bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response
Authors: Wang Dong-Rui , Wu Xian-Lin , Sun Ying-Li 
Published: September 2022

AbstractCancers are highly complex diseases that are characterized by not only the overgrowth of malignant cells but also an altered immune response. The inhibition and reprogramming of the immune system play critical roles in tumor initiation and progression. Immunotherapy aims to reactivate antitumor immune cells and overcome the immune escape mechanisms of tumors. Represented by immune checkpoint blockade and adoptive cell transfer, tumor immunotherapy has seen tremendous success in the clinic, with the capability to induce long-term regression of some tumors that are refractory to all other treatments. Among them, immune checkpoint blocking therapy, represented by PD-1/PD-L1 inhibitors (nivolumab) and CTLA-4 inhibitors (ipilimumab), has shown encouraging therapeutic effects in the treatment of various malignant tumors, such as non-small cell lung cancer (NSCLC) and melanoma. In addition, with the advent of CAR-T, CAR-M and other novel immunotherapy methods, immunotherapy has entered a new era. At present, evidence indicates that the combination of multiple immunotherapy methods may be one way to improve the therapeutic effect. However, the overall clinical response rate of tumor immunotherapy still needs improvement, which warrants the development of novel therapeutic designs as well as the discovery of biomarkers that can guide the prescription of these agents. Learning from the past success and failure of both clinical and basic research is critical for the rational design of studies in the future. In this article, we describe the efforts to manipulate the immune system against cancer and discuss different targets and cell types that can be exploited to promote the antitumor immune response.
Sequential interspecies interactions affect production of antimicrobial secondary metabolites in Pseudomonas protegens DTU9.1
Authors: Hansen Morten Lindqvist , Wibowo Mario , Jarmusch Scott Alexander , Larsen Thomas Ostenfeld , Jelsbak Lars 
Published: September 2022

Abstract
Soil and rhizosphere microbiomes play important roles in suppression of plant pathogens through production of antagonistic secondary metabolites, yet mechanisms that determine the strength of pathogen control are not well understood. Many Pseudomonas species are associated with soil and rhizosphere microbiomes, and their ability to suppress pathogens is well documented. Here, we investigate how interactions within the Pseudomonas genus affect their production of antimicrobial metabolites. From a biosensor-based screen, we identify P. capeferrum species as capable of modulating secondary metabolite production in P. protegens. We show that P. capeferrum alters production of pyoluteorin and 2,4-diacetylphloroglucinol (DAPG) in P. protegens via two distinct and sequential mechanisms that depends on spatial proximity of the two species. Specifically, P. capeferrum secretes a diffusible signal that induce pyoluteorin production up to 100-fold in neighboring P. protegens colonies. In contrast, the interaction results in reduced DAPG production, but only within mixed-species colonies. Additionally, we found that increased pyoluteorin production and cell lysis of P. capeferrum is required for inhibition of DAPG production, suggesting that pyoluteorin-facilitated antibiosis of P. protegens on P. capeferrum leads to release of cell-associated metabolites and subsequent inhibition of DAPG production in P. protegens. As the interaction modulates in vitro bioactivity of the species, genus-specific interactions may assist in improving efficacy of biocontrol strains and consortia.
CAF-derived exosomal WEE2-AS1 facilitates colorectal cancer progression via promoting degradation of MOB1A to inhibit the Hippo pathway
Authors: Yang Peng , Zhang Dongsheng , Wang Tuo , Ji Jiangzhou , Jin Chi , Peng Chaofan , Tan Yuqian , Zhou Jiahui , Wang Lu , Feng Yifei , Sun Yueming 
Published: September 2022

AbstractCancer-associated fibroblasts (CAFs) are the most abundant stromal components in the tumor microenvironment (TME) and closely involved in tumor progression. However, the precise biological functions and molecular mechanisms of CAFs in the TME have yet to be understood. Here, we demonstrate that WEE2-AS1 is highly expressed in the CAF-derived small extracellular vesicles (sEVs). Moreover, WEE2-AS1 is markedly higher in plasma sEVs of CRC patients than in healthy subjects and its high level predicts advanced pathological staging and poor survival. Then, we conducted a series of in vitro and in vivo experiments. Elevated expression of WEE2-AS1 in sEVs increases CRC cell proliferation in vitro. Importantly, aberrant CAF-sEVsWEE2-AS1 leads to tumor formation and progression in BALB/c nude mice and promotes AOM/DSS-induced tumorigenesis. Mechanistically, WEE2-AS1 functions as a modular scaffold for the MOB1A and E3 ubiquitin-protein ligase praja2 complexes, leading to MOB1A degradation via the ubiquitin-proteasome pathway. The Hippo pathway is then inhibited and more YAP are transported into the nucleus, where they activate downstream gene transcription. Together, our data reveal that CAF-sEVsWEE2-AS1 interacts with MOB1A, promotes degradation of MOB1A, inhibits the Hippo pathway, and facilitates the growth of CRC cells. Hence, exosomal WEE2-AS1 may be a promising therapeutic target and circulating biomarker for CRC diagnosis and prognosis.
The therapeutic effect of KSP inhibitors in preclinical models of cholangiocarcinoma
Authors: Shi Yuanyuan , Cui Xiaowen , Jiang Tianyi , Pan Yufei , Lin Yunkai , Feng Xiaofan , Ding Zhiwen , Yang Chun , Tan Yexiong , Wang Hongyang , Dong Liwei 
Published: September 2022

AbstractCholangiocarcinoma (CCA) is an epithelial malignancy with a dismal prognosis owing to limited treatment options. Here, we identified several compound candidates against CCA using a high-throughput drug screen with approved or emerging oncology drugs, among which kinesin spindle protein (KSP) inhibitors showed potent cytotoxic effects on CCA cells. Treatment with KSP inhibitors SB743921 and ARRY520 caused significant tumor suppression in CCA xenograft models in vivo. Mechanistically, KSP inhibitors led to the formation of abnormal monopolar spindles, which further resulted in the mitotic arrest and cell death of CCA cells both in vivo and in vitro. KEGG pathway analysis of transcriptional data confirmed this finding. Moreover, our clinical data as well as the TCGA database showed KIF11 expression was abundant in most CCA tumor specimens and associated with poor outcomes of CCA patients. Our results demonstrate that the therapeutic regimen of KSP inhibitors could be a promising treatment strategy in CCA.
Mutated processes predict immune checkpoint inhibitor therapy benefit in metastatic melanoma
Authors: Patterson Andrew , Auslander Noam 
Published: September 2022

AbstractImmune Checkpoint Inhibitor (ICI) therapy has revolutionized treatment for advanced melanoma; however, only a subset of patients benefit from this treatment. Despite considerable efforts, the Tumor Mutation Burden (TMB) is the only FDA-approved biomarker in melanoma. However, the mechanisms underlying TMB association with prolonged ICI survival are not entirely understood and may depend on numerous confounding factors. To identify more interpretable ICI response biomarkers based on tumor mutations, we train classifiers using mutations within distinct biological processes. We evaluate a variety of feature selection and classification methods and identify key mutated biological processes that provide improved predictive capability compared to the TMB. The top mutated processes we identify are leukocyte and T-cell proliferation regulation, which demonstrate stable predictive performance across different data cohorts of melanoma patients treated with ICI. This study provides biologically interpretable genomic predictors of ICI response with substantially improved predictive performance over the TMB.
The imprint of star formation on stellar pulsations
Authors: Steindl Thomas , Zwintz Konstanze , Vorobyov Eduard 
Published: September 2022

AbstractIn the earliest phases of their evolution, stars gain mass through the acquisition of matter from their birth clouds. The widely accepted classical concept of early stellar evolution neglects the details of this accretion phase and assumes the formation of stars with large initial radii that contract gravitationally. In this picture, the common idea is that once the stars begin their fusion processes, they have forgotten their past. By analysing stellar oscillations in recently born stars, we show that the accretion history leaves a potentially detectable imprint on the stars’ interior structures. Currently available data from space would allow discriminating between these more realistic accretion scenarios and the classical early stellar evolution models. This opens a window to investigate the interior structures of young pulsating stars that will also be of relevance for related fields, such as stellar oscillations in general and exoplanet studies.
Modeling human HSV infection via a vascularized immune-competent skin-on-chip platform
Authors: Sun Sijie , Jin Lei , Zheng Ying , Zhu Jia 
Published: September 2022

AbstractHerpes simplex virus (HSV) naturally infects skin and mucosal surfaces, causing lifelong recurrent disease worldwide, with no cure or vaccine. Biomimetic human tissue and organ platforms provide attractive alternatives over animal models to recapitulate human diseases. Combining prevascularization and microfluidic approaches, we present a vascularized, three-dimensional skin-on-chip that mimics human skin architecture and is competent to immune-cell and drug perfusion. The endothelialized microvasculature embedded in a fibroblast-containing dermis responds to biological stimulation, while the cornified epidermis functions as a protective barrier. HSV infection of the skin-on-chip displays tissue-level key morphological and pathophysiological features typical of genital herpes infection in humans, including the production of proinflammatory cytokine IL-8, which triggers rapid neutrophil trans-endothelial extravasation and directional migration. Importantly, perfusion with the antiviral drug acyclovir inhibits HSV infection in a dose-dependent and time-sensitive manner. Thus, our vascularized skin-on-chip represents a promising platform for human HSV disease modeling and preclinical therapeutic evaluation.
Integrated stem cell signature and cytomolecular risk determination in pediatric acute myeloid leukemia
Authors: Huang Benjamin J. , Smith Jenny L. , Farrar Jason E. , Wang Yi-Cheng , Umeda Masayuki , Ries Rhonda E. , Leonti Amanda R. , Crowgey Erin , Furlan Scott N. , Tarlock Katherine , Armendariz Marcos , Liu Yanling , Shaw Timothy I. , Wei Lisa , Gerbing Robert B. , Cooper Todd M. , Gamis Alan S. , Aplenc Richard , Kolb E. Anders , Rubnitz Jeffrey , Ma Jing , Klco Jeffery M. , Ma Xiaotu , Alonzo Todd A. , Triche Timothy , Meshinchi Soheil 
Published: September 2022

AbstractRelapsed or refractory pediatric acute myeloid leukemia (AML) is associated with poor outcomes and relapse risk prediction approaches have not changed significantly in decades. To build a robust transcriptional risk prediction model for pediatric AML, we perform RNA-sequencing on 1503 primary diagnostic samples. While a 17 gene leukemia stem cell signature (LSC17) is predictive in our aggregated pediatric study population, LSC17 is no longer predictive within established cytogenetic and molecular (cytomolecular) risk groups. Therefore, we identify distinct LSC signatures on the basis of AML cytomolecular subtypes (LSC47) that were more predictive than LSC17. Based on these findings, we build a robust relapse prediction model within a training cohort and then validate it within independent cohorts. Here, we show that LSC47 increases the predictive power of conventional risk stratification and that applying biomarkers in a manner that is informed by cytomolecular profiling outperforms a uniform biomarker approach.
Biosynthesis of plant hemostatic dencichine in Escherichia coli
Authors: Li Wenna , Zhou Zhao , Li Xianglai , Ma Lin , Guan Qingyuan , Zheng Guojun , Liang Hao , Yan Yajun , Shen Xiaolin , Wang Jia , Sun Xinxiao , Yuan Qipeng 
Published: September 2022

AbstractDencichine is a plant-derived nature product that has found various pharmacological applications. Currently, its natural biosynthetic pathway is still elusive, posing challenge to its heterologous biosynthesis. In this work, we design artificial pathways through retro-biosynthesis approaches and achieve de novo production of dencichine. First, biosynthesis of the two direct precursors L−2, 3-diaminopropionate and oxalyl-CoA is achieved by screening and integrating microbial enzymes. Second, the solubility of dencichine synthase, which is the last and only plant-derived pathway enzyme, is significantly improved by introducing 28 synonymous rare codons into the codon-optimized gene to slow down its translation rate. Last, the metabolic network is systematically engineered to direct the carbon flux to dencichine production, and the final titer reaches 1.29 g L−1 with a yield of 0.28 g g−1 glycerol. This work lays the foundation for sustainable production of dencichine and represents an example of how synthetic biology can be harnessed to generate unnatural pathways to produce a desired molecule.
MRI to assess response after neoadjuvant chemotherapy in breast cancer subtypes: a systematic review and meta-analysis
Authors: Janssen L. M. , den Dekker B. M. , Gilhuijs K. G. A. , van Diest P. J. , van der Wall E. , Elias S. G. 
Published: September 2022

AbstractThis meta-analysis aimed to estimate and compare sensitivity, specificity, positive- (PPV) and negative predictive value (NPV) of magnetic resonance imaging (MRI) for predicting pathological complete remission (pCR) after neoadjuvant chemotherapy (NAC) in patients with early-stage breast cancer. We stratified for molecular subtype by immunohistochemistry (IHC) and explored the impact of other factors. Two researchers systematically searched PUBMED and EMBASE to select relevant studies and extract data. For meta-analysis of sensitivity and specificity, we used bivariate random-effects models. Twenty-six included studies contained 4497 patients. There was a significant impact of IHC subtype on post-NAC MRI accuracy (p = 0.0082) for pCR. The pooled sensitivity was 0.67 [95% CI 0.58–0.74] for the HR−/HER2−, 0.65 [95% CI 0.56–0.73] for the HR−/HER2+, 0.55 [95% CI 0.45–0.64] for the HR+/HER2− and 0.60 [95% CI 0.50–0.70] for the HR+/HER2+ subtype. The pooled specificity was 0.85 [95% CI 0.81–0.88] for the HR−/HER2−, 0.81 [95% CI 0.74–0.86] for the HR−/HER2+, 0.88[95% CI 0.84–0.91] for the HR+/HER2− and 0.74 [95% CI 0.63–0.83] for the HR+/HER2+ subtype. The PPV was highest in the HR-/HER2- subtype and lowest in the HR+/HER2− subtype. MRI field strength of 3.0 T was associated with a higher sensitivity compared to 1.5 T (p = 0.00063). The accuracy of MRI for predicting pCR depends on molecular subtype, which should be taken into account in clinical practice. Higher MRI field strength positively impacts accuracy. When intervention trials based on MRI response evaluation are designed, the impact of IHC subtype and field strength on MR accuracy should be considered.
Adjuvant trastuzumab emtansine in HER2-positive breast cancer patients with HER2-negative residual invasive disease in KATHERINE
Authors: Loibl Sibylle , Huang Chiun-Sheng , Mano Max S. , Mamounas Eleftherios P. , Geyer Charles E. , Untch Michael , Thery Jean-Christophe , Schwaner Ingo , Limentani Steven , Loman Niklas , Lübbe Kristina , Chang Jenny C. , Hatschek Thomas , Tesarowski David , Song Chunyan , Lysbet de Haas Sanne , Boulet Thomas , Lambertini Chiara , Wolmark Norman 
Published: September 2022

AbstractFollowing chemotherapy and human epidermal growth factor 2 (HER2)-targeted neoadjuvant therapy for HER2-positive early breast cancer, residual invasive breast cancer at surgery may be HER2-negative on retesting in some patients. We evaluated outcomes with T-DM1 and trastuzumab in patients randomized in the phase III KATHERINE trial based on HER2-positive central testing of the pre-treatment core biopsy with HER2-negative central testing on their corresponding surgical specimen after neoadjuvant treatment. In the 70/845 (8.3%) patients with HER2-negative residual disease on retesting at surgery, there were 11 IDFS events in the 42 trastuzumab-treated patients (26.2%) and none in the 28 T-DM1-treated patients, suggesting that T-DM1 should not be withheld in this patient population.
The evolutionary dynamics of extrachromosomal DNA in human cancers
Authors: Lange Joshua T. , Rose John C. , Chen Celine Y. , Pichugin Yuriy , Xie Liangqi , Tang Jun , Hung King L. , Yost Kathryn E. , Shi Quanming , Erb Marcella L. , Rajkumar Utkrisht , Wu Sihan , Taschner-Mandl Sabine , Bernkopf Marie , Swanton Charles , Liu Zhe , Huang Weini , Chang Howard Y. , Bafna Vineet , Henssen Anton G. , Werner Benjamin , Mischel Paul S. 
Published: September 2022

AbstractOncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance—random identity by descent—is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer.
A prospective cohort study of the association between key family and individual factors and obesity status among youth
Authors: Wang Liang , Morelen Diana , Alamian Arsham 
Published: September 2022

AbstractThere remains a significant gap in our knowledge of the synergistic nature of family dynamics, child characteristics, and child-rearing features in the etiology of obesity from childhood through adolescence. We assessed the associations of family dynamics (poverty, family structure), child characteristics (child temperament), and child-rearing features (maternal depression, maternal sensitivity, and type of child care) with the development of childhood obesity. Children (n = 1240) whose weights and heights were measured at least once for ten time points (from 2 years through 15 years) from the NICHD Study of Early Child Care and Youth Development were included. Generalized estimating equation (GEE) was used to examine the associations of family and individual factors with the childhood obesity after adjusting for covariates. Adjusted GEE models showed that living below poverty level was associated with an increased odds of obesity (odds ratio = 1.62, 95% confidence interval 1.05, 2.53). Among these key family and individual factors, poverty status was observed to be the strongest predictor of obesity of offspring across time. Findings highlight the importance of systemic-level public health changes in obesity reduction efforts and suggest that poverty-reduction based prevention and intervention are likely more effective targets than more individual/family specific targets.
Utility of fatty acid profile and in vitro immune cell activation for chemical and biological standardization of Arthrospira/Limnospira
Authors: Huh Jungmoo , Zhang Jin , Hauerová Radka , Lee Joseph , Haider Saqlain , Wang Mei , Hauer Tomáš , Khan Ikhlas A. , Chittiboyina Amar G. , Pugh Nirmal D. 
Published: September 2022

AbstractCommercially cultivated Limnospira (species formerly classified to genus Arthrospira) is a popular food/supplement consumed by millions of people worldwide for health benefits. The objective of the current research was to advance the standardization technology for Limnospira. Quantitative methods were established to detect fatty acids as potential chemical markers and immune-enhancing activity. Analysis of 20 different batches of biomass obtained from one commercial grower demonstrated that there was a statistically significant relationship between the sum of two fatty acids (linoleic and γ-linolenic) and Toll-like receptor (TLR)2/TLR1-dependent activation (R2 = 0.48, p = 0.0007). Investigation of 12 biomass samples sourced from growers in 10 different countries demonstrated that fatty acid content was again significantly correlated with biological activity (R2 = 0.72, p = 0.0005) and the content of fatty acids varied by twofold and activity by 12.5-fold. This large variation between different samples confirms the need to use the present standardization methods to ensure consistent and properly characterized biomass for consumers and for future scientific research.
Antibody dynamics post-Comirnaty and CoronaVac vaccination in Malaysia
Authors: Tan Cheng Siang , Noni Vaenessa , Melina Whilemena Upam Herman Ulok , Abdorahman Ummi Syafiqah , Bimbang Joseph Niler , Malik Natasya Marliana Abdul , Hossen Mohammad Esa , Rahman Md Mizanur , Su’ut Lela , Said Asri , Chen Claire , Sepop Bego , Samat Morni Abu , Chew John Chee Ming , Mamora Dewi , Tan Sian Kong 
Published: September 2022

AbstractSeveral vaccines have been fast-tracked through clinical trials to mitigate the progression of the SARS‑CoV‑2 pandemic. We analyzed sequential blood samples from 314 recipients of Comirnaty and CoronaVac in East Malaysia for the spike-binding IgG (IgG-S), nucleocapsid-binding IgG (IgG-N), spike-binding IgM (IgM-S) and serum vitamin D (VitD). A subset of samples was analyzed for the neutralizing antibodies (Ig-RBD). Results showed that IgG-S due to Comirnaty was significantly higher than CoronaVac. IgM-S was detected in 80.0% Comirnaty and 69.5% CoronaVac recipients, while IgG-N was detected in 58.1% CoronaVac but not in Comirnaty recipients. All IgG-S-positive vaccines possessed detectable Ig-RBD after the second dose but with a weak to moderate correlation. The serum VitD levels did not influence the antibody magnitude in both vaccines. In essence, SARS-CoV-2 vaccination is an IgG-S-dominant event, Comirnaty was more effective than CoronaVac in mounting IgG-S and Ig-RBD responses, independent of the patient’s VitD level.