, Kevin M. Kaltenbronn, Stanley M. Kanai, Tyson D. Todd, Shiqi Wang, Thomas J. Broekelmann, Prabakar Kumar Rao, John A. Cooper, Kendall J. Blumer. Pharmacologic targeting of Gq reveals new pathways in uveal melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR09.
TRAF4 Inhibits Bladder Cancer Progression by Promoting BMP/SMAD Signaling
Authors: Iyengar Prasanna Vasudevan , Marvin Dieuwke Louise , Lama Dilraj , Tan Tuan Zea , Suriyamurthy Sudha , Xie Feng , van Dinther Maarten , Mei Hailiang , Verma Chandra Shekhar , Zhang Long , Ritsma Laila , ten Dijke Peter
Published: June 2022

Patients with bladder cancer often have a poor prognosis due to the highly invasive and metastatic characteristics of bladder cancer cells. Epithelial-to-mesenchymal transition (EMT) has been causally linked to bladder cancer invasion. The E3 ubiquitin ligase, tumor necrosis factor receptor–associated factor 4 (TRAF4) has been implicated as a tumor promoter in a wide range of cancers. In contrast, here we show that low TRAF4 expression is associated with poor overall survival in patients with bladder cancer. We show that the TRAF4 gene is epigenetically silenced and that ERK mediates TRAF4 phosphorylation, resulting in lower TRAF4 protein levels in bladder cancer cells. In addition, we demonstrate that TRAF4 is inversely correlated with an EMT gene signature/protein marker expression. Functionally, by manipulating TRAF4 expression, we show that TRAF4 regulates EMT genes and epithelial and invasive properties in bladder cancer cells. Transcriptomic analysis of dysregulated TRAF4 expression in bladder cancer cell lines revealed that high TRAF4 expression enhances the bone morphogenetic protein (BMP)/SMAD and inhibits the NF-κB signaling pathway. Mechanistically, we show that TRAF4 targets the E3 ubiquitin ligase SMURF1, a negative regulator of BMP/SMAD signaling, for proteasomal degradation in bladder cancer cells. This was corroborated in patient samples where TRAF4 positively correlates with phospho-SMAD1/5, and negatively correlates with phospho-NFκb-p65. Lastly, we show that genetic and pharmacologic inhibition of SMURF1 inhibits the migration of aggressive mesenchymal bladder cancer cells.

Implications:

Our findings identify E3 ubiquitin ligase TRAF4 as a potential therapeutic target or biomarker for bladder cancer progression.
Umfassender Vergleich von CT, MRT, Positronen-Emissions-Tomographie oder Positronen-Emissions-Tomographie/CT und diffusionsgewichteter MRT zum Nachweis von Lymphknotenmetastasen bei Patientinnen mit Zervixkarzinom: Eine Metaanalyse von 67 Studien
Authors: Liu Bin , Gao Sujuan , Li Shuofeng
Published: June 2022

Ziel: In jüngerer Vergangenheit ist in vielen Publikationen über die diagnostische Performance von CT, MRT, Positronen-Emissions-Tomographie (PET) mit 2-[18F]-Fluor-2-desoxy-D-glucose (FDG) und diffusionsgewichteter (DW) MRT zum Nachweis von Lymphknoten(LK)-Metastasen bei Patientinnen mit Zervixkarzinom berichtet worden. Ziel dieser Studie ist es, den diagnostischen Wert dieser nicht-invasiven Modalitäten für den Nachweis von LK-Metastasen bei Patientinnen mit Zervixkarzinom zu bewerten und zu vergleichen. Methoden: Die Datenbanken PubMed, Medline, Web of Science, Cochrane Library und Embase wurden nach Studien zu nicht-invasiven Modalitäten zum Nachweis von LK-Metastasen durchsucht. Aggregierte positive und negative Likelihood-Quotienten, diagnostisches Odds Ratio (DOR), Fläche unter der Kurve (AUC) und Summary Receiver Operating Characteristic (SROC) wurden als Bewertungsindizes berechnet. Ergebnisse: In der regionen- oder knotenbasierten Analyse waren die AUC der DW-MRT (0,92) und der PET oder PET/CT (0,90) besser als die der CT (0,83); der Unterschied war jeweils signifikant (DW-MRT vs. CT: Z = 4,61, p < 0,001; PET oder PET/CT vs. CT: Z = 3,61, p = 0,001). Schlussfolgerung: Von den vier nicht-invasiven Modalitäten hat die PET oder PET/CT die höchste Spezifität und die DW-MRT die höchste Sensitivität. Übersetzung aus Gynecol Obstet Invest 2017; 82:209-222.
Transient Alteration of Retinal Microvasculature after Refractive Surgery
Authors: Wang Peng , Hu Xiaojun , Zhu Chengcheng , Liu Mingming , Yuan Ying , Ke Bilian
Published: June 2022

Purpose: The purpose of this study was to determine the retinal microvasculature in myopic patients after refractive surgery. Methods: Thirty-six right eyes of 36 patients who undertook femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK) were imaged using optical coherence tomography angiography preoperatively, 1-week, 1-month, and 3-month postoperation, respectively. Vessel density was analyzed after the correction of magnification, and results were correlated with clinical manifestations, including spherical equivalent (SE), amplitude of accommodation, intraocular pressure, and axial length. Results: There was a significant decrease in microvascular density 1-week postoperation compared to preoperative measurement (p < 0.05), and it recovered 1-month postoperation. Microvascular densities in superficial vascular plexus (r = 0.528, p < 0.01), deep vascular plexus (r = 0.500, p < 0.01), and retinal vascular network (r = 0.390, p < 0.05) were all positively correlated with the decrease of the SE 1-week postoperation. Conclusion: The transient alteration of the retinal microvasculature after refractive surgery appeared to recover quickly, which may not impact the visual function after FS-LASIK.
Epidemiology of Huntington’s Disease in the United States Medicare and Medicaid Populations
Authors: Exuzides Alex , Reddy Sheila R. , Chang Eunice , Ta Jamie T. , Patel Anisha M. , Paydar Caleb , Yohrling George J.
Published: June 2022

Introduction: Huntington’s disease (HD) is a rare, genetic, and ultimately fatal neurodegenerative disease, with a devastating impact on individuals and families across generations. Few estimates of HD epidemiology in the United States (US) exist. Methods: This study employed a retrospective cross-sectional design to examine the epidemiology of HD in the US Medicare and Medicaid beneficiary populations using 2016-2017 claims data from the Medicare 100% Research Identifiable Files (RIFs) and 2014 claims data from the Medicaid Analytic eXtract (MAX) files for 17 states. Medicare beneficiaries ≥65 years with a diagnosis of HD (≥1 claim with ICD-10-CM code G10) in 2017 and Medicaid beneficiaries <65 years with a diagnosis of HD (≥1 claim with ICD-9-CM code 333.4) in 2014 were identified. The study outcomes included the 2017 prevalence proportion and incidence rate of HD in the Medicare population and the 2014 prevalence proportion of HD in the Medicaid population. Results: In the Medicare population, 1,941 prevalent and 819 incident cases of HD were identified in 2017, corresponding to a prevalence proportion of 13.1 per 100,000 persons and incidence rate of 6.1 per 100,000 person-years. In the Medicaid population, 353 prevalent cases of HD were identified in 2014, corresponding to a prevalence proportion of 15.2 per 100,000 persons. Conclusion: This study suggests that prevalence and incidence of HD in the US may be higher than previously estimated. This has important implications in raising awareness of HD among providers and payers and ensuring availability of and access to services for HD patients and care partners in the Medicare and Medicaid populations.
Risk of Malignancy Using the Diagnostic Categories Proposed by the World Health Organization International System for Reporting Pancreaticobiliary Cytopathology
Authors: Gocun Pınar Uyar , Simsek Berkay , Ekinci Ozgur , Ekmen Nergis , Arhan Mehmet , Karakan Tarkan , Ibis Mehmet , Cindoruk Mehmet
Published: June 2022

Background: The World Health Organization (WHO) proposed an updated reporting system for pancreaticobiliary cytology, which moves low-grade malignancies to “positive for malignancy” group and serous cystadenoma to “negative for malignancy” group. The WHO system also created two new categories, namely, pancreatic neoplasia-low grade (PaN-Low) and pancreatic neoplasia-high grade (PaN-High), which includes neoplastic mucinous cysts and stratifies them according to their cytologic atypia. The risk of malignancy (ROM) of the new categories of the WHO system needs to be defined. Methods: Cytologic slides of all patients, who underwent endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) biopsy at our institution from January 2010 to December 2021 and had a histopathological or clinical follow-up of at least 6 months, were reviewed and reclassified under the Papanicolaou Society of Cytopathology (PSC) and WHO reporting systems. The absolute ROM was calculated for each category of both reporting systems. Results: A total of 420 EUS-FNA samples from 410 patients were reviewed and reclassified. The absolute ROM for the proposed WHO system was 35% for “nondiagnostic,” 1.0% for “negative for malignancy,” 69.0% for “atypical,” 11% for “PaN-Low,” 100% for “PaN-High,” 91% for “suspicious for malignancy,” and 100% for “malignant.” Comparatively, the absolute ROM under the PSC reporting system was 34% for “nondiagnostic,” 1.0% for negative (for malignancy), 50.0% for “atypical,” 0.0% for “neoplastic: benign,” 16% for “neoplastic: other,” 88% for “suspicious for malignancy,” and 100% for “positive or malignant.” Conclusion: The proposed WHO international reporting system has advantages regarding risk stratification improvement and case management.
Field programmable gate arrays implementation of different standard deviation estimation techniques
Authors: Bamerni Serwan Ali , Al-Sulaifanie Ahmed Kh.
Published: June 2022

Additive white Gaussian noise level estimation has found its application in many fields such as biomedical signal processing, communication system, and image processing. Many methods have been proposed with different output accuracy, system complexity, power consumption, and speed. In this paper, three of the most well-known and largely used algorithms (median based, root mean square (RMS) based, and P84 based methods) have been implemented and investigated in a full comparison between them to find their advantage and disadvantage, and the suitability of each method for a specific application. The three designs are created using Xilinx system generator (XSG) and implemented on Xilinx field programmable gate arrays (FPGA) development board with Zynq series "XC7Z020-1CLG484", to evaluate the design's performance and the results are discussed in the paper.
Quadratic vector support machine algorithm, applied to prediction of university student satisfaction
Authors: Chamorro-Atalaya Omar , Morales-Romero Guillermo , Meza-Chaupis Yeferzon , Auqui-Ramos Elizabeth , Ramos-Cruz Jesús , León-Velarde César , Aybar-Bellido Irma
Published: June 2022

This study aims to identify the most optimal supervised learning algorithm to be applied to the prediction of satisfaction of university students. In this study, the IBM SPSS - 25.0 software was used to test the reliability of the satisfaction questionnaire and the MATLAB R2021b software through the classification learner technique to determine the supervised learning algorithm. The experimental results determine a Cronbach's Alpha reliability of 0.979, in terms of the classification algorithm, it is validate d that the quadratic vector support machine (SVM) has better performance metrics, being correct in 97.8% (a ccuracy) in the predictions of satisfaction of university students, with a r ecall (sensitivity) of 96.5% and an F1 score of 0.968. Likewise, when eva luating the classification model by means of the receiver operating characteristic curve (ROC) technique, it is identified that for the three expected classes of satisfaction the value of the area under the curve (AUC) is equal to 1, in such sense the pred ictive model through the SVM Quadratic algorithm, has a high capacity to distinguish between the 3 classes ; i) d issatisfied, ii) s atisfied and iii) v ery satisfied of satisfaction of university students.
Masked face with facial expression recognition based on deep learning
Authors: Abdullah Nawal Younis , Alkababji Ahmed Mamoon Fadhil
Published: June 2022

Wearing masks contributed to slowing the spread of the coronavirus disease (COVID-19) as the World Health Organization (WHO) recommended wearing face masks especially with the spreading of virus variants like omicron. Although people accept the idea of wearing these masks, it is still unknown the effect of covering parts of the face on social interaction among people in general and children in particular. Moreover, Social isolation affects emotional moods, which causes stress, sadness, and depression. In the current study, we have been exploring the emotional inferences on faces with and without a mask. The system can pick up the universal emotions: fear, disgust, anger, surprise, contempt, sadness, and happiness. The researchers in deep learning are concerned with global pandemic COVID-19 to enhance public health service. The proposed model is developed with a machine learning algorithm through the Haar feature-based cascade classifiers. The built model can detect people's emotions with mask and without a mask with high accuracy.
A dualband bandpass filter with tunable bandwidths for automotive radar and 5G millimeter-wave applications
Authors: Amadou Mouctar Balde Thierno , Manene Franklin , Mbango Franck Moukanda
Published: June 2022

A compact dual wideband bandpass filter for automotive radar (AR) and 5G millimeter-wave (mmWave) applications with adjustable bandwidths is presented in this work. The filter is based on microstrip dual-mode edge-coupled stub-loaded resonators (SLR). The novelty of this configuration is that it allows independent control of the bandwidths which is not obvious for many reported SLR-based filters. To achieve an overall size of 1.23λ_g× 2.02λ_g, these resonators are coupled and bent int o U-shape, T-shape, and E-shape. The U-shaped resonator, based on a quarter-wavelength transmission line, is coupled to the T-shaped element which constitutes the main feed line to obtain the dual-band response. Having a symmetrical structure, the design i s studied using the even-odd mode analysis. The layout is made using the Ansys high-frequency structural simulator (HFSS) and fabricated on Rogers RO3010 with a thickness of 1.28 mm, a dielectric constant of 10.2, and a loss tangent of 0.0022. The measured bandwidths are 660 MHz and 880 MHz at central frequencies of 23.92 GHz and 28.38 GHz respectively. The measured insertion losses are less than 3.9 dB and the return losses are greater than 17 dB in both bands. A good agreement is obtained between simulate d and experimental results.
An efficient authentication and key-distribution protocol for wireless multimedia sensor network
Authors: Patil Basavaraj , Biradar Sangappa Ramachandra
Published: June 2022

To provide security and privacy for multimedia data transmission, efficient techniques for authorizing and authenticating network users and nodes are required. These challenges have made it a vital and significant area of research in the present decade. Du e to resource constraints, existing systems are unable to provide adequate protection against vulnerable behaviors and security assaults such as black-hole, Sybil, man-in-the-middle, and other similar attacks. In this paper, an effective enhanced engineere d cementitious composites (ECC) and crypto-based authentication with a key exchange mechanism is proposed. The method boosts the effective authentication mechanism and reduces the number of vulnerable activities in the network. The simulation results demon strate that the suggested technique is robust to malicious assaults and performs mutual authentication efficiently. A cost-benefit analysis validates that the processing, communication, and storage requirements are much reduced when compared to existing ap proaches. Furthermore, an informal security analysis demonstrates that the suggested protocol is secure and adaptable to real-time scenarios.
Light fidelity performance via hybrid free space optic/fiber optic communication under atmospheric disturbance
Authors: Alnajjar Satea Hikmat , Hameed Ahmed Majid
Published: June 2022

Light f idelity (Li-Fi) considers technology in optical wireless communication (OWC) that utilize visible light for transmission in free space, visible light communication (VLC) technology was chosen to overcome the interference issues of radio frequency (RF) communication and it also has higher bandwidth and is more secure. This paper aims to analyse the influence of atmospheric attenuation on the end-users of VLC system that consisted of five light-emitting diodes (LEDs) distributed in a room, which in t urn linked with the hybrid optical system includes a multi-channel of free space optic (FSO) connected with a fiber-optic channel (FOC). The hybrid system to the end-user was estimated in terms of bit error rate, quality factor, and signal power under dust-rain weather conditions. In the dust scenario, the suggested system achieved acceptable bit-error-rate (BER) to a distance of 1, 100 m. In rainy conditions, the performance accomplished acceptable BER to a distance of 3000 m. The VLC system's end-user also was evaluated under the effectiveness of the variation of irradiance and incident angles. Despite the harsh environmental conditions imposed on the communication network, VLC has proven its ability to maintain acceptable performance in end-user.
Digital platform based on geomarketing as an improvement in micro and small enterprises
Authors: Crisóstomo-Berrocal Teófilo , Sierra-Liñan Fernando , Carbonell-Michael Cabanillas
Published: June 2022

After the situation generated by the pandemic caused by COVID-19, micro and small enterprises (MSEs) faced a complex reality, having to cope with business uncertainty. This research proposes a digital platform based on geomarketing as a growth and support strategy for MSEs, with the objective of improving their labor and capital productivity, through the incorporation of the technological factor, which will have a great impact on them, helping them to continue operating and not having to close their businesses. The platform was developed under the agile Scrum methodology because it is adaptable to the constant changes in the mobile application development process, having as indicators labor productivity and capital productivity. Finally, the results revealed that labor productivity increased by 30.86 percent, meaning that, for every hour worked per person, more sales were made. As for capital productivity, it decreased by 1.47 percent, meaning that investment decreased for each value added of each product sold.
Configuration of an IoT microhydraulic power generation system for education
Authors: Pineda-Rico Zaira , Alcantar Pedro Cruz , Pineda-Rico Ulises , Martinez-Lopez Francisco Javier
Published: June 2022

Internet of things (IoT) involves the communication of all kinds of things embedded with sensors, electronics, software and people connected to the internet. Knowledge of IoT in the classroom provides an experience for engineering students to explore different career options. Under this scope, an IoT platform on the Arduino UNO and Raspberry Pi 3 development boards was built for academic purposes. The IoT platform was configured to monitor a microhydraulic power generation system used for the study of small-scale hydraulic power production, using a hydraulic head provided by a system of hydraulic pumps in series and/or parallel connection. The platform was designed considering a monitoring station for the acquisition of analog, digital, SPI and PWM data; a control station that receives data from the monitoring station and sends data to the cloud. The communication between modules was established using a publication/subscription system. The platform allows to registrate, visualize and process data directly in the cloud. Meaning that the IoT systems connected to this platform can be monitored from a cell phone, tablet or PC with internet access, promoting immediate access to the emerging information generated in the operating system.