bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biochemical characterization of YoAlp®: a sheep-fermented milk obtained with autochthonous starter cultures
Authors: Flutto Tania , Merlet Mathieu , Thedy Laura , Pramotton Rita , Zenato Simona , Vernetti-Prot Luca , Valentini Sabina 
Published: March 2024

AbstractFermented milks are a source of bioactive peptides with different potential benefits on human health and may be considered as functional foods. Sheep milk and fermented milk have been collected and a biochemical characterization, by a proteomic approach, GC/MS and microtiter plate assay methods, have been conducted to evaluate their peptide, fatty acid and aromatic profile, and to assess potential health promoting effects. Furthermore, a comparison between sheep-fermented milk (SFM) made with commercial starter cultures and YoAlp®, a sheep-fermented milk obtained using local strains of lactic acid bacteria, has been performed. Peptide’s profile comparison shows a higher number of amino acidic frequencies using autochthonous starter cultures than commercial ones. Among these peptides, 20.78% and 29.87%, respectively, are supposed to be potentially bioactive. Furthermore, in both products, the fatty acid profile was similar to that of origin sheep milk, and concerning aromatic profile, YoAlp® shows yogurt typical aromatic assets. Considering bioactivity, ACE inhibitor activity is high for both samples. Similar values, as expected by peptide profile analysis, have been obtained. Even in the case of antioxidant capacity, peptide profile bioactivity prediction has been confirmed by the assay showing a DPPH inhibition higher for SFM than for YoAlp®, but this difference is not statistically significant. Local strains of lactic acid bacteria seem to work as well as the commercial, preserving biodiversity and typicality. However, further analyses are needed to understand microbial proteolytic activities and to investigate gastric digestion resistance of bioactive peptides.
Distinctive properties of the pine, oak, chestnut and multifloral blossom and honeydew honeys
Authors: Ucurum Ozgul , Tosunoglu Hakan , Takma Çigdem , Birlik Pınar Manga , Berber Melek , Kolaylı Sevgi 
Published: March 2024

AbstractAlthough blossom and honeydew honeys are produced from different nectar sources, it is very difficult to distinguish them. In this study, physicochemical and biochemical properties were compared to distinguish honeydew and blossom honeys obtained from different botanical sources. The honeys of pine (Pinus spp.) and oak (Quercus, spp.) were used as honeydew honey, and chestnut (Castania sativa L.) and highland honey were used as blossom honey. Turbidity, specific optical rotation (SOR) [α]20, electrical conductivity (EC), CIEL* a*b color parameters, and moisture and pH were assessed as physical parameters. Proline, invertase activity, sugar composition, total phenolic and flavonoid contents, and antioxidant capacity were used as biochemical properties. It was determined that SOR values were the most important parameters in distinguishing honeydew and blossom honeys. Turbidity stands out as a crucial factor in differentiating between pine and oak honeys. Except for chestnut honey, electrical conductivity, CIE color Lab values, and sugar profiles were identified as additional distinguishing factors among the tested honeys.
PGRN inhibits CD8+T cell recruitment and promotes breast cancer progression by up-regulating ICAM-1 on TAM
Authors: Zhou Ting , Qian Husun , Zhang Dian , Fang Wenli , Yao MengLi , Shi He , Chen Tingmei , Chai Chengsen , Guo Bianqin 
Published: March 2024

Abstract
Background
Tumor microenvironment actually reduces antitumor effect against the immune attack by exclusion of CD8+T cells. Progranulin (PGRN) is a multifunctional growth factor with significant pathological effects in multiple tumors; however, its role in immunity evasion of breast cancer (BCa) is not completely understood.

Methods
We depleted GRN (PGRN gene) genetically in mice or specifically in PY8119 murine BCa cell line, and mouse models of orthotopic or subcutaneous transplantation were used. Chimeric mice-deficient of PGRN (Grn−/−) in bone marrow (BM) compartment was also generated. Association of PGRN expression with chemokine production or BCa development was investigated by histological and immunological assays.

Results
We found PGRN was involved in exhaustion of cytotoxic CD8+T cell in BCa with the increasing expressions of M2 markers and intercellular cell adhesion molecule-1 (ICAM-1) on macrophages. Specifically, ablation of PGRN in PY8119 cells reduced tumor burden, accompanied by the infiltrating of cytotoxic CD8+T cells into tumor nests. Moreover, our result revealed that blockade of PD-1 in PGRN-depleted tumors exhibited better antitumor effect in vivo and significantly decreased tumor burden.

Conclusion
These findings suggest that inhibition of PGRN may act as a potential immune-therapeutic strategy by recovering infiltration of CD8+T cell in BCa tissue and thereby enhancing the response to anti-PD-1 therapy.
23-Hydroxybetulinic acid attenuates 5-fluorouracil resistance of colorectal cancer by modulating M2 macrophage polarization via STAT6 signaling
Authors: Fan Zeping , Cui Yaru , Chen Lanying , Liu Peng , Duan Wenbin 
Published: March 2024

AbstractMacrophage polarization is closely associated with the inflammatory processes involved in the development and chemoresistance of colorectal cancer (CRC). M2 macrophages, the predominant subtype of tumor-associated macrophages (TAMs) in a wide variety of malignancies, have been demonstrated to promote the resistance of CRC to multiple chemotherapeutic drugs, such as 5-fluorouracil (5-FU). In our study, we investigated the potential of 23-Hydroxybetulinic Acid (23-HBA), a significant active component of Pulsatilla chinensis (P. chinensis), to inhibit the polarization of M2 macrophages induced by IL-4. Our results showed that 23-HBA reduced the expression of M2 specific marker CD206, while downregulating the mRNA levels of M2 related genes (CD206, Arg1, IL-10, and CCL2). Additionally, 23-HBA effectively attenuated the inhibitory effects of the conditioned medium from M2 macrophages on apoptosis in colorectal cancer SW480 cells. Mechanistically, 23-HBA prevented the phosphorylation and nuclear translocation of the STAT6 protein, resulting in the inhibition of IL-10 release in M2 macrophages. Moreover, it interfered with the activation of the IL-10/STAT3/Bcl-2 signaling pathway in SW480 cells, ultimately reducing M2 macrophage-induced resistance to 5-FU. Importantly, depleting STAT6 expression in macrophages abolished the suppressive effect of 23-HBA on M2 macrophage polarization, while also eliminating its ability to decrease M2 macrophage-induced 5-FU resistance in cancer cells. Furthermore, 23-HBA significantly diminished the proportion of M2 macrophages in the tumor tissues of colorectal cancer mice, simultaneously enhancing the anti-cancer efficacy of 5-FU. The findings presented in this study highlight the capacity of 23-HBA to inhibit M2 macrophage polarization, a process that contributes to reduced 5-FU resistance in colorectal cancer.
Efficacy of immune checkpoint inhibitors differs in various status of carcinoma: a study based on 29 cohorts with 3255 participants
Authors: Wu Chunlan , Ke Yujun , Wan Luying , Xie Xianhe 
Published: March 2024

Abstract
Background
Pre-clinical data have revealed that viral infection, such as Hepatitis B virus (HBV), Hepatitis C virus (HCV), and Human Papilloma virus (HPV), may lead to the development of “hot” or “immune-sensitive” tumors, which may impact the efficacy of immune checkpoint inhibitor (ICIs). Therefore, This study aimed to investigate the impact of viral status on the efficacy of ICIs.

Methods
Electronic databases were searched to identify relevant trials. The primary endpoints were overall survival (OS) and progression-free survival (PFS) measured by hazard ratio (HR). Stratified analyses were accomplished based on viral types, treatment regimens, and patient locations.

Results
A total of 3255 participants were recruited, including 252 cases of gastric cancer, 156 cases of nasopharyngeal carcinoma, 1603 cases of hepatocellular carcinoma, and 1244 cases of head and neck squamous cell carcinoma. Pooled results demonstrated a significant association between viral infection and favorable outcomes in patients receiving ICIs, including improved OS [HR = 0.67, 95%CI (0.57–0.79), P < 0.0001], increased ORR [OR = 1.43, 95%CI (1.14–1.80), P = 0.0018], and a trend toward enhanced PFS [HR = 0.75, 95%CI (0.56–1.00), P = 0.05]. In subgroup analyses, patients treated with ICIs who were exposed to HBV/HCV or HPV infection exhibited an evidently superior OS without heterogeneity, compared to those without infection.

Conclusions
This study indicated that the presence of viral infection was evidently associated with improved outcomes in cancer patients undergoing ICIs, particularly in cases of HBV/HCV and HPV infections.
IL-2 promotes expansion and intratumoral accumulation of tumor infiltrating dendritic cells in pancreatic cancer
Authors: Gong Tingting , Huang Xinyang , Wang Zhuoxin , Chu Ye , Wang Lifu , Wang Qi 
Published: March 2024

AbstractThis study aims to investigate the diagnostic potential of IL-2 for PDAC and develop a method to improve the dendritic cell (DC) based vaccine against PDAC. The gene expression data and clinical characteristics information for 178 patients with PDAC were obtained from The Cancer Genome Atlas (TCGA). DCs were isolated from Human peripheral blood mononuclear cells (PBMCs) and were cultured in 4 different conditions. DCs were pulsed by tumor cell lysates or KRAS G12D1 − 23 peptide, and then used to activate T cells. The mixture of DCs and T cells were administered to xenograft mouse model through the tail vein. The infiltration of DCs and T cells were detected by immunohistochemistry. The generation of KRAS G12D mutation specific cytotoxic T cells was determined by in vitro killing assay. We observed that PDAC patients with higher IL-2 mRNA levels exhibited improved overall survival and increased infiltration of CD8 + T cells, NK cells, naïve B cells, and resting myeloid DCs in the tumor microenvironment. IL-2 alone did not enhance DC proliferation, antigen uptake, or apoptosis inhibition unless co-cultured with PBMCs. DCs co-cultured with PBMCs in IL-2-containing medium demonstrated the strongest tumor repression effect in vitro and in vivo. Compared to DCs obtained through the traditional method (cultured in medium containing GM-CSF and IL-4), DCs cultured with PBMCs, and IL-2 exhibited increased tumor infiltration capacity, potentially facilitating sustained T cell immunity. DCs cultured in the PBMCs-IL-2 condition could promote the generation of cytotoxic T cells targeting tumor cells carrying KRAS G12D mutation.
Characterization of a novel anti-PVRIG antibody with Fc-competent function that exerts strong antitumor effects via NK activation in preclinical models
Authors: Xue Hongyu , Zhang Zhimin , Li Li , Zhu Chenjuan , Fei Keke , Sha Huijun , Wu Zhihai , Lin Xiaomin , Wang Feifei , Zhou Shuaixiang , Deng Xiya , Li Yiming , Chen Bingliang , Xiong Yao , Chen Kai 
Published: March 2024

AbstractPoliovirus receptor-related immunoglobulin domain-containing protein, or PVRIG, is a newly discovered immune checkpoint that has emerged as a promising target for cancer immunotherapy. It is primarily expressed on activated T and natural killer (NK) cells, and once engaged with its ligand, PVRL2, it induces inhibitory signaling in T cells, thereby promoting the functional exhaustion of tumor-infiltrating lymphocytes (TILs). Here, we characterized IBI352g4a, a novel humanized anti-PVRIG antibody with Fc-competent function, explored the mechanism of its antitumor activity in preclinical models, and systemically evaluated the contribution of FcrR engagement to PVRIG blockade-induced antitumor activity. IBI352g4a binds to the extracellular domain of human PVRIG with high affinity (Kd = 0.53 nM) and specificity, and fully blocks the interaction between PVRIG and its ligand PVRL2. Unlike other immune checkpoints, IBI352g4a significantly induced NK cell activation and degranulation, but had a minimal effect on T-cell activation in in vitro functional assays. IBI352g4a induced strong antitumor effect in several preclinic models, through in vivo mechanism analysis we found that both NK and T cells contribute to the antitumor effect, but NK cells play predominant roles. Specifically, a single dose of IBI352g4a induced significant NK cell activation in TILs, but T-cell activation was observed only after the second dose. Moreover, the Fc effector function is critical for both NK cell activation and treatment efficacy in vitro and in vivo. Our study, for the first time, demonstrates that both NK activation and FcrR engagement are required for antitumor efficacy induced by PVRIG blockade.
Role of inflammatory signaling pathways involving the CD40–CD40L–TRAF cascade in diabetes and hypertension—insights from animal and human studies
Authors: Strohm Lea , Daiber Andreas , Ubbens Henning , Krishnankutty Roopesh , Oelze Matthias , Kuntic Marin , Hahad Omar , Klein Veronique , Hoefer Imo E. , von Kriegsheim Alex , Kleinert Hartmut , Atzler Dorothee , Lurz Philipp , Weber Christian , Wild Philipp S. , Münzel Thomas , Knosalla Christoph , Lutgens Esther , Daub Steffen 
Published: March 2024

AbstractCD40L–CD40–TRAF signaling plays a role in atherosclerosis progression and affects the pathogenesis of coronary heart disease (CHD). We tested the hypothesis that CD40L–CD40–TRAF signaling is a potential therapeutic target in hyperlipidemia, diabetes, and hypertension. In mouse models of hyperlipidemia plus diabetes (db/db mice) or hypertension (1 mg/kg/d angiotensin-II for 7 days), TRAF6 inhibitor treatment (2.5 mg/kg/d for 7 or 14 days) normalized markers of oxidative stress and inflammation. As diabetes and hypertension are important comorbidities aggravating CHD, we explored whether the CD40L–CD40–TRAF signaling cascade and their associated inflammatory pathways are expressed in CHD patients suffering from comorbidities. Therefore, we analyzed vascular bypass material (aorta or internal mammary artery) and plasma from patients with CHD with diabetes and/or hypertension. Our Olink targeted plasma proteomic analysis using the IMMUNO-ONCOLOGY panel revealed a pattern of step-wise increase for 13/92 markers of low-grade inflammation with significant changes. CD40L or CD40 significantly correlated with 38 or 56 other inflammatory targets. In addition, specific gene clusters that correlate with the comorbidities were identified in isolated aortic mRNA of CHD patients through RNA-sequencing. These signaling clusters comprised CD40L–CD40–TRAF, immune system, hemostasis, muscle contraction, metabolism of lipids, developmental biology, and apoptosis. Finally, immunological analysis revealed key markers correlated with comorbidities in CHD patients, such as CD40L, NOX2, CD68, and 3-nitrotyrosine. These data indicate that comorbidities increase inflammatory pathways in CHD, and targeting these pathways will be beneficial in reducing cardiovascular events in CHD patients with comorbidities.
Genetic forms of tauopathies: inherited causes and implications of Alzheimer’s disease-like TAU pathology in primary and secondary tauopathies
Authors: Langerscheidt Felix , Wied Tamara , Al Kabbani Mohamed Aghyad , van Eimeren Thilo , Wunderlich Gilbert , Zempel Hans 
Published: March 2024

AbstractTauopathies are a heterogeneous group of neurologic diseases characterized by pathological axodendritic distribution, ectopic expression, and/or phosphorylation and aggregation of the microtubule-associated protein TAU, encoded by the gene MAPT. Neuronal dysfunction, dementia, and neurodegeneration are common features of these often detrimental diseases. A neurodegenerative disease is considered a primary tauopathy when MAPT mutations/haplotypes are its primary cause and/or TAU is the main pathological feature. In case TAU pathology is observed but superimposed by another pathological hallmark, the condition is classified as a secondary tauopathy. In some tauopathies (e.g. MAPT-associated frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Alzheimer's disease (AD)) TAU is recognized as a significant pathogenic driver of the disease. In many secondary tauopathies, including Parkinson's disease (PD) and Huntington's disease (HD), TAU is suggested to contribute to the development of dementia, but in others (e.g. Niemann-Pick disease (NPC)) TAU may only be a bystander. The genetic and pathological mechanisms underlying TAU pathology are often not fully understood. In this review, the genetic predispositions and variants associated with both primary and secondary tauopathies are examined in detail, assessing evidence for the role of TAU in these conditions. We highlight less common genetic forms of tauopathies to increase awareness for these disorders and the involvement of TAU in their pathology. This approach not only contributes to a deeper understanding of these conditions but may also lay the groundwork for potential TAU-based therapeutic interventions for various tauopathies.
Machine learning-based analysis for prediction of surgical necrotizing enterocolitis in very low birth weight infants using perinatal factors: a nationwide cohort study
Authors: Kim Seung Hyun , Oh Yoon Ju , Son Joonhyuk , Jung Donggoo , Kim Daehyun , Ryu Soo Rack , Na Jae Yoon , Hwang Jae Kyoon , Kim Tae Hyun , Park Hyun-Kyung 
Published: March 2024

AbstractEarly prediction of surgical necrotizing enterocolitis (sNEC) in preterm infants is important. However, owing to the complexity of the disease, identifying infants with NEC at a high risk for surgical intervention is difficult. We developed a machine learning (ML) algorithm to predict sNEC using perinatal factors obtained from the national cohort registry of very low birth weight (VLBW) infants. Data were collected from the medical records of 16,385 VLBW infants registered in the Korean Neonatal Network (KNN). Infants who underwent surgical intervention were identified with sNEC, and infants who received medical treatment, with medical NEC (mNEC). We used 38 variables, including maternal, prenatal, and postnatal factors that were obtained within 1 week of birth, for training. A total of 1085 patients had NEC (654 with sNEC and 431 with mNEC). VLBW infants showed a higher incidence of sNEC at a lower gestational age (GA) (p < 0.001). Our proposed ensemble model showed an area under the receiver operating characteristic curve of 0.721 for sNEC prediction. Conclusion: Proposed ensemble model may help predict which infants with NEC are likely to develop sNEC. Through early prediction and prompt intervention, prognosis of sNEC may be improved.

What is Known:• Machine learning (ML)-based techniques have been employed in NEC research for prediction, diagnosis, and prognosis, with promising outcomes.• While most studies have utilized abdominal radiographs and clinical manifestations of NEC as data sources, and have demonstrated their usefulness, they may prove weak in terms of early prediction.

What is New:• We analyzed the perinatal factors of VLBW infants acquired within 7 days of birth and used ML-based analysis to identify which infants with NEC are vulnerable to clinical deterioration and at high risk for surgical intervention using nationwide cohort data.
Vegetation biomass and topography are associated with seasonal habitat selection and fall translocation behavior in Arctic hares
Authors: Landry-Ducharme Ludovic , Lai Sandra , Vézina François , Tam Andrew , Berteaux Dominique 
Published: March 2024

AbstractHabitat selection theory suggests that environmental features selected at coarse scales reveal fundamental factors affecting animal fitness. When these factors vary across seasons, they may lead to large-scale movements, including long-distance seasonal migrations. We analyzed the seasonal habitat selection of 25 satellite-tracked Arctic hares from a population on Ellesmere Island (Nunavut, Canada) that relocated over 100 km in the fall. Since no other lagomorph is known to perform such extensive movements, this population offered an ideal setting to test animal movement and habitat selection theory. On summer grounds hares selected low elevation areas, while on winter grounds they selected high vegetation biomass, high elevation, and steep slopes. During fall relocation, they alternated between stopover and traveling behavioral states (ratio 2:1). Stopover locations were characterized by higher vegetation heterogeneity and lower rugosity than traveling locations, while vegetation biomass and elevation interacted to explain stopover locations in a more complex way. The selected combination of environmental features thus varied across seasons and behavioral states, in a way broadly consistent with predictions based on the changing food and safety needs of hares. Although causality was not demonstrated, our results improve our understanding of long-distance movements and habitat selection in Arctic hares, as well as herbivore ecology in the polar desert. Results also provide strong support to animal movement and habitat selection theory, by showing how some important hypotheses hold when tested in a species phylogenetically distinct from most animal models used in this research field.
A simple method for the selection of valid spinopelvic parameters and lumbar lordosis in patients with transitional lumbosacral vertebrae
Authors: Iplikcioglu Ahmet Celal , Karabag Hamza 
Published: March 2024

Abstract
Purpose
Transitional lumbosacral vertebrae (TLSV) are a congenital anomaly of the lumbosacral region that is characterized by the presence of a vertebra with morphological properties of both the lumbar and sacral vertebrae, with a prevalence of up to 36% in asymptomatic patients and 20% in adolescent idiopathic scoliosis patients. In patients with TLSV, because of these morphological changes and the different numbers of lumbar vertebrae, there are two optional reference sacral endplates that can be selected intently or inadvertently to measure the spinopelvic parameters: upper and lower endplates. The spinopelvic parameters measured using the upper and lower endplates are significantly different from each other as well as from the normative values. Therefore, the selection of a reference endplate changes the spinopelvic parameters, lumbar lordosis (LL), and surgical goals, which can result in surgical over- or under-correction. Because there is no consensus on the selection of sacral endplate among these patients, it is unclear as to which of these parameters should be used in diagnosis or surgical planning. The present study describes a standardization method for measuring the spinopelvic parameters and LL in patients with TLSV.

Methods
Upper and lower endplate spinopelvic parameters (i.e., pelvic incidence [PI], sacral slope [SS], and pelvic tilt) and LL of 108 patients with TLSV were measured by computed tomography. In addition, these parameters were measured for randomly selected subjects without TLSV. The PI value in the TLSV group, which was closer to the mean PI value of the control group, was accepted as valid and then used to create an optimum PI (OPI) group. Finally, the spinopelvic parameters and LL of the OPI and control groups were compared.

Results
Except for SS, all spinopelvic parameters and LL were comparable between the OPI and control groups. In the OPI group, 60% of the patients showed valid upper endplate parameters, and 40% showed valid lower endplate parameters. No difference was noted in the frequency of valid upper or lower endplates between the sacralization and lumbarization groups. Both the OPI and control groups showed nearly comparable correlations between their individual spinopelvic parameters and LL, except for PI and LL in the former.

Conclusions
Because PI is unique for every individual, the endplate whose PI value is closer to the normative value should be selected as the reference sacral endplate in patients with TLSV.