bluuebunny/crossref_metadata_2025 huggingface dataset:
A Design of the Ecotourism Individualized Route Planning System Based on the Ecological Footprint Model
Authors: Lv Hengxiu
Published: June 2022

In this study, aiming at the huge amount of information in the tourism field, the pressure of ecological environment, and tedious personalized route planning, an ecotourism personalized route planning system based on the ecological footprint model is designed. In order to recommend routes that meet the time limit and the starting and ending points of the user’s choice, the tourist route recommendation problem is studied as a directional problem on the basis of comprehensively considering the popularity of scenic spots and the user’s interest preferences as the scenic spots score. The scenic spot scoring strategy is scenic spot scoring, and the iterative local search strategy is used to plan tourist routes according to the optimization goal with the largest route score, and improve the real tourist routes, food, and accommodation strategies. On the basis of launched tourist routes, they recommend tourists’ favorite food and accommodation. The model finally completes the fine arrangement of scenic spots, food, and accommodation in the whole tourist route. The system test results show that the system has obvious advantages in personalized path planning effect, excellent user feedback effect, and certain application value.
Antibacterial Efficacy of Phytosynthesized Multi‐Metal Oxide Nanoparticles against Drug‐Resistant Foodborne Pathogens
Authors: Selvakumar Vijayalakshmi , Muthusamy Karnan , Mukherjee Amitava , S. Shahana Farheen , Chelliah Ramachandran , Barathikannan Kaliyan , Oh Deog-Hwan , Ayyamperumal Ramamoorthy , Karuppannan Shankar
Published: June 2022

Human health is threatened worldwide by microbial infections. Antibiotic overuse and misuse have resulted in antimicrobial‐resistant bacteria. To battle such resistant microbes, we are looking for safe and alternative antimicrobial treatments, and the advent of nanotechnology holds promise in this regard. Metal oxide nanoparticles have emerged as a promising alternative source for combating bacteria resistant to various antibiotics over the last two decades. Due to their diverse physicochemical characteristics, metal oxide nanoparticles can operate as antibacterial agents through various methods. In the present research, six types of metal oxide NPs were synthesized and characterized (XRD, FTIR, SEM with EDAX, and TEM) from different plants such as Hydrangea paniculata (for NiO NP synthesis), Plectranthus amboinicus (for ZnO‐NP synthesis), and Andrographis paniculata (V2O5 NPs). On the other hand, drug‐resistant pathogens were isolated from clinical samples, those who suffered from foodborne illness. V2O5 NPs produced from Andrographis paniculata plant extract have much higher bactericidal efficacy than other metal oxide NPs against all three bacterial strains. Sensitive bacteria included S. aureus and E. coli, followed by K. pneumoniae. As a result, structural characterization was used to further screen V2O5 NPs. The orthorhombic structure of the crystallites was confirmed by XRD, with an average crystallite size of 20 nm. The absorbance spectrum and functional groups were identified using UV‐visible spectral analysis and FTIR. SEM and EDX identified spherical‐shaped NPs, and particle size (58 nm) was confirmed by transmission electron microscopy (TEM). As a result, we hypothesized that bioinspired V2O5‐NPs could be employed as a possible antibacterial agent against drug‐resistant pathogenic bacteria to replace currently existing inefficient antibacterial drugs.
Assessing the Prognostic Value of the Neutrophil-to-Lymphocyte Ratio in Stage I Non-Small-Cell Lung Cancer with Complete Resection
Authors: Liu Wei , Zhang Tiantian , Li Li , Zou Jue , Xu Chunhua
Published: June 2022

Purpose. To explore the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in stage I non-small-cell lung cancer (NSCLC) undergoing surgery. Patients and Methods. Between 2014 and 2016, a total of 190 patients with postoperative pathology of stage I NSCLC who underwent radical surgery at Nanjing Chest Hospital were studied. Clinical data were analyzed and classified into low-risk, moderate-risk, and high-risk groups based on independent risk factors to assess the prognosis. Results. NLR was associated with histological type and gender, and patients with an elevated NLR have poor overall survival (OS). Lymphovascular invasion, red blood cell distribution width-standard deviation (RDW-SD), and carcinoembryonic antigen (CEA) were independent prognostic factors for progression-free survival (PFS) in postoperative patients with stage I NSCLC, while NLR, RDW-SD, and CEA were independent risk factors for OS. Both PFS and OS were shorter in the low-risk group than in the medium-risk and high-risk groups. Conclusions. NLR, RDW-SD, CEA, and lymphovascular invasion are independent risk factors for postoperative prognosis in patients with stage I NSCLC, and the combination has a predictive value.
Characterization of Clinical Salmonella entericas Trains in Huzhou, China
Authors: Xu Deshun , Ji Lei , Yan Wei , Chen Liping
Published: June 2022

Background. Salmonella enterica subspecies enterica causes salmonellosis in humans and animals and is an important antecedent of food infections worldwide. This study collected 105 clinical S. enterica isolates from diarrhoea samples from six sentinel hospitals for active surveillance of foodborne diseases in Huzhou, China, between 2018 and 2020. These represented all the Salmonella isolates collected in Huzhou during that period. Methods. The isolates were characterized by serovar determination, antimicrobial susceptibility tests, and pulse-field gel electrophoresis (PFGE) typing. Results. The 105 Salmonella strains were mainly S. typhimurium (35.24%, 95% CI from 25.95 to 44.53%) and S. enteritidis (18.10%, 95% CI from 10.61 to 25.58%). Testing indicated that the resistance rate of the Salmonella strains ranged from 0.00% to 70.48%, and the highest resistance rate was for ampicillin (70.48%; 74/105), followed by tetracycline (67.62%; 71/105) and doxycycline (65.71%; 69/105). Following XbaI digestion, the 105 strains yielded 93 PFGE patterns, and 15 clones had similarity values >85.00%. Conclusions. Our analyses revealed the serovar distribution of isolates recovered from diarrhoea patients and the characteristics of resistant strains in Huzhou from 2018 to 2020. Our results highlight a serovar shift and a concerning number of multidrug-resistant (MDR) strains. Continued surveillance of Salmonella and their MDR profiles and efforts to control the rapid increase in antimicrobial resistance among Salmonella in Huzhou are needed.
Recent Advances of Phytobiotic Utilization in Carp Farming: A Review
Authors: Kari Zulhisyam Abdul , Wee Wendy , Hamid Noor Khalidah Abdul , Mat Khairiyah , Rusli Nor Dini , Khalid Hazreen Nita Mohd , Sukri Suniza Anis Mohamad , Harun Hasnita Che , Dawood Mahmoud A. O. , Hakim Ali Hanafiah , Khoo Martina Irwan , Abd El-Razek Ibrahim M. , Goh Khang Wen , Wei Lee Seong
Published: June 2022

Carp farming is a popular aquaculture activity that provides affordable protein sources and job opportunities to many people worldwide. As carp farming intensifies, farmers face major issues such as rising feed costs and excessive antibiotic usage. Thus, there is an urgent need to explore alternative resources to ensure the sustainability of the carp farming industry. One of the most promising resources is phytobiotics that possess various properties beneficial for carp production. Furthermore, most phytobiotics are derived from agricultural waste that is abundant and cheap, but some phytobiotics are produced commercially and available in the market. The main topics of this review are highlighted sources, characteristics of phytobiotics, and the usefulness of phytobiotics in improving growth performance, feed utilization efficiency, antioxidant activity, and health of carps against diseases. Furthermore, in this review, recent methods of administration of phytobiotics such as through feeding, bathing, and intraperitoneal injection in carp farming are also discussed and summarised.
Heart Team Intervention for Calcified Left Main Coronary Disease and Jeopardized Left Internal Mammary Artery Graft
Authors: Tomura Nobunari , Fujino Masashi , Kataoka Yu , Yoneda Shuichi , Sasaki Hiroaki , Noguchi Teruo
Published: June 2022

It is sometimes difficult to identify the culprit lesion and treatment strategy in patients with acute coronary syndrome who have complex coronary lesions and jeopardized left internal mammary artery graft. This report describes a heart team approach for a non-ST-segment elevation myocardial infarction case with complex coronary vasculature. A 73-year-old man presented to the emergency department with crescendo angina. He had a history of total aortic arch replacement with concomitant coronary artery bypass graft using left internal mammary artery. Emergent coronary angiography demonstrated severe stenosis at left main trunk bifurcation caused by calcified nodule. While the bypass graft to left anterior descending coronary artery was patent, the proximal segment of left subclavian artery was occluded. Following the prompt discussion with our heart team, we performed percutaneous coronary intervention in the first step for treating the left main stenosis using rotational atherectomy into the unprotected left circumflex artery. After clinical recovery, stress myocardial scintigraphy identified the presence of anteroseptal ischemia, which indicated coronary subclavian steal syndrome due to left subclavian artery occlusion. Contrast-enhanced CT visualized that the occlusion originated from the anastomosis, suggesting the potential procedural risk of endovascular treatment by dilatation. Our heart team discussed again and decided to undergo axillo-axillary artery bypass surgery. He was discharged 8 days after the surgery without any sequelae. This is the rare case report of non-ST-segment elevation myocardial infarction who had similar condition to coronary subclavian steal syndrome after total aortic arch replacement. This case highlights the importance of a collaborative approach of the heart team to identify the best therapeutic strategy in a patient with complex coronary vasculature.
A New Contemporary Profession as Game Boosters: The Behavioural Emergence of Intellectual Opportunism
Authors: Sumiyana Sumiyana , Hadi Caraka , Saputra Muhammad Adlin
Published: June 2022

This study investigates the emergence of intellectual opportunism for game boosters in mobile social networks. It shows the supply and demand for upgrading game levels in mobile social networks. These supply and lucrative demand highlight a new temporary profession as game boosters. Game boosters facilitate framed newbie gamers who want to play at a higher game level without playing for a long time. This emergence of professionally game boosters is due to economic opportunism, promising their potential future incomes. Moreover, opportunistic mobile social networks (OMSNs) support the muscular appearance of the game booster profession. On the other hand, this study demonstrates that mobile social networks exploit hedonistic human needs by reflecting their behaviour and social relationships when building efficient and trustworthy business contracts. This study presents uniqueness supported by critical reasoning. First, it shows that the game booster phenomenon has emerged as a contemporary profession in society, promising future cash inflows above the average salaries of typical jobs. Second, this research demonstrates the sequential logic of economic opportunities, intellectual opportunism, and mobile social networks, constructing game boosters’ income generating. Nevertheless, this study acknowledges that the game booster profession has low integrity due to its members’ inconsistent and unprincipled virtues.
Value of Intensive Nursing Detail Management in Intensive Care Unit Nursing
Authors: Li Yansong , Zhou Lehong , Wei Qin
Published: June 2022

Objective. To evaluate the value of intensive nursing detail management in intensive care unit (ICU) nursing. Methods. In this prospective study, 100 ICU patients in Shiyan Maternal and Child Health Hospital between January 2019 and March 2020 were assessed for eligibility and recruited. They were concurrently randomly assigned (1 : 1) to receive either conventional nursing (control group) or intensive nursing detail management (study group). The clinical endpoint was the nursing efficiency. Results. Intensive nursing detail management was associated with significantly higher scores in basic nursing, quality of nursing, and quality of management versus conventional nursing (

P
<
0.05

). Intensive nursing detail management resulted in a significantly higher adequate nursing rate (96.00%) versus conventional nursing (74.00%) (

P
<
0.05

). The patients given intensive nursing detail management had a shorter hospital stay versus those receiving conventional nursing (

P
<
0.05

). Intensive nursing detail management was associated with a higher nursing satisfaction rate (74.00%) versus conventional nursing (70.00%) (

P
<
0.05

). Conclusion. Intensive nursing detail management is effective and safe in ICU nursing, so it is worthy of clinical application.
circRNA circ_0055724 Inhibits Trophoblastic Cell Line HTR-8/SVneo’s Invasive and Migratory Abilities via the miR-136/N-Cadherin Axis
Authors: Xu Xiaohong , Teng Hong
Published: June 2022

Preeclampsia (PE) is one of the major causes of morbidity and mortality in pregnancy. According to recent research, circular RNAs (circRNA) may act as sponges for microRNAs (miRNAs) and modulate gene expression. Low expression of hsa_circ_0055724 (circ_0055724) in PE tissues was recently reported in literatures. However, its mechanism and function have not been reported. Therefore, we were committed to investigating the role and mechanism of circ_0055724 in PE. Our study first verified the low expression of circ_0055724 in PE tissues. Overexpression or knockdown of circ_0055724 enhances/weakens the trophoblast cell survival, migration, and invasion. Furthermore, CircInteractome predicted the binding sites of circ_0055724 and miR-136, while Starbase predicted miR-136 targeted N-cadherin. Luciferase reporter gene assay confirmed that circ_0055724 directly interacts with miR-136 and miR-136 directly interacts with N-cadherin. More results indicated that high expression of miR-136 and low expression of N-cadherin appeared in PE. Increased expression of circ_0055724 resulted in decreased miR-136 but increased N-cadherin expression. Hence, circ_0055724 and N-cadherin were positively correlated, while circ_0055724 and miR-136 had a negative correlation. In terms of mechanism, circ_0055724 may induce the expression of N-cadherin and regulate the proliferation, migration, and invasion of trophoblast cells through decreasing miR-136, which can be a promising biomarker for early diagnosis and prognosis of patients with PE.
Investigation on the Properties of Multiwall Carbon Nanotube‐, Graphene‐, and Fullerene‐Reinforced Hot‐Extruded AA7075 Matrix Composites
Authors: Ramesh B. , Kumar D. , Chhabria Sarika , Basavarajappa Vijaykumar , Krishnakumari A. , Saravanan M. , Sannakki Basavaraja , Kumaravel D. , Hassen Abdulkadir Aman
Published: June 2022

The tremendous thermal and mechanical capabilities of carbon‐based nanomaterials have drawn from researchers across the world. Composites reinforced with graphene nanoplatelets (GNPs), multiwall carbon nanotubes (MWCNT), and fullerenes (C20) were utilized in this study to increase their strength. A hot extrusion approach and a solution‐based semipowder metallurgical technology were employed. Microscopically and mechanically, the samples were tested. Mechanical properties were assessed through the use of roughness and tensile tests. Even a small amount of nanocarbon (0.25 wt %) significantly improved the toughness and hardness qualities of AA7075. Composite reinforced with C20 was found to have higher hardness and yield strength than any other samples.
[Retracted] Analysis of China’s Population Flow between Urban and Rural Areas and the Reform of Public Health Old‐Age Insurance System under the Background of Sustainable Ecological Environment
Authors: Guo Hailiang , Luo Qiangqiang
Published: June 2022

The future impact of population development trend on social security is extremely huge and far‐reaching, to conform to the law of population mobility to adjust the relevant policies, this study is for the urban and rural flow of the Chinese population, and the public health endowment insurance system analyzes the implementation status of PHEI of China’s floating population and the existing problems of labor dispatch and employee endowment insurance system. Questionnaires were distributed to 3000 high‐quality migrant workers who participated in the training of high‐quality migrant workers in 6 cities in Central China where labor export is concentrated and 1000 fresh graduates from agricultural colleges and universities; through the bivariate t‐check model in SPSS software, this study analyzes the needs of landless farmers, agricultural scientific and technological talents, and employed people for the living environment. The results show that from the population outflow and population inflow process there has been certain influence on the sustainable ecological environment; this study puts forward the reform of public health endowment insurance system of floating population, the strategy means in accelerating the rural talent revitalization, for the sustainable development of rural areas that has a significant positive effect.
NTRU-Based Fully Homomorphic Signature
Authors: Li Ruonan , Wang Fuqun , Zhang Renjun , Chen Kefei
Published: June 2022

Although the fully homomorphic signature (FHS) has made great progress, the low efficiency of existing FHS schemes as one main drawback cannot reach the requirements in practical application. It is well known that Number-Theory-Research-Unit (NTRU)-based cryptography is not only considered to be resistant to the quantum computer but also has high efficiency compared with the standard lattice-based cryptographic systems. In this paper, our goal is to construct a simple and highly efficient FHS scheme. To this end, we first devise an NTRU-based homomorphic trapdoor function (HTDF), which is more effective than the one proposed by Gorbunov et al. (STOC 2015). We then convert it into an efficient NTRU-based FHS scheme. Additionally, the HTDF we constructed is not only collision-resistant but is also claw-free, resulting in our FHS scheme is being strongly unforgeable.
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

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

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

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<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<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

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

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

Although the RAF>MEK>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>RAF>MEK>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>MEK>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

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

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

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

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.
Adenosine-Deaminase-Acting-on-RNA-1 Facilitates T-cell Migration toward Human Melanoma Cells
Authors: Margolis Naama , Moalem Hanna , Meirson Tomer , Galore-Haskel Gilli , Markovits Ettai , Baruch Erez N. , Vizel Bella , Yeffet Avner , Kanterman-Rifman Julia , Debby Assaf , Besser Michal J. , Schachter Jacob , Markel Gal
Published: June 2022

The effect of tumor/T-cell interactions on subsequent immune infiltration is undefined. Here, we report that preexposure of melanoma cells to cognate T cells enhanced the chemotaxis of new T cells in vitro. The effect was HLA class I–restricted and IFNγ-dependent, as it was abolished by β2M-knockdown, MHC-blocking antibodies, JAK1 inhibitors, JAK1-silencing and IFNgR1-blocking antibodies. RNA sequencing (RNA-seq) of 73 melanoma metastases showed a significant correlation between the interferon-inducible p150 isoform of adenosine-deaminase-acting-on-RNA-1 (ADAR1) enzyme and immune infiltration. Consistent with this, cocultures of cognate melanoma/T-cell pairs led to IFNγ-dependent induction of ADAR1-p150 in the melanoma cells, as visualized in situ using dynamic cell blocks, in ovo using fertilized chick eggs, and in vitro with Western blots. ADAR1 staining and RNA-seq in patient-derived biopsies following immunotherapy showed a rise in ADAR1-p150 expression concurrently with CD8+ cell infiltration and clinical response. Silencing ADAR1-p150 abolished the IFNγ-driven enhanced T-cell migration, confirming its mechanistic role. Silencing and overexpression of the constitutive isoform of ADAR1, ADAR1-p110, decreased and increased T-cell migration, respectively. Chemokine arrays showed that ADAR1 controls the secretion of multiple chemokines from melanoma cells, probably through microRNA-mediated regulation. Chemokine receptor blockade eliminated the IFNγ-driven T-cell chemotaxis. We propose that the constitutive ADAR1 downregulation observed in melanoma contributes to immune exclusion, whereas antigen-specific T cells induce ADAR1-p150 by releasing IFNγ, which can drive T-cell infiltration.
Impact of Machine Learning-Associated Research Strategies on the Identification of Peptide-Receptor Interactions in the Post-Omics Era
Authors: Satake Honoo , Osugi Tomohiro , Shiraishi Akira
Published: June 2022

Backgrounds: Elucidation of peptide-receptor pairs is a prerequisite for many studies in the neuroendocrine, endocrine, and neuroscience fields. Recent omics analyses have provided vast amounts of peptide and G protein-coupled receptor (GPCR) sequence data. GPCRs for homologous peptides are easily characterized based on homology searching, and the relevant peptide-GPCR interactions are also detected by typical signaling assays. In contrast, conventional evaluation or prediction methods, including high-throughput reverse-pharmacological assays and tertiary structure-based computational analyses, are not useful for identifying interactions between novel and omics-derived peptides and GPCRs. Summary: Recently, an approach combining machine learning-based prediction of novel peptide-GPCR pairs and experimental validation of the predicted pairs have been shown to breakthrough this bottleneck. A machine learning method, logistic regression for human class A GPCRs and the multiple subsequent signaling assays led to the deorphanization of human class A orphan GPCRs, namely, the identification of 18 peptide-GPCR pairs. Furthermore, using another machine learning algorithm, the support vector machine (SVM), the peptide descriptor-incorporated SVM was originally developed and employed to predict GPCRs for novel peptides characterized from the closest relative of vertebrates, Ciona intestinalis Type A (Ciona robusta). Experimental validation of the predicted pairs eventually led to the identification of 11 novel peptide-GPCR pairs. Of particular interest is that these newly identified GPCRs displayed neither significant sequence similarity nor molecular phylogenetic relatedness to known GPCRs for peptides. Key Messages: These recent studies highlight the usefulness and versatility of machine learning for enabling the efficient, reliable, and systematic identification of novel peptide-GPCR interactions.
Global Prevalence of Myotonic Dystrophy: An Updated Systematic Review and Meta-Analysis
Authors: Liao Qiao , Zhang Yihao , He Jian , Huang Kun
Published: June 2022

Introduction: Myotonic dystrophy (DM), the most common muscular dystrophy in adults, is a group of autosomal inherited neuromuscular disorders characterized by progressive muscle weakness, myotonia, and cardiac conduction abnormalities. Due to the different gene mutations, DM has been subclassified into DM type 1 (DM1) and type 2 (DM2). However, the prevalence studies on DM and its subtypes are insufficient. Methods: The PubMed (1966–2022), MEDLINE (1950–2022), Web of Science (1864–2022), and Cochrane Library (2022) databases were searched for original research articles published in English. The quality of the included studies was assessed by a checklist adapted from Strengthening the Reporting of Observational studies in Epidemiology. To derive the pooled epidemiological prevalence estimates, a meta-analysis was performed using the random-effects model. Heterogeneity was assessed using the Cochrane Q statistic and the I2 statistic. Results: A total of 17 studies were included in the systematic review and meta-analysis. Of the 17 studies evaluated, 14 studies were considered medium quality, 2 studies were considered high quality, and 1 study was considered low quality. The global prevalence of DM varied widely from 0.37 to 36.29 cases per 100,000. The pooled estimate of the prevalence of DM was 9.99 cases (95% CI: 5.62–15.53) per 100,000. The pooled estimate of the prevalence of DM1 was 9.27 cases (95% CI: 4.73–15.21) per 100,000, ranging from 0.37 to 36.29 cases per 100,000. The pooled estimate of the prevalence of DM2 was 2.29 cases (95% CI: 0.17–6.53) per 100,000, ranging from 0.00 to 24.00 cases per 100,000. Conclusion: Our study provided accurate estimates of the prevalence of DM. The high heterogeneity and the lack of high-quality studies highlight the need to conduct higher quality studies on orphan diseases.