bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between the fatty liver index and the risk of fracture among individuals over the age of 50 years: a nationwide population-based study
Authors: Chung Goh Eun , Cho Eun Ju , Kim Min Joo , Yoo Jeong-Ju , Cho Yuri , Lee Kyu-na , Han Kyungdo , Kim Yoon Jun , Yoon Jung-Hwan , Shin Dong Wook , Yu Su Jong
Published: May 2023

Background and purpose

The association between fatty liver and fracture risk has not been firmly established. In this study, we investigated the relationship between the fatty liver index (FLI) and the incidence of fractures among individuals ≥50 years of age, using a nationwide population-based cohort.

Methods

Data from the Korean National Health Insurance System between January 2009 and December 2019 were analyzed using the Cox proportional hazards model. Fatty liver status was defined using FLI. Newly diagnosed fractures were identified based on insurance claim data.

Results

Among the 3,384,457 individuals who met our inclusion criteria over the study period, 444,203 cases of incident fractures were identified over a median follow-up of 10.3 years. On multivariate analysis, the risk of fracture was significantly higher among individuals with a higher FLI score compared to those with an FLI<30, with adjusted hazard ratio [aHR] and 95% confidence interval [CI] as follows: FLI 30-59 group, aHR 1.04 and 95% CI 1.03-1.05; and FLI ≥60 group, aHR 1.12 and 95% CI 1.10–1.13. A higher FLI was associated with a greater risk of hip (aHR 1.23 and 1.52 for the FLI 30-59 and FLI ≥60 group, respectively) and vertebral fracture (aHR 1.08 and 1.16 for the FLI 30-59 and FLI≥60 group, respectively). The association between the risk for fracture and FLI ≥60 was prominent for non-obese than obese individuals (aHR 1.25 and 95% CI, 1.22–1.27 versus 1.06 and 1.05–1.08, respectively).

Conclusions

A high FLI is associated with an increased risk of hip and vertebral fractures among individuals ≥50 years of age, suggestive of an association between a higher FLI and osteoporotic fractures.
Toward an open access genomics database of South Africans: ethical considerations
Authors: Gooden Amy , Thaldar Donrich
Published: May 2023

Genomics research holds the potential to improve healthcare. Yet, a very low percentage of the genomic data used in genomics research internationally relates to persons of African origin. Establishing a large-scale, open access genomics database of South Africans may contribute to solving this problem. However, this raises various ethics concerns, including privacy expectations and informed consent. The concept ofopen consentoffers a potential solution to these concerns by (a) being explicit about the research participant’s data being in the public domain and the associated privacy risks, and (b) setting a higher-than-usual benchmark for informed consent by making use of the objective assessment of prospective research participants’ understanding. Furthermore, in the South African context—where local culture is infused with Ubuntu and its relational view of personhood—community engagement is vital for establishing and maintaining an open access genomics database of South Africans. The South African National Health Research Ethics Council is called upon to provide guidelines for genomics researchers—based on open consent and community engagement—on how to plan and implement open access genomics projects.
Gut microbiome homeostasis and the future of probiotics in cancer immunotherapy
Authors: Singh Ankita , Alexander Sharon Grace , Martin Sunil
Published: May 2023

The gut microbiome has an impact on cancer immune surveillance and immunotherapy, with recent studies showing categorical differences between immunotherapy-sensitive and immunotherapy-resistant cancer patient cohorts. Although probiotics are traditionally being supplemented to promote treatments or sustain therapeutic benefits; the FDA has not approved any for use with immunotherapy. The first step in developing probiotics for immunotherapy is identifying helpful or harmful bacteria down to the strain level. The gut microbiome’s heterogeneity before and during treatment is also being investigated to determine microbial strains that are important for immunotherapy. Moreover, Dietary fiber intake, prebiotic supplementation and fecal microbiota transplantation (FMT) were found to enhance intratumoral CD8+ T cell to T-reg ratio in the clinics. The possibility of probiotic immunotherapy as a “living adjuvant” to CAR treatment and checkpoint blockade resistance is actively being investigated.
Role of the cGAS/STING pathway in the control of Brucella abortus infection acquired through the respiratory route
Authors: Alonso Paiva Iván M. , A. Santos Raiany , Brito Camila B. , Ferrero Mariana C. , Ortiz Wilczyñski Juan Manuel , Silva Eugenio A. Carrera , C. Oliveira Sergio , Baldi Pablo C.
Published: May 2023

Despite the importance of the respiratory route for Brucella transmission, the lung immune response to this pathogen is scarcely characterized. We investigated the role of the cGAS/STING pathway of microbial DNA recognition in the control of respiratory Brucella infection. After in vitro B. abortus infection, CFU numbers were significantly higher in alveolar macrophages (AM) and lung explants from STING KO mice than in samples from wild type (WT) mice, but no difference was observed for cGAS KO samples. CFU were also increased in WT AM and lung epithelial cells preincubated with the STING inhibitor H151. Several proinflammatory cytokines (TNF-α, IL-1β, IL-6, IP-10/CXCL10) were diminished in Brucella-infected lung explants and/or AM from STING KO mice and cGAS KO mice. These cytokines were also reduced in infected AM and lung epithelial cells pretreated with H151. After intratracheal infection with B. abortus, STING KO mice exhibited increased CFU in lungs, spleen and liver, a reduced expression of IFN-β mRNA in lungs and spleen, and reduced levels of proinflammatory cytokines and chemokines in bronchoalveolar lavage fluid (BALF) and lung homogenates. Increased lung CFU and reduced BALF cytokines were also observed in cGAS KO mice. In summary, the cGAS/STING pathway induces the production of proinflammatory cytokines after respiratory Brucella infection, which may contribute to the STING-dependent control of airborne brucellosis.
Cytokine/chemokine profiles in people with recent infection by Mycobacterium tuberculosis
Authors: Herrera Mariana , Keynan Yoav , Lopez Lucelly , Marín Diana , Vélez Lázaro , McLaren Paul J. , Rueda Zulma Vanessa
Published: May 2023

Introduction

The risk of progression to tuberculosis disease is highest within the first year after M. tuberculosis infection (TBI). We hypothesize that people with newly acquired TBI have a unique cytokine/chemokine profile that could be used as a potential biomarker.

Methods

We evaluated socio-demographic variables and 18 cytokines/chemokines in plasma samples from a cohort of people deprived of liberty (PDL) in two Colombian prisons: 47 people diagnosed with pulmonary TB, 24 with new TBI, and 47 non-infected individuals. We performed a multinomial regression to identify the immune parameters that differentiate the groups.

Results

The concentration of immune parameters changed over time and was affected by the time of incarceration. The concentration of sCD14, IL-18 and IP-10 differed between individuals with new TBI and short and long times of incarceration. Among people with short incarceration, high concentrations of MIP-3α were associated with a higher risk of a new TBI, and higher concentrations of Eotaxin were associated with a lower risk of a new TBI. Higher concentrations of sCD14 and TNF-α were associated with a higher risk of TB disease, and higher concentrations of IL-18 and MCP-1 were associated with a lower risk of TB disease.

Conclusions

There were cytokines/chemokines associated with new TBI and TB disease. However, the concentration of immune mediators varies by the time of incarceration among people with new TBI. Further studies should evaluate the changes of these and other cytokines/chemokines over time to understand the immune mechanisms across the spectrum of TB.
Control of enhancer and promoter activation in the type I interferon response by the histone demethylase Kdm4d/JMJD2d
Authors: Chandwani Rohit , Fang Terry C. , Dewell Scott , Tarakhovsky Alexander
Published: May 2023

Introduction

Transcriptional activation depends on the interplay of chromatin modifiers to establish a permissive epigenetic landscape. While histone 3 lysine 9 (H3K9) methylation has long been associated with gene repression, there is limited evidence to support a role for H3K9 demethylases in gene activation.

Methods

We leveraged knockdown and overexpression of JMJD2d / Kdm4d in mouse embryonic fibroblasts, coupled with extensive epigenomic analysesm to decipher the role of histone 3 lysine 9 demethylases in the innate immune response.

Results

Here we describe the H3K9 demethylase Kdm4d/JMJD2d as a positive regulator of type I interferon responses. In mouse embryonic fibroblasts (MEFs), depletion of JMJD2d attenuates the transcriptional response, conferring increased viral susceptibility, while overexpression of the demethylase results in more robust IFN activation. We find that the underlying mechanism of JMJD2d in type I interferon responses consists of an effect both on the transcription of enhancer RNAs (eRNAs) and on dynamic H3K9me2 at associated promoters. In support of these findings, we establish that JMJD2d is associated with enhancer regions throughout the genome prior to stimulation but is redistributed to inducible promoters in conjunction with transcriptional activation.

Discussion

Taken together, our data reveal JMJD2d as a chromatin modifier that connects enhancer transcription with promoter demethylation to modulate transcriptional responses.
Noninvasive mechanical destruction of liver tissue and tissue decellularisation by pressure-modulated shockwave histotripsy
Authors: Pahk Ki Joo , Heo Jeongmin , Joung Chanmin , Pahk Kisoo
Published: May 2023

Introduction

Boiling histotripsy (BH) is a promising High Intensity Focused Ultrasound (HIFU) technique that can be used to mechanically fractionate solid tumours at the HIFU focus noninvasively, promoting tumour immunity. Because of the occurrence of shock scattering phenomenon during BH process, the treatment accuracy of BH is, however, somewhat limited. To induce more localised and selective tissue destruction, the concept of pressure modulation has recently been proposed in our previous in vitro tissue phantom study. The aim of the present study was therefore to investigate whether this newly developed histotripsy approach termed pressure-modulated shockwave histotripsy (PSH) can be used to induce localised mechanical tissue fractionation in in vivo animal model.

Methods

In the present study, 8 Sprague Dawley rats underwent the PSH treatment and were sacrificed immediately after the exposure for morphological and histological analyses (paraffin embedded liver tissue sections were stained with H&E and MT). Partially exteriorised rat’s left lateral liver lobe in vivo was exposed to a 2.0 MHz HIFU transducer with peak positive (P+) and negative (P-) pressures of 89.1 MPa and –14.6 MPa, a pulse length of 5 to 34 ms, a pressure modulation time at 4 ms where P+ and P- decreased to 29.9 MPa and – 9.6 MPa, a pulse repetition frequency of 1 Hz, a duty cycle of 1% and number of pulses of 1 to 20. Three lesions were produced on each animal. For comparison, the same exposure condition but no pressure modulation was also employed to create a number of lesions in the liver.

Results and Discussion

Experimental results showed that a partial mechanical destruction of liver tissue in the form of an oval in the absence of thermal damage was clearly observed at the HIFU focus after the PSH exposure. With a single pulse length of 7 ms, a PSH lesion created in the liver was measured to be a length of 1.04 ± 0.04 mm and a width of 0.87 ± 0.21 mm which was 2.37 times in length (p = 0.027) and 1.35 times in width (p = 0.1295) smaller than a lesion produced by no pressure modulation approach (e.g., BH). It was also observed that the length of a PSH lesion gradually grew towards the opposite direction to the HIFU source along the axial direction with the PSH pulse length, eventually leading to the generation of an elongated lesion in the liver. In addition, our experimental results demonstrated the feasibility of inducing partial decellularisation effect where liver tissue was partially destructed with intact extracellular matrix (i.e., intact fibrillar collagen) with the shortest PSH pulse length. Taken together, these results suggest that PSH could be used to induce a highly localised tissue fractionation with a desired degree of mechanical damage from complete tissue fractionation to tissue decellularisation through controlling the dynamics of boiling bubbles without inducing the shock scattering effect.
Bioinformatics and system biology approach to identify the influences among COVID-19, ARDS and sepsis
Authors: Li Peiyu , Li Tao , Zhang Zhiming , Dai Xingui , Zeng Bin , Li Zhen , Li Zhiwang
Published: May 2023

Background Severe coronavirus disease 2019 (COVID -19) has led to severe pneumonia or acute respiratory distress syndrome (ARDS) worldwide. we have noted that many critically ill patients with COVID-19 present with typical sepsis-related clinical manifestations, including multiple organ dysfunction syndrome, coagulopathy, and septic shock. The molecular mechanisms that underlie COVID-19, ARDS and sepsis are not well understood. The objectives of this study were to analyze potential molecular mechanisms and identify potential drugs for the treatment of COVID-19, ARDS and sepsis using bioinformatics and a systems biology approach. Methods Three RNA-seq datasets (GSE171110, GSE76293 and GSE137342) from Gene Expression Omnibus (GEO) were employed to detect mutual differentially expressed genes (DEGs) for the patients with the COVID-19, ARDS and sepsis for functional enrichment, pathway analysis, and candidate drugs analysis. Results We obtained 110 common DEGs among COVID-19, ARDS and sepsis. ARG1, FCGR1A, MPO, and TLR5 are the most influential hub genes. The infection and immune-related pathways and functions are the main pathways and molecular functions of these three diseases. FOXC1, YY1, GATA2, FOXL, STAT1 and STAT3 are important TFs for COVID-19. mir-335-5p, miR-335-5p and hsa-mir-26a-5p were associated with COVID-19. Finally, the hub genes retrieved from the DSigDB database indicate multiple drug molecules and drug-targets interaction. Conclusion We performed a functional analysis under ontology terms and pathway analysis and found some common associations among COVID-19, ARDS and sepsis. Transcription factors–genes interaction, protein–drug interactions, and DEGs-miRNAs coregulatory network with common DEGs were also identified on the datasets. We believe that the candidate drugs obtained in this study may contribute to the effective treatment of COVID-19.
Loss of interleukin-1 beta is not protective in the lupus-prone NZM2328 mouse model
Authors: Loftus Shannon N. , Liu Jianhua , Berthier Celine C. , Gudjonsson Johann E. , Gharaee-Kermani Mehrnaz , Tsoi Lam C. , Kahlenberg J. Michelle
Published: May 2023

Aberrant activation of the innate immune system is a known driver of lupus pathogenesis. Inhibition of the inflammasome and its downstream signaling components in murine models of lupus has been shown to reduce the severity of disease. Interleukin-1 beta (IL-1β) is a proinflammatory cytokine released from cells following inflammasome activation. Here, we examine how loss of IL-1β affects disease severity in the lupus-prone NZM2328 mouse model. We observed a sex-biased increase in immune complex deposition in the kidneys of female mice in the absence of IL-1β that corresponds to worsened proteinuria. Loss of IL-1β did not result in changes in overall survival, anti-dsDNA autoantibody production, or renal immune cell infiltration. RNA-sequencing analysis identified upregulation of TNF and IL-17 signaling pathways specifically in females lacking IL-1β. Increases in these signaling pathways were also found in female patients with lupus nephritis, suggesting clinical relevance for upregulation of these pathways. Together, these data suggest that inhibition of the inflammasome or its downstream elements that block IL-1β signaling may need to be approached with caution in SLE, especially in patients with renal involvement to prevent potential disease exacerbation.
Dysregulated early transcriptional signatures linked to mast cell and interferon responses are implicated in COVID-19 severity
Authors: MacCann Rachel , Leon Alejandro Abner Garcia , Gonzalez Gabriel , Carr Michael J. , Feeney Eoin R. , Yousif Obada , Cotter Aoife G. , de Barra Eoghan , Sadlier Corinna , Doran Peter , Mallon Patrick W.
Published: May 2023

Background

Dysregulated immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are thought to underlie the progression of coronavirus disease 2019 (COVID-19) to severe disease. We sought to determine whether early host immune-related gene expression could predict clinical progression to severe disease.

Methods

We analysed the expression of 579 immunological genes in peripheral blood mononuclear cells taken early after symptom onset using the NanoString nCounter and compared SARS-CoV-2 negative controls with SARS-CoV-2 positive subjects with mild (SARS+ Mild) and Moderate/Severe disease to evaluate disease outcomes. Biobanked plasma samples were also assessed for type I (IFN-α2a and IFN-β), type II (IFN-γ) and type III (IFN-λ1) interferons (IFNs) as well as 10 additional cytokines using multiplex immunoassays.

Results

We identified 19 significantly deregulated genes in 62 SARS-CoV-2 positive subject samples within 5 days of symptom onset and 58 SARS-CoV-2 negative controls and found that type I interferon (IFN) signalling (MX1, IRF7, IFITM1, IFI35, STAT2, IRF4, PML, BST2, STAT1) and genes encoding proinflammatory cytokines (TNF, TNFSF4, PTGS2 and IL1B) were upregulated in both SARS+ groups. Moreover, we found that FCER1, involved in mast cell activation, was upregulated in the SARS+ Mild group but significantly downregulated in the SARS+ Moderate/Severe group. In both SARS+ groups we discovered elevated interferon type I IFN-α2a, type II IFN and type III IFN λ1 plasma levels together with higher IL-10 and IL-6. These results indicate that those with moderate or severe disease are characterised by deficiencies in a mast cell response together with IFN hyper-responsiveness, suggesting that early host antiviral immune responses could be a cause and not a consequence of severe COVID-19.

Conclusions

This study suggests that early host immune responses linking defects in mast cell activation with host interferon responses correlates with more severe outcomes in COVID-19. Further characterisation of this pathway could help inform better treatment for vulnerable individuals.
Dendritic cell activation and cytokine response in vaccine breakthrough TBE patients after in vitro stimulation with TBEV
Authors: Marušić Miša , Kopitar Andreja Nataša , Korva Miša , Knap Nataša , Bogovič Petra , Strle Franc , Ihan Alojz , Avšič-Županc Tatjana
Published: May 2023

Tick-borne encephalitis (TBE) is a viral infection of the human central nervous system caused by the TBE virus (TBEV). The most effective protective measure against TBE is vaccination. Despite the highly immunogenic vaccine, cases of vaccine breakthroughs (VBTs) occur. One of the first targets of infection is dendritic cells (DC), which represent a fundamental bridge between innate and adaptive immunity through antigen presentation, costimulation, and cytokine production. Therefore, we investigated the activation and maturation of DCs and cytokine production after in vitro TBEV stimulation of peripheral blood mononuclear cells (PBMCs) obtained from VBT and unvaccinated TBE patients. Our results showed that the expression of HLA-DR and CD86 on DCs, was upregulated to a similar extent in both vaccinated and unvaccinated TBE patients but differed in cytokine production after stimulation with TBEV. PBMCs from patients with VBT TBE responded with lower levels of IFN-α and the proinflammatory cytokines IL-12 (p70) and IL-15 after 24- and 48-hour in vitro stimulation with TBEV, possibly facilitating viral replication and influencing the development of cell-mediated immunity. On the other hand, significantly higher levels of IL-6 in addition to an observed trend of higher expression of TNF-α measured after 6 days of in vitro stimulation of PBMC could support disruption of the blood–brain barrier and promote viral and immune cell influx into the CNS, leading to more severe disease in VBT TBE patients.
Vaccine-induced immune thrombotic thrombocytopenia: what do we know hitherto?
Authors: Roytenberg Renat , García-Sastre Adolfo , Li Wei
Published: May 2023

Vaccine-induced immune thrombotic thrombocytopenia (VITT), also known as thrombosis with thrombocytopenia syndrome, is a catastrophic and life-threatening reaction to coronavirus disease 2019 (COVID-19) vaccines, which occurs disproportionately in response to vaccination with non-replicating adenovirus vector (AV) vaccines. The mechanism of VITT is not well defined and it has not been resolved why cases of VITT are predominated by vaccination with AV vaccines. However, virtually all VITT patients have positive platelet-activating anti-platelet factor 4 (PF4) antibody titers. Subsequently, platelets are activated and depleted in an Fcγ-receptor IIa (FcγRIIa or CD32a)-dependent manner, but it is not clear why or how the anti-PF4 response is mounted. This review describes the pathogenesis of VITT and provides insight into possible mechanisms that prompt the formation of a PF4/polyanion complex, which drives VITT pathology, as an amalgam of current experimental data or hypotheses.
A host-specific diaminobutyrate aminotransferase contributes to symbiotic performance, homoserine metabolism, and competitiveness in the Rhizobium leguminosarum/Pisum sativum system
Authors: Ballesteros-Gutiérrez Marta , Albareda Marta , Barbas Coral , López-Gonzálvez Ángeles , Dunn Michael F. , Palacios José M.
Published: May 2023

Rhizobium leguminosarum bv. viciae (Rlv) UPM791 effectively nodulates pea and lentil, but bacteroids contain a number of proteins differentially expressed depending on the host. One of these host-dependent proteins (C189) is similar to a diaminobutyrate-2-oxoglutarate aminotransferase (DABA-AT). DABA-AT activity was demonstrated with cell extracts and with purified protein, so C189 was renamed as Dat. The dat gene was strongly induced in the central, active area of pea nodules, but not in lentil. Mutants defective in dat were impaired in symbiotic performance with pea plants, exhibiting reduced shoot dry weight, smaller nodules, and a lower competitiveness for nodulation. In contrast, there were no significant differences between mutant and wild-type in symbiosis with lentil plants. A comparative metabolomic approach using cell-free extracts from bacteroids induced in pea and lentil showed significant differences among the strains in pea bacteroids whereas no significant differences were found in lentil. Targeted metabolomic analysis revealed that the dat mutation abolished the presence of 2,4-diaminobutyrate (DABA) in pea nodules, indicating that DABA-AT reaction is oriented toward the production of DABA from L-aspartate semialdehyde. This analysis also showed the presence of L-homoserine, a likely source of aspartate semialdehyde, in pea bacteroids but not in those induced in lentil. The dat mutant showed impaired growth when cells were grown with L-homoserine as nitrogen source. Inclusion of DABA or L-homoserine as N source suppressed pantothenate auxotropy in Rlv UPM791, suggesting DABA as source of the pantothenate precursor β-alanine. These data indicate that Rlv UPM791 Dat enzyme is part of an adaptation mechanism of this bacterium to a homoserine-rich environment such as pea nodule and rhizosphere.
Collagen mimetic peptide repair of the corneal nerve bed in a mouse model of dry eye disease
Authors: Wareham Lauren K. , Holden Joseph M. , Bossardet Olivia L. , Baratta Robert O. , Del Buono Brian J. , Schlumpf Eric , Calkins David J.
Published: May 2023

The intraepithelial sub-basal nerve plexus of the cornea is characterized by a central swirl of nerve processes that terminate between the apical cells of the epithelium. This plexus is a critical component of maintaining homeostatic function of the ocular surface. The cornea contains a high concentration of collagen, which is susceptible to damage in conditions such as neuropathic pain, neurotrophic keratitis, and dry eye disease. Here we tested whether topical application of a collagen mimetic peptide (CMP) is efficacious in repairing the corneal sub-basal nerve plexus in a mouse model of ocular surface desiccation. We induced corneal tear film reduction, epithelial damage, and nerve bed degradation through a combination of environmental and pharmaceutical (atropine) desiccation. Mice were subjected to desiccating air flow and bilateral topical application of 1% atropine solution (4× daily) for 2 weeks. During the latter half of this exposure, mice received topical vehicle [phosphate buffered saline (PBS)] or CMP [200 μm (Pro-Pro-Gly)7, 10 μl] once daily, 2 h prior to the first atropine treatment for that day. After euthanasia, cornea were labeled with antibodies against βIII tubulin to visualize and quantify changes to the nerve bed. For mice receiving vehicle only, the two-week desiccation regimen reduced neuronal coverage of the central sub-basal plexus and epithelial terminals compared to naïve, with some corneas demonstrating complete degeneration of nerve beds. Accordingly, both sub-basal and epithelial βIII tubulin-labeled processes demonstrated increased fragmentation, indicative of nerve disassembly. Treatment with CMP significantly reduced nerve fragmentation, expanded both sub-basal and epithelial neuronal coverage compared to vehicle controls, and improved corneal epithelium integrity, tear film production, and corneal sensitivity. Together, these results indicate that topical CMP significantly counters neurodegeneration characteristic of corneal surface desiccation. Repairing underlying collagen in conditions that damage the ocular surface could represent a novel therapeutic avenue in treating a broad spectrum of diseases or injury.
Between life and death: the brain twilight zones
Authors: Charpier Stéphane
Published: May 2023

Clinically, and legally, death is considered a well-defined state of the organism characterized, at least, by a complete and irreversible cessation of brain activities and functions. According to this pragmatic approach, the moment of death is implicitly represented by a discrete event from which all cerebral processes abruptly cease. However, a growing body of experimental and clinical evidence has demonstrated that cardiorespiratory failure, the leading cause of death, causes complex time-dependent changes in neuronal activity that can lead to death but also be reversed with successful resuscitation. This review synthesizes our current knowledge of the succeeding alterations in brain activities that accompany the dying and resuscitation processes. The anoxia-dependent brain defects that usher in a process of potential death successively include: (1) a set of changes in electroencephalographic (EEG) and neuronal activities, (2) a cessation of brain spontaneous electrical activity (isoelectric state), (3) a loss of consciousness whose timing in relation to EEG changes remains unclear, (4) an increase in brain resistivity, caused by neuronal swelling, concomitant with the occurrence of an EEG deviation reflecting the neuronal anoxic insult (the so-called “wave of death,” or “terminal spreading depolarization”), followed by, (5) a terminal isoelectric brain state leading to death. However, a timely restoration of brain oxygen supply—or cerebral blood flow—can initiate a mirrored sequence of events: a repolarization of neurons followed by a re-emergence of neuronal, synaptic, and EEG activities from the electrocerebral silence. Accordingly, a recent study has revealed a new death-related brain wave: the “wave of resuscitation,” which is a marker of the collective recovery of electrical properties of neurons at the beginning of the brain’s reoxygenation phase. The slow process of dying still represents a terra incognita, during which neurons and neural networks evolve in uncertain states that remain to be fully understood. As current event-based models of death have become neurophysiologically inadequate, I propose a new mixed (event-process) model of death and resuscitation. It is based on a detailed description of the different phases that succeed each other in a dying brain, which are generally described separately and without mechanistic linkage, in order to integrate them into a continuum of declining brain activity. The model incorporates cerebral twilight zones (with still unknown neuronal and synaptic processes) punctuated by two characteristic cortical waves providing real-time biomarkers of death- and resuscitation.
Association between diagnostic criteria for severe acute malnutrition and hospital mortality in children aged 6–59 months in the eastern Democratic Republic of Congo: the Lwiro cohort study
Authors: Ngaboyeka Gaylord , Bisimwa Ghislain , Neven Anouk , Mwene-Batu Pacifique , Kambale Richard , Kingwayi Petit Passy , Chiribagula Christian , Battisti Oreste , Dramaix Michèle , Donnen Philippe
Published: May 2023

Background

Few studies have assessed the relationship between weight-for-height (WHZ) and mid-upper arm circumference (MUAC) with hospital mortality considering confounders. The particularity of MUAC for age (MUACZ) is less documented.

Objective

This study aims to investigate this relationship in a region endemic for severe acute malnutrition (SAM).

Methods

This is a retrospective cohort based on a database of children admitted from 1987 to 2008 in South Kivu, eastern DRC. Our outcome was hospital mortality. To estimate the strength of the association between mortality and nutritional indices, the relative risk (RR) with its 95% confidence interval (95% CI) was calculated. In addition to univariate analyses, we constructed multivariate models from binomial regression.

Results

A total of 9,969 children aged 6 to 59 months were selected with a median age of 23 months. 40.9% had SAM (according to the criteria WHZ < -3 and/or MUAC<115 mm and/or the presence of nutritional edema) including 30.2% with nutritional edema and 35.2% had both SAM and chronic malnutrition. The overall hospital mortality was 8.0% and was higher at the beginning of data collection (17.9% in 1987). In univariate analyses, children with a WHZ < -3 had a risk almost 3 times higher of dying than children without SAM. WHZ was more associated with in-hospital mortality than MUAC or MUACZ. Multivariate models confirmed the univariate results. The risk of death was also increased by the presence of edema.

Conclusion

In our study, WHZ was the indicator more associated with hospital death compared with MUAC or MUACZ. As such, we recommend that all criteria shall continue to be used for admission to therapeutic SAM programs. Efforts should be encouraged to find simple tools allowing the community to accurately measure WHZ and MUACZ.
Sarcobesity, but not visceral fat, is an independent risk factor for complications after radical resection of colorectal cancer
Authors: Feng Zhewen , Pang Kai , Tian Mingwei , Gu Xiaozhe , Lin Huajun , Yang Xiaobao , Yang Yingchi , Zhang Zhongtao
Published: May 2023

Background

The influence of body composition on the outcome of colorectal cancer surgery is controversial. The aim of this study was to evaluate the effects of visceral obesity and sarcobesity on the incidence of total and surgical complications after radical resection of colorectal cancer.

Methods

We collected a total of 426 patients who underwent elective radical resection of colorectal cancer at Beijing Friendship Hospital, Capital Medical University from January 2017 to May 2018. According to the inclusion and exclusion criteria, 387 patients were finally included. A CT scan at the level of the L3-L4 intervertebral disk was selected to measure the values of visceral fat area and skeletal muscle area. Multivariate analysis was used to explore the independent risk/protective factors affecting postoperative complications.

Results

128 (33.1%) patients developed complications, and 44 (11.4%) patients developed major complications. Among them, 111 patients developed surgical complications and 21 developed medical complications. Visceral fat area (Z = −3.271, p = 0.001), total fat area (Z = −2.613, p = 0.009), visceral fat area to subcutaneous fat area ratio (V/S, Z = −2.633, p = 0.008), and sarcobesity index (Z = −2.282, p = 0.023) were significantly associated with total complications. Visceral fat area (Z = −2.119, p = 0.034) and V/S (Z = −2.010, p = 0.044) were significantly associated with total surgical complications. Sarcobesity index, smoking, stoma, blood loss, surgery time, and American Society of Anesthesiology (ASA) score were selected as risk factors for total postoperative complications according to LASSO regression. Multivariate logistic regression analysis suggested that sarcobesity index was an independent risk factor for postoperative total complications and surgical complications. Subgroup analysis suggested that albumin level was an independent protective factor for postoperative total complications in male patients. Smoking, operative time, and sarcobesity index were independent risk factors, and cholesterol was an independent protective factor for total postoperative complications in female patients.

Conclusion

Increased sarcobesity index is an independent risk factor for postoperative complications in patients with colorectal cancer, while visceral fat area is not. For female patients, smoking, operation time, and obesity index are independent risk factors for postoperative complications, while cholesterol is an independent protective factor. For male patients, serum albumin is an independent protective factor for postoperative complications.
Harnessing sponge gourd: an alternative source of oil and protein for nutritional security
Authors: Tyagi Ruchi , Bhardwaj Rakesh , Suneja Poonam , Sureja Amish K. , Munshi Anilabh D. , Arya Lalit , Riar Amritbir , Verma Manjusha
Published: May 2023

Luffa cylindrica (L.) Roem. is an important cucurbit crop that assures food security and dietary diversity among the poor communities. In the present study, seeds of 42 genotypes of Luffa cylindrica were evaluated for their potential use as oil seed crop. Seed moisture, oil and protein content and fatty acids profile were estimated along with total phenol and sugar content. Significant differences were observed among the various genotypes where oil content ranged from 15.4–29.8% and protein 19.9–30.8%. Total phenol content was high 6.43–12.84 mg/100 g, which bodes well for the sponge gourd seeds’ ability to act as antioxidants. Significant correlation were found between important constituents studied like protein and oil, palmitic acid, stearic acid and oleic acid. Total unsaturated fatty acids were in higher amount comparable to saturated fatty acids signifying the good quality of Luffa seed oil. Our research revealed that the NDSG-1, Pusa Sneha, DSG-95, DSG-98, DSG-108, and DSG-26 genotypes were very nutritious due to their high levels of protein, oleic acid, and oil output. Additionally, selection of traits having considerable correlation will be beneficial and help in improved varietal development for usage as an alternative oilseed crop. Our research sheds light on the nutritional value of sponge gourd seeds and suggests using them as a potential source for oil and protein, particularly in underdeveloped countries.
The efficacy and safety of lenvatinib plus transarterial chemoembolization in combination with PD-1 antibody in treatment of unresectable recurrent hepatocellular carcinoma: a case series report
Authors: Mu Chunyang , Shen Junyi , Zhu Xinrui , Peng Wei , Zhang Xiaoyun , Wen Tianfu
Published: May 2023

Purpose

To explore the safety and efficacy of lenvatinib in combination with trans-arterial chemoembolization (TACE) and programmed death receptor 1 (PD-1) antibody in the treatment of unresectable recurrent hepatocellular carcinoma (urHCC).

Patients and methods

The clinical data of 16 patients with unresectable recurrent hepatocellular carcinoma admitted to the Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, and received the conversion therapy of lenvatinib + TACE + PD-1 antibody between January 2019 and January 2022 were retrospectively analyzed.

Results

There were 25% (4/16) patients suffering from grade 3 adverse events and no patients suffering from grade 4 or higher adverse events. After 4 months of treatment of 16 patients, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), two, five, three, and six cases were in complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), respectively, and the objective response rate (ORR) was 43.8% (7/16). The 1-year overall survival (OS) rate and 1-year progression-free survival (PFS) rate were 86.2% and 46.9%, respectively. In our subgroup analysis, the ORR of patients with multiple lesions reached up to 60%, which was higher than that of patients with single lesions.

Conclusions

Lenvatinib in combination with TACE and PD-1 antibody is safe and effective in the treatment of unresectable recurrent hepatocellular carcinoma.
PGM3 inhibition shows cooperative effects with erastin inducing pancreatic cancer cell death via activation of the unfolded protein response
Authors: Zerbato Barbara , Gobbi Maximilian , Ludwig Tobias , Brancato Virginia , Pessina Alex , Brambilla Luca , Wegner Andre , Chiaradonna Ferdinando
Published: May 2023

Background

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor patient prognosis. Remarkably, PDAC is one of the most aggressive and deadly tumor types and is notorious for its resistance to all types of treatment. PDAC resistance is frequently associated with a wide metabolic rewiring and in particular of the glycolytic branch named Hexosamine Biosynthetic Pathway (HBP).

Methods

Transcriptional and bioinformatics analysis were performed to obtain information about the effect of the HBP inhibition in two cell models of PDAC. Cell count, western blot, HPLC and metabolomics analyses were used to determine the impact of the combined treatment between an HBP’s Phosphoglucomutase 3 (PGM3) enzyme inhibitor, named FR054, and erastin (ERA), a recognized ferroptosis inducer, on PDAC cell growth and survival.

Results

Here we show that the combined treatment applied to different PDAC cell lines induces a significant decrease in cell proliferation and a concurrent enhancement of cell death. Furthermore, we show that this combined treatment induces Unfolded Protein Response (UPR), NFE2 Like BZIP Transcription Factor 2 (NRF2) activation, a change in cellular redox state, a greater sensitivity to oxidative stress, a major dependence on glutamine metabolism, and finally ferroptosis cell death.

Conclusion

Our study discloses that HBP inhibition enhances, via UPR activation, the ERA effect and therefore might be a novel anticancer mechanism to be exploited as PDAC therapy.
Malignant mediastinal mesothelioma treated with anlotinib: a case report and review of the literature
Authors: Zhang Yishi , He Wan , Zhan Ke , Zhang Luobin , Cao Hua , Xu Ruilian
Published: May 2023

Malignant mesothelioma that originates from mediastinal (MMM) is a rare form of malignant pleural mesothelioma (MPM). The prognosis of advanced stage MPM was poor, and the traditional treatment was chemotherapy. Here, we present a patient with MMM that was treated with anlotinib, a multitargeted tyrosine kinase inhibitor (TKI) who had a 24-month progression-free survival (PFS). Further review of the literature showed that, despite some explorations of applying small-molecule multitargeted TKIs in the treatment of MPM, until today, no large series had a positive result. Anlotinib had been approved by the China Food and Drug Administration on treating non–small cell lung cancer, soft tissue sarcoma, renal cell carcinoma, and medullary thyroid cancer. We assumed that the ability of anlotinib to target more tyrosine kinase receptors than most of other TKIs could contribute to the long duration of PFS in this case, but further study is needed to further validate the efficacy of anlotinib in treatment of MPM.
The value of whole-volume apparent diffusion coefficient histogram analysis in preoperatively distinguishing intracranial solitary fibrous tumor and transitional meningioma
Authors: Wang Gang , Zhou Junlin
Published: May 2023

Purpose

To investigate the value of whole-volume apparent diffusion coefficient (ADC) histogram analysis in preoperatively distinguishing intracranial solitary fibrous tumors (SFT) from transitional meningiomas (TM), thereby assisting the establishment of the treatment protocol.

Methods

Preoperative diffusion-weighted imaging datasets of 24 patients with SFT and 28 patients with TM were used to extract whole-volume ADC histogram parameters, including variance, skewness, kurtosis, and mean, as well as 1st (AP1), 10th (AP10), 50th (AP50), 90th (AP90), and 99th (AP99) percentiles of ADC using MaZda software. The independent t-test or Mann–Whitney U test was used to compare the differences between ADC histogram parameters of SFT and TM. Receiver operating characteristic (ROC) curves were generated to evaluate the performance of significant ADC histogram parameters. Spearman’s correlation coefficients were calculated to evaluate correlations between these parameters and the Ki-67 expression levels.

Results

SFT exhibited significantly higher variance, and lower AP1 and AP10 (all P < 0.05) than TM. The best diagnostic performance was obtained by variance, with an area under the ROC curve of 0.848 (0.722–0.933). However, there was no significant difference in skewness, kurtosis, mean, or other percentiles of ADC between the two groups (all P > 0.05). Significant correlations were also observed between the Ki-67 proliferation index and variance (r = 0.519), AP1 (r = -0.425), and AP10 (r = -0.372) (all P < 0.05).

Conclusion

Whole-volume ADC histogram analysis is a feasible tool for non-invasive preoperative discrimination between intracranial SFT and TM, with variance being the most promising prospective parameter.
Excavation of diagnostic biomarkers and construction of prognostic model for clear cell renal cell carcinoma based on urine proteomics
Authors: Yang Yiren , Pang Qingyang , Hua Meimian , Huangfu Zhao , Yan Rui , Liu Wenqiang , Zhang Wei , Shi Xiaolei , Xu Yifan , Shi Jiazi
Published: May 2023

Purpose

Clear cell renal cell carcinoma (ccRCC) is the most common pathology type in kidney cancer. However, the prognosis of advanced ccRCC is unsatisfactory. Thus, early diagnosis becomes one of the most important research priorities of ccRCC. However, currently available studies about ccRCC lack urine-related further studies. In this study, we applied proteomics to search urinary biomarkers to assist early diagnosis of ccRCC. In addition, we constructed a prognostic model to assist judge patients’ prognosis.

Materials and methods

Urine which was used to perform 4D label-free quantitative proteomics was collected from 12 ccRCC patients and 11 non-tumor patients with no urinary system diseases. The urine of 12 patients with ccRCC confirmed by pathological examination after surgery was collected before operatoin. Bioinformatics analysis was used to describe the urinary proteomics landscape of these patients with ccRCC. The top ten proteins with the highest expression content were selected as the basis for subsequent validation. Urine from 46 ccRCC patients and 45 control patients were collected to use for verification by enzyme linked immunosorbent assay (ELISA). In order to assess the prognostic value of urine proteomics, a prognostic model was constructed by COX regression analysis on the intersection of RNA-sequencing data in The Cancer Genome Atlas (TCGA) database and our urine proteomic data.

Results

133 proteins differentially expressed in the urinary samples were found and 85 proteins (Fold Change, FC>1.5) were identified up-regulated while 48 down-regulated (FC<0.5). Top 10 proteins including S100A14, PKHD1L1, FABP4, ITIH2, C3, C8G, C2, ATF6, ANGPTL6, F13B were performed ELISA to verify. The results showed that PKHD1L1, ANGPTL6, FABP4 and C3 were statistically significant (P<0.05). We performed multivariate logistic regression analysis and plotted a nomogram. Receiver operating characteristic (ROC) curve indicted that the diagnostic efficiency of combined indicators is satisfactory (Aare under curve, AUC=0.835). Furthermore, the prognostic value of the urine proteomics was explored through the intersection between urine proteomics and TCGA RNA-seq data. Thus, COX regression analysis showed that VSIG4, HLA-DRA, SERPINF1, and IGLV2-23 were statistically significant (P<0.05).

Conclusion

Our study indicated that the application of urine proteomics to explore diagnostic biomarkers and to construct prognostic models of renal clear cell carcinoma is of certain clinical value. PKHD1L1, ANGPTL6, FABP4 and C3 can assist to diagnose ccRCC. The prognostic model constituted of VSIG4, HLA-DRA, SERPINF1, and IGLV2-23 can significantly predict the prognosis of ccRCC patients, but this still needs more clinical trials to verify.
Investigation of incidence and geographic distribution of gliomas in Canada from 1992 to 2010: a national population-based study highlighting the importance of exposure to airport operations
Authors: Ji Xinyu , Alakel Akram , Ghazawi Feras M. , Tsang Matthew , Zubarev Andrei , Lasry Oliver J. , Litvinov Ivan V.
Published: May 2023

Background

Gliomas account for over two-thirds of all malignant brain tumors and have few established risk factors beyond family history and exposure to ionizing radiation. Importantly, recent studies highlighted the exposure to ultrafine particles (UFP) as a putative risk factor for malignant brain tumors.

Methods

Clinical and geographic data encompassing all provinces and territories from 1992 to 2010 was obtained from the Canadian Cancer Registry and Le Registre Québécois du Cancer. Linear regression and joinpoint analyses were performed to assess incidence trends. Significantly higher and lower incidence postal codes were then interrogated using Standard Industrial Classification codes to detect significant industrial activity.

Results

In Canada, between 1992 and 2010, there were ~32,360 cases of glioma. Of these, 17,115 (52.9%) were glioblastoma. The overall crude incidence rates of 5.45 and 2.87 cases per 100,000 individuals per year for gliomas and glioblastomas, respectively, were identified. Our findings further revealed increasing crude incidence of gliomas/glioblastomas over time. A male predominance was observed. Provinces leading in glioma incidence included Quebec, Nova Scotia, and New Brunswick. Significantly lower crude incidence of glioma was found in Nunavut, Northwest Territories, Ontario, and Alberta. A putative regional clustering of gliomas was observed, with higher incidence rates in postal code areas correlating with industrial activity related to airport operations.

Conclusion

This study describes the geographic distribution of the glioma disease burden and, potentially, identifies industrial activity related to airport operations as potentially being associated with higher incidence of this cancer.