bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating IL-1β, IL-17, and IP-10 as Potential Predictors of Hepatitis B Virus Infection Prognosis
Authors: Su Zhenzhen , Chen Jie , Zhang Junlong , An Yunfei , Liao Yun , Wu Xiaojuan , Tao Chuanmin , Wang Lanlan , Cai Bei 
Published: June 2022

Circulating cytokines and chemokines play critical roles in hepatitis B virus (HBV) infection. Here, we explored the effects of proinflammatory and anti-inflammatory effector molecules on HBV progression, e antigen seroconversion, and liver function. Our results showed that circulating interleukin (IL)-17 may be helpful in HBV spontaneous clearance [odds ratio

OR

=
1.468

,

95
%
confidence

interval

CI

=
1.080
–
1.995

,

P
=
0.014

] and protective against HBV-related hepatoma development (

OR
=
0.933

,

95
%
CI
=
0.910
–
0.957

,

P
<
0.001

). IL-1β negatively affected HBV clearance (

OR
=
0.052

,

95
%
CI
=
0.005
–
0.534

,

P
=
0.013

). In patients with chronic hepatitis B, interferon-γ-inducible protein-10 (IP-10) levels significantly increased in the group of abnormal liver function (

P
=
0.006

). Furthermore, positive correlations of IP-10 with alanine aminotransferase and aspartate aminotransferase levels were observed (

r

s

=
0.546

and

0.644

, respectively;

P
<
0.001

). In conclusion, inflammatory cytokines and chemokines may be a “double-edged sword” for HBV clearance and progression. Further exploration of the roles of IL-17, IL-1β, and IP-10 in chronic HBV infection is needed.
PRC2 Heterogeneity Drives Tumor Growth in Medulloblastoma
Authors: Yi Jiaqing , Kim BongWoo , Shi Xuanming , Zhan Xiaoming , Lu Q. Richard , Xuan Zhenyu , Wu Jiang 
Published: June 2022

Abstract

Intratumor epigenetic heterogeneity is emerging as a key mechanism underlying tumor evolution and drug resistance. Epigenetic abnormalities frequently occur in medulloblastoma, the most common childhood malignant brain tumor. Medulloblastoma is classified into four subtypes including SHH medulloblastoma, which is characterized by elevated sonic hedgehog (SHH) signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. Here, we report that the histone H3K27 methyltransferase polycomb repressor complex 2 (PRC2) is often heterogeneous within individual SHH medulloblastoma tumors. In mouse models, complete deletion of the PRC2 core subunit EED inhibited medulloblastoma growth, while a mosaic deletion of EED significantly enhanced tumor growth. EED is intrinsically required for CGNP maintenance by inhibiting both neural differentiation and cell death. Complete deletion of EED led to CGNP depletion and reduced occurrence of medulloblastoma. Surprisingly, medulloblastomas with mosaic EED levels grew faster than control wild-type tumors and expressed increased levels of oncogenes such as Igf2, which is directly repressed by PRC2 and has been demonstrated to be both necessary and sufficient for SHH medulloblastoma progression. Insulin-like growth factor 2 (IGF2) mediated the oncogenic effects of PRC2 heterogeneity in tumor growth. Assessing clones of a human medulloblastoma cell line with different EED levels confirmed that EEDlow cells can stimulate the growth of EEDhigh cells through paracrine IGF2 signaling. Thus, PRC2 heterogeneity plays an oncogenic role in medulloblastoma through both intrinsic growth competence and non–cell autonomous mechanisms in distinct tumor subclones.

Significance:
The identification of an oncogenic function of PRC2 heterogeneity in medulloblastoma provides insights into subclone competition and cooperation during heterogeneous tumor evolution.
Inactivating Amplified HER2: Challenges, Dilemmas, and Future Directions
Authors: Moasser Mark M. 
Published: June 2022

Abstract
The pharmaceutical inactivation of driver oncogenes has revolutionized the treatment of cancer, replacing cytotoxic chemotherapeutic approaches with kinase inhibitor therapies for many types of cancers. This approach has not yet been realized for the treatment of HER2-amplified cancers. The monotherapy activities associated with HER2-targeting antibodies and kinase inhibitors are modest, and their clinical use has been in combination with and not in replacement of cytotoxic chemotherapies. This stands in sharp contrast to achievements in the treatment of many other oncogene-driven cancers. The mechanism-based treatment hypothesis regarding the inactivation of HER2 justifies expectations far beyond what is currently realized. Overcoming this barrier requires mechanistic insights that can fuel new directions for pursuit, but scientific investigation of this treatment hypothesis, particularly with regards to trastuzumab, has been complicated by conflicting and confusing data sets, ironclad dogma, and mechanistic conclusions that have repeatedly failed to translate clinically. We are now approaching a point of convergence regarding the challenges and resiliency in this tumor driver, and I will provide here a review and opinion to inform where we currently stand with this treatment hypothesis and where the future potential lies.
Abstract B16: The immune profile of sentinel lymph nodes in melanoma
Authors: Beasley Georgia M. , Holl Eda K. , Farrow Norma E. , Leddy Margaret G. , Salama April K. , Hanks Brent A. , Nair Smita K. 
Published: June 2022

Abstract
Background: Immune cell composition and immune-mediated processes occurring in the sentinel lymph node (SLN) of melanoma patients regulate generation of tumor-specific effector T-cell responses and ultimately tumor control. We hypothesized that comprehensive analysis of these immune-associated processes in the SLN biopsy may identify patients at high risk of melanoma recurrence.
Methods: We analyzed 38 formalin-fixed, paraffin-embedded sentinel lymph nodes from melanoma patients undergoing SLN biopsy from 2009-2012 using the NanoString nCounter® PanCancer Immune Profiling panel. The panel included 770 immune related genes.
Results: Of 38 patients, 19 were SLN negative and 19 were SLN positive. Among SLN-negative patients (n=19), the median Breslow depth was 1.25 mm, and 21% (n=4) had developed recurrence at median follow-up of 6.2 years. Among SLN-positive patients, the median Breslow depth was 3.35 mm and 37% (n=7) had developed recurrence at median follow-up of 6.5 years. There were 31 genes significantly differentially expressed (P&lt;0.01) in SLN positive compared to SLN negative, including higher relative expression of B-cell signaling markers (CD19, CD22, Pax5, CXCR5, CD79B). Among all 38 patients, there were 13 genes differentially expressed (P&lt;0.05) between patients with and without recurrence, including higher relative expression of IL6 in patients with recurrence compared to no recurrence. Further analysis is ongoing.
Conclusion: In this retrospective series, we found the immunologic gene expression profile of melanoma SLNs was significantly different in SLN negative versus SLN positive. There were also significant differences in the profile between patients who developed melanoma recurrence versus no recurrence regardless of SLN status. We aim to build on these pilot data. The goal is to use this profile to predict patients at high risk of recurrence after SLNB who may benefit from adjuvant therapy.
Citation Format: Georgia M. Beasley, Eda K. Holl, Norma E. Farrow, Margaret G. Leddy, April K. Salama, Brent A. Hanks, Smita K. Nair. The immune profile of sentinel lymph nodes 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 B16.
Abstract IA07: Impact of tumor-resident dendritic cells on antitumor immune responses
Authors: Spranger Stefani 
Published: June 2022

Abstract
The responsiveness of tumor towards checkpoint blockade therapy but also other immunotherapies is highly associated with the presence of CD8+ infiltrating T cells. Further, an increasing amount of recent studies revealed a critical role for cross-presenting CD103+ dendritic cells (DC1) in both the induction and maintenance of CD8+ T-cell immunity in the tumor. We have shown that exclusion of DC1 from the tumor microenvironment (TME) can result in both blunted T-cell priming and impaired recruitment of effector T cells into the TME. Thus, exclusion of DC1 represents a mechanism of immune evasion by the tumor and resistance towards immunotherapy. Therefore, elucidating the contributions of different DC subsets to the local tumor microenvironment will be instrumental for the improvement of current immunotherapies. In more recent data we compare models of strong and poor antitumor immune responses with a specific focus on tumor-resident dendritic cells. These experiments reveal the absence of several immune-potentiating dendritic cell subsets in tumors with impaired antitumor immunity.
Citation Format: Stefani Spranger. Impact of tumor-resident dendritic cells on antitumor immune responses [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 IA07.
Abstract IA21: Translating immunotherapy from melanoma to other skin cancers
Authors: Topalian Suzanne L. 
Published: June 2022

Abstract
The PD-1 pathway, including the immune cell receptor Programmed Cell Death 1 (PD-1) and its ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), mediates immunosuppression within the tumor microenvironment. Drugs designed to “release the brakes” on antitumor immunity by blocking PD-1 have demonstrated substantial and durable activity in patients with advanced unresectable melanoma, as well as those with resected melanomas having a high risk for postsurgical relapse. These findings supported FDA approvals for anti-PD-1 drugs in the adjuvant and advanced melanoma settings. Research in melanoma subtypes and other kinds of cancers has identified two tumor markers associated with the likelihood of anti-PD-1 response: PD-L1 protein expression and tumor mutational burden (TMB), reflecting neoantigen load. Cutaneous melanomas are often caused by UV irradiation, harbor high TMBs, and frequently express PD-L1. Other types of skin cancers caused by UV irradiation, such as squamous cell and basal cell carcinomas, harbor high TMBs, express PD-L1, and have shown sensitivity to anti-PD-1. Merkel cell carcinoma has a unique biology, since only ~20% of cases are caused by UV light (high TMB), while the remaining 80% are associated with the oncogenic Merkel cell polyomavirus (very low TMB). Interestingly, both varieties are highly responsive to PD-1 pathway blockade, indicating that a limited number of strong tumor antigens (viral antigens) can compensate for low TMB to elicit antitumor immunity and tumor rejection. Anti-PD-1 has shown promising activity in neoadjuvant (presurgical) trials in melanoma and Merkel cell carcinoma. Neoadjuvant trials afford the opportunity for in-depth tissue analysis, and a variety of tumor markers are under investigation for correlation with treatment outcomes. The continued interrogation of tumor markers potentially predictive of clinical outcomes is expected to further refine the risk:benefit profile for PD-1/PD-L1 antagonists in melanoma and other skin cancers. Future clinical investigations will focus on difficult-to-treat populations such as immunosuppressed patients, including solid organ transplant recipients and those with HIV infection, who are at increased risk to develop aggressive skin cancers. Supported by National Institutes of Health R01 CA142779, Bristol-Myers Squibb, Melanoma Research Alliance, Barney Foundation, Laverna Hahn Charitable Trust, and Moving for Melanoma of Delaware.
Citation Format: Suzanne L. Topalian. Translating immunotherapy from melanoma to other skin cancers [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 IA21.
Abstract IA25: Targeting MEK1/2 inhibitor resistance in RAS-mutated cancers
Authors: Kinsey Conan , Camolotto Soledad , Boespflug Amelie , Gullien Katrin , Truong Amanda , Foth Mona , Shea Jill , Seipp Michael , Yap Jeffrey , Burrell Lance , Lum David , Whisenant Jonathan , Cavalier Courtney , Rehbein Kaitren , Cutler Stephanie , Afotler Kajsa , Welm Alana , Welm Bryan , Scaife Courtney , Snyder Eric , McMahon Martin 
Published: June 2022

Abstract
Although the RAF&gt;MEK&gt;ERK MAP kinase pathway is key to the development of many RAS-mutated cancers, efforts to target this pathway with pharmacologic inhibitors have failed to deliver clinical benefit to patients. Here we show that inhibition of RAS&gt;RAF&gt;MEK&gt;ERK signaling in RAS-mutated cancer cell lines elicits autophagy, a process of cellular recycling that protects cancer cells from the potentially cytotoxic effects of RAF&gt;MEK&gt;ERK pathway inhibition. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic antiproliferative effects against cell lines in vitro and promotes regression of xenografted patient-derived tumors in mice. Finally, treatment of a cancer patient with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking, disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven malignancies such as melanoma, lung, and pancreatic cancer.
Citation Format: Conan Kinsey, Soledad Camolotto, Amelie Boespflug, Katrin Gullien, Amanda Truong, Mona Foth, Jill Shea, Michael Seipp, Jeffrey Yap, Lance Burrell, David Lum, Jonathan Whisenant, Courtney Cavalier, Kaitren Rehbein, Stephanie Cutler, Kajsa Afotler, Alana Welm, Bryan Welm, Courtney Scaife, Eric Snyder, Martin McMahon. Targeting MEK1/2 inhibitor resistance in RAS-mutated cancers [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 IA25.
Abstract PR05: Unique lipid metabolite profiling in BRAFV600E inhibitor drug-resistant melanoma and their potential as drug target
Authors: Chang Meng-Ting , Feng Jia-Hua , Nakagawa-Goto Kyoko , Lee Kuo-Hsiung , Shyur Lie-Fen 
Published: June 2022

Abstract
Melanoma is the most life-threatening skin cancer in the world. Advanced melanoma is highly metastatic, commonly develops drug resistance, and causes low survival rate in patients. PLX4032 (vemurafenib), a BRAFV600E inhibitor, is used to treat patients with late-stage melanoma. It showed initial good clinical responses but relapsed due to acquired drug resistance in tumors. The mechanism of PLX4032-induced resistance in melanoma is not well characterized; in particular, whether PLX4032-induced drug resistance in BRAF mutant melanoma would alter lipid metabolism in cancer is not clear. Understanding the status and role of lipid mediators (oxylipins) in melanoma pathology may be crucial for developing effective approach to overcome drug resistance. Our laboratory has demonstrated that plant sesquiterpene lactone deoxyelephantopin (DET) and its novel derivative DETD-35 effectively suppressed human A375 BRAFV600E melanoma with acquired drug resistance to PLX4032 in vitro and in xenograft mice. In this study we aimed to identify potential biomarkers associated with the resistant melanoma cells (A375-R) in the context of bioactive lipid mediators and to investigate whether DETD-35/DET effects against drug-resistant melanoma are through regulating their dynamics and contents. MS-based metabolomics was used to comprehensively analyze the oxylipin profiles in A375 and A375-R cells, mouse A375/A375-R tumor tissues, and respective sera with vehicle, drug, or compound treatment. We observed that PLX4032-resistant A375R melanoma cells or tumors produce significant and higher amounts of CYP450 enzyme-derived oxylipins than the parental A375, which were decreased after DETD-35 or DET treatment. This study proposes a role of CYP450-derived oxylipins in PLX4032-resistant melanoma cells and its potential to be a drug target.
This abstract is also being presented as Poster B03.
Citation Format: Meng-Ting Chang, Jia-Hua Feng, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee, Lie-Fen Shyur. Unique lipid metabolite profiling in BRAFV600E inhibitor drug-resistant melanoma and their potential as drug target [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 PR05.
Abstract PR08: Identifying the molecular and environmental factors mediating transformation of melanocyte stem cells to melanoma
Authors: Moon Hyeongsun , Donahue Leanne R. , Zhu Jerry , White Andrew C. 
Published: June 2022

Abstract
Cutaneous melanoma is the most lethal form of skin cancer. However, the molecular mechanisms and environmental factors that can promote melanoma initiation and development from skin without an identified precursor lesion are not well defined. In these studies, we found that proinflammatory stress induced by environmental factors such as ultraviolet radiation can generate a sufficient stimulus to induce melanoma initiation from melanocyte stem cells (McSCs) containing Braf and Pten mutations. Moreover, our data demonstrate a role for the nonhistone architectural chromatin factor Hmga2 as an important molecular mediator in the induction of inflammation in murine skin following UVB (ultraviolet B) exposure. Our findings show a reduced recruitment in immune cell populations to the skin after UVB irradiation. Taken together, these data demonstrate that McSCs are sufficient to act as melanoma cells of origin and that UVB-induced inflammation acts to accelerate tumor initiation. Understanding the underlying factors that can cause melanoma initiation can provide valuable insight for melanoma prevention and control.
This abstract is also being presented as Poster A03.
Citation Format: Hyeongsun Moon, Leanne R. Donahue, Jerry Zhu, Andrew C. White. Identifying the molecular and environmental factors mediating transformation of melanocyte stem cells to 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 PR08.
Abstract PR13: PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas
Authors: Hill Kristen S. , Roberts Evan R. , Wang Xue , Koomen John M. , Messina Jane L. , Teer Jamie K. , Kim Youngchul , Wu Jie , Chalfant Charles E. , Kim Minjung 
Published: June 2022

Abstract
Melanoma is one of the most highly mutated cancer types, harboring numerous alterations with unknown significance. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in Kras, Erbb3, and Ptpn11. PTPN11 encodes the SHP2 protein tyrosine phosphatase (PTP) that activates the RAS/RAF/MAPK pathway. Although PTPN11 is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in BRAF wild-type (either NRAS mutant or wild-type) melanoma cells. PTPN11 played oncogenic roles in melanoma by driving anchorage-independent colony formation and tumor growth. In Pten and Cdkn2a null mice, tet-inducible and melanocyte-specific PTPN11E76K expression significantly enhanced melanoma tumorigenesis. Melanoma cells derived from this mouse model showed doxycycline-dependent tumor growth in nude mice. Silencing PTPN11E76K expression by doxycycline withdrawal caused regression of established tumors by induction of apoptosis and senescence and suppression of proliferation. Moreover, the PTPN11 inhibitor (SHP099) also caused regression of NRASQ61K-mutant melanoma. Using a quantitative tyrosine phospho-proteomics approach, we identified GSK3α/β as one of the key substrates that were differentially tyrosine-phosphorylated in these experiments modulating PTPN11. This study demonstrates that PTPN11 plays oncogenic roles in melanoma and regulates RAS and GSK3α/β signaling pathways. This study also identifies PTPN11 as a novel and actionable therapeutic target for BRAF wild-type melanoma.
This abstract is also being presented as Poster A14.
Citation Format: Kristen S. Hill, Evan R. Roberts, Xue Wang, John M. Koomen, Jane L. Messina, Jamie K. Teer, Youngchul Kim, Jie Wu, Charles E. Chalfant, Minjung Kim. PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas [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 PR13.
Abstract PR18: Comparative screening of skin-derived NCSCs, melanocytes, and melanoma developmental programs reveals LPAR1 in MAPKi resistance
Authors: Rebecca Vito W. , Liu Jianglan , Connelly Thomas , Flaherty Keith , Ronai Ze’ev , Herlyn Meenhard 
Published: June 2022

Abstract
Despite the high efficacy of BRAFi/MEKi in BRAF-MT melanomas, resistance arises in the majority of cases. Melanoma hijacks developmental pathways that drive aggressiveness; however, gene signatures shared by melanocyte progenitor cells and melanoma cells remain poorly understood. Here, we define common dependencies in neural crest stem cells (NCSCs) and melanoma cells not present in melanocytes through computational transcriptome analyses and targeted siRNA screens against shared developmental genes. Secondary validation coupled with Ingenuity Pathway Analysis identified the LPAR1-RAPGEF5-RAP1A axis as the top pathway critical for stem cell maintenance and melanoma aggressiveness. Genome-wide gene expression data in the CCLE demonstrates LPAR1 correlates with the MITFlo/AXLhi intrinsic MAPKi resistance signature. In agreement, LPAR1 is elevated in MAPKi-resistant PDX models, and in a subset of post-treatment tumor biopsies from patients who relapsed on MAPKi, relative to respective paired pretreatment biopsies. Melanocytes and fibroblasts express low levels of LPAR1 and are not sensitive to LPAR1i. In contrast, genetic silencing of LPAR1 and pharmacologic inhibition of LPAR1 with HA130, an upstream LPAR1 inhibitor, triggers cell cycle arrest and antitumor activity in MAPKi-resistant cells in vivo. Mechanistically, genetic and pharmacologic targeting of LPAR1 downregulates genes involved in the PI3K/mTOR and Hippo/YAP. Concurrent depletion of YAP and S6K cells significantly impairs melanoma viability relative to knockdown of YAP or S6K alone, suggesting that Hippo/YAP and mTOR/S6K pathways are main downstream effectors of LPAR1 signaling in melanoma. Our data identify novel pathways responsible for the escape of BRAF mutant melanoma from MAPKi therapy, and our hypothesis is that concurrent BRAFi/MEKi/LPAR1i may have therapeutic efficacy.
This abstract is also being presented as Poster B02.
Citation Format: Vito W. Rebecca, Jianglan Liu, Thomas Connelly, Keith Flaherty, Ze’ev Ronai, Meenhard Herlyn. Comparative screening of skin-derived NCSCs, melanocytes, and melanoma developmental programs reveals LPAR1 in MAPKi resistance [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 PR18.