bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of initial chemotherapy cycles and clinical characteristics on outcomes for HIV-associated diffuse large B cell lymphoma patients: The Central and Western China AIDS Lymphoma League 001 study (CALL-001 study)
Authors: Wang Chaoyu , Wu Yan , Liu Jun , Min Haiyan , Huang Yunhong , Wei Guo , Zhang Wei , Wang Min , Tang Xiaoqiong , Zhou Hui , Chen Yaokai , Liu Yao
Published: March 2023

Introduction

Little is known about the first line induction chemotherapy cycles for HIV-associated diffuse large B-cell lymphoma (DLBCL) as these are less common than HIV-negative lymphoma. Currently, the optimal treatment cycles option remains undefined. Therefore, we performed a multi-center study to analyze the clinical characteristics and outcomes of HIV-associated DLBCL patients in different treatment modes in China.

Methods

Totally 273 newly diagnosed HIV-associated DLBCL patients at eleven large academic centers from October 2008 to October 2021, were analyzed.

Results

In the entire cohort, the median age was 47 years (range, 21-90) at lymphoma diagnosis, and 223 patients were male (81.7%). One hundred and ninety-four (71.1%) patients were germinal center B-cell-like lymphoma (GCB) subtype. Most patients (65.2%, 178/273) had elevated lactate dehydrogenase (LDH), and advanced Ann Arbor stage (78.9% 213/273) at diagnosis. High international prognostic index (IPI) score (3-5) at diagnosis was found in 65.2% (178/273) of patients. One hundred and fifty-five patients (56.8%) had extranodal involvement. The median CD4 cell count was 168/μl (range, 2-1067), of whom 174 (63.7%) had a CD4 cell count below 200/μl. The median follow‐up of our cohort was 10.1 (0.1-160) months. The overall 2-year OS rates 58.0%. Median OS times in the 0, 1-3, 4-6, and >6 cycles chemotherapy cohort were 7.1 months, 20.0 months, not reached, and not reached, respectively (Hazard Ratio (HR)=0.549, 95% Confidence interval (CI) 0.451-0.667; p<0.001). Cox multivariate analysis showed that age ≥60 (HR=2.207, 95%CI 1.321-3.690; p=0.003), high IPI score (3-5) (HR=2.926, 95% CI 1.716-4.988; p<0.001), B symptoms (HR=1.928, 95%CI 1.192-3.119; p=0.007), elevated LDH (HR=1.696, 95%CI 1.031-2.791; p=0.038) and received less than 4 cycles chemotherapy (HR=0.520, 95%CI 0.424-0.637; p<0.001) were independent risk factor for adverse prognosis based on overall survival (OS).

Discussion

These results demonstrated that 4-6 cycles chemotherapy were significantly associated with improved outcomes in HIV-associated DLBCL patients. However, >6 cycles chemotherapy did not further improve the survival of patients.
Antibody diversity in IVIG: Therapeutic opportunities for novel immunotherapeutic drugs
Authors: von Gunten Stephan , Schneider Christoph , Imamovic Lejla , Gorochov Guy
Published: March 2023

Significant progress has been made in the elucidation of human antibody repertoires. Furthermore, non-canonical functions of antibodies have been identified that reach beyond classical functions linked to protection from pathogens. Polyclonal immunoglobulin preparations such as IVIG and SCIG represent the IgG repertoire of the donor population and will likely remain the cornerstone of antibody replacement therapy in immunodeficiencies. However, novel evidence suggests that pooled IgA might promote orthobiotic microbial colonization in gut dysbiosis linked to mucosal IgA immunodeficiency. Plasma-derived polyclonal IgG and IgA exhibit immunoregulatory effects by a diversity of different mechanisms, which have inspired the development of novel drugs. Here we highlight recent insights into IgG and IgA repertoires and discuss potential implications for polyclonal immunoglobulin therapy and inspired drugs.
Immunometabolic interference between cancer and COVID-19
Authors: Consonni Francesca Maria , Durante Barbara , Manfredi Marcello , Bleve Augusto , Pandolfo Chiara , Garlatti Valentina , Vanella Virginia Vita , Marengo Emilio , Barberis Elettra , Bottazzi Barbara , Bombace Sara , My Ilaria , Condorelli Gianluigi , Torri Valter , Sica Antonio
Published: March 2023

Even though cancer patients are generally considered more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the mechanisms driving their predisposition to severe forms of coronavirus disease 2019 (COVID-19) have not yet been deciphered. Since metabolic disorders are associated with homeostatic frailty, which increases the risk of infection and cancer, we asked whether we could identify immunometabolic pathways intersecting with cancer and SARS-CoV-2 infection. Thanks to a combined flow cytometry and multiomics approach, here we show that the immunometabolic traits of COVID-19 cancer patients encompass alterations in the frequency and activation status of circulating myeloid and lymphoid subsets, and that these changes are associated with i) depletion of tryptophan and its related neuromediator tryptamine, ii) accumulation of immunosuppressive tryptophan metabolites (i.e., kynurenines), and iii) low nicotinamide adenine dinucleotide (NAD+) availability. This metabolic imbalance is accompanied by altered expression of inflammatory cytokines in peripheral blood mononuclear cells (PBMCs), with a distinctive downregulation of IL-6 and upregulation of IFNγ mRNA expression levels. Altogether, our findings indicate that cancer not only attenuates the inflammatory state in COVID-19 patients but also contributes to weakening their precarious metabolic state by interfering with NAD+-dependent immune homeostasis.
Effect of the cutoff wall on the fate of nitrate in coastal unconfined aquifers under tidal action
Authors: Kong Jun , Gao Chao , Jiang Chaohua , Wang Jun , Gao Xinyu , Jing Li
Published: March 2023

This paper investigates the effects of the cutoff wall on the fate of nitrate (NO3-), the NO3- removal rate, and the salinity distribution in a coastal aquifer under tidal action. A numerical study was performed based on a coupled model with variable-saturation and variable-density flow and a convection-diffusion-reaction equation for solute transport in a coastal unconfined aquifer. The results showed that the cutoff wall led to a larger upper salinity plume (USP) and that the saltwater wedge (SW) further retreated seaward. The recirculation pathways of saltwater and groundwater were largely modified by the wall. The cutoff wall within the tidal range could increase the NO3- mass of denitrification and the NO3- removal efficiency and decrease the length of the SW and the freshwater flux. This modification of the saltwater and groundwater recirculation pathways was enhanced with increasing wall depth. A deeper cutoff wall led to a further retreated SW, lower freshwater flux, and greater improvements in the NO3- mass of denitrification and the NO3- removal efficiency. In addition, the cutoff wall significantly decreased the terrestrial dissolved organic carbon (TDOC) discharge into the sea. Dissolved organic carbon source (SDOC) promoted a higher NO3- removal efficiency. This study provides us with a better understanding of coastal physical-biogeochemical processes and dynamic mechanisms, as well as a guide for designing engineering measures to mitigate NO3- contamination and thus enhance groundwater quality management.
Geochemical characteristics of sediment and pore water affected by cold seeps in southern South China Sea
Authors: Chen Chongmin , Wu Xuewan , Wan Zhifeng , Shang Jiujing , Huang Wei , Zhang Wei , Liang Jinqiang , Xiao Zebang , Zhou Wei , Zhong Lifeng
Published: March 2023

Cold seep, characterized by active material circulation and methane seepage, is of great importance to reconstruct the paleo-marine environment and trace the origin of life and the occurrence of minerals. Southern South China Sea (SCS) with ample oil and gas resources is an ideal platform for cold seep study, but information and researches on cold seeps here are rather deficient. We studied the geochemical characteristics of sediment cores and pore water combined with seismic profile information in the Beikang Basin, aiming to further understand the nature of cold seeps in this area. Results show the extremely low δ 13CDIC of pore water in each core and we also found sulfate content decreases with depth, the high content of inorganic carbon (DIC) and the corresponding minimumδ 13CDIC in pore water, the kink-type depth profiles of Sr, Ba and Ni enrichment factors and Sr/Mg in the sediments of BH-CL37, the reducing sedimentary environment constrained by the features of Mo, U and REE. The extremely negative δ 13CDIC in the pore water of the sediment cores indicates strong AOM effect in cold seeps and the main biogenic origin of methane. The SO42- depth variation trends of pore water, the high DIC content and the lowest value of δ 13CDIC can define the approximate SMTZ depth of each sediment core effectively. We thought that fluid fluxes and tectonic settings greatly influence the sedimentary environment and geochemistry, leading to the manifest regional differences in the properties and activities of cold seeps. This study of cold seep in southern SCS proves the variation of cold seep in time and space, stressing the necessity of further region-specific analysis towards different cold seeps; and the complex conditions of SCS do function well in offering multiple types of cold seeps.
Mepolizumab therapy improves the most bothersome symptoms in patients with hypereosinophilic syndrome
Authors: Roufosse Florence , Butterfield Joseph , Steinfeld Jonathan , Bentley Jane H. , von Maltzahn Robyn , Kwon Namhee , Nelsen Linda
Published: March 2023

Background

Hypereosinophilic syndrome (HES) is characterized by persistent elevated blood and/or tissue eosinophil levels and eosinophil-mediated organ damage. Presentation is highly heterogenous; patients may experience symptoms affecting multiple organ systems.

Objectives

To assess the effects of mepolizumab, which targets interleukin-5, on HES-related symptom burden, based on HES daily symptoms (HES-DS) questionnaire data collected during the Phase III (ClinicalTrials.gov ID: NCT02836496) study of mepolizumab in patients with HES.

Methods

Each of the six HES-related symptoms were rated (0–10) daily by patients, recalling worst symptom experience in the prior 24 hours; change from baseline at Week 32 was also calculated for mepolizumab versus placebo.

Results

Mepolizumab versus placebo reduced HES-related symptom burden severity in patients with HES at Week 32. Improvements in the median change from baseline scores were seen across all symptom groups except skin for patients treated with mepolizumab; greatest improvement from baseline was observed for breathing symptoms.

Conclusion

These data highlight the considerable symptom burden associated with HES and further support the clinical benefits of mepolizumab treatment for these patients.
Dynamic changes in gut microbiota during pregnancy among Chinese women and influencing factors: A prospective cohort study
Authors: Li Muxia , Zhang Guohua , Cui Lijun , Zhang Lin , Zhou Qian , Mu Chenxue , Chi Ruixin , Zhang Na , Ma Guansheng
Published: March 2023

Gut microbiota (GM) dynamics during pregnancy vary among different populations and are affected by many factors, such as living environments and diet. This study aims to observe and evaluate the changes in the structure and function of the GM from the first to the third trimester of pregnancy in Chinese women, and to explore the main factors affecting the changes in intestinal microecology. Fifty-five Chinese pregnant women were recruited for this study and their fecal samples were collected during the first (P1), second (P2), and third trimesters (P3) of pregnancy. We exploited metagenomic sequencing to compare the composition and function of the GM in different pregnancy periods. Bioinformatic analysis revealed that there were differences in the composition of the GM among P1, P2, and P3, as indicated by the increase in α-diversity and β-diversity of the GM and the differences in the relative abundances of distinct bacterial phyla. Gestational diabetes mellitus (GDM) was the main factor (P < 0.05) that affected the changes in GM at various stages of pregnancy. There were also disparities in the structure of the GM between the GDM group and non-GDM group in the P1, P2, and P3. The GDM group exhibited increased abundances in Ruminococcus_gnavus, Akkermansia_muciniphila, Alistipes_shahii, Blautia_obeum, and Roseburia_intestinalis; while, the abundances of Bacteroides coprocola, Bacteroides plebeius, Erysipelatoclostridium ramosum, and Prevotella copri were increased in the non-GDM group. Three of the four species enriched in the non-GDM group manifestied significantly negative correlations with the insulin-signaling pathway and lipopolysaccharide biosynthesis (r ≤ −0.3, adjusted P < 0.05). In the GDM group, Bacteroides vulgatus and Ruminococcus gnavus were significantly and positively correlated with insulin signaling pathway and lipopolysaccharide biosynthesis (r ≤ −0.3, adjusted P < 0.05) among the species enriched from early pregnancy. Virtually all of the species enriched in P2 and P3 were positively correlated with steroid hormone biosynthesis. These results suggest a potential role for the GM in the development of GDM, enabling the potential prevention of GDM by targeting the GM.
Longitudinal analysis of SARS-CoV-2 reinfection reveals distinct kinetics and emergence of cross-neutralizing antibodies to variants of concern
Authors: Facciuolo Antonio , Van Kessel Jill , Kroeker Andrea , Liao Mingmin , Lew Jocelyne M. , Falzarano Darryl , Kelvin Alyson A. , Gerdts Volker , Napper Scott
Published: March 2023

The ongoing evolution of SARS-CoV-2 continues to raise new questions regarding the duration of immunity to reinfection with emerging variants. To address these knowledge gaps, controlled investigations in established animal models are needed to assess duration of immunity induced by each SARS-CoV-2 lineage and precisely evaluate the extent of cross-reactivity and cross-protection afforded. Using the Syrian hamster model, we specifically investigated duration of infection acquired immunity to SARS-CoV-2 ancestral Wuhan strain over 12 months. Plasma spike- and RBD-specific IgG titers against ancestral SARS-CoV-2 peaked at 4 months post-infection and showed a modest decline by 12 months. Similar kinetics were observed with plasma virus neutralizing antibody titers which peaked at 2 months post-infection and showed a modest decline by 12 months. Reinfection with ancestral SARS-CoV-2 at regular intervals demonstrated that prior infection provides long-lasting immunity as hamsters were protected against severe disease when rechallenged at 2, 4, 6, and 12 months after primary infection, and this coincided with the induction of high virus neutralizing antibody titers. Cross-neutralizing antibody titers against the B.1.617.2 variant (Delta) progressively waned in blood over 12 months, however, re-infection boosted these titers to levels equivalent to ancestral SARS-CoV-2. Conversely, cross-neutralizing antibodies to the BA.1 variant (Omicron) were virtually undetectable at all time-points after primary infection and were only detected following reinfection at 6 and 12 months. Collectively, these data demonstrate that infection with ancestral SARS-CoV-2 strains generates antibody responses that continue to evolve long after resolution of infection with distinct kinetics and emergence of cross-reactive and cross-neutralizing antibodies to Delta and Omicron variants and their specific spike antigens.
Disease alleviating effects following prophylactic lemon and coriander essential oil treatment in mice with acute campylobacteriosis
Authors: Mousavi Soraya , Weschka Dennis , Bereswill Stefan , Heimesaat Markus M.
Published: March 2023

Introduction

Given the worldwide increasing prevalence of human Campylobacter jejuni infections and the emergence of multi-drug resistant enteropathogenic strains, antibiotic-independent approaches applying non-toxic natural compounds for the treatment and prophylaxis of campylobacteriosis appear utmost desirable. In our placebo-controlled intervention study, we surveyed potential disease-alleviating including anti-pathogenic and immune-modulatory effects upon prophylactic oral application of lemon-essential oil (LEM-EO) and coriander-essential oil (COR-EO) in acute experimental campylobacteriosis.

Methods

Therefore, secondary abiotic IL-10−/− mice were orally challenged with either LEM-EO or COR-EO starting seven days prior to peroral C. jejuni infection.

Results and discussion

Six days post-infection, slightly lower pathogen loads were assessed in the colon of mice from the LEM-EO as opposed to the COR-EO cohort if compared to placebo counterparts. Prophylactic application of both EOs improved the clinical outcome of acute campylobacteriosis which was paralleled by less distinct pathogen-induced colonic epithelial cell apoptosis. Moreover, mice subjected to LEM-EO and COR-EO prophylaxis displayed lower colonic numbers of macrophages/monocytes and of T lymphocytes, respectively, whereas in both verum groups, basal IL-6 and IFN-γ concentrations were measured in mesenteric lymph nodes on day 6 post-infection. The oral challenge with either EOs resulted in diminished secretion of distinct pro-inflammatory mediators in the kidney as well as serum samples derived from the infected mice. In conclusion, the results from our preclinical in vivo study provide evidence that LEM-EO and COR-EO constitute promising prophylactic measures to prevent severe campylobacteriosis which may help to reduce the risk for development of post-infectious sequelae in C. jejuni infected individuals.
DNA accelerates the protease inhibition of a bacterial serpin chloropin
Authors: Xu Jiawei , Ye Wei , Yang Ting Ting , Yan Teng , Cai Haiyan , Zhou Aiwu , Yang Yufeng
Published: March 2023

Serine protease inhibitors (Serpins) are the most widely distributed protease inhibitors in nature and have been identified from all kingdoms of life. Eukaryotic serpins are most abundant with their activities often subject to modulation by cofactors; however, little is known about the regulation of prokaryotic serpins. To address this, here we prepared a recombinant bacteria serpin, termed chloropin, derived from green sulfur bacteria Chlorobium limicola and solved its crystal structure at 2.2 Å resolution. This showed a canonical inhibitory serpin conformation of native chloropin with a surface-exposed reactive loop and a large central beta-sheet. Enzyme activity analysis showed that chloropin could inhibit multiple proteases, such as thrombin and KLK7 with second order inhibition rate constants at 2.5×104 M−1s−1 and 4.5×104 M−1s−1 respectively, consistent with its P1 arginine residue. Heparin could accelerate the thrombin inhibition by ∼17-fold with a bell-shaped dose-dependent curve as seen with heparin-mediated thrombin inhibition by antithrombin. Interestingly, supercoiled DNA could accelerate the inhibition of thrombin by chloropin by 74-fold, while linear DNA accelerated the reaction by 142-fold through a heparin-like template mechanism. In contrast, DNA did not affect the inhibition of thrombin by antithrombin. These results indicate that DNA is likely a natural modulator of chloropin protecting the cell from endogenous or exogenous environmental proteases, and prokaryotic serpins have diverged during evolution to use different surface subsites for activity modulation.
A rapid direct-differential agglutination assay for Brucella detection using antibodies conjugated with functionalized gold nanoparticles
Authors: Hans Richa , Yadav Pranjal Kumar , Zaman M. Burhanuz , Poolla Rajaram , Thavaselvam Duraipandian
Published: March 2023

Brucellosis is the most widespread and serious zoonotic disease worldwide which affects livestock, sylvatic wildlife, marine dwellers, and humans. It is acquired through Alphaproteobacteria which belong to the genus Brucella and is categorized as a potential bio-threat agent. In this study, we developed a rapid and direct differential whole cell (WC) agglutination-based assay for its on-field detection. The recombinant outer membrane (rOmp28) protein-derived specific mice IgG polyclonal antibodies (pAbs) of Brucella were purified using affinity chromatography and conjugated with functionalized gold nanoparticles (AuNPs) for rapid agglutination. A positive blot of 32 kDa protein revealed specific immuno-reactivity of rOmp28-pAbs using immunoblot analysis. For the synthesis of AuNPs, the conventional “Turkevich method” was optimized at a concentration < 1 mM of gold precursor for obtaining 50-nm-sized particles. Also, their physico-chemical characteristics were analyzed using UV-visible spectrophotometry, Fourier transform infra-red spectroscopy (FT-IR), Raman spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), dynamic light scattering (DLS), zeta potential (ζ, ZP), and fluorescence spectroscopy. Furthermore, these AuNPs were functionalized with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) to prepare modified carboxylated AuNPs. For bioconjugation with Brucella rOmp28 IgG pAbs, antibody-conjugated functionalized AuNP constructs were prepared and characterized using FT-IR analysis with strong N–H deformations. Subsequently, these bioconjugated AuNPs were used to develop a direct-differential slide agglutination assay with a detection limit of 104 CFU mL−1. The sensitivity of this assay was compared with standard double-antibody sandwich ELISA (S-ELISA) using rOmp28 IgG pAbs with an LOD of 103 CFU mL−1 and a detection range of 102–108 CFU mL−1. No intraspecies cross-reactivity was observed based on evaluation of its specificity with a battery of closely related bacterial species. In conclusion, the increased sensitivity and specificity of the developed agglutination assay obtained using bioconjugated functionalized AuNPs is ≥ 98% for the detection of Brucella. Therefore, it can be used as an alternate rapid method of direct WC detection of bacteria as it is simple, robust, and cost-effective, with minimal time of reaction in the case of early disease diagnosis.
Dorsal root ganglion neurons recapitulate the traumatic axonal injury of CNS neurons in response to a rapid stretch in vitro
Authors: Adams Alexandra A. , Li Ying , Kim Haesun A. , Pfister Bryan J.
Published: March 2023

Introduction:In vitro models of traumatic brain injury (TBI) commonly use neurons isolated from the central nervous system. Limitations with primary cortical cultures, however, can pose challenges to replicating some aspects of neuronal injury associated with closed head TBI. The known mechanisms of axonal degeneration from mechanical injury in TBI are in many ways similar to degenerative disease, ischemia, and spinal cord injury. It is therefore possible that the mechanisms that result in axonal degeneration in isolated cortical axons after in vitro stretch injury are shared with injured axons from different neuronal types. Dorsal root ganglia neurons (DRGN) are another neuronal source that may overcome some current limitations including remaining healthy in culture for long periods of time, ability to be isolated from adult sources, and myelinated in vitro.

Methods: The current study sought to characterize the differential responses between cortical and DRGN axons to mechanical stretch injury associated with TBI. Using an in vitro model of traumatic axonal stretch injury, cortical and DRGN neurons were injured at a moderate (40% strain) and severe stretch (60% strain) and acute alterations in axonal morphology and calcium homeostasis were measured.

Results: DRGN and cortical axons immediately form undulations in response to severe injury, experience similar elongation and recovery within 20 min after the initial injury, and had a similar pattern of degeneration over the first 24 h after injury. Additionally, both types of axons experienced comparable degrees of calcium influx after both moderate and severe injury that was prevented through pre-treatment with tetrodotoxin in cortical neurons and lidocaine in DRGNs. Similar to cortical axons, stretch injury also causes calcium activated proteolysis of sodium channel in DRGN axons that is prevented by treatment with lidocaine or protease inhibitors.

Discussion: These findings suggest that DRGN axons share the early response of cortical neurons to a rapid stretch injury and the associated secondary injury mechanisms. The utility of a DRGN in vitro TBI model may allow future studies to explore TBI injury progression in myelinated and adult neurons.
Evolutionary game model of migraine based on the human brain hypersensitivity
Authors: Han Dong-Gyun
Published: March 2023

Based on all studies published up to 2020, the prevalence of migraine worldwide is approximately 14%, although it varies regionally. Despite being one of the most disabling diseases, migraine still exists through natural selection and is prevalent today. This raises the question of what evolutionary advantages have led to the survival of migraine. The ultimate answer to this question should be found in evolution; however, there is no clear explanation yet. Notably, all the genes that cause migraine make the sensory organs and cortex of the migraine sufferer hypersensitive. In a state of hypersensitivity, the brain could recognize external threats easily. Game theory is a useful tool for explaining evolution in terms of genes. Just as the Hawk–Dove game, which has two strategies (aggressive and passive) and four fitness values, an evolutionary game between a migraineur and a non-migraineur, which shows two phenotypes (more sensitive and less sensitive) and four fitness values, can be played if a migraineur quickly recognizes a predator and informs a non-migraineur of its appearance and the non-migraineur later helps the migraineur escape from danger. This study aimed to explore the evolutionary mechanics of migraine that can be modeled. Furthermore, it tried to define why the human brain's hypersensitivity is a prerequisite for developing this evolutionary game model.
Spatial CT perfusion data helpful in automatically locating vessel occlusions for acute ischemic stroke patients
Authors: Peerlings Daan , de Jong Hugo W. A. M. , Bennink Edwin , Dankbaar Jan W. , Velthuis Birgitta K. , Emmer Bart J. , Majoie Charles B. L. M. , Marquering Henk A.
Published: March 2023

Introduction

Locating a vessel occlusion is important for clinical decision support in stroke healthcare. The advent of endovascular thrombectomy beyond proximal large vessel occlusions spurs alternative approaches to locate vessel occlusions. We explore whether CT perfusion (CTP) data can help to automatically locate vessel occlusions.

Methods

We composed an atlas with the downstream regions of particular vessel segments. Occlusion of these segments should result in the hypoperfusion of the corresponding downstream region. We differentiated between seven-vessel occlusion locations (ICA, proximal M1, distal M1, M2, M3, ACA, and posterior circulation). We included 596 patients from the DUtch acute STroke (DUST) multicenter study. Each patient CTP data set was processed with perfusion software to determine the hypoperfused region. The downstream region with the highest overlap with the hypoperfused region was considered to indicate the vessel occlusion location. We assessed the indications from CTP against expert annotations from CTA.

Results

Our atlas-based model had a mean accuracy of 86% and could achieve substantial agreement with the annotations from CTA according to Cohen's kappa coefficient (up to 0.68). In particular, anterior large vessel occlusions and occlusions in the posterior circulation could be located with an accuracy of 80 and 92%, respectively.

Conclusion

The spatial layout of the hypoperfused region can help to automatically indicate the vessel occlusion location for acute ischemic stroke patients. However, variations in vessel architecture between patients seemed to limit the capacity of CTP data to distinguish between vessel occlusion locations more accurately.
Global research on cancer and sleep: A bibliometric and visual analysis of the last two decades
Authors: Sun Jiaru , Wang Caihua , Hui Zhaozhao , Han Wenjin , Wang Xiaoqin , Wang Mingxu
Published: March 2023

Objective

The study aimed to analyze the research status, hotspots, and frontiers of global research on cancer and sleep through bibliometrics and provide references and guidance for future research.

Methods

The literature regarding cancer and sleep from 2002 to 2022 was searched from the Web of Science Core Collection (WoSCC) database. CiteSpace 5.6.R3 was performed for visualization analysis.

Results

A total of 1,172 publications were identified. The number of publications in the field has gradually increased over the past two decades. The United States had the most prominent contributions. Taipei Medical University and the University of California, San Francisco, and David Gozal were the most prolific institutions and author, respectively. The most published academic journal was Supportive Care in Cancer. The research hotspots can be summarized into the symptom cluster intervention for cancer survivors and the association between cancer and melatonin and/or obstructive sleep apnea (OSA). The complex interaction between cancer and sleep disruption and the influencing factors of sleep quality may be the emerging trends of research.

Conclusion

This study systematically analyzed the hotspots and frontiers in the field of cancer and sleep and called for strengthening cooperation among countries, institutions, and authors. In addition, intervention measures for the cancer symptom cluster, the bioavailability of exogenous melatonin, the causal relationship between OSA and cancer, the mechanism of tumor-induced sleep disruption, the dose–response relationship between sleep duration and cancer risk, and the path relationship between sleep quality influencing factors may be the focus of future research.
Prenatal anesthetic exposure and offspring neurodevelopmental outcomes—A narrative review
Authors: Zhou Nannan , Liang Shuang , Yue Xinying , Zou Wangyuan
Published: March 2023

While it is common for pregnant women to take anesthesia during surgery, the effects of prenatal anesthesia exposure (PAE) on the long-term neurodevelopment of the offspring remain to be clarified. Preclinical animal research has shown that in utero anesthetic exposure causes neurotoxicity in newborns, which is mainly characterized by histomorphological changes and altered learning and memory abilities. Regional birth cohort studies that are based on databases are currently the most convenient and popular types of clinical studies. Specialized questionnaires and scales are usually employed in these studies for the screening and diagnosis of neurodevelopmental disorders in the offspring. The time intervals between the intrauterine exposure and the onset of developmental outcomes often vary over several years and accommodate a large number of confounding factors, which have an even greater impact on the neurodevelopment of the offspring than prenatal anesthesia itself. This narrative review summarized the progress in prenatal anesthetic exposure and neurodevelopmental outcomes in the offspring from animal experimental research and clinical studies and provided a brief introduction to assess the neurodevelopment in children and potential confounding factors.
Single-cell RNA sequencing depicts metabolic changes in children with aplastic anemia
Authors: Zhou Qin , Huang Lifen , Liu Yong , Huang Junbin , Wen Luping , Yang Jing , Liang Jintang , Chen Yun , Chen Chun
Published: March 2023

Introduction

Aplastic anemia (AA) is a bone marrow hematopoietic failure syndrome mediated by immune cells. The mechanism of this immune disorder is not well understood and therapeutic strategies still need to be improved.

Methods

Studies have found that abnormalities in metabolisms promote the survival of AA cells. In recent years, an increasing number of studies have reported the immunosuppressive therapy for the treatment of AA. In this study, we analyzed the transcriptome of AA from peripheral blood compared with healthy donors by single-cell sequencing and identified the affected metabolic pathways including lysine degradation. We demonstrated that the metabolic abnormalities of T lymphocytes mainly focus on glycolysis/gluconeogenesis. In addition, the metabolic abnormalities of natural killer cells concentrated in oxidative phosphorylation.

Results

The key genes involved in abnormal metabolic processes were Neustein neurotrophic factor (NENF), inositol polyphosphate-4-phosphatase type II B (INPP4B), aldo-keto reductase family 1, member C3 (AKR1C3), and carbohydrate (N-acetylglucosamine-6-O) sulfotransferase 2 (CHST2) by differential gene expression analysis.

Discussion

Molecule interaction analysis showed that tumor necrosis factor superfamily, member 12 (TNFSM12) in tumor necrosis factor (TNF) signaling was broadly activated in AA. In conclusion, we suppose that the treatment of the immune cells’ abnormal metabolic pathway may contribute to the development of novel strategies to treat AA.
Clinicopathological characteristics and prognosis of early-stage HER2 low-expression breast cancer: A single-center retrospective study
Authors: Liu Chang-Gen , Li Yi-Fan , Ma Tian-Yi , Lv Meng , Lv Zhi-Dong , Wang Yuan-Yuan , Liu Xiang-Ping , Mao Yan , Wang Hai-Bo
Published: March 2023

Background

Owing to the emergence of drugs targeting human epidermal growth factor receptor 2 (HER2), remarkable prognostic enhancement has been seen for patients with HER2-positive breast carcinoma. However, anti-HER2 medicines are applicable merely to individuals with HER2-positive tumors, and the benefit for those with low HER2 expression is unclear. The DESTINY-Breast04 phase III and RC48 clinical trial results showed the benefit of antibody-drug couples for low HER2-expressing individuals with breast carcinoma, challenging the traditional dichotomy between HER2-negative and -positive tumors. Hence, the purposes of the present work are to explore the clinicopathological traits and prognostic differences in the HER2-low expression Chinese population with early-stage breast carcinoma.

Methods

Data from the database of the Breast Center of the Affiliated Hospital of Qingdao University were collected from January 2008 to December 2017. We screened a total of 4,598 patients, of which 2,837 had HER2-0 tumors and 1,761 had HER2-low tumors. Additionally, clinicopathological characteristics, survival, and prognostic information were obtained. Difference comparisons were made between HER2-0 and HER2-low groups regarding the clinical traits and outcomes.

Results

We enrolled 4598 patients, with the HR-positive subjects suffering from HER2-low breast carcinoma higher in proportion than the HR-negative patients. In contrast to HER2-0 tumors, the HER2-low tumors were linked to an older median age at diagnosis, T1 tumors, N1 stage, a higher Ki-67 index, as well as inferior histological grade. Insignificant inter-group difference was noted regarding overall survival (OS), although the HER2–0 group exhibited better disease-free survival (DFS) than the HER2-low group for the entire (P = 0.003), lymph node-negative (P = 0.009) and HR-positive (P = 0.007) populations. According to the multivariate regression finding, low HER2 expression was an inferior DFS prognostic factor in the HER2-negative population with early-stage breast cancer (HR,1.33;95% CI, 1.06-1.66; P = 0.013).

Conclusion

The clinical traits of the HER2-low carcinomas differed from those of HER2–0 tumors. Despite the insignificant inter-group difference in OS, the differences in DFS were found for the overall, lymph node-negative and HR-positive subjects, suggesting the possibility of HER2-low as an inferior prognostic factor for disease progression in early-stage breast cancer.
Comprehensive analysis of the expression and prognosis for RAI2: A promising biomarker in breast cancer
Authors: Jiao Ying , Li Shiyu , Gong Juejun , Zheng Kun , Xie Ya
Published: March 2023

Introduction

Retinoic acid-induced 2 (RAI2) was initially related to cell differentiation and induced by retinoic acid. RAI2 has been identified as an emerging tumor suppressor in breast cancer and colorectal cancer.

Methods

In this study, we performed systematic analyses of RAI2 in breast cancer. Meta-analysis and Kaplan-Meier survival curves were applied to identify the survival prediction potential of RAI2. Moreover, the association between RAI2 expression and the abundance of six tumor-infiltrating immune cells was investigated by TIMER, including B cells, CD8+ T cells, CD4+ T cells, B cells, dendritic cells, neutrophils, and macrophages. The expression profiles of high and low RAI2 mRNA levels in GSE7390 were compared to identify differentially expressed genes (DEGs) and the biological function of these DEGs was analyzed by R software, which was further proved in GSE7390.

Results

Our results showed that the normal tissues had more RAI2 expression than breast cancer tissues. Patients with high RAI2 expression were related to a favorable prognosis and more immune infiltrates. A total of 209 DEGs and 182 DEGs were identified between the expression profiles of high and low RAI2 mRNA levels in the GSE7390 and GSE21653 databases, respectively. Furthermore, Gene Ontology (GO) enrichment indicated that these DEGs from two datasets were both mainly distributed in “biological processes” (BP), including “organelle fission” and “nuclear division”. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis demonstrated that these DEGs from two datasets were both significantly enriched in the “cell cycle”. Common hub genes between the DEGs in GSE7390 and GSE21653 were negatively associated with RAI2 expression, including CCNA2, MAD2L1, MELK, CDC20, and CCNB2.

Discussions

These results above suggested that RAI2 might play a pivotal role in preventing the initiation and progression of breast cancer. The present study may contribute to understanding the molecular mechanisms of RAI2 and enriching biomarkers to predict patient prognosis in breast cancer.
RETRACTED: A novel therapeutic strategy of combined camrelizumab and apatinib for the treatment of advanced hepatocellular carcinoma
Authors: Yang Qing , Li Gengyu , Wu Xiaoqiu , Lin Haiying , Wu Wanrui , Xie Xiangpang , Zhu Yu , Cai Wei , Shi Changsheng , Zhuo Shengye
Published: March 2023

Methods

83 patients with hepatocellular carcinoma (HCC) admitted to the interventional oncology department were randomly divided into two groups. Apatinib and camrelizumab were administered to 42 patients in group A, whereas sorafenib was administered to 41 patients in group B for three months. The clinical efficacy was evaluated in terms of objective response rate (ORR), and disease control rate (DCR). Certain tumor markers like alpha-fetoprotein (AFP), carbohydrate antigen 199 (CA199), carcinoembryonic antigen (CEA), hypoxia-inducible factor (HIF-1), immune function T lymphocyte subsets (CD3+, CD4+, CD8+, CD4+/CD8+) were determined before and after treatment. The serum levels of vascular endothelial growth factor (VEGF), osteopontin (OPN), aspartate aminotransferase (AST), and epidermal growth factor 7 (EGF7)] were observed. The survival time between the two groups was compared, such as progression-free survival (PFS) and median survival (MS). Finally, the toxicity and side effects data were also obtained.

Results

The ORR and DCR of group A were 69.05% and 88.10%, respectively, which were significantly higher (P<0.05) than group B (ORR=53.66% and DCR=70.73%). After treatment, the AFP, CA199, CEA, and HIF-1 levels of both groups decreased significantly (P<0.05), and the respective biomarker levels of group A were lower than those of group B (P<0.05). Following treatment, CD3+, CD4+, CD4+/CD8+ index in group A significantly increased (P<0.05) while CD8+ level was significantly decreased (P<0.05). Compared to group B, a significant increase was observed in group A’s CD3+, CD4+, and CD4+/CD8+ index. There were no significant changes in CD3+, CD4+, CD8+, CD4+/CD8+ indexes before and after treatment in group B (P>0.05). The serum level of VEGF, OPN, EGF-7 and AST indexes of group A&B were decreased significantly (P<0.05). Compared with group B, the VEGF, OPN, EGF7 and AST indexes of group A were significantly reduced (P<0.05). PFS and MS in group A were significantly higher than in group B (P<0.05). There was no significant difference between groups A and B in terms of toxicity and adverse effects (P>0.05).

Conclusion

In treating HCC, combining apatinib and camrelizumab can reduce tumor markers, enhance the immune system and curative effect, and prolong patient survival. The underline mechanism is related to the down-regulation of VEGF, OPN and HIF-1 indexes.
Multimodality MRI radiomics analysis of TP53 mutations in triple negative breast cancer
Authors: Sun Kun , Zhu Hong , Chai Weimin , Yan Fuhua
Published: March 2023

Objectives

To explore the value of T1-weighted imaging (T1WI), T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) radiomics features reflecting TP53 mutations in patients with triple negative breast cancer (TNBC).

Study design

This retrospective study enrolled 91 patients with TNBC with TP53 testing (64 patients in the training cohort and 27 patients in the validation cohort). A total of 2832 radiomics features were extracted from the first phase of dynamic contrast-enhanced T1WI, T2WI and ADC maps. Analysis of variance (ANOVA) and the Kruskal-Wallis-test were used for feature selection. Then, linear discriminant analysis (LDA), multilayer perceptron (MLP), logistic regression (LR), LR with LASSO, decision tree (DT), naïve Bayes (NB), random forest (RF), and support vector machine (SVM) models were used for classification.

Results

The validation AUCs of the eight classifiers ranged from 0.74 (NB) to 0.85 (SVM). SVM attained the highest AUC (0.85) and diagnostic accuracy (0.82) of all tested models. The top 3 ranking features in the SVM model were T1-square-first order-skewness (coefficient: 1.735), T2-wavelet-LHH-GLCM-joint energy, and T2-wavelet-LHH-GLCM-inverse difference moment (coefficient: -0.654, -0.634).

Conclusions

Radiomics-based analysis with the SVM model is recommended for the detection of TP53 mutations in TNBC. Furthermore, T1WI- and T2WI-related features could be used as noninvasive biomarkers for predicting TP53 mutations.
HPV genotyping of cervical histologic specimens of 61, 422 patients from the largest women hospital in China
Authors: Zhong Fangfang , Li Zaibo , Sun Yihua , Xiao Yaoxing , Li Juan , Zhou Xianrong , Cong Qing , Sui Long , Tao Xiang , Zhao Chengquan
Published: March 2023

Objectives

We investigated HPV genotypes in a large cohort of patients with definitive cervical histologic diagnosis.

Methods

HPV testing was performed by real-time PCR assay, including 18 high-risk HPV (hrHPV) and 3 low-risk HPV (lrHPV). Totally 61,422 patients with documented HPV genotyping results within 6 months before cervical histologic diagnoses were included.

Results

HrHPV positive rate was 55.1% among all tested cases with the highest in adenosquamous carcinoma (94.1%), followed by squamous cell carcinoma (SCC) (93.7%), cervical intraepithelial neoplasia 2/3 (CIN2/3) (92.8%). HrHPV positive rates were significantly higher in high-grade squamous lesions than in those in glandular lesions. HPV16 was the most common genotype followed by HPV52 and HPV58 in CIN2/3. The most frequent hrHPV genotype in adenocarcinoma in situ (AIS) was HPV18, followed by HPV16, HPV45 and HPV52. In SCC cases, HPV16 was the most common type followed by HPV58, HPV52, HPV18 and HPV33. However, HPV18 showed significantly higher prevalence in adenocarcinoma and adenosquamous carcinoma than in that in SCC. Theoretically, the protective rates of 2/4-valent and 9-valent vaccine were 69.1% and 85.8% for cervical cancers.

Conclusions

The prevalence of HPV genotypes in Chinese population was different from that in Western population. Some hrHPV types were identified in cervical precancerous lesions and cancers, which are not included in current HPV vaccines. These data provide baseline knowledge for future HPV vaccine development.
Impact of a TAK-1 inhibitor as a single or as an add-on therapy to riociguat on the metabolic reprograming and pulmonary hypertension in the SUGEN5416/hypoxia rat model
Authors: Morales-Cano Daniel , Izquierdo-García Jose Luis , Barreira Bianca , Esquivel-Ruiz Sergio , Callejo Maria , Pandolfi Rachele , Villa-Valverde Palmira , Rodríguez Ignacio , Cogolludo Angel , Ruiz-Cabello Jesus , Perez-Vizcaino Francisco , Moreno Laura
Published: March 2023

Background: Despite increasing evidence suggesting that pulmonary arterial hypertension (PAH) is a complex disease involving vasoconstriction, thrombosis, inflammation, metabolic dysregulation and vascular proliferation, all the drugs approved for PAH mainly act as vasodilating agents. Since excessive TGF-β signaling is believed to be a critical factor in pulmonary vascular remodeling, we hypothesized that blocking TGFβ-activated kinase 1 (TAK-1), alone or in combination with a vasodilator therapy (i.e., riociguat) could achieve a greater therapeutic benefit.

Methods: PAH was induced in male Wistar rats by a single injection of the VEGF receptor antagonist SU5416 (20 mg/kg) followed by exposure to hypoxia (10%O2) for 21 days. Two weeks after SU5416 administration, vehicle, riociguat (3 mg/kg/day), the TAK-1 inhibitor 5Z-7-oxozeaenol (OXO, 3 mg/kg/day), or both drugs combined were administered for 7 days. Metabolic profiling of right ventricle (RV), lung tissues and PA smooth muscle cells (PASMCs) extracts were performed by magnetic resonance spectroscopy, and the differences between groups analyzed by multivariate statistical methods.

Results:In vitro, riociguat induced potent vasodilator effects in isolated pulmonary arteries (PA) with negligible antiproliferative effects and metabolic changes in PASMCs. In contrast, 5Z-7-oxozeaenol effectively inhibited the proliferation of PASMCs characterized by a broad metabolic reprogramming but had no acute vasodilator effects. In vivo, treatment with riociguat partially reduced the increase in pulmonary arterial pressure (PAP), RV hypertrophy (RVH), and pulmonary vascular remodeling, attenuated the dysregulation of inosine, glucose, creatine and phosphocholine (PC) in RV and fully abolished the increase in lung IL-1β expression. By contrast, 5Z-7-oxozeaenol significantly reduced pulmonary vascular remodeling and attenuated the metabolic shifts of glucose and PC in RV but had no effects on PAP or RVH. Importantly, combined therapy had an additive effect on pulmonary vascular remodeling and induced a significant metabolic effect over taurine, amino acids, glycolysis, and TCA cycle metabolism via glycine-serine-threonine metabolism. However, it did not improve the effects induced by riociguat alone on pulmonary pressure or RV remodeling. None of the treatments attenuated pulmonary endothelial dysfunction and hyperresponsiveness to serotonin in isolated PA.

Conclusion: Our results suggest that inhibition of TAK-1 induces antiproliferative effects and its addition to short-term vasodilator therapy enhances the beneficial effects on pulmonary vascular remodeling and RV metabolic reprogramming in experimental PAH.