bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence of microvascular dysfunction is increased in hyperlipidemic mice, reducing cerebral blood flow and impairing remote memory
Authors: Hernandez Torres Luis Daniel , Rezende Flavia , Peschke Eva , Will Olga , Hövener Jan-Bernd , Spiecker Frauke , Özorhan Ümit , Lampe Josephine , Stölting Ines , Aherrahrou Zouhair , Künne Carsten , Kusche-Vihrog Kristina , Matschl Urte , Hille Susanne , Brandes Ralf P. , Schwaninger Markus , Müller Oliver J. , Raasch Walter
Published: February 2024

Introduction

The development of cognitive dysfunction is not necessarily associated with diet-induced obesity. We hypothesized that cognitive dysfunction might require additional vascular damage, for example, in atherosclerotic mice.

Methods

We induced atherosclerosis in male C57BL/6N mice by injecting AAV-PCSK9DY (2x1011 VG) and feeding them a cholesterol-rich Western diet. After 3 months, mice were examined for cognition using Barnes maze procedure and for cerebral blood flow. Cerebral vascular morphology was examined by immunehistology.

Results

In AAV-PCSK9DY-treated mice, plaque burden, plasma cholesterol, and triglycerides are elevated. RNAseq analyses followed by KEGG annotation show increased expression of genes linked to inflammatory processes in the aortas of these mice. In AAV-PCSK9DY-treated mice learning was delayed and long-term memory impaired. Blood flow was reduced in the cingulate cortex (-17%), caudate putamen (-15%), and hippocampus (-10%). Immunohistological studies also show an increased incidence of string vessels and pericytes (CD31/Col IV staining) in the hippocampus accompanied by patchy blood-brain barrier leaks (IgG staining) and increased macrophage infiltrations (CD68 staining).

Discussion

We conclude that the hyperlipidemic PCSK9DY mouse model can serve as an appropriate approach to induce microvascular dysfunction that leads to reduced blood flow in the hippocampus, which could explain the cognitive dysfunction in these mice.
Key genes involved in nonalcoholic steatohepatitis improvement after bariatric surgery
Authors: Chen Xiyu , Deng Shi-Zhou , Sun Yuze , Bai Yunhu , Wang Yayun , Yang Yanling
Published: February 2024

Background

Nonalcoholic steatohepatitis (NASH) is the advanced stage of nonalcoholic fatty liver disease (NAFLD), one of the most prevalent chronic liver diseases. The effectiveness of bariatric surgery in treating NASH and preventing or even reversing liver fibrosis has been demonstrated in numerous clinical studies, but the underlying mechanisms and crucial variables remain unknown.

Methods

Using the GSE135251 dataset, we examined the gene expression levels of NASH and healthy livers. Then, the differentially expressed genes (DEGs) of patients with NASH, at baseline and one year after bariatric surgery, were identified in GSE83452. We overlapped the hub genes performed by protein-protein interaction (PPI) networks and DEGs with different expression trends in both datasets to obtain key genes. Genomic enrichment analysis (GSEA) and genomic variation analysis (GSVA) were performed to search for signaling pathways of key genes. Meanwhile, key molecules that regulate the key genes are found through the construction of the ceRNA network. NASH mice were induced by a high-fat diet (HFD) and underwent sleeve gastrectomy (SG). We then cross-linked the DEGs in clinical and animal samples using quantitative polymerase chain reaction (qPCR) and validated the key genes.

Results

Seven key genes (FASN, SCD, CD68, HMGCS1, SQLE, CXCL10, IGF1) with different expression trends in GSE135251 and GSE83452 were obtained with the top 30 hub genes selected by PPI. The expression of seven key genes in mice after SG was validated by qPCR. Combined with the qPCR results from NASH mice, the four genes FASN, SCD, HMGCS1, and CXCL10 are consistent with the biological analysis. The GSEA results showed that the ‘cholesterol homeostasis’ pathway was enriched in the FASN, SCD, HMGCS1, and SQLE high-expression groups. The high-expression groups of CD68 and CXCL10 were extremely enriched in inflammation-related pathways. The construction of the ceRNA network obtained microRNAs and ceRNAs that can regulate seven key genes expression.

Conclusion

In summary, this study contributes to our understanding of the mechanisms by which bariatric surgery improves NASH, and to the development of potential biomarkers for the treatment of NASH.
Canopy specialist Hylaeus bees highlight sampling biases and resolve Michener’s mystery
Authors: Dorey James B. , Davies Olivia K. , Magnacca Karl N. , Schwarz Michael P. , Gilpin Amy-Marie , Ramage Thibault , Tuiwawa Marika , Groom Scott V. C. , Stevens Mark I. , Parslow Ben A.
Published: February 2024

Large parts of the Pacific were thought to host low bee diversity. In Fiji alone, our recent estimates of native bee diversity have rapidly increased by a factor of five (from 4 to >22). Here, we show how including sampling of the forest canopy has quickly uncovered a new radiation of Hylaeus (Hymenoptera: Colletidae) bees in Fiji. We also show that Hylaeus are more common across the Pacific than previously thought and solve one of Charles Michener’s mysteries by linking the previously enigmatic French Polynesian Hylaeus tuamotuensis to relatives in Fiji. We use systematic techniques to describe eight new Hylaeus species in Fiji (n = 6), French Polynesia (n = 1), and Micronesia (n = 1), and discuss impressive dispersal events by this genus. These clades also double the number of Hylaeus dispersals out of Australia from two to four. Our discovery highlights the severe impact of bee sampling methods on ecological interpretations and species discovery, specifically that canopy sampling is needed to correctly assess forest bee diversity even where there is a very long record of sampling. It further highlights the potential for forests to host higher-than-anticipated diversity and conservation value. This has broad methodological and regulatory impacts for land managers seeking to make choices about pollination services and diversity. The new species are Hylaeus (Euprosopoides) chuukensis Dorey, Davies, and Parslow; H. (Prosopisteron) albaeus Dorey, Davies, and Parslow; H. (P.) apertus Dorey, Davies, and Parslow; H. (P.) aureaviridis Dorey, Magnacca, and Parslow; H. (P.) breviflavus Magnacca; H. (P.) derectus Dorey, Davies, and Parslow; H. (P.) navai Dorey, Davies, and Parslow; and H. (P.) veli Dorey, Davies, and Parslow.
Carbon stocks and effluxes in mangroves converted into aquaculture: a case study from Banten province, Indonesia
Authors: Royna Milkah , Murdiyarso Daniel , Sasmito Sigit D. , Arriyadi Desra , Rahajoe Joeni Setijo , Zahro Mufidah Ghina , Ardhani Trialaksita Sari Priska
Published: February 2024

Aquaculture is one of the main drivers of mangrove loss across Southeast Asian countries. The conversion of mangroves to aquaculture generates substantial loss of carbon stocks and reduces carbon storage capacity. Here, we present total ecosystem carbon stocks (TECS), carbon dioxide (CO2) and methane (CH4) effluxes obtained from mangrove forests (fringe and interior mangroves), silvofishery aquaculture ponds (dense and sparse mangroves), and non-silvofishery aquaculture ponds in Sawah Luhur, Banten, Indonesia. We found no significant difference in TECS across five land uses, ranging from 261 ± 14 Mg C ha-1 in non-silvofishery ponds to 574 ± 119 Mg C ha-1 in fringe mangroves. Most of these stocks were found in the soil carbon pool (87%) in fringe and interior mangroves. However, the conversion of mangroves to aquaculture ponds resulted in soil carbon loss from -6% to 60%. The highest soil CO2 effluxes during dry and wet seasons were observed in interior mangroves (151 ± 12 mg CO2 m-2 h-1). The highest soil CH4 effluxes were found in fringe mangroves with 0.13 ± 0.04 mg CH4 m-2 h-1. The highest aquatic CO2 and CH4 effluxes were found in dense silvofishery ponds, at 118 ± 7 mg CO2 m-2 h-1 and 0.38 ± 0.04 mg CH4 m-2 h-1, respectively. Our findings suggest that land use that includes mangroves (i.e., mangrove forest and/or silvofishery ponds) tends to have higher carbon stocks, soil, and aquatic CO2 and CH4 effluxes, compared to aquaculture ponds without mangroves. It is therefore crucial to maintain mangroves for natural carbon capture and storage through carbon stock enhancement.
Fire frequency, intensity, and burn severity in Kalimantan’s threatened Peatland areas over two Decades
Authors: Schmidt Andres , Ellsworth Lisa M. , Boisen Grace A. , Novita Nisa , Malik Anjelita , Gangga Adi , Albar Israr , Dwi Nurhayati Ati , Putra Ritonga Rasis , Asyhari Adibtya , Kauffman J. Boone
Published: February 2024

Kalimantan, the Indonesian portion of the Island of Borneo, has an estimated 45,000 km2 of tropical peatland and represents one of the largest stocks of tropical peat carbon. However, over the last three decades, the peatlands of Indonesia, and Kalimantan in particular, have been heavily degraded or destroyed by drainage of peatland swamps, deforestation, land cover change for agriculture, and intentional burning. Many studies have examined degradation of peat forests and the associated frequency of fires, often focusing on specific regions of Kalimantan over limited periods. Here, we present our results of a spatially comprehensive, long-term analysis of peatland fires in Kalimantan over more than two decades from early 2001 to the end of 2021. We examined the effects of changing climate conditions, land cover change, and the regulatory framework on the total burned area and frequency and severity of peatland fires over a 21-year period by combining extensive datasets of medium-resolution and high-resolution satellite imagery. Moreover, surface fire intensity was modeled for four dominant land use/land cover types to determine how land use change alters fire behavior. Our results confirm a consistent and strong spatiotemporal correlation between hydro-climatological drivers associated with El Niño conditions on peatland fire frequencies and burned peatland area. Changes in the number of fires and burn severity are visible over time and are caused by a combination of large-scale meteorological patterns and changing regulations. A significant relative increase of the “high” and “very high” severity across all peatland fires in Kalimantan was found for the latest period from 2015 through 2021 by 12.1 and 13.4%, compared to the two previous 7-year periods from 2001 to 2007 period and from 2008 to 2014, respectively, whereas the total peatland area burned decreased in 2015 to 2021 by 28.7% on average compared to the previous periods. The results underline the importance of a comprehensive approach considering physical aspects of overarching climate conditions while improving political and regulatory frameworks to mitigate the negative effects of burning tropical peatlands.
Differentially expressed microRNAs targeting genes in key pathways in keratoconus
Authors: Nowak-Malczewska Dorota M. , Swierkowska Joanna , Gajecka Marzena
Published: February 2024

Introduction: Keratoconus (KTCN) is a corneal ectasia, characterized by a progressive thinning and protrusion of the cornea, with a complex etiology involving genetic, behavioral, lifestyle, and environmental factors. Previous studies indicated that microRNAs (miRNAs) could be involved in KTCN pathogenesis. This in silico study aimed to identify precursor microRNAs (pre-miRNAs) differentially expressed in KTCN corneas and to characterize mature miRNAs and their target genes.

Materials and methods: Expression levels of pre-miRNAs were retrieved from our previously obtained RNA sequencing data of 25 KTCN and 25 non-KTCN human corneas (PMID:28145428, PMID:30994860). Differential expression with FDR ≤0.01 and ≥1.5-fold changes were considered significant. Lists of target genes (target score ≥90) of mature miRNAs were obtained from miRDB. Revealed up-/downregulated miRNAs and their target genes were assessed in databases and literature. Enrichment analyses were completed applying the DAVID database.

Results: From a total of 47 pre-miRNAs, six were remarkably upregulated (MIR184, MIR548I1, MIR200A, MIR6728, MIR429, MIR1299) and four downregulated (MIR6081, MIR27B, MIR23B, MIR23A) in KTCN corneas. Out of the 1,409 target genes, 220 genes with decreased and 57 genes with increased expression levels in KTCN samples vs non-KTCN samples were found. The extracellular matrix (ECM) organization, response to mechanical stimulus, regulation of cell shape, and signal transduction processes/pathways were identified as distinctive in enrichment analyses. Also, processes associated with the regulation of transcription and DNA binding were listed.

Conclusion: Indicated miRNAs and their target genes might be involved in KTCN pathogenesis via disruption of crucial molecular processes, including ECM organization and signal transduction.
An integrative mechanistic model of thymocyte dynamics
Authors: Kulesh Victoria , Peskov Kirill , Helmlinger Gabriel , Bocharov Gennady
Published: February 2024

Background

The thymus plays a central role in shaping human immune function. A mechanistic, quantitative description of immune cell dynamics and thymic output under homeostatic conditions and various patho-physiological scenarios are of particular interest in drug development applications, e.g., in the identification of potential therapeutic targets and selection of lead drug candidates against infectious diseases.

Methods

We here developed an integrative mathematical model of thymocyte dynamics in human. It incorporates mechanistic features of thymocyte homeostasis as well as spatial constraints of the thymus and considerations of age-dependent involution. All model parameter estimates were obtained based on published physiological data of thymocyte dynamics and thymus properties in mouse and human. We performed model sensitivity analyses to reveal potential therapeutic targets through an identification of processes critically affecting thymic function; we further explored differences in thymic function across healthy subjects, multiple sclerosis patients, and patients on fingolimod treatment.

Results

We found thymic function to be most impacted by the egress, proliferation, differentiation and death rates of those thymocytes which are most differentiated. Model predictions also showed that the clinically observed decrease in relapse risk with age, in multiple sclerosis patients who would have discontinued fingolimod therapy, can be explained mechanistically by decreased thymic output with age. Moreover, we quantified the effects of fingolimod treatment duration on thymic output.

Conclusions

In summary, the proposed model accurately describes, in mechanistic terms, thymic output as a function of age. It may be further used to perform predictive simulations of clinically relevant scenarios which combine specific patho-physiological conditions and pharmacological interventions of interest.
USP50 regulates NLRP3 inflammasome activation in duodenogastric reflux-induced gastric tumorigenesis
Authors: Zhao Chenye , Mu Mingchao , Li Xiaopeng , Dong Zepeng , Wang Jiahao , Yao Chengzhi , Zheng Jianbao , Sun Xuejun , Yu Junhui
Published: February 2024

Duodenogastric reflux (DGR) has been linked to the onset of gastric cancer (GC), although the precise mechanism is yet obscure. Herein, we aimed to investigate how refluxed bile acids (BAs) and macrophages are involved in gastric carcinogenesis. In both active human bile reflux gastritis and the murine DGR model, ubiquitin specific protease 50 (USP50) was dramatically raised, and macrophages were the principal leukocyte subset that upregulated USP50 expression. Enhancing USP50 expression amplified bile acid-induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and subsequent high-mobility group box protein 1 (HMGB1) release, while USP50 deficiency resulted in the reversed alteration. Mechanistically, USP50 interacted with and deubiquitinated apoptosis-associated speck-like protein containing CARD (ASC) to activate NLRP3 inflammasome. The release of HMGB1 contributes to gastric tumorigenesis by PI3K/AKT and MAPK/ERK pathways. These results may provide new insights into bile reflux-related gastric carcinogenesis and options for the prevention of DGR-associated GC.
Case report: Successful treatment of an anti-D2R and DPPX antibody-associated autoimmune encephalitis patient with high-dose methylprednisolone and intravenous immunoglobulin
Authors: Lin Zhangliang , Zhou Feng , Ni Lili , Dong Shiye , Fu Guoping , Zhao Jiangman
Published: February 2024

Background

Autoimmune encephalitis is a neurological condition caused by abnormal immune responses, manifesting as cognitive impairments, behavioral abnormalities, and seizures. Its diagnosis depends on the detecting neuronal surface antibodies in serum or cerebrospinal fluid. Despite recent advances in understanding, clinical recognition remains challenging, especially with rare antibodies such as anti-dopamine D2 receptor (D2R) and anti-dipeptidyl-peptidase-like protein 6 (DPPX) antibodies. Delayed diagnosis can lead to severe complications. This case presentation emphasizes the diagnostic intricacies and effective treatment of the anti-D2R and DPPX antibody-associated autoimmune encephalitis.

Case description

The patient presented with a 3-day history of fatigue and limb soreness followed by a 3-h episode of confusion and limb convulsions. Upon admission to our facility, the initial diagnosis included status epilepticus, aspiration pneumonia, metabolic acidosis, respiratory alkalosis, and suspected encephalitis. Despite receiving antiepileptic, anti-infection, and antivirus therapy, the patient’s condition deteriorated. Both computed tomography (CT) scan and magnetic resonance imaging (MRI) of the brain showed no significant abnormalities. No pathogen was identified in the cerebrospinal fluid (CSF). However, further CSF and serum examination revealed positive results of anti-D2R and anti-DPPX antibodies, confirming a diagnosis of anti-D2R and DPPX antibody-associated autoimmune encephalitis. The patient underwent a comprehensive treatment regimen, including high-dose methylprednisolone pulse therapy combined with intravenous immunoglobulin (IVIG), antiviral and anti-infection treatments, and antiepileptic medications. Significant clinical improvement was observed, and by the 18th day of admission, the patient was stable and coherent.

Conclusions

The current patient represents the first reported case of double-positive autoimmune encephalitis for anti-D2R and DPPX antibodies, with epilepsy as a prominent feature. High-dose methylprednisolone pulse therapy combined with IVIG has shown significant safety and efficacy in treating anti-D2R and DPPX antibody-positive autoimmune encephalitis-associated epilepsy.
Histidine-rich glycoprotein in metabolic dysfunction-associated steatohepatitis-related disease progression and liver carcinogenesis
Authors: Foglia Beatrice , Sutti Salvatore , Cannito Stefania , Rosso Chiara , Maggiora Marina , Casalino Alice , Bocca Claudia , Novo Erica , Protopapa Francesca , Ramavath Naresh Naik , Provera Alessia , Gambella Alessandro , Bugianesi Elisabetta , Tacke Frank , Albano Emanuele , Parola Maurizio
Published: February 2024

Background

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously non-alcoholic fatty liver disease (NAFLD), is a leading cause of chronic liver disease worldwide. In 20%–30% of MASLD patients, the disease progresses to metabolic dysfunction-associated steatohepatitis (MASH, previously NASH) which can lead to fibrosis/cirrhosis, liver failure as well as hepatocellular carcinoma (HCC). Here we investigated the role of histidine-rich glycoprotein (HRG), a plasma protein produced by hepatocytes, in MASLD/MASH progression and HCC development.

Methods

The role of HRG was investigated by morphological, cellular, and molecular biology approaches in (a) HRG knock-out mice (HRG−/− mice) fed on a CDAA dietary protocol or a MASH related diethyl-nitrosamine/CDAA protocol of hepatocarcinogenesis, (b) THP1 monocytic cells treated with purified HRG, and (c) well-characterized cohorts of MASLD patients with or without HCC.

Results

In non-neoplastic settings, murine and clinical data indicate that HRG increases significantly in parallel with disease progression. In particular, in MASLD/MASH patients, higher levels of HRG plasma levels were detected in subjects with extensive fibrosis/cirrhosis. When submitted to the pro-carcinogenic protocol, HRG−/− mice showed a significant decrease in the volume and number of HCC nodules in relation to decreased infiltration of macrophages producing pro-inflammatory mediators, including IL-1β, IL-6, IL-12, IL-10, and VEGF as well as impaired angiogenesis. The histopathological analysis (H-score) of MASH-related HCC indicate that the higher HRG positivity in peritumoral tissue significantly correlates with a lower overall patient survival and an increased recurrence. Moreover, a significant increase in HRG plasma levels was detected in cirrhotic (F4) patients and in patients carrying HCC vs. F0/F1 patients.

Conclusion

Murine and clinical data indicate that HRG plays a significant role in MASLD/MASH progression to HCC by supporting a specific population of tumor-associated macrophages with pro-inflammatory response and pro-angiogenetic capabilities which critically support cancer cell survival. Furthermore, our data suggest HRG as a possible prognostic predictor in HCC patients with MASLD/MASH-related HCCs.
Small extracellular vesicles purification and scale-up
Authors: Zheng Xinya , Ai Hongru , Qian Kewen , Li Guangyao , Zhang Shuyi , Zou Yitan , Lei Changhai , Fu Wenyan , Hu Shi
Published: February 2024

Exosomes are small extracellular vesicles (sEVs) secreted by cells. With advances in the study of sEVs, they have shown great potential in the diagnosis and treatment of disease. However, sEV therapy usually requires a certain dose and purity of sEVs to achieve the therapeutic effect, but the existing sEV purification technology exists in the form of low yield, low purity, time-consuming, complex operation and many other problems, which greatly limits the application of sEVs. Therefore, how to obtain high-purity and high-quality sEVs quickly and efficiently, and make them realize large-scale production is a major problem in current sEV research. This paper discusses how to improve the purity and yield of sEVs from the whole production process of sEVs, including the upstream cell line selection and cell culture process, to the downstream isolation and purification, quality testing and the final storage technology.
Brain imaging derived phenotypes: a biomarker for the onset of inflammatory bowel disease and a potential mediator of mental complications
Authors: Li Fan , Zhao Qi , Tang Tongyu , Liu Yuyuan , Wang Zhaodi , Wang Zhi , Han Xiaoping , Xu Zifeng , Chang Yu , Li Yuqin
Published: February 2024

Background and aims

Inflammatory bowel disease (IBD), mainly categorized into Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic relapsing gastrointestinal disorder that significantly impairs patients’ quality of life. IBD patients often experience comorbidities such as anxiety and depression, and the underlying mechanisms and treatment strategies remain areas of investigation.

Methods

We conducted a Mendelian randomization(MR) analysis utilizing brain image derived phenotypes (IDP) from the UK Biobank database to investigate the causal relationships between IBD and alterations in brain structural morphology and connectivity of neural tracts. This study aimed to identify biological evidence linking IBD to psychiatric disorders such as anxiety and depression.

Results

Specifically, the volume of grey matter in the Left Frontal Orbital Cortex exhibited a negative association with the onset of Crohn’s disease (odds ratio (OR) [95% confidence interval (CI)]: 0.315[0.180~0.551], adjusted P=0.001), while the volume of the superior frontal cortex in the right hemisphere showed a positive correlation with the development of Ulcerative colitis (OR [95% CI]: 2.285[1.793~2.911], adjusted P<0.001), and the volume of lateral occipital cortex in the left hemisphere demonstrated a positive relationship with Crohn’s disease onset (OR [95% CI]: 1.709[1.671~1.747], adjusted P<0.001). In the context of reverse causality, the onset of UC or CD has led to alterations in imaging derived phenotypes associated with five disorders (anxiety, depression, schizophrenia, bipolar disorder, pain) and three functions (memory, emotion, language).

Conclusion

Our study has demonstrated a causal relationship between IBD and IDPs. IDPs may serve as potential biomarkers for the progression of IBD and as predictive intermediaries for the development of neurological diseases in IBD patients.
Abnormal functional lymphoid tolerance and enhanced myeloid exocytosis are characteristics of resting and stimulated PBMCs in cystic fibrosis patients
Authors: Gaudin Clémence , Ghinnagow Reem , Lemaire Flora , Villeret Bérengère , Sermet-Gaudelus Isabelle , Sallenave Jean-Michel
Published: February 2024

Introduction

Cystic Fibrosis (CF) is the commonest genetically inherited disease (1 in 4,500 newborns) and 70% of people with CF (pwCF) harbour the F508Del mutation, resulting in misfolding and incorrect addressing of the channel CFTR to the epithelial membrane and subsequent dysregulation of fluid homeostasis. Although studies have underscored the importance and over-activation of myeloid cells, and in particular neutrophils in the lungs of people with CF (pwCF), relatively less emphasis has been put on the potential immunological bias in CF blood cells, at homeostasis or following stimulation/infection.

Methods

Here, we revisited, in an exhaustive fashion, in pwCF with mild disease (median age of 15, median % FEV1 predicted = 87), whether their PBMCs, unprimed or primed with a ‘non specific’ stimulus (PMA+ionomycin mix) and a ‘specific’ one (live P.a =PAO1 strain), were differentially activated, compared to healthy controls (HC) PBMCs.

Results

1) we analysed the lymphocytic and myeloid populations present in CF and Control PBMCs (T cells, NKT, Tgd, ILCs) and their production of the signature cytokines IFN-g, IL-13, IL-17, IL-22. 2) By q-PCR, ELISA and Luminex analysis we showed that CF PBMCs have increased background cytokines and mediators production and a partial functional tolerance phenotype, when restimulated. 3) we showed that CF PBMCs low-density neutrophils release higher levels of granule components (S100A8/A9, lactoferrin, MMP-3, MMP-7, MMP-8, MMP-9, NE), demonstrating enhanced exocytosis of potentially harmful mediators.

Discussion

In conclusion, we demonstrated that functional lymphoid tolerance and enhanced myeloid protease activity are key features of cystic fibrosis PBMCs.
Reduced toxicity matched sibling bone marrow transplant results in excellent outcomes for severe congenital neutropenia
Authors: Oved Joseph H. , Gibson Nora M. , Venella Kimberly , Elgarten Caitlin W. , Wray Lisa , Warren Julia T. , Olson Timothy S.
Published: February 2024

Severe congenital neutropenia (SCN) is caused by germline mutations, most commonly in ELANE, impacting neutrophil maturation and leading to high risk of life-threatening infections. Most patients with ELANE-mutant SCN can achieve safe neutrophil counts with chronic Granulocyte-Colony Stimulating Factor (G-CSF). However, up to 10% of patients have neutropenia refractory to G-CSF and require allogeneic stem cell transplant. Traditional conditioning for these patients includes busulfan and cyclophosphamide which is associated with significant toxicities. We present five patients with SCN without myeloid malignancy transplanted using a reduced toxicity regimen of busulfan, fludarabine and thymoglobulin. 5 pediatric patients with SCN underwent matched sibling donor bone marrow transplant (MSD-BMT) between 2014-2022 on or per CHP14BT057 (NCT02928991), a prospective, single center trial testing elimination of cyclophosphamide from conditioning in pediatric patients with single lineage inherited BMF syndromes. All patients had MSDs and no evidence of MDS. Conditioning consisted of PK-adjusted busulfan, fludarabine, and thymoglobulin, with calcineurin inhibitor and mycophenolate mofetil GVHD prophylaxis. With median follow-up of 48.4 months, overall and event-free survival were 100%. There was no acute GVHD and one instance of chronic limited GVHD. Patients exhibited >95% donor myeloid chimerism at 5 years post-BMT. Two patients experienced CMV reactivation without end-organ disease, and no other viral reactivation or significant infections occurred. MSD-BMT with reduced toxicity myeloablation for SCN provides excellent outcomes while minimizing toxicity. These data suggest that busulfan, fludarabine, and ATG can be considered an efficacious, low-toxicity standard of care regimen for patients with SCN undergoing MSD-BMT.
Association between the risk of malnutrition and sarcopenia at 4.2 years of follow-up in community-dwelling older adults
Authors: Vidaña-Espinoza Helen J. , López-Teros Miriam T. , Esparza-Romero Julián , Rosas-Carrasco Oscar , Luna-López Armando , Alemán Mateo Heliodoro
Published: February 2024

Introduction

Currently, there is only scarce evidence of a causal association between risk of malnutrition (RM) by the mini-nutritional assessment (MNA) and the incidence of sarcopenia. This study was designed to assess such an association at 4.2 years of follow-up in community-dwelling subjects over 60 years old.

Methods

The data used were from the FraDySMex cohort study. The exposition variables were RM diagnosed by the long forma of the MNA (MNA-LF) and short form (MNA-SF). The last one included the body mass index and calf circumference at baseline, while sarcopenia was diagnosed by the EWGSOP2 at follow-up and taken as the response variable. Several covariates involved in the association were also considered. A multiple logistic regression analysis was performed to test the association.

Results

At baseline, 27.0 and 37.9% of subjects had RM by the MNA-LF and MNA-SF, respectively. The incidence of sarcopenia was 13.7%. The fat mass variable significantly modified the association, so it was tested in each stratum. Two independent models showed that subjects with RM by the MNA-LF in the normal fat mass stratum were at a higher risk for developing sarcopenia at follow-up than those without RM (OR 9.28; IC 95% 1.57–54.76) after adjusting for age, sex, and waist circumference. No association was found for the excess fat mass stratum subjects. Subjects with RM by the MNA-SF in the excess fat mass stratum were more likely to develop sarcopenia at follow-up than those without RM by the MNA-SF (OR 3.67; IC 95% 1.29–10.43). This association was not found in the subjects in the normal fat mass stratum.

Conclusion

The association was dependent on the variable fat mass. The two forms of the MNA should not be applied indistinctly with older adults. Based on these results, it is clear that the risk of malnutrition precedes the onset of sarcopenia.
Characterization of hyperpolarization-activated cyclic nucleotide-gated channels in oligodendrocytes
Authors: Lyman Kyle A. , Han Ye , Robinson Andrew P. , Weinberg Samuel E. , Fisher Daniel W. , Heuermann Robert J. , Lyman Reagan E. , Kim Dong Kyu , Ludwig Andreas , Chandel Navdeep S. , Does Mark D. , Miller Stephen D. , Chetkovich Dane M.
Published: February 2024

Mature oligodendrocytes (OLG) are the myelin-forming cells of the central nervous system. Recent work has shown a dynamic role for these cells in the plasticity of neural circuits, leading to a renewed interest in voltage-sensitive currents in OLG. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and their respective current (Ih) were recently identified in mature OLG and shown to play a role in regulating myelin length. Here we provide a biochemical and electrophysiological characterization of HCN channels in cells of the oligodendrocyte lineage. We observed that mice with a nonsense mutation in the Hcn2 gene (Hcn2ap/ap) have less white matter than their wild type counterparts with fewer OLG and fewer oligodendrocyte progenitor cells (OPCs). Hcn2ap/ap mice have severe motor impairments, although these deficits were not observed in mice with HCN2 conditionally eliminated only in oligodendrocytes (Cnpcre/+; Hcn2F/F). However, Cnpcre/+; Hcn2F/F mice develop motor impairments more rapidly in response to experimental autoimmune encephalomyelitis (EAE). We conclude that HCN2 channels in OLG may play a role in regulating metabolism.
Retinal structure and vessel density changes in cerebral small vessel disease
Authors: Wang Dandan , Wang Lina , Wang Jinjin , Du Yang , Wang Kaiyue , Wang Meizi , Yang Liu , Zhao Xingquan
Published: February 2024

Background

Cerebral small vessel disease (CSVD) attaches people’s attention in recent years. In this study, we aim to explore retinal structure and vessel density changes in CSVD patients.

Methods

We collected information on retinal metrics assessed by optical coherence tomography (OCT) and OCT angiography and CSVD characters. Logistic and liner regression was used to analyze the relationship between retinal metrics and CSVD.

Results

Vessel density of superficial retinal capillary plexus (SRCP), foveal density- 300 length (FD-300), radial peripapillary capillary (RPC) and thickness of retina were significantly lower in CSVD patients, the difference only existed in the thickness of retina after adjusted relevant risk factors (OR (95% CI): 0.954 (0.912, 0.997), p = 0.037). SRCP vessel density showed a significant downward trend with the increase of CSVD scores (β: −0.087, 95%CI: −0.166, −0.008, p = 0.031). SRCP and FD-300 were significantly lower in patients with lacunar infarctions and white matter hypertensions separately [OR (95% CI): 0.857 (0.736, 0.998), p = 0.047 and OR (95% CI): 0.636 (0.434, 0.932), p = 0.020, separately].

Conclusion

SRCP, FD-300 and thickness of retina were associated with the occurrence and severity of total CSVD scores and its different radiological manifestations. Exploring CSVD by observing alterations in retinal metrics has become an optional research direction in future.
Iron quantification in basal ganglia: quantitative susceptibility mapping as a potential biomarker for Alzheimer’s disease – a systematic review and meta-analysis
Authors: Ghaderi Sadegh , Mohammadi Sana , Nezhad Nahid Jashire , Karami Shaghayegh , Sayehmiri Fatemeh
Published: February 2024

Introduction

Alzheimer’s disease (AD), characterized by distinctive pathologies such as amyloid-β plaques and tau tangles, also involves deregulation of iron homeostasis, which may accelerate neurodegeneration. This meta-analysis evaluated the use of quantitative susceptibility mapping (QSM) to detect iron accumulation in the deep gray matter (DGM) of the basal ganglia in AD, contributing to a better understanding of AD progression, and potentially leading to new diagnostic and therapeutic approaches.

Methods

Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched the PubMed, Scopus, Web of Sciences, and Google Scholar databases up to October 2023 for studies employing QSM in AD research. Eligibility criteria were based on the PECO framework, and we included studies assessing alterations in magnetic susceptibility indicative of iron accumulation in the DGM of patients with AD. After initial screening and quality assessment using the Newcastle-Ottawa Scale, a meta-analysis was conducted to compare iron levels between patients with AD and healthy controls (HCs) using a random-effects model.

Results

The meta-analysis included nine studies comprising 267 patients with AD and 272 HCs. There were significantly higher QSM values, indicating greater iron deposition, in the putamen (standardized mean difference (SMD) = 1.23; 95% CI: 0.62 to 1.84; p = 0.00), globus pallidus (SMD = 0.79; 95% CI: 0.07 to 1.52; p = 0.03), and caudate nucleus (SMD = 0.72; 95% CI: 0.39 to 1.06; p = 0.00) of AD patients compared to HCs. However, no significant differences were found in the thalamus (SMD = 1.00; 95% CI: −0.42 to 2.43; p = 0.17). The sensitivity analysis indicated that no single study impacted the overall results. Age was identified as a major contributor to heterogeneity across all basal ganglia nuclei in subgroup analysis. Older age (>69 years) and lower male percentage (≤30%) were associated with greater putamen iron increase in patients with AD.

Conclusion

The study suggests that excessive iron deposition is linked to the basal ganglia in AD, especially the putamen. The study underscores the complex nature of AD pathology and the accumulation of iron, influenced by age, sex, and regional differences, necessitating further research for a comprehensive understanding.
Biopterin metabolism and nitric oxide recoupling in cancer
Authors: Clark Gene Chatman , Lai Alan , Agarwal Aashri , Liu Zheng , Wang Xiang-Yang
Published: February 2024

Tetrahydrobiopterin is a cofactor necessary for the activity of several enzymes, the most studied of which is nitric oxide synthase. The role of this cofactor-enzyme relationship in vascular biology is well established. Recently, tetrahydrobiopterin metabolism has received increasing attention in the field of cancer immunology and immunotherapy due to its involvement in the cytotoxic T cell response. Past research has demonstrated that when the availability of BH4 is low, as it is in chronic inflammatory conditions and tumors, electron transfer in the active site of nitric oxide synthase becomes uncoupled from the oxidation of arginine. This results in the production of radical species that are capable of a direct attack on tetrahydrobiopterin, further depleting its local availability. This feedforward loop may act like a molecular switch, reinforcing low tetrahydrobiopterin levels leading to altered NO signaling, restrained immune effector activity, and perpetual vascular inflammation within the tumor microenvironment. In this review, we discuss the evidence for this underappreciated mechanism in different aspects of tumor progression and therapeutic responses. Furthermore, we discuss the preclinical evidence supporting a clinical role for tetrahydrobiopterin supplementation to enhance immunotherapy and radiotherapy for solid tumors and the potential safety concerns.
Impact of oseltamivir on the risk of cancer
Authors: Chuang Pei-Hua , Tzang Bor-Show , Tzang Chih-Chen , Chiu Chun-Ching , Lin Chun-Yu , Hsu Tsai-Ching
Published: February 2024

Purpose

Mounting evidence has revealed the anti-cancer activity of various anti-viral drugs. Oseltamivir phosphate (OP), namely Tamiflu®, is routinely used to combat influenza infections. Although evidence has indicated the anti-cancer effects of OP in vitro and in vivo, little information is known about the effect of OP use on cancers in humans.

Methods

A nationwide population-based cohort study involving 13,977,101 cases with 284,733 receiving OP was performed to examine the association between OP use and cancers using the National Health Insurance Research Database in Taiwan between 2009 and 2018.

Results

The cohort study found that OP users showed a significantly lower incidence of lung cancer, colon cancer, liver, and intrahepatic bile duct cancer, oral cancer, pancreas cancer, esophagus cancer, stomach cancer, and prostate cancer. Additionally, OP users exhibited a lower risk of cancer-related mortality (adjusted HR=0.779; 95% confidence interval [CI] 0.743-0.817; p<0.001) and a reduced risk of developing liver cancer (adjusted HR=0.895; 95% CI 0.824-0.972; p=0.008), esophagus cancer (adjusted HR=0.646; 95% CI 0.522-0.799; p<0.001) and oral cancer (adjusted HR=0.587; 95% CI 0.346-0.995; p=0.048). Notably, OP users had a significant reduction in liver cancer occurrence over a 10-year period follow-up and a lower cancer stage at liver cancer diagnosis.

Conclusion

These findings first suggest the beneficial effects and therapeutic potential of OP use for certain cancers, especially liver cancer.
Unveiling the mystery: a rare case of localized malignant pericardial mesothelioma—case report
Authors: Zhang Yan , Pang Mingjie
Published: February 2024

Primary malignant pericardial mesothelioma (PMPM) is a rare pericardial malignant tumor. Most manifestations of PMPM are localized or diffuse masses surrounding the heart. The prognosis of diffuse PMPM is poor due to the difficulty of surgical resection. Although the edge of localized PMPM is clear and can be easily resected, the diagnosis of this disease is difficult. Timely diagnosis and proper treatment are key to a good prognosis. Here, we report a patient with localized PMPM and describe the method for the diagnosis of this disease.
Ferroptosis and EMT resistance in cancer: a comprehensive review of the interplay
Authors: Zhang Huiming , Chen Naifeng , Ding Chenglong , Zhang Huinan , Liu Dejiang , Liu Shuang
Published: February 2024

Ferroptosis differs from traditional cell death mechanisms like apoptosis, necrosis, and autophagy, primarily due to its reliance on iron metabolism and the loss of glutathione peroxidase activity, leading to lipid peroxidation and cell death. The dysregulation of iron metabolism is a hallmark of various cancers, contributing to tumor progression, metastasis, and notably, drug resistance. The acquisition of mesenchymal characteristics by epithelial cells is known as Epithelial–Mesenchymal Transition (EMT), a biological process intricately linked to cancer development, promoting traits such as invasiveness, metastasis, and resistance to therapeutic interventions. EMT plays a pivotal role in cancer progression and contributes significantly to the complex dynamics of carcinogenesis. Research findings indicate that mesenchymal cancer cells exhibit greater susceptibility to ferroptosis compared to their epithelial counterparts. The induction of ferroptosis becomes more effective in eliminating drug-resistant cancer cells during the process of EMT. The interplay between ferroptosis and EMT, a process where epithelial cells transform into mobile mesenchymal cells, is crucial in understanding cancer progression. EMT is associated with increased cancer metastasis and drug resistance. The review delves into how ferroptosis and EMT influence each other, highlighting the role of key proteins like GPX4, which protects against lipid peroxidation, and its inhibition can induce ferroptosis. Conversely, increased GPX4 expression is linked to heightened resistance to ferroptosis in cancer cells. Moreover, the review discusses the implications of EMT-induced transcription factors such as Snail, Zeb1, and Twist in modulating the sensitivity of tumor cells to ferroptosis, thereby affecting drug resistance and cancer treatment outcomes. Targeting the ferroptosis pathway offers a promising therapeutic strategy, particularly for tumors resistant to conventional treatments. The induction of ferroptosis in these cells could potentially overcome drug resistance. However, translating these findings into clinical practice presents challenges, including understanding the precise mechanisms of ferroptosis induction, identifying predictive biomarkers, and optimizing combination therapies. The review underscores the need for further research to unravel the complex interactions between ferroptosis, EMT, and drug resistance in cancer. This could lead to the development of more effective, targeted cancer treatments, particularly for drug-resistant tumors, offering new hope in cancer therapeutics.
Phase IV study on the use of benzydamine mouthwash in radiation-induced oral mucositis in patients with head and neck cancer
Authors: Bossi Paolo , Tellone Valeria , Di Loreto Giorgio , Fioravanti Sara , Salvatori Enrica , Comandini Alessandro
Published: February 2024

Introduction

Oral mucositis (OM) is a main side effect of treatment for head and neck cancer (HNC) and causes severe pain, reduces quality of life, and may interrupt HNC treatment. This study assessed the activity and feasibility of benzydamine mouthwash in the prevention and treatment of radiation-induced OM in patients with HNC during radiation therapy (RT).

Methods

This phase IV, international, open-label, single-group study conducted from December 2021 to September 2022. In total, 89 patients were enrolled across seven centers in Hungary and Poland. Patients used benzydamine mouthwash at home two to three times daily. Data were collected during clinical visits at baseline (V0, start of RT) and then weekly for seven visits (V1–V7). The safety population and the modified intention-to-treat (m-ITT) analysis sets contained 89 patients; the per protocol (PP) analysis set contained 67 patients.

Results

The m-ITT set was 80.9% male; mean age was 61.4 years. At baseline, 73.0% of patients had stage T3-T4, 23.6% had stage T1-T2, 61.8% had stage N2-N3, and 34.9% had stage N0-N1. Within the m-ITT population, 33.7% (n=30) responded to treatment (NRS < 5) during the study. The PP set responded similarly (29.9%). Most patients were treatment compliant (n=77; 86.5%). OM severity was assessed using the WHO OM grading scale. No patients had severe mucositis at baseline or V1. At V7, 34.1% had mild mucositis, 45.1% had moderate mucositis, 15.9% had severe mucositis, and 1.2% had life-threatening mucositis. In total, 26 patients (29.2%) developed severe mucositis during the study period (V2–V7). From V1 to V4, one patient reported hospitalization due to mucositis or associated complications, two patients at V5, three patients at V6, and four patients at 7.

Discussion

This was the first study to assess feasibility of a treatment for radiation-induced OM with benzydamine mouthwash in patients with HNC. Treatment compliance suggested that benzydamine was well tolerated in patients with moderate to severe mucositis. Benzydamine’s anesthetic and anti-inflammatory properties might have reduced pain, which potentially influenced patients’ compliance with RT. Few patients in the study required hospitalization for OM or an associated complication, suggesting that benzydamine might improve healthcare resource utilization.
Promoting employee flourishing and performance: the roles of perceived leader emotional intelligence, positive team emotional climate, and employee emotional intelligence
Authors: A'yuninnisa Rizqi N. , Carminati Lara , Wilderom Celeste P. M.
Published: February 2024

Introduction

Through the lens of the of Emotion as Social Information (EASI) model, we examined the influence of perceived leader emotional intelligence on employee job flourishing and performance, produced via employee emotional intelligence, under the condition of positive team emotional climate.

Methods

We collected data with a two-wave survey design involving 1,210 primary school teachers and their 169 leaders. The hypothesized model was then tested using a multilevel structural equation model in Mplus.

Results

As hypothesized, the results suggest that perceived leader emotional intelligence positively affects the emotional intelligence level of followers, which enhances their job flourishing and performance. Reflecting the emotional display rules within the team, positive team emotional climate moderates this effect from leader to followers, in such a way that the relationship between perceived leader emotional intelligence and employee emotional intelligence is stronger when this positive team emotional climate is high rather than low.

Discussion

Our findings shed light on the affective impact of leaders and their teams as relevant sources of socio-emotional information for employees at work. Limitations of the present study and directions for future studies are included in the paper.