bluuebunny/crossref_metadata_2025 huggingface dataset:
Forest Fire Risk Management at the Country Scale: The Case of Turkey
Authors: Gültekin Yaşar Selman , Gültekin Pınar
Published: March 2024

Forest fires cause hazards and damage to both ecosystems and humans increasing attention in the globalizing world. Forest fire risk analysis and management issues cover the prevention of forest fires, response to forest fires and what to do after the forest fires. This chapter is focused on the evaluation of forest fire risk management from socio-economic, landscape planning and risk management perspectives at the country scale. In this context, national policies, strategies, documents and practices are scrutinized in terms of forest fire mitigation acts in Turkey. As a result of the examination policy makers and decision-makers should increase pay attention to their primary stakeholders for better engagement in forest fires. There is an urgent need to obtain an annual forest fire risk assessment report from public institutions. Participatory approaches need to be applied through good governance to mitigate forest fires and decrease forest fire risks in Turkey.
Vulnerability to Wildfires and Peri-urban Areas: An Integrated Socioenvironmental Assessment
Authors: Imbrenda Vito , Coluzzi Rosa , Nosova Bogdana , Cudlin Pavel , Turco Rosario , Salvati Luca , Lanfredi Maria
Published: March 2024

Assuming landscape transformations as a process fueling the local level of vulnerability to wildfires, this work investigates the spatial distribution of selected land-use classes for two years (1975 and 2018) in a metropolitan region of the Mediterranean basin (Athens, central Greece). Built-up settlements and cropland expanded moderately over time, facing a slight decline in forests and semi-natural areas. These changes resulted in the inherent growth in local vulnerability to wildfires estimated using a composite indicator, namely the Fire Risk (FR) index developed in the framework of the MEDALUS international research project financed by the European Commission. Crop mosaics and discontinuous settlements were the classes contributing the most to FR growth. The empirical findings of our work suggest how the conversion of fringe landscapes toward simplified (and, likely, low-quality) cropland and pasture land, as well as the inherent fragmentation of natural/semi-natural landscape patches, is detrimental to environmental quality, increasing the potential exposure to peri-urban fires.
Wildland Firefighters: A Crucial Weapon for Forest Fire Management. Which Health Risks Do They Face?
Authors: Esteves Filipa , Madureira Joana , Teixeira João Paulo , Costa Solange
Published: March 2024

Fire when uncontrolled can become a destructive force that risks wildlife, property, and human lives. Global warming has contributed to the increase and severity of wildfires in the last decades, requiring greater political and local authority involvement to protect people. Wildland firefighters are an essential tool for the management of any forest fire. However, they face unique occupational risks characterized by physically demanding tasks, long hours in severe conditions, and exposure to various health risks (e.g., burning, fractures, smoke inhalation), including exposure to carcinogenic pollutants emitted from smoke. These pollutants, including particulate matter, carbon monoxide, nitrogen dioxide, and volatile organic compounds, can cause acute adverse health effects but also long-term effects, such as cancer. Yet, evidence linking wildland firefighters’ occupational exposure and health outcomes is limited. The increasing risk of wildfire occurrences and longer fire seasons highlight the need for occupational studies among these professionals commonly exposed to hazardous pollutants. Scientific evidence has contributed to the establishment of measures related to firefighters’ health promotion. Regular monitoring, surveillance and health promotion activities, innovative firefighting techniques, safer personal protective equipment, and the implementation of written policies and procedures, such as decontaminating fire station equipment and spaces, are crucial to reduce firefighters’ adverse health effects.
Introduction
Authors: O’Malley Eoin
Published: March 2024

The first part of this chapter introduces the Celtic tiger boom, presenting facts and figures on trends in economic growth rates, average incomes and employment with international comparisons, as well as trends in unemployment, emigration and immigration. The second part of the chapter sets out the approach and structure of the book. It notes that the general approach is to treat Ireland as a relative latecomer to economic development and it explains what that implies. It then sets out the structure of the book, outlining the content and issues to be included in each chapter. It is noted here that a fundamental objective of the book is to explain what caused the long boom.
Foreign-Owned Companies
Authors: O’Malley Eoin
Published: March 2024

A prolonged surge in FDI became the main driver of the boom, especially in the 1990s. Initially, this mainly involved high-tech manufacturing, with services becoming increasingly prominent later. The high-tech manufacturing sectors were less important in terms of net foreign earnings than they appeared to be in terms of exports, while the reverse was true for services. The purchasing linkages and R&D intensity of foreign-owned firms did not develop strongly during the boom, but they did increase their skill levels as more advanced activities were introduced. The overall effect was probably to make them more embedded in the Irish economy and more capable of sustaining higher pay levels, although less integrated than they would be in their home countries. The surge in FDI was not primarily caused by new policies in Ireland. Rather, it was mainly a result of new developments outside Ireland, particularly the introduction of the single European market and the rise of new fast-growing high-tech industries. At the same time, however, existing tax and grant incentives and other conditions in Ireland were very well suited to taking advantage of the new opportunities to attract FDI.
Migrationskontext: Herkunftsgesellschaft und Aufnahmegesellschaft
Authors: Tkotzyk Vanessa
Published: March 2024

Im Sinne von Berry (1997: 15) werden in den nachfolgenden Kapiteln die Herkunftsgesellschaft, Japan, und die Aufnahmegesellschaft, Deutschland, beschrieben. Zunächst werden in Abschnitt 3.1 die politischen, wirtschaftlichen und demographischen Rahmenbedingungen Japans betrachtet. Dabei liegt der Fokus auf den Entwicklungen nach dem Zweiten Weltkrieg. Anschließend werden in Abschnitt 3.2 die Akkulturationsanforderungen der Aufnahmegesellschaft, Deutschland, und deren Einstellung zu Migration und Integration dargestellt, um so aufzuzeigen, vor welchem Hintergrund sich die Zugewanderten in die neue Gesellschaft integrieren sollen.
Methodik
Authors: Tkotzyk Vanessa
Published: March 2024

Um festzustellen, aus welchen Gründen Japanerinnen und Japaner in der Gegenwart nach Deutschland migrieren und inwieweit permanent ansässige Japanerinnen und Japaner in die deutsche Gesellschaft integriert sind, wurde eine qualitativ-empirische Fallstudie mit Leitfadeninterviews durchgeführt. Die Integrationsindikatoren, die die Grundlage für den Leitfaden bilden, leiten sich aus dem in Abschnitt 1.2 wiedergegebenen Forschungsstand zur Migration und Integration japanischer Migrantinnen und Migranten, aus der sozialwissenschaftlichen Forschung zur Eingliederung von Zugewanderten in Deutschland und aus den normativ-politischen Konzepten ab (Abschnitt 2.3). Nachfolgend werden sowohl Methodik als auch Methodologie der qualitativen Studie erläutert.
Auswertung der qualitativen Studie
Authors: Tkotzyk Vanessa
Published: March 2024

Während der Migrationsanlass bei den japanischen Expatriates offensichtlich und in ihrer Versetzung ins Ausland zu wirtschaftlichen Zwecken begründet ist, somit also nicht unbedingt freiwillig erfolgt, sondern von der Firma initiiert wird, stellt sich die Frage, was die untersuchten permanent ansässigen Japanerinnen und Japaner, die selbstinitiiert nach Deutschland gekommen sind, dazu bewegt hat, auszuwandern und sich hier niederzulassen. Als Grundlage für die Beantwortung dieser Frage dienen in erster Linie die Äußerungen in den Interviews auf die Erzählaufforderung: „Bitte schildern Sie den Anlass, nach Deutschland auszuwandern“.
Non-smooth integrability theory
Authors: Hosoya Yuhki
Published: March 2024

We study a method for calculating the utility function from a candidate of a demand function that is not differentiable, but is locally Lipschitz. Using this method, we obtain two new necessary and sufficient conditions for a candidate of a demand function to be a demand function. The first concerns the Slutsky matrix, and the second is the existence of a concave solution to a partial differential equation. Moreover, we show that the upper semi-continuous weak order that corresponds to the demand function is unique, and that this weak order is represented by our calculated utility function. We provide applications of these results to econometric theory. First, we show that, under several requirements, if a sequence of demand functions converges to some function with respect to the metric of compact convergence, then the limit is also a demand function. Second, the space of demand functions that have uniform Lipschitz constants on any compact set is compact under the above metric. Third, the mapping from a demand function to the calculated utility function becomes continuous. We also show a similar result on the topology of pointwise convergence.
A problem formulation framework for the application of in silico toxicology methods in chemical risk assessment
Authors: Achar Jerry , Cronin Mark T. D. , Firman James W. , Öberg Gunilla
Published: March 2024

The first step in the hazard or risk assessment of chemicals should be to formulate the problem through a systematic and iterative process aimed at identifying and defining factors critical to the assessment. However, no general agreement exists on what components an in silico toxicology problem formulation (PF) should include. The present work aims to develop a PF framework relevant to the application of in silico models for chemical toxicity prediction. We modified and applied a PF framework from the general risk assessment literature to peer reviewed papers describing PFs associated with in silico toxicology models. Important gaps between the general risk assessment literature and the analyzed PF literature associated with in silico toxicology methods were identified. While the former emphasizes the need for PFs to address higher-level conceptual questions, the latter does not. There is also little consistency in the latter regarding the PF components addressed, reinforcing the need for a PF framework that enable users of in silico toxicology models to answer the central conceptual questions aimed at defining components critical to the model application. Using the developed framework, we highlight potential areas of uncertainty manifestation in in silico toxicology PF in instances where particular components are missing or implicitly described. The framework represents the next step in standardizing in silico toxicology PF component. The framework can also be used to improve the understanding of how uncertainty is apparent in an in silico toxicology PF, thus facilitating ways to address uncertainty.
Cornelian cherry (Cornus mas L.) as a promising source of antioxidant phenolic substances and minerals
Authors: Lidiková Judita , Čeryová Natália , Grygorieva Olga , Bobková Alica , Bobko Marek , Árvay Július , Šnirc Marek , Brindza Ján , Ňorbová Monika , Harangozo Ľuboš , Kňazovická Vladimíra
Published: March 2024

This study aimed to evaluate the mineral content, and content of bioactive compounds in fruits of Cornelian cherry (Cornus mas L.). Neochlorogenic acid, chlorogenic acid, caffeic acid, and rutin were determined in the samples. Vitamin C content ranged from 610.36 to 1344 mg kg−1 FW. Content of K, Ca, P, Mg, and Na in samples ranged from 1750.8 to 2645.7 mg kg−1 FW, from 281.14 to 561.62 mg kg−1 FW, from 180.38 to 294.95 mg kg−1 FW, from 68.19 to 115.43 mg kg−1 FW, and from 2.48 to 71.33 mg kg−1 FW respectively. Content of Fe, Zn, Cu, Mn, Ni, Cr, and Co in samples ranged from 2.77 to 4.88 mg kg−1 FW, from 0.49 to 0.99 mg kg−1 FW, from 0.25 to 0.53 mg kg−1 FW, from 0.07 to 0.17 mg kg−1 FW, from 0.02 to 0.13 mg kg−1 FW, from 0.01 to 0.02 mg kg−1 FW, and from 0.01 to 0.08 mg kg−1 FW respectively. Variations across cultivars were found to be statistically significant, indicating that genetics is a key factor influencing the concentration of bioactive compounds and minerals in Cornelian cherry fruits. Understanding the genetic factors influencing mineral and bioactive compound content in cornelian cherry cultivars is essential for targeted breeding programs, crop improvement, and the development of cultivars with enhanced nutritional and health-promoting attributes. This knowledge contributes to sustainable agriculture and supports the production of crops that align with consumer preferences and health trends.
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

Fermented 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

Although 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.
Local Galois representations associated to additive polynomials
Authors: Tsushima Takahiro
Published: March 2024

For an additive polynomial and a positive integer, we define an irreducible smooth representation of a Weil group of a non-archimedean local field. We study several invariants of this representation. We obtain a necessary and sufficient condition for it to be primitive.
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

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

Macrophage 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

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

This 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

Poliovirus 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

CD40L–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

Tauopathies 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

Early 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

Habitat 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

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.
A sample average approximation-based heuristic for the stochastic production routing problem
Authors: Geiger Andreas
Published: March 2024

The Production Routing Problem under demand uncertainty is an integrated problem containing production, inventory, and distribution decisions. At the planning level, the aim is to meet retailers demand, when only the demand distribution is known in advance, while minimizing the corresponding costs. In this study, a two-stage formulation is presented in which the routing can be adjusted at short notice. In the first stage, only production decisions are made, while delivery and inventory quantities and retailer visit schedules are determined in the second stage. To handle a large number of scenarios, two solution methods based on Sample Average Approximation are introduced. Furthermore, the impact of the routing quality is explored by applying a simple heuristic and an effective metaheuristic on the routing part. It is shown that, on average, the simple heuristic within an adjustable Sample Average Approximation approach provides better objective function values than the metaheuristic within a non-adjustable approach. Also all solution approaches outperform an expected value based approach in terms of runtime and objective function value.
Stability of the Gaussian Faber–Krahn inequality
Authors: Carbotti Alessandro , Cito Simone , La Manna Domenico Angelo , Pallara Diego
Published: March 2024

We prove a quantitative version of the Gaussian Faber–Krahn type inequality proved in (Betta et al. in Z. Angew. Math. Phys. 58:37–52, 2007) for the first Dirichlet eigenvalue of the Ornstein–Uhlenbeck operator, estimating the deficit in terms of the Gaussian Fraenkel asymmetry. As expected, the multiplicative constant only depends on the prescribed Gaussian measure.
Interventional treatment of refractory non-traumatic chylous effusions in patients with lymphoproliferative disorders
Authors: Wagenpfeil Julia , Hoß Katharina , Henkel Andreas , Kütting Daniel , Luetkens Julian Alexander , Feldmann Georg , Brossart Peter , Attenberger Ulrike Irmgard , Pieper Claus Christian
Published: March 2024

To report results of interventional treatment of refractory non-traumatic abdomino-thoracic chylous effusions in patients with lymphoproliferative disorders. 17 patients (10 male; mean age 66.7 years) with lymphoproliferative disorders suffered from non-traumatic chylous effusions (chylothorax n = 11, chylous ascites n = 3, combined abdomino-thoracic effusion n = 3) refractory to chemotherapy and conservative therapy. All underwent x-ray lymphangiography with iodized-oil to evaluate for and at the same time treat lymphatic abnormalities (leakage, chylo-lymphatic reflux with/without obstruction of central drainage). In patients with identifiable active leakage additional lymph-vessel embolization was performed. Resolution of effusions was deemed as clinical success. Lymphangiography showed reflux in 8/17 (47%), leakage in 2/17 (11.8%), combined leakage and reflux in 3/17 (17.6%), lymphatic obstruction in 2/17 (11.8%) and normal findings in 2/17 cases (11.8%). 12/17 patients (70.6%) were treated by lymphangiography alone; 5/17 (29.4%) with leakage received additional embolization (all technically successful). Effusions resolved in 15/17 cases (88.2%); 10/12 (83.3%) resolved after lymphangiography alone and in 5/5 patients (100%) after embolization. Time-to-resolution of leakage was significantly shorter after embolization (within one day in all cases) than lymphangiography (median 9 [range 4–30] days; p = 0.001). There was no recurrence of symptoms or post-interventional complications during follow-up (median 445 [40–1555] days). Interventional-radiological treatment of refractory, non-traumatic lymphoma-induced chylous effusions is safe and effective. Lymphangiography identifies lymphatic abnormalities in the majority of patients and leads to resolution of effusions in > 80% of cases. Active leakage is found in only a third of patients and can be managed by additional embolization.
External validation of a four-tiered grading system for chromophobe renal cell carcinoma
Authors: Liu Shuai , Hou Mingyu , Yao Yu , Mei Jingchang , Sun Lijiang , Zhang Guiming
Published: March 2024

This study aimed to validate the prognostic value of a four-tiered grading system recently proposed by Avulova et al. and to explore the prognostic ability of another four-tiered classification grading system in which there is a separate Grade 3 for tumor necrosis. Grading of chromophobe renal cell carcinoma (ChRCC) by the Fuhrman system is not feasible because of the inherent nuclear atypia in ChRCC. We collected relevant data of 263 patients with ChRCC who had undergone surgery in our hospital from 2008 to 2020. The Kaplan–Meier method was used to calculate the survival rate and Cox proportional hazard regression models to assess associations with cancer-specific survival and distant metastasis-free survival by hazard ratios (HRs) and 95% confidence intervals (CIs). Ten patients died from ChRCC, and 12 developed metastases. The 5 year CSS rates were 95.9%. Grades 2 (HR = 10.9; CI 1.11–106.4; P = 0.04), 3 (HR = 33.6, CI 3.32–339.1; P = 0.003), and 4 (HR = 417.4, CI 35.0–4976.2; P < 0.001) in a four-tiered grading system were significantly associated with CSS in a multivariate setting. However, the difference in CSS between Grades 2 and 3 was not significant (HR = 2.14, 95% CI 0.43–10.63; P = 0.35). The HRs of the associations between an exploratory grading system that includes a separate Grade 3 for tumor necrosis and CSS were as follows: Grade 2, 10.2 (CI 1.06–97.9, P = 0.045); Grade 3, 11.4 (CI 1.18–109.6, P = 0.04); and Grade 4, 267.9 (CI 27.6–2603.3, P < 0.001). Similarly, Grades 2 and 3 did not differ significantly. The four-tiered grading system studied is useful for predicting death from ChRCC and metastasis. However, Grade 3 did not more accurately predict risk of death and metastasis than did Grade 2. This was also true for the novel exploratory grading system that classifies tumors with necrosis into a separate Grade 3.
Multi-omics and artificial intelligence predict clinical outcomes of immunotherapy in non-small cell lung cancer patients
Authors: Mei Ting , Wang Ting , Zhou Qinghua
Published: March 2024

In recent years, various types of immunotherapy, particularly the use of immune checkpoint inhibitors targeting programmed cell death 1 or programmed death ligand 1 (PD-L1), have revolutionized the management and prognosis of non-small cell lung cancer. PD-L1 is frequently used as a biomarker for predicting the likely benefit of immunotherapy for patients. However, some patients receiving immunotherapy have high response rates despite having low levels of PD-L1. Therefore, the identification of this group of patients is extremely important to improve prognosis. The tumor microenvironment contains tumor, stromal, and infiltrating immune cells with its composition differing significantly within tumors, between tumors, and between individuals. The omics approach aims to provide a comprehensive assessment of each patient through high-throughput extracted features, promising a more comprehensive characterization of this complex ecosystem. However, features identified by high-throughput methods are complex and present analytical challenges to clinicians and data scientists. It is thus feasible that artificial intelligence could assist in the identification of features that are beyond human discernment as well as in the performance of repetitive tasks. In this paper, we review the prediction of immunotherapy efficacy by different biomarkers (genomic, transcriptomic, proteomic, microbiomic, and radiomic), together with the use of artificial intelligence and the challenges and future directions of these fields.
Impact of age and cardiovascular risk factors on the incidence of adverse events in patients with rheumatoid arthritis treated with Janus Kinase inhibitors: data from a real-life multicentric cohort
Authors: Gentileschi Stefano , Gaggiano Carla , Damiani Arianna , Coccia Carmela , Bernardini Pamela , Cazzato Massimiliano , D’Alessandro Francesco , Vallifuoco Giulia , Terribili Riccardo , Bardelli Marco , Baldi Caterina , Cantarini Luca , Mosca Marta , Frediani Bruno , Guiducci Serena
Published: March 2024

Inhibiting Janus Kinases (JAK) is a crucial therapeutic strategy in rheumatoid arthritis (RA). However, the use of JAK inhibitors has recently raised serious safety concerns. The study aims to evaluate the safety profile of JAKi in patients with RA and identify potential risk factors (RFs) for adverse events (AEs). Data of RA patients treated with JAKi in three Italian centers from January 2017 to December 2022 were retrospectively analyzed. 182 subjects (F:117, 64.3%) underwent 193 treatment courses. 78.6% had at least one RF, including age ≥ 65 years, obesity, smoking habit, hypertension, dyslipidemia, hyperuricemia, diabetes, previous VTE or cancer, and severe mobility impairment. We identified 70 AEs (28/100 patients/year), among which 15 were serious (6/100 patients/year). A high disease activity was associated with AEs occurrence (p = 0.03 for CDAI at T0 and T6; p = 0.04 for SDAI at T0 and T6; p = 0.01 and p = 0.04 for DAS28ESR at T6 and T12, respectively). No significant differences in AEs occurrence were observed after stratification by JAKi molecules (p = 0.44), age groups (p = 0.08) nor presence of RFs (p > 0.05 for all of them). Neither the presence of any RFs, nor the cumulative number of RFs shown by the patient, nor age ≥ 65 did predict AEs occurrence. Although limited by the small sample size and the limited number of cardiovascular events, our data do not support the correlation between cardiovascular RFs—including age—and a higher incidence of AEs during JAKi therapy. The role of uncontrolled disease activity in AEs occurrence should by emphasized.