bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase Behaviour of Colloidal Rods Mixed with Depletants
Authors: Lekkerkerker Henk N. W. , Tuinier Remco , Vis Mark
Published: March 2024

So far, we have considered the phase behaviour of colloidal spheres mixed with depletants. In Chap. 3, we considered the simplest type of depletant, the penetrable hard sphere (PHS). We then extended this treatment to ideal and excluded volume polymers in Chap. 4; and in Chap. 6, we considered small colloidal spheres (including micelles). Colloidal rods as depletants were addressed in Chap. 7; however, Chap. 7 only considered dilute dispersions of rods, in which the rods assume all configurations and are hence isotropic. In this chapter, we consider the phase behaviour of mixtures of colloidal rods and polymeric depletants, and we also account for higher rod concentrations and the corresponding phase states. Colloidal rods can be subdivided into synthetic inorganic rods, rod-like clay particles and biological rods (see also [1]). Examples are given in Fig. 8.1. Suspensions of rod-like particles exhibit interesting phase transitions and can assume various phase states.
Hartle-Hawking state and its factorization in 3d gravity
Authors: Chua Wan Zhen , Jiang Yikun
Published: March 2024

Abstract

We study 3d quantum gravity with two asymptotically anti-de Sitter regions, in particular, using its relation with coupled Alekseev-Shatashvili theories and Liouville theory. Expressions for the Hartle-Hawking state, thermal 2n-point functions, torus wormhole correlators and Wheeler-DeWitt wavefunctions in different bases are obtained using the ZZ boundary states in Liouville theory. Exact results in 2d Jackiw-Teitelboim (JT) gravity are uplifted to 3d gravity, with two copies of Liouville theory in 3d gravity playing a similar role as Schwarzian theory in JT gravity. The connection between 3d gravity and the Liouville ZZ boundary states are manifested by viewing BTZ black holes as Maldacena-Maoz wormholes, with the two wormhole boundaries glued along the ZZ boundaries. In this work, we also study the factorization problem of the Hartle-Hawking state in 3d gravity. With the relevant defect operator that imposes the necessary topological constraint for contractibility, the trace formula in gravity is modified in computing the entanglement entropy. This trace matches with the one from von Neumann algebra considerations, further reproducing the Bekenstein-Hawking area formula from entanglement entropy. Lastly, we propose a calculation for off-shell geometrical quantities that are responsible for the ramp behavior in the late time two-point functions, which follows from the understanding of the Liouville FZZT boundary states in the context of 3d gravity, and the identification between Verlinde loop operators in Liouville theory and “baby universe” operators in 3d gravity.
Obesogenic diet in pregnancy disrupts placental iron handling and ferroptosis and stress signalling in association with fetal growth alterations
Authors: Zaugg Jonas , Lopez-Tello Jorge , Musial Barbara , Vaughan Owen R. , Fowden Abigail L. , Albrecht Christiane , Sferruzzi-Perri Amanda N.
Published: March 2024

Obesity and gestational diabetes (GDM) impact fetal growth during pregnancy. Iron is an essential micronutrient needed for energy-intense feto-placental development, but if mis-handled can lead to oxidative stress and ferroptosis (iron-dependent cell death). In a mouse model showing maternal obesity and glucose intolerance, we investigated the association of materno-fetal iron handling and placental ferroptosis, oxidative damage and stress signalling activation with fetal growth. Female mice were fed a standard chow or high fat, high sugar (HFHS) diet during pregnancy and outcomes were measured at day (d)16 or d19 of pregnancy. In HFHS-fed mice, maternal hepcidin was reduced and iron status maintained (tissue iron levels) at both d16 and d19. However, fetal weight, placental iron transfer capacity, iron deposition, TFR1 expression and ERK2-mediated signalling were reduced and oxidative damage-related lipofuscin accumulation in the placenta was increased in HFHS-fed mice. At d19, whilst TFR1 remained decreased, fetal weight was normal and placental weight, iron content and iron transporter genes (Dmt1, Zip14, and Fpn1) were reduced in HFHS-fed mice. Furthermore, there was stress kinase activation (increased phosphorylated p38MAPK, total ERK and JNK) in the placenta from HFHS-fed mice at d19. In summary, a maternal HFHS diet during pregnancy impacts fetal growth trajectory in association with changes in placental iron handling, ferroptosis and stress signalling. Downregulation of placental iron transporters in HFHS mice may protect the fetus from excessive oxidative iron. These findings suggest a role for alterations in placental iron homeostasis in determining perinatal outcomes of pregnancies associated with GDM and/or maternal obesity.

Graphical Abstract
Macrophage re-programming by JAK inhibitors relies on MAFB
Authors: López-Navarro Baltasar , Simón-Fuentes Miriam , Ríos Israel , Schiaffino María Teresa , Sanchez Alicia , Torres-Torresano Mónica , Nieto-Valle Alicia , Castrejón Isabel , Puig-Kröger Amaya
Published: March 2024

Monocyte-derived macrophages play a key pathogenic role in inflammatory diseases. In the case of rheumatoid arthritis (RA), the presence of specific synovial tissue-infiltrating macrophage subsets is associated with either active disease or inflammation resolution. JAK inhibitors (JAKi) are the first targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) approved for treatment of RA with comparable efficacy to biologics. However, the effects of JAKi on macrophage specification and differentiation are currently unknown. We have analyzed the transcriptional and functional effects of JAKi on human peripheral blood monocyte subsets from RA patients and on the differentiation of monocyte-derived macrophages promoted by granulocyte-macrophage colony-stimulating factor (GM-CSF), a factor that drives the development and pathogenesis of RA. We now report that JAKi Upadacitinib restores the balance of peripheral blood monocyte subsets in RA patients and skewed macrophages towards the acquisition of an anti-inflammatory transcriptional and functional profile in a dose-dependent manner. Upadacitinib-treated macrophages showed a strong positive enrichment of the genes that define synovial macrophages associated to homeostasis/inflammation resolution. Specifically, Upadacitinib-treated macrophages exhibited significantly elevated expression of MAFB and MAFB-regulated genes, elevated inhibitory phosphorylation of GSK3β, and higher phagocytic activity and showed an anti-inflammatory cytokine profile upon activation by pathogenic stimuli. These outcomes were also shared by macrophages exposed to other JAKi (baricitinib, tofacitinib), but not in the presence of the TYK2 inhibitor deucravacitinib. As a whole, our results indicate that JAKi promote macrophage re-programming towards the acquisition of a more anti-inflammatory/pro-resolution profile, an effect that correlates with the ability of JAKi to enhance MAFB expression.
Sectoral–regional resilience and productive specialization: a comparison among the last three crises
Authors: Sánchez Andrés Maroto , Cuadrado-Roura Juan Ramón
Published: March 2024

The objective of this paper is to compare the economic resilience of industries and regions along the last four decades, which include the three last major crises for the advanced countries (90s, Great Recession in 2007 and recent COVID-19 pandemic). Productive structure and sectoral specialization are introduced as explaining factor for the different regional behaviors. For this purpose, we estimate both resilience and specialization indices based on employment data. To analyze the relationship between specialization and resilience, a cross-sectional descriptive analysis is complemented by a panel data model that includes some controls. Finally, a regional shift-share analysis contributes to exert some other regional effects affecting economic resilience. The results of this research show some continuities and other significant changes in the regional impact of crises from one to the next. Although there are other effects to have played a role, results show economic specialization is found to have exerted influence on the recovery of certain regions during this period. Recovery periods differ from each crisis and the results might be affected for this dimensionality limitation. Due to the characteristics of the database, the study includes only six sectors. However, general results are generalizable to other regions as the response of employment growth to crises is similar in many advanced regions and specialization patterns does not significantly differ among regions. The paper carries a structural long-term comparison between the last major crises for Spanish regions, which clearly differentiates one from another in their causes and effects. We introduce specialization to explain the different regional resilience patterns. Methodologically, we estimate both sectoral and regional resilience indices for these three crises and relate this resilience to specialization and other explaining factors.
Viruses exploit growth factor mechanisms to achieve augmented pathogenicity and promote tumorigenesis
Authors: Sabourirad Sarvenaz , Dimitriadis Evdokia , Mantamadiotis Theo
Published: March 2024

Cellular homeostasis is regulated by growth factors (GFs) which orchestrate various cellular processes including proliferation, survival, differentiation, motility, inflammation and angiogenesis. Dysregulation of GFs in microbial infections and malignancies have been reported previously. Viral pathogens exemplify the exploitation of host cell GFs and their signalling pathways contributing to viral entry, virulence, and evasion of anti-viral immune responses. Viruses can also perturb cellular metabolism and the cell cycle by manipulation of GF signaling. In some cases, this disturbance may promote oncogenesis. Viral pathogens can encode viral GF homologues and induce the endogenous biosynthesis of GFs and their corresponding receptors or manipulate their activity to infect the host cells. Close investigation of how viral strategies exploit and regulate GFs, a will shed light on how to improve anti-viral therapy and cancer treatment. In this review, we discuss and provide insights on how various viral pathogens exploit different GFs to promote viral survival and oncogenic transformation, and how this knowledge can be leveraged toward the design of more efficient therapeutics or novel drug delivery systems in the treatment of both viral infections and malignancies.
PBTK model-based analysis of CYP3A4 induction and the toxicokinetics of the pyrrolizidine alkaloid retrorsine in man
Authors: Lehmann Anja , Geburek Ina , Hessel-Pras Stefanie , Enge Anne-Margarethe , Mielke Hans , Müller-Graf Christine , Kloft Charlotte , Hethey Christoph
Published: March 2024

Cytochrome P450 (CYP)3A4 induction by drugs and pesticides plays a critical role in the enhancement of pyrrolizidine alkaloid (PA) toxicity as it leads to increased formation of hepatotoxic dehydro-PA metabolites. Addressing the need for a quantitative analysis of this interaction, we developed a physiologically-based toxicokinetic (PBTK) model. Specifically, the model describes the impact of the well-characterized CYP3A4 inducer rifampicin on the kinetics of retrorsine, which is a prototypic PA and contaminant in herbal teas. Based on consumption data, the kinetics after daily intake of retrorsine were simulated with concomitant rifampicin treatment. Strongest impact on retrorsine kinetics (plasma AUC$$_{24}$$

24

and $$C_{{\text {max}}}$$

C
max

reduced to 67% and 74% compared to the rifampicin-free reference) was predicted directly after withdrawal of rifampicin. At this time point, the competitive inhibitory effect of rifampicin stopped, while CYP3A4 induction was still near its maximum. Due to the impacted metabolism kinetics, the cumulative formation of intestinal retrorsine CYP3A4 metabolites increased to 254% (from 10 to 25 nmol), while the cumulative formation of hepatic CYP3A4 metabolites was not affected (57 nmol). Return to baseline PA toxicokinetics was predicted 14 days after stop of a 14-day rifampicin treatment. In conclusion, the PBTK model showed to be a promising tool to assess the dynamic interplay of enzyme induction and toxification pathways.
Biocatalytic transesterification of salmon oil in ionic liquid media to obtain concentrates of omega-3 polyunsaturated fatty acids
Authors: Fuster Marta G. , Moulefera Imane , Montalbán Mercedes G. , Víllora Gloria
Published: March 2024

In this study, a biphasic system combining oil and ionic liquid was utilized for lipase-catalyzed transesterification of salmon oil and alcohol to concentrate n-3 PUFAs, notably EPA and DHA. Various process variables, such as enzyme type, quantity, alcohol chain length, temperature, reactant proportions, and ionic liquid selection, were systematically assessed to optimize the process and enhance the yield of these valuable fatty acids. It was found that the Novozym 435 and Lipolase 100L Type EX emerged as the most effective enzymes. The impact of varying alcohol chain lengths (C1–C8) was examined, revealing that the Novozym 435 enzyme displayed its peak synthetic activity with 2-propanol. The results revealed a substantial increase in the overall activity during the transesterification reaction when employing ILs featuring hydrophobic cations and anions with low nucleophilicity. Specifically, the [omim+][NTf2−] ionic liquid exhibited the highest level of activity. This research holds promise for more efficiently and sustainably obtaining concentrated n-3 PUFAs from fish oil while reducing environmental impact relative to other existing concentration processes.
[3H]-NFPS binding to the glycine transporter 1 in the hemi-parkinsonian rat brain
Authors: Frouni Imane , Kim Esther , Shaqfah Judy , Bédard Dominique , Kwan Cynthia , Belliveau Sébastien , Huot Philippe
Published: March 2024

L-3,4-dihydroxyphenylalanine (L-DOPA) is the main treatment for Parkinson’s disease (PD) but with long term administration, motor complications such as dyskinesia are induced. Glycine transporter 1 (GlyT1) inhibition was shown to produce an anti-dyskinetic effect in parkinsonian rats and primates, coupled with an improvement in the anti-parkinsonian action of L-DOPA. The expression of GlyT1 in the brain in the dyskinetic state remains to be investigated. Here, we quantified the levels of GlyT1 across different brain regions using [3H]-NFPS in the presence of Org-25,935. Brain sections were chosen from sham-lesioned rats, L-DOPA-naïve 6-hydroxydopamine (6-OHDA)-lesioned rats and 6-OHDA-lesioned rats exhibiting mild or severe abnormal involuntary movements (AIMs). [3H]-NFPS binding decreased in the ipsilateral and contralateral thalamus, by 28% and 41%, in 6-OHDA-lesioned rats with severe AIMs compared to sham-lesioned animals (P < 0.01 and 0.001). [3H]-NFPS binding increased by 21% in the ipsilateral substantia nigra of 6-OHDA-lesioned rats with severe AIMs compared to 6-OHDA-lesioned rats with mild AIMs (P < 0.05). [3H]-NFPS binding was lower by 19% in the contralateral primary motor cortex and by 20% in the contralateral subthalamic nucleus of 6-OHDA-lesioned rats with mild AIMs animals compared to rats with severe AIMs (both P < 0.05). The severity of AIMs scores positively correlated with [3H]-NFPS binding in the ipsilateral substantia nigra (P < 0.05), ipsilateral entopeduncular nucleus (P < 0.05) and contralateral primary motor cortex (P < 0.05). These data provide an anatomical basis to explain the efficacy of GlyT1 inhibitors in dyskinesia in PD.
Exploring the Unknown: Evaluating ChatGPT's Performance in Uncovering Novel Aspects of Plastic Surgery and Identifying Areas for Future Innovation
Authors: Lim Bryan , Seth Ishith , Xie Yi , Kenney Peter Sinkjaer , Cuomo Roberto , Rozen Warren M.
Published: March 2024

Background

Artificial intelligence (AI) has emerged as a powerful tool in various medical fields, including plastic surgery. This study aims to evaluate the performance of ChatGPT, an AI language model, in elucidating historical aspects of plastic surgery and identifying potential avenues for innovation.

Methods

A comprehensive analysis of ChatGPT's responses to a diverse range of plastic surgery-related inquiries was performed. The quality of the AI-generated responses was assessed based on their relevance, accuracy, and novelty. Additionally, the study examined the AI's ability to recognize gaps in existing knowledge and propose innovative solutions. ChatGPT’s responses were analysed by specialist plastic surgeons with extensive research experience, and quantitatively analysed with a Likert scale.

Results

ChatGPT demonstrated a high degree of proficiency in addressing a wide array of plastic surgery-related topics. The AI-generated responses were found to be relevant and accurate in most cases. However, it demonstrated convergent thinking and failed to generate genuinely novel ideas to revolutionize plastic surgery. Instead, it suggested currently popular trends that demonstrate great potential for further advancements. Some of the references presented were also erroneous as they cannot be validated against the existing literature.

Conclusion

Although ChatGPT requires major improvements, this study highlights its potential as an effective tool for uncovering novel aspects of plastic surgery and identifying areas for future innovation. By leveraging the capabilities of AI language models, plastic surgeons may drive advancements in the field. Further studies are needed to cautiously explore the integration of AI-driven insights into clinical practice and to evaluate their impact on patient outcomes.

Level of Evidence V

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266
Extreme dry advection dominates the record-breaking Yangtze River heatwave in midsummer of 2022
Authors: Hu Shuai , Zhou Tianjun , Peng Dongdong , Jiang Wanyi , Lu Bo , Wu Bo , Chen Xiaolong , Zhang Lixia , Zhang Wenxia
Published: March 2024

The Yangtze River Valley (YRV) experienced an unprecedented heatwave in midsummer of 2022. Still, the detailed physical processes involved in the influence of abnormal large-scale atmospheric circulation on the heatwave remain unexplored. Here, we show that the positive meridional gradient of anomalous atmospheric moisture at the middle-lower troposphere and associated extreme dry air advection over the YRV are vital prerequisites for forming the 2022 YRV heatwave. The 2022 YRV heatwave is dominated by interannual variability, contributing 72.7% to the total temperature anomalies. Diagnosis of the surface heat budget equation indicates that the surface cloud radiative forcing is the most critical process in driving the 2022 YRV heatwave, which is dominated by the positive surface short-wave cloud radiative forcing associated with the suppressed precipitation and the middle-low clouds. The suppressed precipitation is induced by the vertical dynamical processes of anomalous moisture advection caused by the abnormal descending flows over the YRV, which are driven by the negative advection of anomalous latent heat energy by climatological meridional wind (anomalous dry air advection) according to the atmospheric moist static energy equation. Simulations from the Lagrangian model FLEXPART further indicate that the moisture anomaly over the north of YRV mainly originated from the surface evaporation in the YRV, implying that there is a positive land-air feedback during the life cycle of the YRV heatwave. Our study enriches the mechanism understanding of the 2022 YRV heatwave from the perspective of surface energy budget and land-air feedback.
Enhanced spring warming of the Tibetan Plateau amplifies summer heat stress in Eastern Europe
Authors: Yang Xiaoye , Shen Cheng , Zhang Guwei , Chen Deliang
Published: March 2024

The Tibetan Plateau (TP), often referred to as the “Roof of the World”, has experienced rapid warming in recent decades. This warming has had significant impacts on downstream regions, while its effects on upstream regions are less well-defined. This study explores the relationship between TP warming and the occurrence of summer heat stress days in Europe, with a particular focus on Eastern Europe (EEU). Our analysis reveals a robust correlation between TP warming in both the summer and the preceding spring, and the frequency of heat stress days in EEU, demonstrating a significant interannual connection. During the spring, pronounced warming in the southern TP generates a strong local Rossby wave source, triggering a substantial divergence anomaly that amplifies the warming effect. This mechanism weakens the subtropical jet and strengthens the polar jet during the summer, setting the stage for anticyclonic anomalies over EEU. Furthermore, anomalies induced by TP warming, characterized by local upward movement and divergence at upper levels, intensify convergence and sinking airflow in the upstream region, leading to increased adiabatic heating in EEU. The dynamic response of the summer circulation anomaly, exemplified by the anticyclone anomaly over EEU, to prior TP warming is further corroborated through numerical simulations.
A systematic review of Sandifer syndrome in children with severe gastroesophageal reflux
Authors: Kato Daiki , Uchida Hiroo , Amano Hizuru , Yokota Kazuki , Shirota Chiyoe , Tainaka Takahisa , Sumida Wataru , Makita Satoshi , Yasui Akihiro , Gohda Yousuke , Maeda Takuya , Hinoki Akinari
Published: March 2024

Purpose

Sandifer syndrome (SS), which combines gastroesophageal reflux (GER) and a neurological or psychiatric disorder, is an uncommon condition that often takes a long time to diagnosis. We aimed to systematically review available papers regarding SS.

Methods

After presenting our two cases of SS, we systematically reviewed articles published in MEDILINE/PubMed, Cochrane Library, and Web of Science.

Results

The meta-analysis included 54 reported cases and 2 of our own cases. Our results showed that all cases achieved symptom improvement with appropriate treatment for GER. Notably, 19 of the 56 cases exhibited anatomical anomalies, such as hiatal hernia and malrotation. Significantly more patients with than without anatomical anomalies required surgery (p < 0.001). However, 23 of the 29 patients without anatomical anomalies (79%) achieved symptom improvement without surgery. Patients who did not undergo surgery had a median (interquartile range) duration to symptom resolution of 1 (1–1) month.

Conclusion

The primary care providers should keep SS in the differential diagnosis of patients presenting with abnormal posturing and no apparent neuromuscular disorders. Fundoplication may be effective especially for patients with anatomical anomalies or those whose symptoms do not improve after more than 1 month with nonsurgical treatment.
Insulin and glycolysis dependency of cardioprotection by nicotinamide riboside
Authors: Xiao Y. , Wang Q. , Zhang H. , Nederlof R. , Bakker D. , Siadari B. A. , Wesselink M. W. , Preckel B. , Weber N. C. , Hollmann M. W. , Schomakers B. V. , van Weeghel M. , Zuurbier C. J.
Published: March 2024

Decreased nicotinamide adenine dinucleotide (NAD+) levels contribute to various pathologies such as ageing, diabetes, heart failure and ischemia–reperfusion injury (IRI). Nicotinamide riboside (NR) has emerged as a promising therapeutic NAD+ precursor due to efficient NAD+ elevation and was recently shown to be the only agent able to reduce cardiac IRI in models employing clinically relevant anesthesia. However, through which metabolic pathway(s) NR mediates IRI protection remains unknown. Furthermore, the influence of insulin, a known modulator of cardioprotective efficacy, on the protective effects of NR has not been investigated. Here, we used the isolated mouse heart allowing cardiac metabolic control to investigate: (1) whether NR can protect the isolated heart against IRI, (2) the metabolic pathways underlying NR-mediated protection, and (3) whether insulin abrogates NR protection. NR protection against cardiac IRI and effects on metabolic pathways employing metabolomics for determination of changes in metabolic intermediates, and 13C-glucose fluxomics for determination of metabolic pathway activities (glycolysis, pentose phosphate pathway (PPP) and mitochondrial/tricarboxylic acid cycle (TCA cycle) activities), were examined in isolated C57BL/6N mouse hearts perfused with either (a) glucose + fatty acids (FA) (“mild glycolysis group”), (b) lactate + pyruvate + FA (“no glycolysis group”), or (c) glucose + FA + insulin (“high glycolysis group”). NR increased cardiac NAD+ in all three metabolic groups. In glucose + FA perfused hearts, NR reduced IR injury, increased glycolytic intermediate phosphoenolpyruvate (PEP), TCA intermediate succinate and PPP intermediates ribose-5P (R5P) / sedoheptulose-7P (S7P), and was associated with activated glycolysis, without changes in TCA cycle or PPP activities. In the “no glycolysis” hearts, NR protection was lost, whereas NR still increased S7P. In the insulin hearts, glycolysis was largely accelerated, and NR protection abrogated. NR still increased PPP intermediates, with now high 13C-labeling of S7P, but NR was unable to increase metabolic pathway activities, including glycolysis. Protection by NR against IRI is only present in hearts with low glycolysis, and is associated with activation of glycolysis. When activation of glycolysis was prevented, through either examining “no glycolysis” hearts or “high glycolysis” hearts, NR protection was abolished. The data suggest that NR’s acute cardioprotective effects are mediated through glycolysis activation and are lost in the presence of insulin because of already elevated glycolysis.
Association between physical fitness and perceived work ability among Finnish population: a cross-sectional study
Authors: Pohjola Valtteri , Sarttila Katariina , Kuusela Markus , Nikander Riku , Lundqvist Annamari , Lahti Jouni
Published: March 2024

Objective

This cross-sectional study aims to examine association between different components of physical fitness and perceived work ability among working age population.

Methods

The population-based study sample included 2050 participants aged 18–74 from the Finnish national Health 2011 study. Physical fitness was assessed by the single leg stand test, the modified push-up test, the vertical jump test and the six-minute walk test, and perceived work ability was assessed via interview. Logistic regression was used for examining the associations between physical fitness and work ability.

Results

After adjusting for potential confounders (age, sex, marital status, educational level, work characteristics, total physical activity, daily smoking, BMI and number of diseases), odds ratios indicated that good work ability was more likely among those who had better balance in single leg stand test (OR = 1.54; 95% CI 1.07–2.24), and who belonged in the high fitness thirds in six-minute walking test (OR = 2.08; 95% CI 1.24–3.49) and in vertical jump test (OR = 2.51; 95% CI 1.23–5.12) compared to lowest third. Moreover, moderate (OR = 1.76; 95% CI 1.02–3.05) to high fitness (OR = 2.87; 95% CI 1.40–5.92) in modified push-up test increased the likelihood of good work ability compared to lowest third.

Conclusion

These study results indicate that good musculoskeletal as well as cardiorespiratory fitness are associated with better perceived work ability. Promoting physical fitness in individual and societal level may be potential targets for maintaining good work ability in working age population.
COVID-19-associated secondary sclerosing cholangitis with liver transplantation
Authors: Fischer Anne Kristin , Stippel Dirk , Canbay Ali , Nierhoff Dirk , Thomas Michael , Best Jan , Büttner Reinhard , Drebber Uta
Published: March 2024

We report on two cases of orthotopic liver transplantation (OLTX) due to SARS-Cov2-associated secondary sclerosing cholangitis (SSC) following long-term artificial respiration and extra-corporal membrane oxygenation in intensive care. Under these conditions, SSC is a rapidly progredient biliary disease featuring degenerative cholangiopathy, loss of bile ducts, ductular and parenchymal cholestasis, biliary fibrosis, and finally cirrhosis. Reduced perfusion and oxygenation of the peribiliary plexus, severe concurrent infections, and secondary medico-toxic effects appear to play a crucial role in the pathogenesis of the disease. A direct cytopathic effect of SARS-Cov2 on endothelial cells followed by thrombosis and fibrosing obliteration in all parts of the vascular bed of the liver may enhance the virus-associated liver disease and particularly SSC.
Osteopontin promotes tumor growth and metastasis and GPX4-mediated anti-lipid peroxidation in triple-negative breast cancer by activating the PI3k/Akt/mTOR pathway
Authors: Guo Man , Liu Mengyue , Li Weihan , Wang Cao , Zhang Lu , Zhang Hao
Published: March 2024

Purpose

Triple-negative breast cancer (TNBC) features high aggressiveness, metastasis rate, drug resistance as well as poor prognosis. Osteopontin (OPN) is a key protein in the process of osteogenesis and has emerged as a new tumor marker in recent years.

Methods

Cell viability was tested with the CCK-8 kit. Transwell and wound healing were adopted to test cell invasive and migratory abilities. Tumor sphere formation was detected by tumor sphere formation assay. Human umbilical vein endothelial cell (HUVEC) tube formation assay was used to measure the angiogenesis of tumor cells. Western blot was applied for the estimation of the expression of cancer stem cell markers, angiogenesis-, signaling pathway-related proteins as well as OPN. Bioinformatics tools predicted OPN expression in breast cancer tissues. The levels of oxidative stress-related markers were assessed with ELISA. Following the overexpression of OPN in MD-MB-436 cells and the addition of the PI3K/AKT/mTOR pathway inhibitor LY294002, the aforementioned functional experiments were implemented again to investigate the mechanism. Finally, in vivo experiments of tumor-bearing mice were performed for further verification.

Results

The proliferative, invasive, migratory and tumor sphere formation capabilities as well as angiogenesis of TNBC cells were conspicuously increased in contrast to non-TNBC cell lines. OPN expression in TNBC tissues and cells was dramatically enhanced. OPN upregulation significantly elevated cell proliferative, invasive and migratory capabilities as well as tumor sphere formation and angiogenesis. The mechanism might be achieved by activating PI3K/AKT/mTOR signaling to regulate glutathione peroxidase 4 (GPX4)-mediated anti-lipid peroxidation.

Conclusion

OPN promoted tumor sphere formation and angiogenesis in TNBC by activating the PI3K/AKT/mTOR pathway to regulate GPX4-mediated anti-lipid peroxidation levels.
Phlebotomine sand fly (Diptera: Phlebotominae) diversity in the foci of cutaneous leishmaniasis in the Surxondaryo Region of Uzbekistan: 50 years on
Authors: Usarov Gofur X. , Turitsin Vladimir S. , Sattarova Xulkar G. , Sádlová Jovana , Mustanov Javokhir Abdusamat ugli , Saura Andreu , Yurchenko Vyacheslav
Published: March 2024

In Uzbekistan, the number of reported leishmaniasis cases is rising at the alarming rate. In this work, we studied the phlebotomine sand fly (Diptera: Phlebotominae) diversity in the foci of cutaneous leishmaniasis in the Surxondaryo Region of Uzbekistan and compared it with the data obtained for the same area 50 years ago, when infection prevalence was reportedly low. We found that the implicated vector for zoonotic leishmaniasis, P. papatasi, remained eudominant; the proportion of implicated anthroponotic leishmaniasis vector, P. sergenti, rose significantly from averaged 5.4 to 41.4%; Phlebotomus alexandri, a suspected visceral leishmaniasis vector, was eudominant at two sites, and a second suspected vector for this disease, P. longiductus, was newly recorded in the region. We conclude that the increase in the documented cases of cutaneous leishmaniasis in the Surxondaryo Region of Uzbekistan may be connected to the changes in fauna of sand flies vectoring Leishmania spp.
The crucial prognostic signaling pathways of pancreatic ductal adenocarcinoma were identified by single-cell and bulk RNA sequencing data
Authors: Wang Wenwen , Chen Guo , Zhang Wenli , Zhang Xihua , Huang Manli , Li Chen , Wang Ling , Lu Zifan , Xia Jielai
Published: March 2024

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis and high mortality. Although a large number of studies have explored its potential prognostic markers using traditional RNA sequencing (RNA-Seq) data, they have not achieved good prediction effect. In order to explore the possible prognostic signaling pathways leading to the difference in prognosis, we identified differentially expressed genes from one scRNA-seq cohort and four GEO cohorts, respectively. Then Cox and Lasso regression analysis showed that 12 genes were independent prognostic factors for PDAC. AUC and calibration curve analysis showed that the prognostic model had good discrimination and calibration. Compared with the low-risk group, the high-risk group had a higher proportion of gene mutations than the low-risk group. Immune infiltration analysis revealed differences in macrophages and monocytes between the two groups. Prognosis related genes were mainly distributed in fibroblasts, macrophages and type 2 ducts. The results of cell communication analysis showed that there was a strong communication between cancer-associated fibroblasts (CAF) and type 2 ductal cells, and collagen formation was the main interaction pathway.
Chronic postsurgical pain (CPSP): an underestimated problem after incisional hernia treatment
Authors: Widder A. , Reese L. , Lock J. F. , Wiegering A. , Germer C.-T. , Rittner H. L. , Dietz U. A. , Schlegel N. , Meir M.
Published: March 2024

Background

Chronic postsurgical pain (CPSP) is a potential long-term problem following open incisional hernia repair which may affect the quality of life of patients despite successful anatomical repair of the hernia. The aim of this manuscript was to identify the incidence and outcome of patients following open incisional hernia repair in respect of risk factors to develop CPSP.

Methods

A single-center retrospective analysis of patients who underwent open incisional hernia repair between 2015 and 2021 was performed. Pre-existing conditions (e.g., diabetes mellitus and malignancy), hernia complexity, postoperative complications, and postoperative pain medication were analyzed using the local database. Quality of life and CPSP were assessed using the EuraHS Quality of Life (QoL) questionnaire.

Results

A total of 182 cases were retrospectively included in a detailed analysis based on the complete EuraHS (QoL) questionnaire. During the average follow-up period of 46 months, this long-term follow-up revealed a 54.4% incidence of CPSP and including a rate of 14.8% for severe CPSP (sCPSP) after open incisional hernia surgery. The complexity of the hernia and the demographic variables were not different between the group with and without CPSP. Patients with CPSP reported significantly reduced QoL. The analgesics score which includes the need of pain medication in the initial days after surgery was significantly higher in patients with CPSP than in those without (no CPSP: 2.86 vs. CPSP: 3.35; p = 0.047).

Conclusion

The presence of CPSP after open incisional hernia repair represents a frequent and underestimated long-term problem which has been not been recognized to this extent before. CPSP impairs QoL in these patients. Patients at risk to develop CPSP can be identified in the perioperative setting by the need of high doses of pain medication using the analgesics score. Possibly timely adjustment of pain medication, even in the domestic setting, could alleviate the chronicity or severity of CPSP.
Convergence rates for sums-of-squares hierarchies with correlative sparsity
Authors: Korda Milan , Magron Victor , Ríos-Zertuche Rodolfo
Published: March 2024

This work derives upper bounds on the convergence rate of the moment-sum-of-squares hierarchy with correlative sparsity for global minimization of polynomials on compact basic semialgebraic sets. The main conclusion is that both sparse hierarchies based on the Schmüdgen and Putinar Positivstellensätze enjoy a polynomial rate of convergence that depends on the size of the largest clique in the sparsity graph but not on the ambient dimension. Interestingly, the sparse bounds outperform the best currently available bounds for the dense hierarchy when the maximum clique size is sufficiently small compared to the ambient dimension and the performance is measured by the running time of an interior point method required to obtain a bound on the global minimum of a given accuracy.
A real-world study of treatment sequences and second-line clinical outcomes in patients with HER2-positive metastatic breast cancer in US community practice
Authors: Varghese Della , Cruz Giovanna I. , Johanson Colden , Toland Liz , Miranda Miguel , Faherty Eleanor C. , Harland David , Kaplan Henry G.
Published: March 2024

Purpose

Standard-of-care for HER2-positive metastatic breast cancer (HER2 + mBC) patients consists of trastuzumab ± pertuzumab with chemotherapy in first-line (1L), and ado-trastuzumab emtansine (T-DM1) or the more recently approved trastuzumab deruxtecan (T-DXd) in second-line (2L). Contemporary data on treatment sequencing and real-world effectiveness is limited. This study aims to report 2L treatments and outcomes among HER2 + mBC patients in the United States (US).

Methods

HER2 + mBC patients initiating 2L treatment (index date) between January 2014 and February 2021 were identified from the Syapse Learning Health Network (LHN) database. Summary statistics for patient characteristics, treatment received, reasons for 2L discontinuation and time to 2L-clinical outcomes are reported.

Results

Of the 312 patients initiating 2L treatment, had a median age of 59 years (interquartile range [IQR], 50–66) at the start of 2L. The majority were white (69%) and had de novo mBC (62%). Top three 2L regimens included T-DM1 ± endocrine therapy (29%), trastuzumab/pertuzumab/taxane (10%) and T-DM1/trastuzumab (8%). Around 88% discontinued 2L and 63% received subsequent treatment. Median time-to-next-treatment was 10.6 months (95% CI, 8.8–13.3) and real-world progression-free-survival was 7.9 months (95% CI, 7.0–9.9). Among 274 patients who discontinued 2L, 47% discontinued due to progression and 17% because of intolerance/toxicity, respectively.

Conclusion

This real-world US study showed that approximately two-thirds of 2L patients received subsequent therapy and disease progression was the most common reason for 2L discontinuation highlighting the need for timely 2L treatment with the most efficacious drug to allow patients to achieve longer treatment duration and delayed progression.
PD-L1 expression and microsatellite instability (MSI) in cancer of unknown primary site
Authors: Junior João Neif Antonio , Preto Daniel D.’Almeida , Lazarini Maria Eduarda Zanatta Neder , de Lima Marcos Alves , Bonatelli Murilo , Berardinelli Gustavo Noriz , da Silva Vinicius Duval , Pinheiro Céline , Reis Rui Manuel , Cárcano Flavio Mavignier
Published: March 2024

Background

Cancer of unknown primary site (CUP) is a heterogeneous group of tumors for which the origin remains unknown. Clinical outcomes might be influenced by regulatory processes in its microenvironment. Microsatellite instability (MSI) is a predictive biomarker for cancer immunotherapy and its status, as well as co-occurrence with PD-L1 expression, is poorly evaluated. We aim to evaluate the expression of PD-L1 and the status of MSI in CUP and their possible associations with clinical–pathological features.

Methods

The combined positive score (CPS) PD-L1 expression was evaluated by immunohistochemistry. MSI status was assessed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis.

Results

Among the 166 cases, MSI analysis was conclusive in 120, with two cases being MSI positive (1.6%). PD-L1 expression was positive in 18.3% of 109 feasible cases. PD-L1 expression was significantly associated with non-visceral metastasis and a dominance of nodal metastasis. The median overall survival (mOS) was 3.7 (95% CI 1.6–5.8) months and patients who expressed PD-L1 achieved a better mOS compared to those who did not express PD-L1 (18.7 versus 3.0 months, p-value: < .001). ECOG-PS equal to or more than two and PD-L1 expression were independent prognostic factors in multivariate analysis (2.37 and 0.42, respectively).

Conclusion

PD-L1 is expressed in a subset (1/5) of patients with CUP and associated with improved overall survival, while MSI is a rare event. There is a need to explore better the tumor microenvironment as well as the role of immunotherapy to change such a bad clinical outcome.
Contest competition and injury in adult male sub-Antarctic fur seals
Authors: Bester M. N. , Rossouw G. J. , van Staden P. J.
Published: March 2024

We recorded intra-sexual behaviour of adult male sub-Antarctic fur seals Arctocephalus tropicalis at Gough Island, Southern Ocean, during the 1975/76 summer breeding season. Our re-analysed data address male ‘contest competition’, which relates to the costs of intra-sexual disputes, including fights. We considered the risks/benefits of fighting through investigation of injuries (n = 353) sustained by adult males (n = 124) in fights. Injuries were predominantly on the forequarters, especially around the insertion areas of the front flippers (41%) with its sparse pelage, compared to the neck and chest areas combined (29%), an area which is well protected by thick pelage. The infliction of serious, sometimes debilitating, injuries to competitors increases a male’s access to females. Injuries predominate in injured, defeated males that gather at non-breeding sites, suggesting that injuries inflicted by dominant males were successful in excluding competing males from breeding sites.
Targeted HIV Self-Testing Identifies Persons with Undiagnosed HIV and Active Engagement Links them to Care: The GetaKit Study
Authors: O’Byrne Patrick , Kroch Abigail , Orser Lauren , Ho Nikki , Musten Alexandra , Haines Marlene , Lindsay Jennifer
Published: March 2024

Current international HIV testing guidelines recommend that HIV negative persons from HIV priority groups complete repeat screening every 3–6 months; local guidelines in our jurisdiction recommend that such retesting should occur every 3 months. Such an approach allows for timely HIV diagnosis and linkage to care – and aligns with the UNAIDS 95-95-95 targets to have 95% of undiagnosed persons be aware of their HIV status. To meet these aims, new approaches to HIV testing have been developed, including our HIV self-testing initiative, GetaKit.ca, which uses an online screening algorithm to determine eligibility and has built in pathways for re-test reminders, linkage HIV prevention care, and rapid follow-up for positive test results. To understand self-testing frequency in relation to our local recommendations for resting every 3 months, we evaluated data from participants who ordered repeat HIV self-tests through GetaKit.ca. Descriptive analyses were performed on participant characteristics and chi-square tests were performed on aggregated participant risk data. During the study period, 5235 HIV self-tests were distributed to 3627 participants, of whom, 26% ordered more than once and 27% belonged to an HIV priority population. Participants who retested were more likely to have been white, male, and part of an HIV priority population; they were also more likely to have completed prior STI or HIV testing or had a prior STI diagnosis, compared to those who did not. We identified 16 new HIV diagnoses, 2 of which were among repeat testers. Our results suggest that HIV self-testing can be useful to help meet UNAIDS targets to identify undiagnosed infections; however, such efforts are less likely to be successful without adequate linkage to follow-up services, including HIV treatment and prevention care.
Constructing a Novel Amino Acid Metabolism Signature: A New Perspective on Pheochromocytoma Diagnosis, Immune Landscape, and Immunotherapy
Authors: Yan Zechen , Luan Yongkun , Wang Yu , Ren Yilin , Li Zhiyuan , Zhao Luyang , Shen Linnuo , Yang Xiaojie , Liu Tonghu , Gao Yukui , Sun Weibo
Published: March 2024

Pheochromocytoma/paraganglioma (PGPG) is a rare neuroendocrine tumor. Amino acid metabolism is crucial for energy production, redox balance, and metabolic pathways in tumor cell proliferation. This study aimed to build a risk model using amino acid metabolism-related genes, enhancing PGPG diagnosis and treatment decisions. We analyzed RNA-sequencing data from the PCPG cohort in the GEO dataset as our training set and validated our findings using the TCGA dataset and an additional clinical cohort. WGCNA and LASSO were utilized to identify hub genes and develop risk prediction models. The single-sample gene set enrichment analysis, MCPCOUNTER, and ESTIMATE algorithm calculated the relationship between amino acid metabolism and immune cell infiltration in PCPG. The TIDE algorithm predicted the immunotherapy efficacy for PCPG patients. The analysis identified 292 genes with differential expression, which are involved in amino acid metabolism and immune pathways. Six genes (DDC, SYT11, GCLM, PSMB7, TYRO3, AGMAT) were identified as crucial for the risk prediction model. Patients with a high-risk profile demonstrated reduced immune infiltration but potentially higher benefits from immunotherapy. Notably, DDC and SYT11 showed strong diagnostic and prognostic potential. Validation through quantitative Real-Time Polymerase Chain Reaction and immunohistochemistry confirmed their differential expression, underscoring their significance in PCPG diagnosis and in predicting immunotherapy response. This study’s integration of amino acid metabolism-related genes into a risk prediction model offers critical clinical insights for PCPG risk stratification, potential immunotherapy responses, drug development, and treatment planning, marking a significant step forward in the management of this complex condition.