bluuebunny/crossref_metadata_2025 huggingface dataset:
MRGPRX2 signaling involves the Lysyl-tRNA synthetase and MITF pathway
Authors: Guo Yanru , Ollé Laia , Proaño-Pérez Elizabeth , Aparicio Cristina , Guerrero Mario , Muñoz-Cano Rosa , Martín Margarita
Published: May 2023

MRGPRX2, a G-protein-coupled-seven transmembrane domain receptor, is mainly expressed in mast cells and neurons and is involved in skin immunity and pain. It is implicated in the pathophysiology of non-IgE-mediated immediate hypersensitivity and has been related to adverse drug reactions. Moreover, a role has been proposed in asthma, atopic dermatitis, contact dermatitis, and chronic spontaneous urticaria. Although it has a prominent role in disease, its signaling transduction is poorly understood. This study shows that MRGPRX2 activation with substance P increased Lysyl t-RNA synthetase (LysRS) translocation to the nucleus. LysRS is a moonlighting protein with a dual role in protein translation and IgE signaling in mast cells. Upon allergen- IgE-FcεRI crosslinking, LysRS is translocated to the nucleus and activates microphthalmia-associated transcription factor (MITF) activity. In this study, we found that MRGPRX2 triggering led to MITF phosphorylation and increased MITF activity. Therefore, overexpression of LysRS increased MITF activity after MRGPRX2 activation. MITF silencing reduced MRGPRX2-dependent calcium influx and mast cell degranulation. Furthermore, a MITF pathway inhibitor, ML329, impaired MITF expression, calcium influx, and mast cell degranulation. Moreover, drugs such as atracurium, vancomycin, and morphine, reported to induce MRGPRX2-dependent degranulation, increased MITF activity. Altogether, our data show that MRGPRX2 signaling enhances MITF activity, and its abrogation by silencing or inhibition resulted in defective MRGPRX2 degranulation. We conclude that MRGPRX2 signaling involves the LysRS and MITF pathway. Thus, MITF and MITF-dependent targets may be considered therapeutic approaches to treat pathologies where MRGPRX2 is implicated.
Tertiary lymphoid structures predict the prognosis and immunotherapy response of cholangiocarcinoma
Authors: Shang Taiyu , Jiang Tianyi , Lu Tao , Wang Hui , Cui Xiaowen , Pan Yufei , Xu Mengyou , Pei Mengmiao , Ding Zhiwen , Feng Xiaofan , Lin Yunkai , Li Xin , Tan Yexiong , Feng Feiling , Dong Hui , Wang Hongyang , Dong Liwei
Published: May 2023

Introduction

Cholangiocarcinoma (CCA) is a malignant tumor of the biliary epithelium with a poor prognosis. The lack of biomarkers to predict therapeutic response and prognosis is one of the major challenges for CCA treatment. Tertiary lymphoid structures (TLS) provide a local and pivotal microenvironment for tumor immune responses. The prognostic value and clinical relevance of TLS in CCA remain unclear. We aimed to explore the characteristics and clinical significance of TLS in CCA.

Methods

We investigated the prognostic value and clinical relevance of TLS in CCA using a surgery cohort containing 471 CCA patients (cohort 1) and an immunotherapy cohort containing 100 CCA patients (cohort 2). Hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining were used to evaluate the maturity of TLS. Multiplex IHC (mIHC) was employed to characterize the composition of TLS.

Results

Different maturity of TLS were observed in CCA tissue sections. Strong staining of the four-gene signature including PAX5, TCL1A, TNFRSF13C, and CD79A were found in TLS regions. A high density of intra-tumoral TLS (T-score high) were significantly correlated with longer overall survival (OS) both in CCA cohort 1 (p = 0.002) and cohort 2 (p = 0.01), whereas a high density of peri-tumoral TLS (P-score high) were associated with shorter OS in these two cohorts (p = 0.003 and p = 0.03, respectively).

Conclusion

The established four-gene signature efficiently identified the TLS in CCA tissues. The abundance and spatial distribution of TLS were significantly correlated with the prognosis and immune checkpoint inhibitors (ICIs) immunotherapy response of CCA patients. The presence of intra-tumoral TLS are positive prognostic factors for CCA, which provide a theoretical basis for the future diagnosis and treatment of CCA.
Lactobacillus brevis alleviates the progress of hepatocellular carcinoma and type 2 diabetes in mice model via interplay of gut microflora, bile acid and NOTCH 1 signaling
Authors: Chen Shujia , Han Ping , Zhang Qian , Liu Peiyan , Liu Jie , Zhao Lili , Guo Lianyi , Li Jia
Published: May 2023

Type 2 diabetes (T2DM) clinically exhibits a higher incidence of hepatocellular carcinoma (HCC), contributing to a lousy prognosis in patients harboring both diseases. Microflora-based therapy draws attention with low side effects. Accumulating evidence shows that Lactobacillus brevis can improve blood glucose and body weight of the T2DM mice model and reduce several cancer incidences. However, the therapeutic effect of Lactobacillus brevis in affecting the prognosis of T2DM+HCC remains unknown. In this study, we aim to explore this question via an established T2DM+HCC mice model. We observed a significant alleviation after the probiotic intervention. Lactobacillus brevis improves blood glucose and insulin resistance and ameliorates Mechanically. Combined with a multi-omics approach including 16SrDNA, GC-MS, and RNA-seq, we identified distinct intestinal microflora composition and metabolites after Lactobacillus brevis intervention. Furthermore, we found that Lactobacillus brevis delayed disease progression by regulating MMP9 and NOTCH 1 signaling pathways, potentially through gut microflora and BA interaction. This study indicates that Lactobacillus brevis may improve the prognosis of T2DM + HCC, providing novel therapeutic opportunities via targeting intestinal flora for patients with T2DM+HCC.
New tools for immunologists: models of lymph node function from cells to tissues
Authors: Ozulumba Tochukwu , Montalbine Alyssa N. , Ortiz-Cárdenas Jennifer E. , Pompano Rebecca R.
Published: May 2023

The lymph node is a highly structured organ that mediates the body’s adaptive immune response to antigens and other foreign particles. Central to its function is the distinct spatial assortment of lymphocytes and stromal cells, as well as chemokines that drive the signaling cascades which underpin immune responses. Investigations of lymph node biology were historically explored in vivo in animal models, using technologies that were breakthroughs in their time such as immunofluorescence with monoclonal antibodies, genetic reporters, in vivo two-photon imaging, and, more recently spatial biology techniques. However, new approaches are needed to enable tests of cell behavior and spatiotemporal dynamics under well controlled experimental perturbation, particularly for human immunity. This review presents a suite of technologies, comprising in vitro, ex vivo and in silico models, developed to study the lymph node or its components. We discuss the use of these tools to model cell behaviors in increasing order of complexity, from cell motility, to cell-cell interactions, to organ-level functions such as vaccination. Next, we identify current challenges regarding cell sourcing and culture, real time measurements of lymph node behavior in vivo and tool development for analysis and control of engineered cultures. Finally, we propose new research directions and offer our perspective on the future of this rapidly growing field. We anticipate that this review will be especially beneficial to immunologists looking to expand their toolkit for probing lymph node structure and function.
Immunoglobulin E-virus phenotypes of infant bronchiolitis and risk of childhood asthma
Authors: Shibata Ryohei , Zhu Zhaozhong , Ooka Tadao , Freishtat Robert J. , Mansbach Jonathan M. , Pérez-Losada Marcos , Ramos-Tapia Ignacio , Teach Stephen , Camargo Carlos A. , Hasegawa Kohei
Published: May 2023

Background

Bronchiolitis is the leading cause of infant hospitalization in U.S. and is associated with increased risk for childhood asthma. Immunoglobulin E (IgE) not only plays major roles in antiviral immune responses and atopic predisposition, but also offers a potential therapeutic target.

Objective

We aimed to identify phenotypes of infant bronchiolitis by using total IgE (tIgE) and virus data, to determine their association with asthma development, and examine their biological characteristics.

Methods

In a multicenter prospective cohort study of 1,016 infants (age <1 year) hospitalized for bronchiolitis, we applied clustering approaches to identify phenotypes by integrating tIgE and virus (respiratory syncytial virus [RSV], rhinovirus [RV]) data at hospitalization. We examined their longitudinal association with the risk of developing asthma by age 6 years and investigated their biological characteristics by integrating the upper airway mRNA and microRNA data in a subset (n=182).

Results

In infants hospitalized for bronchiolitis, we identified 4 phenotypes: 1) tIgElowvirusRSV-high, 2) tIgElowvirusRSV-low/RV, 3) tIgEhighvirusRSV-high, and 4) tIgEhighvirusRSV-low/RV phenotypes. Compared to phenotype 1 infants (resembling “classic” bronchiolitis), phenotype 4 infants (tIgEhighvirusRSV-low/RV) had a significantly higher risk for developing asthma (19% vs. 43%; adjOR, 2.93; 95% CI, 1.02–8.43; P=.046). Phenotypes 3 and 4 (tIgEhigh) had depleted type I interferon and enriched antigen presentation pathways; phenotype 4 also had depleted airway epithelium structure pathways.

Conclusions

In this multicenter cohort, tIgE-virus clustering identified distinct phenotypes of infant bronchiolitis with differential risks of asthma development and unique biological characteristics.
Transcriptomics and physiological analyses unveil the distinct mechanisms of ATP and glucose-6-phosphate utilization in Phaeodactylum tricornutum
Authors: Zhang Xiaohua , Cheng Shuang , Gao Zhengquan , Cui Yulin , Yao Qingshou , Qin Jiayang , Liu Xiangyong , Lin Senjie
Published: May 2023

Phosphoesters are a dominant component of marine dissolved organic phosphorus (DOP) and an important source of the phosphorus nutrient for phytoplankton, but the molecular mechanisms of their utilization by phytoplankton are divergent and poorly understood. In this study, we used the model diatom Phaeodactylum tricornutum to investigate and compare the utilization mechanisms of two different phosphoesters, adenosine triphosphate (ATP) and glucose-6-phosphate (G6P). We found that ATP and G6P can both be efficiently used to support the growth of P. tricornutum. Cells grown on ATP or G6P showed lower pigment contents and photosynthetic rates but higher cellular lipids relative to those grown on NaH2PO4 (DIP). Surprisingly, in neither the ATP nor the G6P group were significant increases in whole-cell alkaline phosphatase (AP) activity detected, suggesting that utilization of both DOPs was not reliant on extracellular AP. Yet, ATP-grown cultures released DIP into the medium (i.e., ATP hydrolyzed extracellularly) whereas G6P-grown cultures did not. Furthermore, transcriptomic and RT-qPCR results showed that the gene encoding 5’ nucleotidase (5NT) in the ATP group and PhoD in the G6P group was upregulated. These results indicated that different pathways are involved in the use of these two DOPs, with ATP being hydrolyzed extracellularly likely by 5NT (PHATRDRAFT_44177) to release DIP for uptake, and G6P being directly absorbed and hydrolyzed intracellularly likely by PhoD (PHATRDRAFT_45757). Nevertheless, P. tricornutum under ATP and G6P conditions showed more similar transcriptomic profiles to each other than either compared to DIP-grown cultures, indicating similar metabolic functions of these two DOPs. These findings demonstrate that despite the high similarity in transcriptomic response to ATP and G6P conditions, the utilization mechanisms of these phosphoesters in the same species can be totally different, and the lack of AP activity does not necessarily signal the absence of DIP deficiency or the absence of DOP utilization.
Biocrust carbon exchange varies with crust type and time on Chihuahuan Desert gypsum soils
Authors: Hoellrich Mikaela R. , James Darren K. , Bustos David , Darrouzet-Nardi Anthony , Santiago Louis S. , Pietrasiak Nicole
Published: May 2023

Introduction

In dryland systems, biological soil crusts (biocrusts) can occupy large areas of plant interspaces, where they fix carbon following rain. Although distinct biocrust types contain different dominant photoautotrophs, few studies to date have documented carbon exchange over time from various biocrust types. This is especially true for gypsum soils. Our objective was to assess the carbon exchange of biocrust types established at the world’s largest gypsum dune field at White Sands National Park.

Methods

We sampled five different biocrust types from a sand sheet location in three different years and seasons (summer 2020, fall 2021, and winter 2022) for carbon exchange measurements in controlled lab conditions. Biocrusts were rehydrated to full saturation and light incubated for 30 min, 2, 6, 12, 24, and 36 h. Samples were then subject to a 12-point light regime with a LI-6400XT photosynthesis system to determine carbon exchange.

Results

Biocrust carbon exchange values differed by biocrust type, by incubation time since wetting, and by date of field sampling. Lichens and mosses had higher gross and net carbon fixation rates than dark and light cyanobacterial crusts. High respiration rates were found after 0.5 h and 2 h incubation times as communities recovered from desiccation, leveling off after 6 h incubation. Net carbon fixation of all types increased with longer incubation time, primarily as a result of decreasing respiration, which suggests rapid recovery of biocrust photosynthesis across types. However, net carbon fixation rates varied from year to year, likely as a product of time since the last rain event and environmental conditions preceding collection, with moss crusts being most sensitive to environmental stress at our study sites.

Discussion

Given the complexity of patterns discovered in our study, it is especially important to consider a multitude of factors when comparing biocrust carbon exchange rates across studies. Understanding the dynamics of biocrust carbon fixation in distinct crust types will enable greater precision of carbon cycling models and improved forecasting of impacts of global climate change on dryland carbon cycling and ecosystem functioning.
Predicting bacterial transport through saturated porous media using an automated machine learning model
Authors: Chen Fengxian , Zhou Bin , Yang Liqiong , Chen Xijuan , Zhuang Jie
Published: May 2023

Escherichia coli, as an indicator of fecal contamination, can move from manure-amended soil to groundwater under rainfall or irrigation events. Predicting its vertical transport in the subsurface is essential for the development of engineering solutions to reduce the risk of microbiological contamination. In this study, we collected 377 datasets from 61 published papers addressing E. coli transport through saturated porous media and trained six types of machine learning algorithms to predict bacterial transport. Eight variables, including bacterial concentration, porous medium type, median grain size, ionic strength, pore water velocity, column length, saturated hydraulic conductivity, and organic matter content were used as input variables while the first-order attachment coefficient and spatial removal rate were set as target variables. The eight input variables have low correlations with the target variables, namely, they cannot predict target variables independently. However, using the predictive models, input variables can effectively predict the target variables. For scenarios with higher bacterial retention, such as smaller median grain size, the predictive models showed better performance. Among six types of machine learning algorithms, Gradient Boosting Machine and Extreme Gradient Boosting outperformed other algorithms. In most predictive models, pore water velocity, ionic strength, median grain size, and column length showed higher importance than other input variables. This study provided a valuable tool to evaluate the transport risk of E.coli in the subsurface under saturated water flow conditions. It also proved the feasibility of data-driven methods that could be used for predicting other contaminants’ transport in the environment.
Pathogenicity and epidemiological survey of fowl adenovirus in Shandong Province from 2021 to 2022
Authors: Wang Tailong , Meng Fanliang , Chen Changxiu , Shen Yesheng , Li Peixun , Xu Jie , Feng Zhaoyang , Qu Xiuchao , Wang Fuyong , Li Baoquan , Liu Mengda
Published: May 2023

In recent years, the poultry industry had been markedly affected by adenoviral diseases such as hydropericardium syndrome and inclusion body hepatitis caused by fowl adenovirus (FAdV), which have become increasingly prevalent in China. Shandong Province, China, is an important area for poultry breeding where various complex and diverse FAdV serotypes were isolated. However, the dominant strains and their pathogenic characteristics are not yet reported. Therefore, a pathogenicity and epidemiological survey of FAdV was conducted, showing that the local dominant serotypes of FAdV epidemics were FAdV-2, FAdV-4, FAdV-8b, and FAdV-11. Their mortality rates in the 17-day-old specific-pathogen-free (SPF) chicks ranged from 10 to 80%; clinical signs included mental depression, diarrhea, and wasting. The maximum duration of viral shedding was 14 days. The highest incidence in all infected groups was on days 5–9, and then gradual regression occurred thereafter. The most pronounced symptoms occurred in chicks infected with FAdV-4, including pericardial effusion and inclusion body hepatitis lesions. Our results add to the current epidemiological data on FAdV in poultry flocks in Shandong and elucidate the pathogenicity of dominant serotypes. This information may be important for FAdV vaccine development and comprehensive epidemic prevention and control.
HCMV-IE2 promotes atherosclerosis by inhibiting vascular smooth muscle cells’ pyroptosis
Authors: Ma Guixin , Yu Zhongjie , Nan Fulong , Zhang Xianjuan , Jiang Shasha , Wang Yunyang , Wang Bin
Published: May 2023

Atherosclerosis is still the main cause of death in developed and developing countries. Vascular smooth muscle cells (VSMCs) death disorder is a key pathogens of atherosclerosis. During the early stage of human cytomegalovirus (HCMV) infection, immediate early protein 2 (IE2) is critical in regulating its host cell death to ensure HCMV replication. Abnormal cell death induced by HCMV infection contributes to the development of numerous diseases, including atherosclerosis. Hitherto, the underlying mechanism of HCMV involved in the progression of atherosclerosis is still unclear. In this study, the infection models in vitro and in vivo were constructed to explore the pathogenesis of HCMV-related atherosclerosis. Our results indicated that HCMV could contribute to the progression of atherosclerosis by enhancing the proliferation, invasion, and inhibiting the pyroptosis of VSMCs under inflammatory conditions. Meanwhile, IE2 played a key role in these events. Our present research revealed a novel pathogenesis of HCMV-related atherosclerosis, which might help develop new therapeutic strategies.
Discovery of plastic-degrading microbial strains isolated from the alpine and Arctic terrestrial plastisphere
Authors: Rüthi Joel , Cerri Mattia , Brunner Ivano , Stierli Beat , Sander Michael , Frey Beat
Published: May 2023

Increasing plastic production and the release of some plastic in to the environment highlight the need for circular plastic economy. Microorganisms have a great potential to enable a more sustainable plastic economy by biodegradation and enzymatic recycling of polymers. Temperature is a crucial parameter affecting biodegradation rates, but so far microbial plastic degradation has mostly been studied at temperatures above 20°C. Here, we isolated 34 cold-adapted microbial strains from the plastisphere using plastics buried in alpine and Arctic soils during laboratory incubations as well as plastics collected directly from Arctic terrestrial environments. We tested their ability to degrade, at 15°C, conventional polyethylene (PE) and the biodegradable plastics polyester-polyurethane (PUR; Impranil®); ecovio® and BI-OPL, two commercial plastic films made of polybutylene adipate-co-terephthalate (PBAT) and polylactic acid (PLA); pure PBAT; and pure PLA. Agar clearing tests indicated that 19 strains had the ability to degrade the dispersed PUR. Weight-loss analysis showed degradation of the polyester plastic films ecovio® and BI-OPL by 12 and 5 strains, respectively, whereas no strain was able to break down PE. NMR analysis revealed significant mass reduction of the PBAT and PLA components in the biodegradable plastic films by 8 and 7 strains, respectively. Co-hydrolysis experiments with a polymer-embedded fluorogenic probe revealed the potential of many strains to depolymerize PBAT. Neodevriesia and Lachnellula strains were able to degrade all the tested biodegradable plastic materials, making these strains especially promising for future applications. Further, the composition of the culturing medium strongly affected the microbial plastic degradation, with different strains having different optimal conditions. In our study we discovered many novel microbial taxa with the ability to break down biodegradable plastic films, dispersed PUR, and PBAT, providing a strong foundation to underline the role of biodegradable polymers in a circular plastic economy.
Geometric and network organization of visceral organ epithelium
Authors: Liu Betty S. , Sutlive Joseph , Wagner Willi L. , Khalil Hassan A. , Chen Zi , Ackermann Maximilian , Mentzer Steven J.
Published: May 2023

Mammalian epithelia form a continuous sheet of cells that line the surface of visceral organs. To analyze the epithelial organization of the heart, lung, liver and bowel, epithelial cells were labeled in situ, isolated as a single layer and imaged as large epithelial digitally combine montages. The stitched epithelial images were analyzed for geometric and network organization. Geometric analysis demonstrated a similar polygon distribution in all organs with the greatest variability in the heart epithelia. Notably, the normal liver and inflated lung demonstrated the largest average cell surface area (p < 0.01). In lung epithelia, characteristic wavy or interdigitated cell boundaries were observed. The prevalence of interdigitations increased with lung inflation. To complement the geometric analyses, the epithelia were converted into a network of cell-to-cell contacts. Using the open-source software EpiGraph, subgraph (graphlet) frequencies were used to characterize epithelial organization and compare to mathematical (Epi-Hexagon), random (Epi-Random) and natural (Epi-Voronoi5) patterns. As expected, the patterns of the lung epithelia were independent of lung volume. In contrast, liver epithelia demonstrated a pattern distinct from lung, heart and bowel epithelia (p < 0.05). We conclude that geometric and network analyses can be useful tools in characterizing fundamental differences in mammalian tissue topology and epithelial organization.
Variations on the theme: focus on cerebellum and emotional processing
Authors: Ciapponi Camilla , Li Yuhe , Osorio Becerra Dianela A. , Rodarie Dimitri , Casellato Claudia , Mapelli Lisa , D’Angelo Egidio
Published: May 2023

The cerebellum operates exploiting a complex modular organization and a unified computational algorithm adapted to different behavioral contexts. Recent observations suggest that the cerebellum is involved not just in motor but also in emotional and cognitive processing. It is therefore critical to identify the specific regional connectivity and microcircuit properties of the emotional cerebellum. Recent studies are highlighting the differential regional localization of genes, molecules, and synaptic mechanisms and microcircuit wiring. However, the impact of these regional differences is not fully understood and will require experimental investigation and computational modeling. This review focuses on the cellular and circuit underpinnings of the cerebellar role in emotion. And since emotion involves an integration of cognitive, somatomotor, and autonomic activity, we elaborate on the tradeoff between segregation and distribution of these three main functions in the cerebellum.
The unhealthy-tasty intuition in dining out situations: the role of health inferences and taste expectations
Authors: Garaus Marion , Wolfsteiner Elisabeth , Hu Jennifer
Published: May 2023

Introduction

Increasing obesity rates around the globe have challenged policymakers to find strategies to prompt healthier eating habits. While unhealthy eating takes place in many different contexts, dining out is a context where individuals often choose an unhealthy option despite the availability of healthier alternatives. One possible explanation for this behavior is the unhealthy-tasty intuition, which refers to the belief that unhealthy food is tastier than healthy food. Nevertheless, many policymakers and restaurant managers follow the – in this context – counterintuitive approach of using health claims to nudge people towards more healthy eating choices or habits.

Methods

The current research employs an online experiment with 137 participants and investigates how health claims and sensory claims impact on the purchase intention of healthy options for desserts. Furthermore, it explores how health inferences and taste expectations mediate the intention to purchase.

Results and discussion

Findings from the online experiment confirm that health claims prompt positive health inferences, while also stimulating unfavorable taste expectations, resulting in a lower intention to purchase. Surprisingly, we found no effect of a sensory claim on taste expectations. The findings of our experiment contradict the unhealthy-tasty intuition by revealing a significant positive correlation between taste expectations and health inferences. While both health inferences and taste expectations impact positively on purchasing intentions for the health-claim condition, the indirect effect of taste expectations was stronger than the indirect effect of health inferences.
Activity of TNT: a phase 2 study using talimogene laherparepvec, nivolumab and trabectedin for previously treated patients with advanced sarcomas (NCT# 03886311)
Authors: Chawla Sant P. , Tellez Walter Andree , Chomoyan Hripsime , Valencia Chrysler , Ahari Amir , Omelchenko Nadezhda , Makrievski Stefan , Brigham Don A. , Chua-Alcala Victoria , Quon Doris , Moradkhani Ania , Gordon Erlinda M.
Published: May 2023

Background

Intratumoral injection of talimogene laherparepvec evokes a cytotoxic immune response. Therefore, the combination of talimogene laherparepvec with trabectedin and nivolumab may have synergistic effects in advanced sarcomas.

Patients and methods

This phase 2 trial was conducted from May 30, 2019 to January 31, 2022. Endpoints: Primary: Progression free survival rate at month 12. Secondary: Best overall response, progression free survival rate at 6 and 9 months, overall survival rate at 6, 9, and 12 months, incidence of conversion of an unresectable tumor to a resectable tumor, and incidence of adverse events. Eligible patients had to be ≥ 18 years of age, have advanced histologically proven sarcoma, at least 1 previous chemotherapy regimen, and at least one accessible tumor for intratumoral injection. Treatment: Trabectedin intravenously (1.2 mg/m2 q3 weeks), nivolumab intravenously (3 mg/kg q2 weeks), and intratumoral talimogene laherparepvec (1x108 plaque forming units/ml q2 weeks).

Results

Median time of follow-up: 15.2 months. Efficacy analysis: Thirty-nine patients who had completed at least one treatment cycle and had a follow-up computerized tomography were evaluable for efficacy analysis. Median number of prior therapies: 4 (range 1-11). Progression free survival rate at month 12, 36.7%. Confirmed Best Overall Response by Response Evaluation Criteria in Solid Tumors v1.1 = 3 partial responses, 30 stable disease, 6 progressive disease. Best Overall Response Rate, 7.7%, Disease Control Rate, 84.6%; median progression free survival, 7.8 (95% Confidence Intervals: 4.1-13.1) months; 6-, 9-, 12-month progression free survival rates, 54.5%/45.9%/36.7%; median overall survival 19.3 (95% Confidence Intervals: 12.8 -.) months; 6-, 9- and 12-month overall survival rate, 86.9%/73.3%/73.3%. One patient had a complete surgical resection. Fifty percent of patients had a ≥ grade 3 treatment related adverse events which included anemia (6%), thrombocytopenia (6%), neutropenia (4%), increased alanine transaminase (4%), decreased left ventricular ejection fraction (4%), dehydration (4%), hyponatremia (4%).

Conclusions

Taken together these data suggest that the TNT regimen is effective and safe for advanced previously treated sarcomas, and is worth being further studied in a randomized phase 3 trial as first- or second- line treatment for patients with advanced sarcomas.
Gas6/AXL pathway: immunological landscape and therapeutic potential
Authors: Zhai Xiaoqian , Pu Dan , Wang Rulan , Zhang Jiabi , Lin Yiyun , Wang Yuqing , Zhai Ni , Peng Xuan , Zhou Qinghua , Li Lu
Published: May 2023

Cancer is a disease with ecological and evolutionary unity, which seriously affects the survival and quality of human beings. Currently, many reports have suggested Gas6 plays an important role in cancer. Binding of gas6 to TAM receptors is associated with the carcinogenetic mechanisms of multiple malignancies, such as in breast cancer, chronic lymphocytic leukemia, non-small cell lung cancer, melanoma, prostate cancer, etc., and shortened overall survival. It is accepted that the Gas6/TAM pathway can promote the malignant transformation of various types of cancer cells. Gas6 has the highest affinity for Axl, an important member of the TAM receptor family. Knockdown of the TAM receptors Axl significantly affects cell cycle progression in tumor cells. Interestingly, Gas6 also has an essential function in the tumor microenvironment. The Gas6/AXL pathway regulates angiogenesis, immune-related molecular markers and the secretion of certain cytokines in the tumor microenvironment, and also modulates the functions of a variety of immune cells. In addition, evidence suggests that the Gas6/AXL pathway is involved in tumor therapy resistance. Recently, multiple studies have begun to explore in depth the importance of the Gas6/AXL pathway as a potential tumor therapeutic target as well as its broad promise in immunotherapy; therefore, a timely review of the characteristics of the Gas6/AXL pathway and its value in tumor treatment strategies is warranted. This comprehensive review assessed the roles of Gas6 and AXL receptors and their associated pathways in carcinogenesis and cancer progression, summarized the impact of Gas6/AXL on the tumor microenvironment, and highlighted the recent research progress on the relationship between Gas6/AXL and cancer drug resistance.
The clinical relevance and prediction efficacy from therapy of tumor microenvironment related signature score in colorectal cancer
Authors: Jun Xiang , Gao Shengnan , Yu Lei , Wang Guiyu
Published: May 2023

Introduction

As the top 3 cancer in terms of incidence and mortality, the first-line treatment for CRC includes FOLFOX, FOLFIRI, Cetuximab or immunotherapy. However, the drug sensitivity of patients to regimens is different. There has been increasing evidence that immune components of TME can affect the sensitivity of patients to drugs. Therefore, it is necessary to define novo molecular subtypes of CRC based on TME immune components, and screen patients who are sensitive to the treatments, to make personalized therapy possible.

Methods

We analyzed the expression profiles and 197 TME-related signatures of 1775 patients using ssGSEA, univariate Cox proportional risk model and LASSO-Cox regression model, and defined a novo molecular subtype (TMERSS) of CRC. Simultaneously, we compared the clinicopathological factors, antitumor immune activity, immune cell abundance and differences of cell states in different TMERSS subtypes. In addition, patients sensitive to the therapy were screened out by correlation analysis between TMERSS subtypes and drug responses.

Results

Compared with low TMERSS subtype, high TMERSS subtype has a better outcome, which may be associated to higher abundance of antitumor immune cell in high TMERSS subtype. Our findings suggested that the high TMERSS subtype may have a higher proportion of respondents to Cetuximab agent and immunotherapy, while the low TMERSS subtype may be more suitable for treatment with FOLFOX and FOLFIRI regimens.

Discussion

In conclusion, the TMERSS model may provide a partial reference for the prognosis evaluation of patients, the prediction of drug sensitivity, and the implementation of clinical decision-making.
Intraoperative microscopic autofluorescence detection and characterization in brain tumors using stimulated Raman histology and two-photon fluorescence
Authors: Fürtjes Gina , Reinecke David , von Spreckelsen Niklas , Meißner Anna-Katharina , Rueß Daniel , Timmer Marco , Freudiger Christian , Ion-Margineanu Adrian , Khalid Florian , Watrinet Konstantin , Mawrin Christian , Chmyrov Andriy , Goldbrunner Roland , Bruns Oliver , Neuschmelting Volker
Published: May 2023

Introduction

The intrinsic autofluorescence of biological tissues interferes with the detection of fluorophores administered for fluorescence guidance, an emerging auxiliary technique in oncological surgery. Yet, autofluorescence of the human brain and its neoplasia is sparsely examined. This study aims to assess autofluorescence of the brain and its neoplasia on a microscopic level by stimulated Raman histology (SRH) combined with two-photon fluorescence.

Methods

With this experimentally established label-free microscopy technique unprocessed tissue can be imaged and analyzed within minutes and the process is easily incorporated in the surgical workflow. In a prospective observational study, we analyzed 397 SRH and corresponding autofluorescence images of 162 samples from 81 consecutive patients that underwent brain tumor surgery. Small tissue samples were squashed on a slide for imaging. SRH and fluorescence images were acquired with a dual wavelength laser (790 nm and 1020 nm) for excitation. In these images tumor and non-tumor regions were identified by a convolutional neural network that reliably differentiates between tumor, healthy brain tissue and low quality SRH images. The identified areas were used to define regions.of- interests (ROIs) and the mean fluorescence intensity was measured.

Results

In healthy brain tissue, we found an increased mean autofluorescence signal in the gray (11.86, SD 2.61, n=29) compared to the white matter (5.99, SD 5.14, n=11, p<0.01) and in the cerebrum (11.83, SD 3.29, n=33) versus the cerebellum (2.82, SD 0.93, n=7, p<0.001), respectively. The signal of carcinoma metastases, meningiomas, gliomas and pituitary adenomas was significantly lower (each p<0.05) compared to the autofluorescence in the cerebrum and dura, and significantly higher (each p<0.05) compared to the cerebellum. Melanoma metastases were found to have a higher fluorescent signal (p<0.01) compared to cerebrum and cerebellum.

Discussion

In conclusion we found that autofluorescence in the brain varies depending on the tissue type and localization and differs significantly among various brain tumors. This needs to be considered for interpreting photon signal during fluorescence-guided brain tumor surgery.
FOXD1 is associated with poor outcome and maintains tumor-promoting enhancer–gene programs in basal-like breast cancer
Authors: Kumegawa Kohei , Yang Liying , Miyata Kenichi , Maruyama Reo
Published: May 2023

Breast cancer biology varies markedly among patients. Basal-like breast cancer is one of the most challenging subtypes to treat because it lacks effective therapeutic targets. Despite numerous studies on potential targetable molecules in this subtype, few targets have shown promise. However, the present study revealed that FOXD1, a transcription factor that functions in both normal development and malignancy, is associated with poor prognosis in basal-like breast cancer. We analyzed publicly available RNA sequencing data and conducted FOXD1-knockdown experiments, finding that FOXD1 maintains gene expression programs that contribute to tumor progression. We first conducted survival analysis of patients grouped via a Gaussian mixture model based on gene expression in basal-like tumors, finding that FOXD1 is a prognostic factor specific to this subtype. Then, our RNA sequencing and chromatin immunoprecipitation sequencing experiments using the basal-like breast cancer cell lines BT549 and Hs578T with FOXD1 knockdown revealed that FOXD1 regulates enhancer–gene programs related to tumor progression. These findings suggest that FOXD1 plays an important role in basal-like breast cancer progression and may represent a promising therapeutic target.
Effects of isolated central nervous system involvement evaluated by multiparameter flow cytometry prior to allografting on outcomes of patients with acute lymphoblastic leukemia
Authors: Ma Ling , Xu Lan-Ping , Wang Yu , Zhang Xiao-Hui , Chen Huan , Chen Yu-Hong , Wang Feng-Rong , Han Wei , Sun Yu-Qian , Yan Chen-Hua , Lv Meng , Tang Fei-Fei , Mo Xiao-Dong , Wang Zhi-Dong , Jiang Qian , Lu Jin , Jiang Hao , Liu Yan-Rong , Liu Kai-Yan , Chang Ying-Jun , Huang Xiao-Jun
Published: May 2023

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a major strategy to cure patients with acute lymphoblastic leukemia (ALL). The aim of this study was to evaluate whether isolated flow cytometry (FCM)-positive central nervous system (CNS) involvement before allo-HSCT is clinically significant.

Methods

The effects of isolated FCM-positive CNS involvement prior to transplantation on the outcomes of 1406 ALL patients with complete remission (CR) were retrospectively investigated.

Results

Patients were classified into isolated FCM-positive CNS involvement (n=31), cytology-positive CNS involvement (n = 43), and negative CNS involvement (n = 1332) groups. Among the three groups, the 5-year cumulative incidence of relapse (CIR) values were 42.3%, 48.8%, and 23.4%, respectively (P<0.001). The 5-year leukemia-free survival (LFS) values were 44.7%, 34.9%, and 60.8%, respectively (P<0.001). Compared with the negative CNS group (n=1332), the 5-year CIR of the pre-HSCT CNS involvement group (n=74) was higher (46.3% vs. 23.4%, P<0.001], and the 5-year LFS was inferior (39.1% vs. 60.8%, P<0.001). Multivariate analysis indicated that four variables, T-cell ALL, in second complete remission or beyond (CR2+) at HSCT, pre-HSCT measurable residual disease positivity, and pre-HSCT CNS involvement, were independently associated with a higher CIR and inferior LFS. A new scoring system was developed using the following four variables: low-risk, intermediate-risk, high-risk, and extremely high-risk groups. The 5-year CIR values were 16.9%, 27.8%, 50.9%, and 66.7%, respectively (P<0.001), while the 5-year LFS values were 67.6%, 56.9%, 31.0%, and 13.3%, respectively (P<0.001).

Conclusion

Our results suggest that ALL patients with isolated FCM-positive CNS involvement are at a higher risk of recurrence after transplantation. Patients with pre-HSCT CNS involvement had higher CIR and inferior survival outcomes.
Lactate mediated metabolic crosstalk between cancer and immune cells and its therapeutic implications
Authors: Mortazavi Farsani Seyedeh Sahar , Verma Vivek
Published: May 2023

Metabolism is central to energy generation and cell signaling in all life forms. Cancer cells rely heavily on glucose metabolism wherein glucose is primarily converted to lactate even in adequate oxygen conditions, a process famously known as “the Warburg effect.” In addition to cancer cells, Warburg effect was found to be operational in other cell types, including actively proliferating immune cells. According to current dogma, pyruvate is the end product of glycolysis that is converted into lactate in normal cells, particularly under hypoxic conditions. However, several recent observations suggest that the final product of glycolysis may be lactate, which is produced irrespective of oxygen concentrations. Traditionally, glucose-derived lactate can have three fates: it can be used as a fuel in the TCA cycle or lipid synthesis; it can be converted back into pyruvate in the cytosol that feeds into the mitochondrial TCA; or, at very high concentrations, accumulated lactate in the cytosol may be released from cells that act as an oncometabolite. In immune cells as well, glucose-derived lactate seems to play a major role in metabolism and cell signaling. However, immune cells are much more sensitive to lactate concentrations, as higher lactate levels have been found to inhibit immune cell function. Thus, tumor cell-derived lactate may serve as a major player in deciding the response and resistance to immune cell-directed therapies. In the current review, we will provide a comprehensive overview of the glycolytic process in eukaryotic cells with a special focus on the fate of pyruvate and lactate in tumor and immune cells. We will also review the evidence supporting the idea that lactate, not pyruvate, is the end product of glycolysis. In addition, we will discuss the impact of glucose-lactate-mediated cross-talk between tumor and immune cells on the therapeutic outcomes after immunotherapy.
Automated machine learning to predict the difficulty for endoscopic resection of gastric gastrointestinal stromal tumor
Authors: Liu Luojie , Zhang Rufa , Shi Dongtao , Li Rui , Wang Qinghua , Feng Yunfu , Lu Fenying , Zong Yang , Xu Xiaodan
Published: May 2023

Background

Accurate preoperative assessment of surgical difficulty is crucial to the success of the surgery and patient safety. This study aimed to evaluate the difficulty for endoscopic resection (ER) of gastric gastrointestinal stromal tumors (gGISTs) using multiple machine learning (ML) algorithms.

Methods

From December 2010 to December 2022, 555 patients with gGISTs in multi-centers were retrospectively studied and assigned to a training, validation, and test cohort. A difficult case was defined as meeting one of the following criteria: an operative time ≥ 90 min, severe intraoperative bleeding, or conversion to laparoscopic resection. Five types of algorithms were employed in building models, including traditional logistic regression (LR) and automated machine learning (AutoML) analysis (gradient boost machine (GBM), deep neural net (DL), generalized linear model (GLM), and default random forest (DRF)). We assessed the performance of the models using the areas under the receiver operating characteristic curves (AUC), the calibration curve, and the decision curve analysis (DCA) based on LR, as well as feature importance, SHapley Additive exPlanation (SHAP) Plots and Local Interpretable Model Agnostic Explanation (LIME) based on AutoML.

Results

The GBM model outperformed other models with an AUC of 0.894 in the validation and 0.791 in the test cohorts. Furthermore, the GBM model achieved the highest accuracy among these AutoML models, with 0.935 and 0.911 in the validation and test cohorts, respectively. In addition, it was found that tumor size and endoscopists’ experience were the most prominent features that significantly impacted the AutoML model’s performance in predicting the difficulty for ER of gGISTs.

Conclusion

The AutoML model based on the GBM algorithm can accurately predict the difficulty for ER of gGISTs before surgery.
Insulin-like growth factor 2 hypermethylation in peripheral blood leukocytes and colorectal cancer risk and prognosis: a propensity score analysis
Authors: Sun HongRu , Liu YanLong , Zhang YuXue , Wang Yibaina , Zhao YaShuang , Liu YuPeng
Published: May 2023

Background

To comprehensively assess and validate the associations between insulin-like growth factor 2 (IGF2) gene methylation in peripheral blood leukocytes (PBLs) and colorectal cancer (CRC) risk and prognosis.

Methods

The association between IGF2 methylation in PBLs and CRC risk was initially evaluated in a case-control study and then validated in a nested case-control study and a twins’ case-control study, respectively. Meanwhile, an initial CRC patient cohort was used to assess the effect of IGF2 methylation on CRC prognosis and then the finding was validated in the EPIC-Italy CRC cohort and TCGA datasets. A propensity score (PS) analysis was performed to control for confounders, and extensive sensitivity analyses were performed to assess the robustness of our findings.

Results

PBL IGF2 hypermethylation was associated with an increased risk of CRC in the initial study (ORPS-adjusted, 2.57, 95% CI: 1.65 to 4.03, P<0.0001), and this association was validated using two independent external datasets (ORPS-adjusted, 2.21, 95% CI: 1.28 to 3.81, P=0.0042 and ORPS-adjusted, 10.65, 95% CI: 1.26 to 89.71, P=0.0295, respectively). CRC patients with IGF2 hypermethylation in PBLs had significantly improved overall survival compared to those patients with IGF2 hypomethylation (HRPS-adjusted, 0.47, 95% CI: 0.29 to 0.76, P=0.0019). The prognostic signature was also observed in the EPIC-Italy CRC cohort, although the HR did not reach statistical significance (HRPS-adjusted, 0.69, 95% CI: 0.37 to 1.27, P=0.2359).

Conclusions

IGF2 hypermethylation may serve as a potential blood-based predictive biomarker for the identification of individuals at high risk of developing CRC and for CRC prognosis.
Predicting sUAS conflicts in the national airspace with interacting multiple models and Haversine-based conflict detection system
Authors: Wells James Z. , Kumar Manish
Published: May 2023

In this paper, a conflict detection system for small Unmanned Aerial Vehicles (sUAS), composed of an interacting multiple model state predictor and a Haversine-distance based conflict detector, is proposed. The conflict detection system was developed and tested via a random recursive simulation in the ROS-Gazebo physics engine environment. The simulation consisted of ten small unmanned aerial vehicles flying along randomly assigned way-point navigation missions within a confined airspace. Way-points are generated from a uniform distribution and then sent to each vehicle. The interacting multiple model state predictor runs on a ground-based system and only has access to current vehicle positional information. It does not have access to the future way-points of individual vehicles. The state predictor is based on Kalman filters that utilize constant velocity, constant acceleration, and constant turn models. It generates near-future position estimates for all vehicles operating within an airspace. These models are probabilistically fused together and projected into the near-future to generate state predictions. These state predictions are then passed to the Haversine distance-based conflict detection algorithm to compare state estimates and identify probable conflicts. The conflicts are detected and flagged based on tunable threshold values which compare distances between predictions for the vehicles operating within the airspace. This paper discusses the development of the random recursive simulation for the ROS-Gazebo framework and the derivation of the interacting multiple model along-with the Haversine-based future conflict detector. The results are presented via simulation to highlight mid-air conflict detection application for sUAS operations in the National Airspace.