bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression and Clinical Significance of HKII and HIF-1α in Grade Groups of Prostate Cancer
Authors: Sun Xueqi , Huang Qirui , Peng Fang , Wang Jian , Zhao Weidong , Guo Guangxiu
Published: June 2021

Prostate cancer (PCA) is the second leading cause of cancer-related mortality in men. The glycolytic enzymes hexokinase II (HKII) and the major regulator hypoxia-inducible factor-1α (HIF-1α) are PCA-specific biomarkers. Some studies have shown that HKII and HIF-1α are highly expressive in PCA and are associated with the growth and metastasis of treatment. Whether HKII and HIF-1α regulate the different differentiation of PCA remains largely unknown. Therefore, the study aims to explore the value of HKII and HIF-1α in different grade groups of PCA. Our data indicated that compared with normal prostate tissues, the level of mRNA and protein of HKII and HIF-1α in PCA increased significantly, besides the results showed the high expression of HKII and HIF-1α had a tendency to promote the progression and differentiation of PCA. The study also found that HKII expression was positively correlated with the expression of HIF-1α. HKII and HIF-1α were related to the degree of differentiation PCA, especially in high-grade PCA. Furthermore, the high expression of HKII was significantly associated with Gleason score and histological differentiation in clinicopathological characteristics of patients with PCA. These results were further used to confirm that the expression of HKII and HIF-1α was associated with the progression and differentiation of PCA. These experiments indicated that HKII and HIF-1α might be novel biomarkers of PCA with potential clinical application value, provide a new potential target for PCA treatment, and are expected to be used for individualized treatment in patients with PCA.
Increased Expression of PDK4 Was Displayed in Gastric Cancer and Exhibited an Association With Glucose Metabolism
Authors: Liu Bin , Zhang Yang , Suo Jian
Published: June 2021

Previous studies reported that pyruvate dehydrogenase kinase 4 (PDK4) is closely related to diabetes, heart disease, and carcinomas. Nevertheless, the role of PDK4 in gastric cancer (GC) occurrence and development is yet poorly understood. Our experiments were taken to evaluate PDK4’s function in GC. The Cancer Genome Atlas tumor genome map database was employed to validate the levels of PDK family in different grades and stages of GC. The survival ratio of PDK families in GC was detected by the Kaplan–Meier plotter database. The links existing in the expression of PDK family and the level of tumor-infiltrating immune cells were investigated by tumor immunity assessment resource (TIMER). PDK4-associated signal pathways in GC were analyzed by the Kyoto Encyclopedia of Genes and Genomes pathway analysis. PDK4 mRNA level in the GC cells was measured by qRT-PCR. Cell counting kit-8 and Transwell assays were separately carried out to evaluate PDK4-induced influence on GC cell proliferation, migration, and invasion. Our data suggested that GC cells highly expressed PDK4, and PDK4 expression presented a significant relation with the staging, grade, and survival rate of GC. PDK4 expression presented a positive correlation with the types of different infiltrating immune cells, comprising B cells, CD4+T cells, and dendritic cells. Meanwhile, PDK4 expression exhibited a strong association with macrophages. Survival analysis revealed that the expression of PDK4 displayed a relationship with the prognosis of patients. Therefore, PDK4 was liable to be a biomarker for prognosis. Our results further displayed that PDK4 might modulate the glycolysis level in GC cells, and its expression was associated with GC cell proliferation, migration, and invasion. These data may provide insights into designing a new treatment strategy for GC.
Consideration of Therapeutic Plasma Exchange in Association With Inflammatory Lesions in ANCA-Associated Glomerulonephritis: A Real-World Retrospective Study From a Single Center
Authors: Tampe Désirée , Ströbel Philipp , Korsten Peter , Hakroush Samy , Tampe Björn
Published: June 2021

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic vasculitis, most frequently presenting as microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA). Pathogenic ANCAs trigger a deleterious immune response resulting in pauci-immune necrotizing and crescentic glomerulonephritis (GN). Standard therapeutical regimens include aggressive immunosuppressive therapy. Since some patients require renal replacement therapy (RRT) despite intensive immunosuppressive therapy, additional therapeutic plasma exchange (PEX) to deplete pathogenic ANCAs has been recommended but its value has recently been questioned. Because therapeutic decision making is crucial in these critically ill patients, we here aimed to identify inflammatory lesions in association with PEX consideration in a retrospective study from a single center tertiary hospital in a real-world population of 46 patients with severe AAV requiring intensive care treatment. The decision to consider PEX was more likely in patients with need for intensive care treatment and severe renal dysfunction. In contrast, short-term outcomes did not depend on clinical, or laboratory characteristics assessed at admission. Histopathological analysis confirmed active disease reflected by increased glomerular necrosis and crescents, but these histopathological findings did not associate with short-term outcome either. Interestingly, only increased global glomerular sclerosis in renal biopsies associated with a detrimental short-term outcome. In conclusion, our study investigated determinants for the consideration of therapeutic PEX in patients with severe AAV requiring intensive care treatment. This aspect underscores the need for renal biopsy and requires further investigation in a prospective controlled setting for therapeutic decision making especially in patients with severe AAV requiring intensive care treatment, especially important for treating intensivists.
Immunogenicity and Efficacy of Pneumococcal Conjugate Vaccine (Prevenar13®) in Preventing Acquisition of Carriage of Pneumococcal Vaccine Serotypes in Tanzanian Children With HIV/AIDS
Authors: Makenga Geofrey , Mtove George , Yin J. Kevin , Mziray Abubakary , Bwana Veneranda M. , Kisinza William , Mjema Julius , Amos Ben , Antony Laura , Shingadia Delane , Oftadeh Shahin , Booy Robert
Published: June 2021

In every year, up to one million children die due to pneumococcal disease. Children infected with Human Immunodeficiency Virus (HIV) are mostly affected, as they appear to have higher rates of pneumococcal carriage and invasive disease. Successful immunity is dependent on mounting a sufficient immune response to the vaccine. We conducted a double blinded crossover randomised controlled trial to determine the serum antibody response (≥4-fold and geometric mean concentration) to pneumococcal vaccine (PCV13) serotypes at 3 months after second vaccination. We also determined the number and proportion of children carrying new (not present at baseline) vaccine serotypes of S. pneumoniae isolated from nasopharynx at 6 months post initial vaccination in recipients of Prevenar13® compared with those given Haemophilus influenzae-type b (Hib) vaccine (control). The study was conducted at St Augustine's also known as Teule Hospital in Muheza, Tanga Tanzania. 225 HIV infected children aged 1-14 years were enrolled from Jan 2013 to Nov 2013 and randomised to Prevenar13® or Hib vaccines each given at baseline and 2-3 months later. Nasopharyngeal and serum samples were collected at baseline and 4-6 months later. Serotyping was done by Quellung Reaction using Staten antisera. Serum antibodies were ELISA quantified. The study revealed a non-significant reduction in the acquisition of new vaccine serotypes of S. pneumoniae in the recipients of PCV13 by nearly a third compared to those who received Hib vaccine. The vaccine efficacy was 30.5% (95% confidence interval [CI] –6.4-54.6%, P = 0.100)]. The antibody response was not enough to induce a 4-fold rise in GMC in 7 of the 13 vaccine serotypes. When combining the effects of preventing new acquisition and clearing existing vaccine type carriage, the overall efficacy was 31.5% (95% CI 1.5-52.4%, P = 0.045). In the PCV13 group, the proportion of participants carrying vaccine serotype was significantly lower after 2 doses of PCV13 (30%; 32/107), compared with the baseline proportion (48%; 51/107). The introduction of PCV13 targeting HIV-positive children in a setting similar to Tanzania is likely to be associated with appreciable decrease in the acquisition and carriage of pneumococci, which is an important marker of the likely effect of the vaccine on pneumococcal disease.

Clinical Trial Registration

https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=335579, identifier ACTRN12610000999033.
Cerebrospinal Fluid Findings in 541 Patients With Clinically Isolated Syndrome and Multiple Sclerosis: A Monocentric Study
Authors: Berek Klaus , Bsteh Gabriel , Auer Michael , Di Pauli Franziska , Zinganell Anne , Berger Thomas , Deisenhammer Florian , Hegen Harald
Published: June 2021

Background

Reports on typical routine cerebrospinal fluid (CSF) findings are outdated owing to novel reference limits (RL) and revised diagnostic criteria of Multiple Sclerosis (MS).

Objective

To assess routine CSF parameters in MS patients and the frequency of pathologic findings by applying novel RL.

Methods

CSF white blood cells (WBC), CSF total protein (CSF-TP), CSF/serum albumin quotient (Qalb), intrathecal synthesis of immunoglobulins (Ig) A, M and G, oligoclonal IgG bands (OCB) were determined in patients with clinically isolated syndrome (CIS) and MS.

Results

Of 541 patients 54% showed CSF pleocytosis with a WBC count up to 40/μl. CSF cytology revealed lymphocytes, monocytes and neutrophils in 99%, 41% and 9% of patients. CSF-TP and Qalb were increased in 19% and 7% applying age-corrected RL as opposed to 34% and 26% with conventional RL. Quantitative intrathecal IgG, IgA and IgM synthesis were present in 65%, 14% and 21%; OCB in 95% of patients. WBC were higher in relapsing than progressive MS and predicted, together with monocytes, the conversion from CIS to clinically definite MS. Intrathecal IgG fraction was highest in secondary progressive MS.

Conclusions

CSF profile in MS varies across disease courses. Blood-CSF-barrier dysfunction and intrathecal IgA/IgM synthesis are less frequent when the novel RL are applied.
Safety and Efficacy of Fecal Microbiota Transplantation for Grade IV Steroid Refractory GI-GvHD Patients: Interim Results From FMT2017002 Trial
Authors: Zhao Ye , Li Xuewei , Zhou Yujing , Gao Jin , Jiao Yang , Zhu Baoli , Wu Depei , Qi Xiaofei
Published: June 2021

Gastrointestinal (GI) tract graft-versus-host disease (GvHD) is a major cause of post-allo-HSCT (hematopoietic stem cell transplantation) morbidity and mortality. Patients with steroid-refractory GI-GvHD have a poor prognosis and limited therapeutic options. FMT2017002 trial (#NCT03148743) was a non-randomized, open-label, phase I/II clinical study of FMT for treating patients with grade IV steroid-refractory GI-GvHD. A total of 55 patients with steroid-refractory GI-GvHD were enrolled in this study. Forty-one patients with grade IV steroid-refractory GI-GvHD were included in the final statistical analysis. Of them, 23 patients and 18 patients were assigned to the FMT group and the control group, respectively. On days 14 and 21 after FMT, clinical remission was significantly greater in the FMT group than in the control group. Within a follow-up period of 90 days, the FMT group showed a better overall survival (OS). At the end of the study, the median survival time was >539 days in the FMT group and 107 days in the control group (HR=3.51; 95% CI, 1.21–10.17; p=0.021). Both the event-free survival time (EFS) (HR=2.3, 95% CI, 0.99–5.4; p=0.08) and OS (HR=4.4, 95% CI, 1.5–13.04; p=0.008) were higher in the FMT group during the follow-up period. Overall, the mortality rate was lower in the FMT group (HR=3.97; 95% CI, 1.34–11.75; p=0.013). No differences in the occurrence of any other side effects were observed. Our data suggest that the diversity of the intestinal microbiota could be affected by allo-HSCT. Although its effectiveness and safety need further evaluation, FMT may serve as a therapeutic option for grade IV steroid-refractory GI-GvHD.

Clinical Trial Registration

[ClinicalTrials.gov], identifier [NCT03148743].
Influence of Tumor Immune Infiltration on Immune Checkpoint Inhibitor Therapeutic Efficacy: A Computational Retrospective Study
Authors: Liu Rong , Yang Fang , Yin Ji-Ye , Liu Ying-Zi , Zhang Wei , Zhou Hong-Hao
Published: June 2021

The tumor immune microenvironment (TIME) is likely an important determinant of sensitivity to immune checkpoint inhibitor (ICI) treatment. However, a comprehensive analysis covering the complexity and diversity of the TIME and its influence on ICI therapeutic efficacy is still lacking. Data from 782 samples from 10 ICI clinical trials were collected. To infer the infiltration of 22 subsets of immune cells, CIBERSORTx was applied to the bulk tumor transcriptomes. The associations between each cell fraction and the response to ICI treatment, progression-free survival (PFS) and overall survival (OS) were evaluated, modeling cellular proportions as quartiles. Activity of the interferon-γ pathway, the cytolytic activity score and the MHC score were associated with good prognosis in melanoma. Of the immune cells investigated, M1 macrophages, activated memory CD4+ T cells, T follicular helper (Tfh) cells and CD8+ T cells correlated with response and prolonged PFS and OS, while resting memory CD4+ T cells was associated with unfavorable prognosis in melanoma and urothelial cancer. Consensus clustering revealed four immune subgroups with distinct responses to ICI therapy and survival patterns. The cluster with high proportions of infiltrated CD8+ T cells, activated memory CD4+ T cells, and Tfh cells and low levels of resting memory CD4+ T cells exhibited a higher tumor mutation burden and neoantigen load in melanoma and conferred a higher probability of response and improved survival. Local systemic immune cellular differences were associated with outcomes after ICI therapy. Further investigations of the tumor-infiltrating cellular immune response will lay the foundation for achieving durable efficacy.
Chronic Immune Activation and CD4+ T Cell Lymphopenia in Healthy African Individuals: Perspectives for SARS-CoV-2 Vaccine Efficacy
Authors: Wolday Dawit , Ndungu Francis M. , Gómez-Pérez Gloria P. , de Wit Tobias F. Rinke
Published: June 2021

Chronic immune activation has been considered as the driving force for CD4+T cell depletion in people infected with HIV-1. Interestingly, the normal immune profile of adult HIV-negative individuals living in Africa also exhibit chronic immune activation, reminiscent of that observed in HIV-1 infected individuals. It is characterized by increased levels of soluble immune activation markers, such as the cytokines interleukin (IL)-4, IL-10, TNF-α, and cellular activation markers including HLA-DR, CD-38, CCR5, coupled with reduced naïve and increased memory cells in CD4+and CD8+subsets. In addition, it is accompanied by low CD4+T cell counts when compared to Europeans. There is also evidence that mononuclear cells from African infants secrete less innate cytokines than South and North Americans and Europeansin vitro. Chronic immune activation in Africans is linked to environmental factors such as parasitic infections and could be responsible for previously observed immune hypo-responsiveness to infections and vaccines. It is unclear whether the immunogenicity and effectiveness of anti-SARS-CoV-2 vaccines will also be reduced by similar mechanisms. A review of studies investigating this phenomenon is urgently required as they should inform the design and delivery for vaccines to be used in African populations.
Multi-Omics Sequencing Provides Insights Into Age-Dependent Susceptibility of Grass Carp (Ctenopharyngodon idellus) to Reovirus
Authors: He Libo , Zhu Denghui , Liang Xinyu , Li Yongming , Liao Lanjie , Yang Cheng , Huang Rong , Zhu Zuoyan , Wang Yaping
Published: June 2021

Grass carp (Ctenopharyngodon idellus) is an important aquaculture species in China that is affected by serious diseases, especially hemorrhagic disease caused by grass carp reovirus (GCRV). Grass carp have previously shown age-dependent susceptibility to GCRV, however, the mechanism by which this occurs remains poorly understood. Therefore, we performed transcriptome and metabolome sequencing on five-month-old (FMO) and three-year-old (TYO) grass carp to identify the potential mechanism. Viral challenge experiments showed that FMO fish were susceptible, whereas TYO fish were resistant to GCRV. RNA-seq showed that the genes involved in immune response, antigen presentation, and phagocytosis were significantly upregulated in TYO fish before the GCRV infection and at the early stage of infection. Metabolome sequencing showed that most metabolites were upregulated in TYO fish and downregulated in FMO fish after virus infection. Intragroup analysis showed that arachidonic acid metabolism was the most significantly upregulated pathway in TYO fish, whereas choline metabolism in cancer and glycerophospholispid metabolism were significantly downregulated in FMO fish after virus infection. Intergroup comparison revealed that metabolites from carbohydrate, amino acid, glycerophospholipid, and nucleotide metabolism were upregulated in TYO fish when compared with FMO fish. Moreover, the significantly differentially expressed metabolites showed antiviral effects both in vivo and in vitro. Based on these results, we concluded that the immune system and host biosynthesis and metabolism, can explain the age-dependent viral susceptibility in grass carp.
Comparison of POC-CCA with Kato-Katz in Diagnosing Schistosoma mansoni Infection in a Pediatric L-Praziquantel Clinical Trial
Authors: Yin Xiaoyan , N’Goran Eliézer K. , Ouattara Mamadou , Aka NAD. , Diakité Nana R. , Bassa Fidèle K. , Kourany-Lefoll Elly , Tappert Aliona , Yalkinoglu Özkan , Huber Eric , Bezuidenhout Deon , Bagchus Wilhelmina M. , Hayward Brooke
Published: June 2021

Introduction

TraditionallySchistosoma mansoniinfection is diagnosed by the Kato-Katz method. Thick smears from each stool sample are prepared on slides and eggs are counted microscopically. Commercially available point-of-care circulating cathodic antigen (POC-CCA) cassette tests detect schistosomiasis antigens from urine samples in 20 minutes. POC-CCA results are qualitative or semi-quantitative: signal intensity is an indicator of the amount of worm antigens in the sample. Both methods were used in a phase II trial investigating the efficacy and safety of new pediatric formulations of praziquantel (PZQ) among children ≤6 years (NCT02806232). This secondary analysis evaluated the consistency of results between the Kato-Katz and POC-CCA methods.

Methods

POC-CCA was used to pre-screen forS. mansoniinfection. Children with positive results were tested by the Kato-Katz method, and those with positive Kato-Katz results (>1 egg/1 occurrence) were enrolled. Participants (N=444) were treated with different formulations and doses of PZQ. POC-CCA and Kato-Katz were performed at 2–3 weeks after treatment to evaluate drug efficacy. Cure rate (CR) was defined as the proportion of participants with a negative result per POC-CCA, or no eggs in the stool samples per Kato-Katz. Kappa statistic was used to assess the agreement on cure status, and Spearman correlation between POC-CCA positivity and Kato-Katz egg counts was evaluated. Sensitivity and specificity of POC-CCA were calculated using Kato-Katz as a reference standard.

Results

CR per POC-CCA, measured 2–3 weeks after treatment, was 52% [95% confidence interval (CI): 48%, 57%] across all treatment arms except in infants aged 3–12 months. CR per Kato-Katz was 83% (95% CI: 79%, 87%). Kappa statistic was 0.16 (95% CI: 0.09, 0.23), indicating that the agreement was slightly better than by chance. Relative to Kato-Katz, POC-CCA’s sensitivity to detect infection was 70% and specificity was 57%. Spearman correlation coefficient between POC-CCA positivity and Kato-Katz egg counts was 0.26 (95% CI: 0.17, 0.34).

Conclusion

POC-CCA is sensitive and rapid for diagnosingS. mansoniinfection, but its performance and consistency with Kato-Katz requires further investigation among young children.
Pathways, Volume Transport, and Seasonal Variability of the Lower Deep Limb of the Pacific Meridional Overturning Circulation at the Yap-Mariana Junction
Authors: Wang Jianing , Wang Fan , Lu Youyu , Ma Qiang , Pratt Larry J. , Zhang Zhixiang
Published: June 2021

The lower deep branch of the Pacific Meridional Overturning Circulation (L-PMOC) is responsible for the deep-water transport from Antarctic to the North Pacific and is a key ingredient in the regulation of global climate through its influence on the storage and residence time of heat and carbon. At the Pacific Yap-Mariana Junction (YMJ), a major gateway for deep-water flowing into the Western Pacific Ocean, we deployed five moorings from 2018 to 2019 in the Eastern, Southern, and Northern Channels in order to explore the pathways and variability of L-PMOC. We have identified three main patterns for L-PMOC pathways. In Pattern 1, the L-PMOC intrudes into the YMJ from the East Mariana Basin (EMB) through the Eastern Channel and then flows northward into the West Mariana Basin (WMB) through the Northern Channel and southward into the West Caroline Basin (WCB) through the Southern Channel. In Pattern 2, the L-PMOC intrudes into the YMJ from both the WCB and the EMB and then flows into the WMB. In Pattern 3, the L-PMOC comes from the WCB and then flows into the EMB and WMB. The volume transports of L-PMOC through the Eastern, Southern, and Northern Channels all exhibit seasonality. During November–April (May–October), the flow pathway conforms to Pattern 1 (Patterns 2 and 3), and the mean and standard deviation of L-PMOC transports are −4.44 ± 1.26 (−0.30 ± 1.47), −0.96 ± 1.13 (1.75 ± 1.49), and 1.49 ± 1.31 (1.07 ± 1.10) Sv in the Eastern, Southern, and Northern Channels, respectively. Further analysis of numerical ocean modeling results demonstrates that L-PMOC transport at the YMJ is forced by a deep pressure gradient between two adjacent basins, which is mainly determined by the sea surface height (SSH) and water masses in the upper 2,000-m layer. The seasonal variability of L-PMOC transport is attributed to local Ekman pumping and westward-propagating Rossby waves. The L-PMOC transport greater than 3,500 m is closely linked to the wind forcing and the upper ocean processes.
Metabolic Reliance on Photosynthesis Depends on Both Irradiance and Prey Availability in the Mixotrophic Ciliate, Strombidium cf. basimorphum
Authors: Hughes Erin Ann , Maselli Maira , Sørensen Helle , Hansen Per Juel
Published: June 2021

Many species of the ciliate genus Strombidium can acquire functional chloroplasts from a wide range of algal prey and are thus classified as generalist non-constitutive mixotrophs. Little, however, is known about the influence of irradiance and prey availability on their ability to exploit the photosynthetic potential of the chloroplasts, and how this may explain their spatial and temporal distribution in nature. In this study, inorganic carbon uptake, growth, and ingestion rates were measured for S. cf. basimorphum under three different irradiances (10, 40, and 120 μmol photons m–2 s–1) when acclimated to three different prey densities (5 × 103, 1 × 104, and 4 × 104 cells mL–1), as well as when allowed to deplete the prey. After prey depletion, cultures survived without prey longest (∼6 days) at the medium irradiance treatment (40 μmol photons m–2 s–1), while ciliate density, inorganic carbon uptake rates, and cellular chl-a content declined fastest at the highest irradiance treatment. This indicates that the ciliates may be unable to maintain the chloroplasts functionally without replacement at high irradiances. Ingestion rates were not shown to be significantly influenced by irradiance. The maximum gross growth efficiency (GGE) in this study (1.1) was measured in cultures exposed to the medium test irradiance and lowest prey density treatment (5 × 103 cells mL–1). The relative contribution of inorganic carbon uptake to the ciliate carbon budget was also highest in this treatment (42%). A secondary GGE peak (0.99) occurred when cultures were exposed to the highest test irradiance and the medium prey density. These and other results suggest that S. cf. basimorphum, and other generalist non-constitutive mixotrophs, can flexibly exploit many different environmental conditions across the globe.
Self-Regulation of Cerebral Metabolism and Its Neuroprotective Effect After Hypoxic-Ischemic Injury: Evidence From 1H-MRS
Authors: Li Kexin , Zheng Yang , Wang Xiaoming
Published: June 2021

1H-MRS technology can be used to non-invasively detect the content of cerebral metabolites, to assess the severity of hypoxic-ischemic (HI) injury, and to predict the recovery of compromised neurological function. However, changes to the cerebral self-regulation process after HI are still unclear. This study investigated the changes in cerebral metabolites and the potential relationship with the number of neurons and neural stem/progenitor cells (NSPC) using 1H-MRS, and finally clarifies the self-regulation of cerebral metabolism and neuroprotection after HI injury. Newborn Yorkshire pigs (28 males, 1.0–1.5 kg) aged 3–5 days were used for the HI model in this study. The pigs were randomly divided into the HI group (n = 24) and the control group (n = 4), then the experimental group was subdivided according to different recovery time after HI into the following groups: 0–2 h (n = 4), 2–6 h (n = 4), 6–12 h (n = 4), 12–24 h (n = 4), 24–48 h (n = 4), and 48–72 h (n = 4). Following the HI timepoints, 1H-MRS scans were performed and processed using LCModel software, and brain tissue was immunohistochemically stained for Nestin and NeuN. Immunofluorescence staining of creatine phosphokinase-BB (CK-BB), N-acetylaspartylglutamate synthetase (NAAGS), glutamate carboxypeptidase II (GCP-II), glutamate-cysteine ligase catalytic subunit (GCLC), glutathione synthase (GS), and excitatory amino acid carrier 1 (EAAC1) was then performed. The 1H-MRS results showed that cerebral N-acetylaspartylglutamate (NAAG), glutathione (GSH), and creatine (Cr) content reached their peaks at 12–24 h, which was consistent with the recovery time of hippocampal NSPCs and neurons, indicating a potential neuroprotective effect of NAAG, GSH, and Cr after HI injury.
Clinical Features of Patients With Progressive Supranuclear Palsy in an US Insurance Claims Database
Authors: Viscidi Emma , Litvan Irene , Dam Tien , Juneja Maneesh , Li Li , Krzywy Henry , Eaton Susan , Hall Susan , Kupferman Joseph , Höglinger Günter U.
Published: June 2021

Background: Progressive supranuclear palsy is a rare neurodegenerative movement disorder and little is known about its epidemiology.

Objective: Estimate age-adjusted prevalence of progressive supranuclear palsy and describe antecedent diagnoses and progressive supranuclear palsy patient features in the 5 years before first diagnostic code.

Methods: In a nested case-control study in the IBM MarketScan Commercial and Medicare Supplemental Databases, a large set of US insurance databases containing medical service and prescription drug claims from employer-based commercial and Medicare supplemental health insurance plans, progressive supranuclear palsy cases (identified via International Statistical Classification of Diseases 9th/10th revision codes) and controls were included if enrollment was ≥1 month in the study period (October 1, 2015–October 31, 2017). Two controls with no diagnosis codes for PSP were matched to cases on birth year, sex, enrollment time in the database, and pharmacy benefit eligibility. Controls were assigned a randomly selected index date from their eligibility period. Prevalence of progressive supranuclear palsy was estimated in 2016 among patients with ≥1 month of continuous enrollment in that year. Prevalence ratios for comorbidities (claim/diagnosis codes) were examined in the ≤ 5 years before index date (first progressive supranuclear palsy claim date).

Results: Age-adjusted progressive supranuclear palsy prevalence was 2.95/100,000 in 2016. The most common diagnosis codes in cases vs. controls in the 5 years pre-index were gait abnormalities (79.3 vs. 21.8%), pain in joint (54.9 vs. 36.0%), Parkinson's disease (54.6 vs. 1.0%), fatigue (49.8 vs. 21.6%), and cerebrovascular disease (45.6 vs. 16.4%).

Conclusions: In this large database analysis, based on preliminary analyses, the prevalence of diagnosed progressive supranuclear palsy was 2.95/100,000, which is lower than many prior studies. Typical symptoms suggestive of progressive supranuclear palsy were present before index date, indicating a potential delay in time to diagnosis. The identification of diagnostic codes for clinical features of progressive supranuclear palsy that occurred before index date may be used to develop predictive models to identify potential progressive supranuclear palsy patients earlier in their disease course.
Inferior Frontal Gyrus-Based Resting-State Functional Connectivity and Medium Dispositional Use of Reappraisal Strategy
Authors: Li Wenjuan , Xie Ke , Ngetich Ronald K. , Zhang Junjun , Jin Zhenlan , Li Ling
Published: June 2021

The previous neuroimaging functional connectivity analyses have indicated that the association between the inferior frontal gyrus (IFG) and other brain regions results in better emotion regulation in reappraisal tasks. However, no study has explored the relationship between IFG-based resting-state functional connectivity (rsFC) and the dispositional use of reappraisal strategy. Therefore, the present study examined the potential associations between rsFC patterns of both left and right IFG and dispositional reappraisal use. One hundred healthy participants completed the Emotion Regulation Questionnaire (ERQ) and underwent a resting-state functional magnetic resonance imaging (fMRI) acquisition. An approach of the seed-based rsFC analysis was recruited to estimate the functional connectivity maps of bilateral IFG with other brain regions, and the reappraisal scores from the ERQ were then correlated with the functional maps. Our findings showed that IFG-based rsFC was positively correlated with dispositional reappraisal only in the range of 4 to 5.5 points [medium reappraisal group (MRG)]. Specifically, medium dispositional reappraisal was positively correlated with rsFC between left/right IFG and bilateral temporal gyrus. Besides, medium dispositional reappraisal was positively correlated with rsFC between left IFG and bilateral superior parietal lobe (SPL), middle cingulate cortex (MCC), and right insula, as well as between right IFG and dorsomedial prefrontal cortex (DMPFC) and anterior cingulate cortex (ACC). In conclusion, these results indicate that bilateral IFG plays an important role in the medium use of the reappraisal strategy.
Synaptic Plasticity and Oscillations in Alzheimer’s Disease: A Complex Picture of a Multifaceted Disease
Authors: Andrade-Talavera Yuniesky , Rodríguez-Moreno Antonio
Published: June 2021

Brain plasticity is widely accepted as the core neurophysiological basis of memory and is generally defined by activity-dependent changes in synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD). By using diverse induction protocols like high-frequency stimulation (HFS) or spike-timing dependent plasticity (STDP), such crucial cognition-relevant plastic processes are shown to be impaired in Alzheimer’s disease (AD). In AD, the severity of the cognitive impairment also correlates with the level of disruption of neuronal network dynamics. Currently under debate, the named amyloid hypothesis points to amyloid-beta peptide 1–42 (Aβ42) as the trigger of the functional deviations underlying cognitive impairment in AD. However, there are missing functional mechanistic data that comprehensively dissect the early subtle changes that lead to synaptic dysfunction and subsequent neuronal network collapse in AD. The convergence of the study of both, mechanisms underlying brain plasticity, and neuronal network dynamics, may represent the most efficient approach to address the early triggering and aberrant mechanisms underlying the progressive clinical cognitive impairment in AD. Here we comment on the emerging integrative roles of brain plasticity and network oscillations in AD research and on the future perspectives of research in this field.
Visualizing Synaptic Multi-Protein Patterns of Neuronal Tissue With DNA-Assisted Single-Molecule Localization Microscopy
Authors: Narayanasamy Kaarjel K. , Stojic Aleksandar , Li Yunqing , Sass Steffen , Hesse Marina R. , Deussner-Helfmann Nina S. , Dietz Marina S. , Kuner Thomas , Klevanski Maja , Heilemann Mike
Published: June 2021

The development of super-resolution microscopy (SRM) has widened our understanding of biomolecular structure and function in biological materials. Imaging multiple targets within a single area would elucidate their spatial localization relative to the cell matrix and neighboring biomolecules, revealing multi-protein macromolecular structures and their functional co-dependencies. SRM methods are, however, limited to the number of suitable fluorophores that can be imaged during a single acquisition as well as the loss of antigens during antibody washing and restaining for organic dye multiplexing. We report the visualization of multiple protein targets within the pre- and postsynapse in 350–400 nm thick neuronal tissue sections using DNA-assisted single-molecule localization microscopy (SMLM). In a single labeling step, antibodies conjugated with short DNA oligonucleotides visualized multiple targets by sequential exchange of fluorophore-labeled complementary oligonucleotides present in the imaging buffer. This approach avoids potential effects on structural integrity when using multiple rounds of immunolabeling and eliminates chromatic aberration, because all targets are imaged using a single excitation laser wavelength. This method proved robust for multi-target imaging in semi-thin tissue sections with a lateral resolution better than 25 nm, paving the way toward structural cell biology with single-molecule SRM.
Effects of Pasteurization and High-Pressure Processing of Camel and Bovine Cheese Quality, and Proteolysis Contribution to Camel Cheese Softness
Authors: Mbye Mustapha , Mohamed Huda , Ramachandran Tholkappiyan , Hamed Fathalla , AlHammadi Ahlam , Kamleh Rabih , Kamal-Eldin Afaf
Published: June 2021

The effects of high-pressure processing (HPP) compared to thermal treatments on the quality of camel vs. bovine cheeses were studied. The study showed that camel milk has a lower microbial load compared to bovine milk, which is maintained during 7 days' storage of the processed milk. The effect of three HPP treatments (350, 450, and 550 MPa for 5 min at 4°C) and two pasteurization treatments (65°C for 30 min and 75°C for 30 s) on the quality of soft unripened camel and bovine milk cheeses were accessed. The cheeses were evaluated for pH, yield, proximate composition, textural and rheological properties, microstructure, and protein profile by SDS-PAGE electrophoresis. The effects of the treatments on cheese's hardness were different between the camel and bovine cheeses; while heat treatment at 65°C for 30 min gave the hardest bovine milk cheese (1,253 ± 20), HPP treatment at 350 MPa for 5 min gave the highest value for camel milk cheese (519 ± 5) (p < 0.05). The hardness of the cheeses was associated with low yield and moisture content. SDS-PAGE electrophoresis revealed that extensive proteolysis might have contributed to the softness of camel cheeses compared to bovine and suggested the involvement of some residual enzyme activities.
Dietary Moutan Cortex Radicis Improves Serum Antioxidant Capacity and Intestinal Immunity and Alters Colonic Microbiota in Weaned Piglets
Authors: Bai Miaomiao , Liu Hongnan , Wang Shanshan , Shu Qingyan , Xu Kang , Zhou Jian , Xiong Xia , Huang Ruilin , Deng Jinping , Yin Yulong , Liu Zheng'an
Published: June 2021

Background:Moutan cortex radicis (MCR), as a common traditional Chinese medicine, has been widely used as an antipyretic, antiseptic, and anti-inflammatory agent in China.

Objectives: This study aimed to investigate the effects of dietary MCR supplementation on the antioxidant capacity and intestinal health of the pigs and to explore whether MCR exerts positive effects on intestinal health via regulating nuclear factor kappa-B (NF-κB) signaling pathway and intestinal microbiota.

Methods: MCR powder was identified by LC-MS analysis. Selected 32 weaned piglets (21 d of age, 6.37 ± 0.10 kg average BW) were assigned (8 pens/diet, 1 pig/pen) to 4 groups and fed with a corn-soybean basal diet supplemented with 0, 2,000, 4,000, and 8,000 mg/kg MCR for 21 d. After the piglets were sacrificed, antioxidant indices, histomorphology examination, and inflammatory signaling pathway expression were assessed. The 16s RNA sequencing was used to analyze the effects of MCR on the intestinal microbiota structure of piglets.

Results: Supplemental 4,000 mg/kg MCR significantly increased (P < 0.05) the average daily weight gain (ADG), average daily feed intake (ADFI), total antioxidative capability, colonic short-chain fatty acids (SCFA) concentrations, and the crypt depth in the jejunum but decreased (P < 0.05) the mRNA expression levels of interferon γ, tumor necrosis factor-α, interleukin-1β, inhibiting kappa-B kinase β (IKKβ), inhibiting nuclear factor kappa-B (IκBα), and NF-κB in the jejunum and ileum. Microbiota sequencing identified that MCR supplementation significantly increased the microbial richness indices (Chao1, ACE, and observed species, P < 0.05) and the relative abundances of Firmicutes and Lactobacillus (P < 0.05), decreased the relative abundances of Bacteroides, Parabacteroides, unidentified_Lachnospiraceae, and Enterococcus (P < 0.05) and had no significant effects on the diversity indices (Shannon and Simpson, P > 0.05). Microbial metabolic phenotypes analysis also showed that the richness of aerobic bacteria and facultative anaerobic bacteria, oxidative stress tolerance, and biofilm forming were significantly increased (P < 0.05), and the richness of anaerobic bacteria and pathogenic potential of gut microbiota were reduced (P < 0.05) by MCR treatment. Regression analysis showed that the optimal MCR supplemental level for growth performance, serum antioxidant capacity, and intestinal health of weaned piglets was 3,420 ~ 4,237 mg/kg.

Conclusions: MCR supplementation improved growth performance and serum antioxidant capacity, and alleviated intestinal inflammation by inhibiting the IKKβ/IκBα/NF-κB signaling pathway and affecting intestinal microbiota in weaned piglets.
Determination of the Geographical Origin of Coffee Beans Using Terahertz Spectroscopy Combined With Machine Learning Methods
Authors: Yang Si , Li Chenxi , Mei Yang , Liu Wen , Liu Rong , Chen Wenliang , Han Donghai , Xu Kexin
Published: June 2021

Different geographical origins can lead to great variance in coffee quality, taste, and commercial value. Hence, controlling the authenticity of the origin of coffee beans is of great importance for producers and consumers worldwide. In this study, terahertz (THz) spectroscopy, combined with machine learning methods, was investigated as a fast and non-destructive method to classify the geographic origin of coffee beans, comparing it with the popular machine learning methods, including convolutional neural network (CNN), linear discriminant analysis (LDA), and support vector machine (SVM) to obtain the best model. The curse of dimensionality will cause some classification methods which are struggling to train effective models. Thus, principal component analysis (PCA) and genetic algorithm (GA) were applied for LDA and SVM to create a smaller set of features. The first nine principal components (PCs) with an accumulative contribution rate of 99.9% extracted by PCA and 21 variables selected by GA were the inputs of LDA and SVM models. The results demonstrate that the excellent classification (accuracy was 90% in a prediction set) could be achieved using a CNN method. The results also indicate variable selecting as an important step to create an accurate and robust discrimination model. The performances of LDA and SVM algorithms could be improved with spectral features extracted by PCA and GA. The GA-SVM has achieved 75% accuracy in a prediction set, while the SVM and PCA-SVM have achieved 50 and 65% accuracy, respectively. These results demonstrate that THz spectroscopy, together with machine learning methods, is an effective and satisfactory approach for classifying geographical origins of coffee beans, suggesting the techniques to tap the potential application of deep learning in the authenticity of agricultural products while expanding the application of THz spectroscopy.
Integrated Analysis of Genomic and Immunological Features in Lung Adenocarcinoma With Micropapillary Component
Authors: Zhang Shirong , Xu Yang , Zhao Pan , Bao Hua , Wang Xiyong , Liu Rui , Xu Rujun , Xiang Jingjing , Jiang Hong , Yan Junrong , Wu Xue , Shao Yang , Liang Jiafeng , Wu Qiong , Zhang Zhihao , Lu Shun , Ma Shenglin
Published: June 2021

Background

Micropapillary adenocarcinoma is one of the most aggressive histologic subtypes of lung adenocarcinoma (LADC), and even a minor proportion of micropapillary component (MPC) within the LADC could contribute to poor prognosis. Comprehensive analysis of genetic and immunological features of LADC with different percentages of MPC would help better understand cancer biology of this LADC subtype and direct future treatments.

Methods

We performed next-generation sequencing (NGS) for a discovery cohort of 43 LADC patients whose tumors were micro-dissected to separate MPC and non-MPC lesions and a reference cohort of 113 LADC patients. MPC-enriched genetic alterations that were detected in the discovery cohort were then confirmed using a validation cohort of 183 LADC patients. Immunological staining was also conducted on the MPC-containing samples in the discovery cohort.

Results

Tumors with a higher percentage of MPC tended to harbor more tumor mutation burdens (TMBs) and chromosome instability (CIN). Some rare genetic events may serve as the genetic landscape to drive micropapillary tumor progression. Specifically, alterations in transcription termination factor 1 (TTF1), brain-specific angiogenesis inhibitor 3 (BAI3), mammalian target of rapamycin (MTOR), and cyclin-dependent kinase inhibitor 2A (CDKN2A) were cross-validated to be enriched in MPC-contained LADC. Additionally, tumors with a higher percentage of MPC were associated with a higher percentage of CD4+, CD8+, and PD-L1+ staining, and some genetic changes that were enriched in MPC, including MET amplification and MTOR mutation, were correlated with increased PD-L1 expression.

Conclusion

We identified multiple novel MPC-enriched genetic changes that could help us understand the nature of this aggressive cancer subtype. High MPC tumors tended to have elevated levels of TMBs, T cell infiltration, and immunosuppression than low MPC tumors, implying the potential link between MPC content and sensitivity to immunotherapy.
Total Lesion Glycolysis Estimated by a Radiomics Model From CT Image Alone
Authors: Si Hongwei , Hao Xinzhong , Zhang Lianyu , Xu Xiaokai , Cao Jianzhong , Wu Ping , Li Li , Wu Zhifang , Zhang Shengyang , Li Sijin
Published: June 2021

Purpose

In this study, total lesion glycolysis (TLG) on positron emission tomography images was estimated by a trained and validated CT radiomics model, and its prognostic ability was explored among lung cancer (LC) and esophageal cancer patients (EC).

Methods

Using the identical features between the combined and thin-section CT, the estimation model of SUVsum (summed standard uptake value) was trained from the lymph nodes (LNs) of LC patients (n = 1239). Besides LNs of LC patients from other centers, the validation cohorts also included LNs and primary tumors of LC/EC from the same center. After calculating TLG (accumulated SUVsum of each individual) based on the model, the prognostic ability of the estimated and measured values was compared and analyzed.

Results

In the training cohort, the model of 3 features was trained by the deep learning and linear regression method. It performed well in all validation cohorts (n = 5), and a linear regression could correct the bias from different scanners. Additionally, the absolute biases of the model were not significantly affected by the evaluated factors whether they included LN metastasis or not. Between the estimated natural logarithm of TLG (elnTLG) and the measured values (mlnTLG), significant difference existed among both LC (n = 137, bias = 0.510 ± 0.519, r = 0.956, P<0.001) and EC patients (n = 56, bias = 0.251± 0.463, r = 0.934, P<0.001). However, for both cancers, the overall shapes of the curves of hazard ratio (HR) against elnTLG or mlnTLG were quite alike.

Conclusion

Total lesion glycolysis can be estimated by three CT features with particular coefficients for different scanners, and it similar to the measured values in predicting the outcome of cancer patients.
Atrophic Pigmented Dermatofibrosarcoma Protuberans: A Case Report and Literature Review
Authors: Bai Juan , Liu Bin , Liu Taoming , Qiao Jianjun , Fang Hong
Published: June 2021

Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue sarcoma characterized by the proliferation of spindle cells arranged in a storiform pattern. Here we report a case of DFSP presenting as a bluish-black atrophic plaque. The tumor had the histopathologic characteristics of both the pigmented and atrophic variants of DFSP. We describe the histopathologic, molecular, and imaging features of this patient and review other cases of DFSP that have been reported in the literature. Early identification of this DFSP variant can help clinicians implement clinical management strategies to prevent recurrence.
Evolution of Our Understanding of XIAP Deficiency
Authors: Mudde Anne C. A. , Booth Claire , Marsh Rebecca A.
Published: June 2021

X-linked inhibitor of apoptosis (XIAP) deficiency is a rare inborn error of immunity first described in 2006. XIAP deficiency is characterised by immune dysregulation and a broad spectrum of clinical manifestations, including haemophagocytic lymphohistiocytosis (HLH), inflammatory bowel disease (IBD), hypogammaglobulinemia, susceptibility to infections, splenomegaly, cytopaenias, and other less common autoinflammatory phenomena. Since the first description of the disease, many XIAP deficient patients have been identified and our understanding of the disease has grown. Over 90 disease causing mutations have been described and more inflammatory disease manifestations, such as hepatitis, arthritis, and uveitis, are now well-recognised. Recently, following the introduction of reduced intensity conditioning (RIC), outcomes of allogeneic haematopoietic stem cell transplantation (HSCT), the only curative treatment option for XIAP deficiency, have improved. The pathophysiology of XIAP deficiency is not fully understood, however it is known that XIAP plays a role in both the innate and adaptive immune response and in immune regulation, most notably through modulation of tumour necrosis factor (TNF)-receptor signalling and regulation of NLRP3 inflammasome activity. In this review we will provide an up to date overview of both the clinical aspects and pathophysiology of XIAP deficiency.