bluuebunny/crossref_metadata_2025 huggingface dataset:
The evolution of PRRT for the treatment of neuroendocrine tumors; What comes next?
Authors: Harris Philip E. , Zhernosekov Konstantin
Published: October 2022

Lu-177 has been developed for the treatment of patients with peptide receptor radionuclide therapy (PRRT). A second generation pure no-carrier-added Lu-177 has a high specific activity and has waste disposal advantages over the first generation carrier-added Lu-177. PRRT has recently been developed for the treatment of neuroendocrine tumors (NETs). The majority of pancreatic and gastroenteric NETs (GEP-NETs) express the somatostatin receptors (SSTRs) 2 and 5. These receptors can be specifically targeted with a somatostatin peptide analogue (DOTATOC/DOTATATE) which can be chelated to a positron emission tomography (PET) emitting radioisotope such as Ga-68 for imaging or to a β-emitting radioisotope Lu-177 for therapy. A key advantage of this approach is that the receptor expression can be demonstrated by PET imaging before the patient is treated. Clinical studies in G1 and G2 GEP-NETS have demonstrated that PRRT is extremely effective in terms of progression free survival (PFS), symptom control and quality of life, with a well-established safety profile. A beneficial effect on outcome survival awaits to be confirmed. The first commercially available product Lu-177-DOTATATE was approved following the NETTER-1 trial in G1 and G2 GE-NETS. Lu-177-DOTATATE 7,4 GBq every 8 weeks for 4 cycles, together with octreotide LAR 30 mg monthly, demonstrated a median PFS of 28,4 months compared to 8,5 months for octreotide LAR 60 mg monthly. A second pivotal study COMPETE is currently in progress, comparing no carrier-added (n.c.a.) Lu-177-DOTATOC to the m-TOR inhibitor Everolimus in both GE-NETs and PNETs. Two studies, NETTER-2 and COMPOSE are currently underway in patients with high grade G2 and G3 NETs. Novel SSTR antagonists are being developed as next generation targeting molecules for SSTR2-expressing tumors. Antagonists have a higher tumor binding to receptors than agonists, opening up the potential indications for SSTR2 targeting to tumors which have a relatively lower expression of SSTR2 compared to NET such as small cell lung cancer, hepatocellular carcinoma and breast cancer. In addition to Lu-177, radioisotopes with different radiation properties such as Tb-161 and the α-emitter Ac-225 are being developed which have the potential to improve treatment efficacy across the range of G1 to G3 NETs.
Effective artificial neural network-based wind power generation and load demand forecasting for optimum energy management
Authors: Jamii Jannet , Mansouri Majdi , Trabelsi Mohamed , Mimouni Mohamed Fouazi , Shatanawi Wasfi
Published: October 2022

The variability of power production from renewable energy sources (RESs) presents serious challenges in energy management (EM) and power system stability. Power forecasting plays a crucial role in optimal EM and grid security. Then, accurate power forecasting ensures optimum scheduling and EM. Therefore, this study proposes an artificial neural network- (ANN-) based paradigm to predict wind power (WP) generation and load demand, where the meteorological parameters, including wind speed, temperature, and atmospheric pressure, are fed to the model as inputs. The normalized root mean square error (NRMSE) and normalized mean absolute error (NMAE) criteria are used to evaluate the forecasting technique. The performance of ANN was compared to four machine learning methods: LASSO, decision tree (DT), regression vector machines (RVM), and kernel ridge regression (KRR). The obtained results show that ANN provides high effectiveness and accuracy for WP forecasting. Furthermore, ANN has proven to be an interesting tool in ensuring optimum scheduling and EM.
The global human settlement layer sets a new standard for global urban data reporting with the urban centre database
Authors: Melchiorri Michele
Published: October 2022

Monitoring of sustainable development goals (SDGs) requires a wealth of updated, reliable, and comparable data on planet Earth with respect to societal activities and society–environment interactions. Despite the massive big-data archives available today, salient data are missing for key thematic domains and geographical areas. Even for cities, which are the most prominent manifestations of human agglomeration, the data are scarce, sectoral, and scattered. Earth observation may help reconcile the disparities between data-rich and data-poor territories. The Global Human Settlement Layer (GHSL) project of the European Commission has generated an open-source global dataset on cities—the GHSL Urban Centre Database (GHS-UCDB). This database describes more than 10,000 Urban Centres in 2015, with their locations, extent, and sets of geographical, socio-economic, and environmental attributes, as well as multi-temporal data records (covering a time span of up to 40 years) (Figure 6). The database combines information extracted from satellite imagery with physical and socio-economic information from several voluminous and heterogeneous sources provided by researchers and institutions as open geospatial data. The paradigm introduced with the GHS-UCDB relies on massive geospatial data integration and harmonisation conducted in the GIS environment (mainly via spatial joins and zonal statistics). The range and depth of geospatial and statistical variables in this dataset represent a new standard foundation for information on cities—more than doubling the number of cities usually reported by international organisations and offering the capacity to understand dynamics, e.g., on population, greenness, economic productivity, night-time light, and pollutant emissions. Moreover, the database offers the basis to estimate SDG indicators and other essential variables for the Post 2015 Development Agenda.
Breeding phenology and landscape use in all amphibian species from the Republic of Korea based on open-source data
Authors: Groffen Jordy , Andersen Desiree , Borzée Amaël
Published: October 2022

Biodiversity is declining worldwide with habitat loss and climate change being among the main threats. While it is easy to quantify habitat loss, the impacts of climate change are less obvious. It is therefore important to understand species habitat use and breeding phenology before a significant shift results in the loss of knowledge. Here, we determined the habitat use and breeding phenology for all Korean amphibian species based on citizen science (8,763 observations), collected between 1997–2020. We found the breeding seasons as we defined them to be generally shorter than described in the literature despite large variations between species. Species were further dichotomised into early and late breeders with breeding periods peaking in mid-March and mid-June respectively. We found early breeding species to have a shortened hibernating period with only six days being consistently devoid of observations over the 23 years of the period studied for the species with the shortest inactive season. Habitat use was significantly different between all species, with pair-wise comparisons highlighting greater differences among rather than within genera, highlighting the threats to species across all genera. In addition, our results set a baseline for future analyses about climate change and habitat use.
A review of malaria epidemiology and control in Papua New Guinea 1900 to 2021: Progress made and future directions
Authors: Cleary Eimear , Hetzel Manuel W. , Clements Archie C. A.
Published: October 2022

The research and control of malaria has a long history in Papua New Guinea, sometimes resulting in substantial changes to the distribution of infection and transmission dynamics in the country. There have been four major periods of malaria control in PNG, with the current control programme having commenced in 2004. Each previous control programme was successful in reducing malaria burden in the country, but multiple factors led to programme failures and eventual breakdown. A comprehensive review of the literature dating from 1900 to 2021 was undertaken to summarize control strategies, epidemiology, vector ecology and environmental drivers of malaria transmission in PNG. Evaluations of historical control programs reveal poor planning and communication, and difficulty in sustaining financial investment once malaria burden had decreased as common themes in the breakdown of previous programs. Success of current and future malaria control programs in PNG is contingent on adequate planning and management of control programs, effective communication and engagement with at-risk populations, and cohesive targeted approaches to sub-national and national control and elimination.
Behavioral plasticity mediates adaptation to changes in food provisioning following the COVID-19 lockdown in black-headed gulls (Larus ridibundus)
Authors: Xu Hongying , Zhao Xuebing , Jia Ru , Chen Lixia , Yang Zeyu , Zhang Guogang
Published: October 2022

The 2020 COVID-19 lockdown provides an opportunity to assess how the anthropause affected the behavior of birds. Black-headed gulls (Larus ridibundus) wintering at Dianchi Lake (Yunnan Province, southwestern China) prefer to forage on easily accessible human-provided food at various sites along the lake. Following the closure of the lake because of the pandemic, synthetic food was provided at a single location. We expected that the home range size and distribution of gulls would change in response to these changes in food provisioning. A total of 91 gulls were tagged with satellite transmitters in November 2018 and March 2019, and their movements were tracked during the winter months. We analyzed their home range size and spatial distribution in four periods, SCP2019, SOP2019, SCP2020, and SOP2020 (Scenic Opening/Closing Period in 2019/2020), and the difference between SOP2019 and SCP2019 was used as the control group. The eutrophication level in the wintering periods “Nov. 2018–Apr. 2019” and “Oct. 2019–Apr. 2020” was determined using the Normalized Difference Vegetation Index (NDVI), and the coverage ratio of algal blooms and NDVI were used as indicators of the amount of naturally available food. The home range sizes of gulls were reduced in SCP2020 compared with SOP2019, SCP2019, and SOP2020. The gulls were most abundant in the 600–900 m buffer zone and least abundant in the 0–300 m buffer zone in SCP2019; they were most abundant in the 0–300 m buffer zone and least abundant in the 900–2000 m buffer zone in SCP2020. These patterns were consistent with variation in the NDVI and the coverage ratio of algal blooms among buffer zones. Changes in wintering behaviors in SCP2020 relative to other periods suggested that gulls modified their behavior following anthropause-related changes in the distribution and provisioning of food. Our findings provide insights into the role of behavioral plasticity in mediating adaptation to changes in human activities in birds.
Case Report: Prenatal diagnosis of fetal tetrasomy 9p initially identified by non-invasive prenatal testing
Authors: Yu Jialing , Chen Na , Chen Min , Shen Min , Qian Yeqing , Dong Minyue
Published: October 2022

Tetrasomy 9p is a rare syndrome characterized by fetal growth restriction, Dandy-Walker malformation, cardiac anomalies, and facial abnormalities and is discovered by ultrasound during the prenatal examination. Herein, we report a fetus of tetrasomy 9p without obvious phenotypic manifestations during the first trimester that was identified by non-invasive prenatal testing (NIPT). NIPT revealed that the gain of 9p24.3–9p11 that was approximately 46.36 Mb in size. Karyotyping of amniocytes indicated an additional marker in all metaphase. Chromosome microarray and fluorescence in situ hybridization on uncultured amniocytes revealed tetrasomic of 9p24.3q13, and that the supernumerary chromosome is a dicentric isochromosome consisted of two copies of the 9p arm. Taken together, it was indicated that the fetal karyotype was 47,XY,+idic (9) (q13), and that multiple techniques are crucial to the prenatal diagnosis.
Prognostic value of nutritional and inflammatory indicators in females with esophageal squamous cell cancer: A propensity score matching study
Authors: Li Yuping , Luo Huaichao , Ye Bo , Zhang Kaijiong , Liu Chang , Zu Ruiling , Ni Sujiao , He Qiao , Rao Lubei , Wang Qifeng , Wang Dongsheng
Published: October 2022

Background: Esophageal squamous cell cancer (ESCC) is a disease with a male predominance. Accordingly, the applicability of prognostic indicators values previously set for the general population with ESCC has not been reported for determining the physical state in females.

Methods: Patients with ESCC were pooled from 2009 to 2017 at Sichuan Cancer Hospital. We determined the differences in the nutritional and inflammatory indicators between gender by sex-stratified survival analysis in all cohorts (n = 2,660) and matching cohorts (n = 483 pairs) separately. Propensity score matching (PSM) was employed to eliminate selection bias between genders. We further performed the prognostic value of total cholesterol (TC) by subgroup analysis in the female cohort. The area ROC curve was used to assess the predictive performance of TC in females.

Results: There were a total of 2,660 patients with ESCC, of whom 2,173 (81.7%) were male and 487 (18.3%) were female. Before PSM, the prognostic nutritional index was an independent factor for OS in males but not in females. For cohort with or without matching, TC was an independent prognostic factor in females not for males. Furthermore, female patients with high TC level had significant poor OS in stages III and IV. The AUCs of TC were 0.63 and 0.70 for predicting 3- and 5-year OS, respectively.

Conclusion: Based on a much larger cohort, we confirmed that gender was a significant prognostic factor for ESCC patients. Interestingly, we found a significant difference in TC related to ESCC prognosis between genders. Collectively, TC might be an independent prognostic factor in females with ESCC.
Differences of macrophages in the tumor microenvironment as an underlying key factor in glioma patients
Authors: Wang Yangyang , Liu Yan , Zhang Chengkai , Zhang Chuanbao , Guan Xiudong , Jia Wang
Published: October 2022

Background

Macrophages, the major immune cells in glioma microenvironment, are closely related to tumor prognosis. Further studies are needed to investigate macrophages, which will be helpful to fully understand the role of it and early achieve clinical translation.

Methods

A total of 1334 glioma cases were enrolled in this study from 3 databases. In our works, the single cell cohorts from GSE89567, GSE84465, and the Chinese Glioma Genome Atlas (CGGA) datasets were used to analyze the key genes of macrophage. The bulk sequencing data from the Cancer Genome Atlas (TCGA) and CGGA datasets were respectively divided into the training set and validation set to test prognostic value of the key genes from single cell analysis.

Results

Quantitative and functional differences significantly emerge in macrophage clusters between LGG and GBM. Firstly, we used the Seurat R package to identify 281 genes differentially expressed genes in macrophage clusters between LGG and GBM. Furthermore, based on these genes, we developed a predictive risk model to predict prognosis and reflect the immune microenvironment in glioma. The risk score calculation formula was yielded as follows: Risk score = (0.11 × EXPMACC1) + (−0.31 × EXPOTUD1) + (−0.09 × EXPTCHH) + (0.26 × EXPADPRH) + (-0.40× EXPABCG2) + (0.21 × EXPPLBD1) + (0.12 × EXPANG) + (0.29 × EXPQPCT). The risk score was independently related to prognosis. Further, significant differences existed in immunological characteristics between the low- and high-risk score groups. What is more, mutation analysis found different genomic patterns associated with the risk score.

Conclusion

This study further confirms that the proportion of macrophage infiltration is not only significantly different, but the function of them is also different. The signature, identified from the differentially expressed macrophage-related genes impacts poor prognosis and short overall survival and may act as therapeutic targets in the future.
Superior humoral immunity in vaccinated SARS-CoV-2 convalescence as compared to SARS-COV-2 infection or vaccination
Authors: Paniskaki Krystallenia , Konik Margarethe J. , Anft Moritz , Meister Toni L. , Marheinecke Corinna , Pfaender Stephanie , Jäger Jasmin , Krawczyk Adalbert , Zettler Markus , Dolff Sebastian , Westhoff Timm H. , Rohn Hana , Stervbo Ulrik , Witzke Oliver , Babel Nina
Published: October 2022

Emerging variants of concern (VOC) raise obstacles in shaping vaccination strategies and ending the pandemic. Vaccinated SARS-CoV-2 convalescence shapes the current immune dynamics. We analyzed the SARS-CoV-2 VOC-specific cellular and humoral response of 57 adults: 42 convalescent mRNA vaccinated patients (C+V+), 8 uninfected mRNA vaccinated (C-V+) and 7 unvaccinated convalescent individuals (C+V-). While C+V+ demonstrated a superior humoral SARS-CoV-2 response against all analyzed VOC (alpha, delta, omicron) compared to C-V+ and C+V-, SARS-CoV-2 reactive CD4+ and CD8+ T cells, which can cross-recognize the alpha, delta and omicron VOC after infection and/or vaccination were observed in all there groups without significant differences between the groups. We observed a preserved cross-reactive C+V+ and C-V+ T cell memory. An inferior humoral response but preserved cross-reactive T cell memory in C+V- compared to C+V+ was observed, as well as an inferior humoral response but preserved cross-reactive T cell memory in C+V- compared to C-V+. Adaptive immunity generated after SARS-CoV-2 infection and vaccination leads to superior humoral immune response against VOC compared to isolated infection or vaccination. Despite the apparent loss of neutralization potential caused by viral evolution, a preserved SARS-CoV-2 reactive T cell response with a robust potential for cross-recognition of the alpha, delta and omicron VOC was detected in all studied cohorts. Our results may have implications on current vaccination strategies.
IL-2 availability regulates the tissue specific phenotype of murine intra-hepatic Tregs
Authors: Kurt Ada S. , Strobl Karoline , Ruiz Paula , Osborn Gabriel , Chester Tonika , Dawson Lauren , Warwas Karsten M. , Grey Elizabeth H. , Mastoridis Sotiris , Kodela Elisavet , Safinia Niloufar , Sanchez-Fueyo Alberto , Martinez-Llordella Marc
Published: October 2022

CD4+CD25+Foxp3+ Tregs are known to acquire tissue-specific features and exert cytoprotective and regenerative functions. The extent to which this applies to liver-resident Tregs is unknown. In this study, we aimed to explore the phenotypic and functional characteristics of adult murine liver resident Tregs during homeostasis. Additionally, we investigated their role in ameliorating liver inflammation and tissue damage. Quantification of Foxp3+CD4+CD25+ cells comparing different tissues showed that the liver contained significantly fewer resident Tregs. A combination of flow cytometry phenotyping and microarray analysis of intra-hepatic and splenic Tregs under homeostatic conditions revealed that, although intra-hepatic Tregs exhibited the core transcriptional Treg signature, they expressed a distinct transcriptional profile. This was characterized by reduced CD25 expression and increased levels of pro-inflammatory Th1 transcriptsIl1bandIfng.In vivoablation of Tregs in the Foxp3-DTR mouse model showed that Tregs had a role in reducing the magnitude of systemic and intra-hepatic inflammatory responses following acute carbon tetrachloride (CCl₄) injury, but their absence did not impact the development of hepatocyte necrosis. Conversely, the specific expansion of Tregs by administration of IL-2 complexes increased the number of intra-hepatic Tregs and significantly ameliorated tissue damage following CCl₄ administration in C57BL/6 mice. The cytoprotective effect observed in response to IL-2c was associated with the increased expression of markers known to regulate Treg suppressive function. Our results offer insight into the transcriptome and complex immune network of intra-hepatic Tregs and suggest that strategies capable of selectively increasing the pool of intra-hepatic Tregs could constitute effective therapies in inflammatory liver diseases.
Construction and protective efficacy of a novel Streptococcus pneumoniae fusion protein vaccine NanAT1-TufT1-PlyD4
Authors: Cui Yali , Miao Chenglin , Chen Wen , Shang Wenling , Qi Qianqian , Zhou Wei , Wang Xia , Li Yingying , Yan Ziyi , Jiang Yongmei
Published: October 2022

During the past decades, with the implementation of pneumococcal polysaccharide vaccine (PPV) and pneumococcal conjugate vaccines (PCVs), a dramatic reduction in vaccine type diseases and transmissions has occurred. However, it is necessary to develop a less expensive, serotype-independent pneumococcal vaccine due to the emergence of nonvaccine-type pneumococcal diseases and the limited effect of vaccines on colonization. As next-generation vaccines, conserved proteins, such as neuraminidase A (NanA), elongation factor Tu (Tuf), and pneumolysin (Ply), are promising targets against pneumococcal infections. Here, we designed and constructed a novel fusion protein, NanAT1-TufT1-PlyD4, using the structural and functional domains of full-length NanA, Tuf and Ply proteins with suitable linkers based on bioinformatics analysis and molecular cloning technology. Then, we tested whether the protein protected against focal and lethal pneumococcal infections and examined its potential protective mechanisms. The fusion protein NanAT1-TufT1-PlyD4 consists of 627 amino acids, which exhibits a relatively high level of thermostability, high stability, solubility and a high antigenic index without allergenicity. The purified fusion protein was used to subcutaneously immunize C57BL/6 mice, and NanAT1-TufT1-PlyD4 induced a strong and significant humoral immune response. The anti-NanAT1-TufT1-PlyD4 specific IgG antibody assays increased after the first immunization and reached the highest value at the 35th day. The results from in vitro experiments showed that anti-NanAT1-TufT1-PlyD4 antisera could inhibit the adhesion of Streptococcus pneumoniae (S. pneumoniae) to A549 cells. In addition, immunization with NanAT1-TufT1-PlyD4 significantly reduced S. pneumoniae colonization in the lung and decreased the damage to the lung tissues induced by S. pneumoniae infection. After challenge with a lethal dose of serotype 3 (NC_WCSUH32403), a better protection effect was observed with NanAT1-TufT1-PlyD4-immunized mice than with the separate full-length proteins and the adjuvant control; the survival rate was 50%, which met the standard of the marketed vaccine. Moreover, we showed that the humoral immune response and the Th1, Th2 and Th17-cellular immune pathways are involved in the immune protection of NanAT1-TufT1-PlyD4 to the host. Collectively, our results support that the novel fusion protein NanAT1-TufT1-PlyD4 exhibits extensive immune stimulation and is effective against pneumococcal challenges, and these properties are partially attributed to humoral and cellular-mediated immune responses.
HLA-DR3 restricted environmental epitopes from the bacterium Clostridium tetani have T cell cross-reactivity to the SLE-related autoantigen SmD
Authors: Zhao Zhenhuan , Anderson Ashley N. , Kannapell Carol C. , Kwok William W. , Gaskin Felicia , Fu Shu Man
Published: October 2022

HLA-DR3 (DR3) is one of the dominant HLA-DR alleles associated with systemic lupus erythematosus (SLE) susceptibility. Our previous studies showed multiple intramolecular DR3 restricted T cell epitopes in the Smith D (SmD) protein, from which we generated a non-homologous, bacterial epitope mimics library. From this library we identified ABC247-261 Mimic as one new DR3 restricted bacterial T cell epitope from the ABC transporter ATP-binding protein in Clostridium tetani. It activated and induced autoreactive SmD66-80-specific T cells and induced autoantibodies to lupus-related autoantigens in vivo. Compared to healthy donors, SLE patients have a greater percentage of cross-reactive T cells to ABC247-261 Mimic and SmD66-80. In addition, we analyzed the ability of single DR3 restricted Tetanus toxoid (TT) T cell epitopes to induce autoimmune T cells. We found that the immunodominant TT epitope TT826-845 stimulated SmD66-80 reactive T cells but failed to induce persistent anti-SmD autoantibodies compared to the ABC247-261 Mimic. Thus, exposure to the ABC247-261 Mimic epitope may contribute to autoimmunity in susceptible DR3 individuals.
Sepsis causes neutrophil infiltration in muscle leading to muscle atrophy and weakness in mice
Authors: Nakanishi Nobuto , Ono Yuko , Miyazaki Yusuke , Moriyama Naoki , Fujioka Kazumichi , Yamashita Kimihiro , Inoue Shigeaki , Kotani Joji
Published: October 2022

Background

Sepsis-induced muscle atrophy leads to prolonged physical dysfunction. Although the interaction of muscle atrophy and macrophage has been reported in sepsis, the role of neutrophils in muscle atrophy has not been thoroughly investigated. This study sought to investigate the long-term changes in muscle-localized neutrophils after sepsis induction and their possible role in sepsis.

Methods

Sepsis was induced in seven-week-old male C57BL/6J mice 8-12 (cecal slurry [CS] model) via intraperitoneal injection of 1 mg/g cecal slurry. The percentage change in body weight and grip strength was evaluated. The tibialis anterior muscles were dissected for microscopic examination of the cross-sectional area of myofibers or Fluorescence-activated cell sorting (FACS) analysis of immune cells. These changes were evaluated in the following conditions: (1) Longitudinal change until day 61, (2) CS concentration-dependent change on day 14 at the low (0.3 mg/g), middle (1.0 mg/g), and high (2.0 mg/g) concentrations, and (3) CS mice on day 14 treated with an anti-Ly6G antibody that depletes neutrophils.

Results

Body weight and grip strength were significantly lower in the CS model until day 61 (body weight: 123.1% ± 1.8% vs. 130.3% ± 2.5%, p = 0.04; grip strength: 104.5% ± 3.8% vs. 119.3% ± 5.3%, p = 0.04). Likewise, cross-sectional muscle area gradually decreased until day 61 from the CS induction (895.6 [606.0–1304.9] μm2 vs. 718.8 [536.2–937.0] μm2, p < 0.01). The number of muscle-localized neutrophils increased from 2.3 ± 0.6 cell/mg on day 0 to 22.2 ± 13.0 cell/mg on day 14, and decreased thereafter. In terms of CS concentration–dependent change, cross-sectional area was smaller (484.4 ± 221.2 vs. 825.8 ± 436.2 μm2 [p < 0.001]) and grip strength was lower (71.4% ± 12.8% vs. 116.3% ± 7.4%, p = 0.01) in the CS High group compared with the control, with increased neutrophils (p = 0.03). Ly6G-depleted mice demonstrated significant increase of muscle cross-sectional area and grip strength compared with control mice (p < 0.01).

Conclusions

Sepsis causes infiltration of neutrophils in muscles, leading to muscle atrophy and weakness. Depletion of neutrophils in muscle reverses sepsis-induced muscle atrophy and weakness. These results suggest that neutrophils may play a critical role in sepsis-induced muscle atrophy and weakness.
Tapasin-mediated editing of the MHC I immunopeptidome is epitope specific and dependent on peptide off-rate, abundance, and level of tapasin expression
Authors: Boulanger Denise S. M. , Douglas Leon R. , Duriez Patrick J. , Kang Yoyel , Dalchau Neil , James Edd , Elliott Tim
Published: October 2022

Tapasin, a component of the major histocompatibility complex (MHC) I peptide loading complex, edits the repertoire of peptides that is presented at the cell surface by MHC I and thereby plays a key role in shaping the hierarchy of CD8+ T-cell responses to tumors and pathogens. We have developed a system that allows us to tune the level of tapasin expression and independently regulate the expression of competing peptides of different off-rates. By quantifying the relative surface expression of peptides presented by MHC I molecules, we show that peptide editing by tapasin can be measured in terms of “tapasin bonus,” which is dependent on both peptide kinetic stability (off-rate) and peptide abundance (peptide supply). Each peptide has therefore an individual tapasin bonus fingerprint. We also show that there is an optimal level of tapasin expression for each peptide in the immunopeptidome, dependent on its off-rate and abundance. This is important, as the level of tapasin expression can vary widely during different stages of the immune response against pathogens or cancer and is often the target for immune escape.
The efficacy and safety analysis of first-line immune checkpoint inhibitors in pulmonary sarcomatoid carcinoma
Authors: Zeng Zhimin , Qian Xiaoying , Liu Fanrong , Wang Yong , Yuan Yong , Fang Chen , Zhang Xinwei , Yuan Shangkun , Chen Renfang , Yu Biao , Wang Tong , Yin Yan , Li Yong , Liu Anwen
Published: October 2022

Background

Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive disease without standardized treatment strategies. The efficacy of second-line or beyond immune checkpoint inhibitors (ICIs) has been proven in recent studies, whereas the evidence for first-line immunotherapy for PSC is still limited to case reports and remains poorly understood.

Materials and methods

This was a multicenter, retrospective analysis of 21 patients with a histological diagnosis of PSC who received ICI as first-line therapy from January 2019 to March 2022. The expression of PD-L1 was evaluated by immunohistochemistry (IHC) using the monoclonal antibody 22C3. Low and high PD-L1 expressions were defined using the tumor proportion score (TPS), with cutoffs of 1 and 50%, respectively.

Results

All eight patients had PD-L1 positivity who underwent PD-L1 expression assessment, and six patients (6/8, 75.0%) had high PD-L1 expression. Among the 21 PSC patients, seven received tislelizumab, six received camrelizumab, four received sintilimab, three received pembrolizumab, and one received durvalumab. Among them, 18 PSCs received combination therapy, whereas another three PSCs received immunotherapy alone. Out of the 21 PSC patients, 12 (57.1%) achieved a partial response (PR), and five patients had stable disease (SD) as the best response, whereas four PSCs experienced dramatic progressive disease (PD). The median progression-free survival (PFS) was 9.2 (95% CI [4.3, 14.1]) months, and the median OS was 22.8 (95% CI [4.0, 41.5]) months. Among the three treatment groups (immunotherapy alone, immunotherapy combined with anlotinib, and chemoimmunotherapy), the median PFS was 8.0, 9.4, and 9.6 months, and the median OS was 19.0, 22.8, and 30.6 months, respectively. There was no difference in PFS and OS between the three treatment regimen groups (P = 0.86 and P = 0.34, respectively) and different immunotherapies (P = 0.10 and P = 0.23, respectively). No serious adverse events (grade ≥ 3) were noted.

Conclusion

First-line immunotherapy has promising therapeutic potential in the treatment of PSC. More studies are warranted to confirm these findings.
SARS-CoV-2 tetrameric RBD protein blocks viral infection and induces potent neutralizing antibody response
Authors: Liu Zheng , Yang Chenglu , Zhang Haokun , Cao Guojie , Wang Senzhen , Yin Siwen , Wang Yanming
Published: October 2022

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed serious threats to global health and economy and calls for the development of safe treatments and effective vaccines. The receptor-binding domain in the spike protein (SRBD) of SARS-CoV-2 is responsible for its binding to angiotensin-converting enzyme 2 (ACE2) receptor. It contains multiple dominant neutralizing epitopes and serves as an important antigen for the development of COVID-19 vaccines. Here, we showed that dimeric SRBD-Fc and tetrameric 2xSRBD-Fc fusion proteins bind ACE2 with different affinity and block SARS-CoV-2 pseudoviral infection. Immunization of mice with SRBD-Fc fusion proteins elicited high titer of RBD-specific antibodies with robust neutralizing activity against pseudoviral infections. As such, our study indicates that the polymeric SRBD-Fc fusion protein can serve as a treatment agent as well as a vaccine for fighting COVID-19.
Single-cell RNA-sequencing uncovers compound kushen injection synergistically improves the efficacy of chemotherapy by modulating the tumor environment of breast cancer
Authors: Liu Xinkui , Bai Meirong , Li Huiying , Ye Peizhi , Duan Xiaoxia , Wu Chao , Huang Zhihong , Lu Shan , Zhang Jingyuan , Zhao Zihan , Guo Fengying , You Rongli , Qin Wenjie , Wang Wei , Han Aiqing , Shen Liangliang , Wang Yitao , Zhao Zheng , Luo Hua , Wu Jiarui
Published: October 2022

Background

Due to lack of enough specific targets and the immunosuppressive tumor microenvironment (TME) of triple-negative breast cancer (TNBC), TNBC patients often cannot benefit from a single treatment option. This study aims to explore the regulatory effects of Compound kushen injection (CKI) plus chemotherapy on the TME of TNBC from a single cell level.

Methods

A mouse TNBC model in BALB/c mice was established to evaluate the antitumor efficacy and toxicity of CKI combined with chemotherapy. Flow cytometry was used to observe the influence of CKI on the lymphocyte populations in the tumor bearing mice. Both bulk RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) were applied to portray the modulation of CKI combined with chemotherapy on the TME of TNBC mice.

Results

CKI significantly enhanced the anticancer activity of chemotherapy in vivo with no obvious side effects. Flow cytometry results revealed a significantly higher activation of CD8+ T lymphocytes in the spleens and tumors of the mice with combination therapy. Bulk RNA-seq indicated that CKI could promote the cytotoxic immune cell infiltrating into tumor tissues. Meanwhile, scRNA-seq further revealed that CKI combined with chemotherapy could enhance the percentage of tumor-infiltrating CD8+ T cells, inhibit tumor-promoting signaling pathways, and promote T cell activation and positive regulation of immune response. In addition, CKI showed obvious anticancer activity against MDA-MB-231 breast tumor cells in vitro.

Conclusions

The combination of CKI and chemotherapy might provide a higher efficiency and lower toxicity strategy than a single chemotherapy drug for TNBC. CKI potentiates the anti-TNBC effects of chemotherapy by activating anti-tumor immune response in mice.
Effectiveness, safety, and immunogenicity of half dose ChAdOx1 nCoV-19 COVID-19 Vaccine: Viana project
Authors: Valim Valéria , Martins-Filho Olindo Assis , Gouvea Maria da Penha Gomes , Camacho Luiz Antônio Bastos , Villela Daniel Antunes Maciel , de Lima Sheila Maria Barbosa , Azevedo Adriana Souza , Neto Lauro Ferreira Pinto , Domingues Carla Magda Allan Santos , de Medeiros Junior Nésio Fernandes , Moulaz Isac Ribeiro , Dias Laiza Hombre , Miyamoto Samira Tatiyama , Teixeira-Carvalho Andréa , Mill José Geraldo ,   Half Dose ChAdOx Study Group
Published: October 2022

Fractional dose is an important strategy to increase access to vaccines. This study evaluated the effectiveness, safety, and immunogenicity of half dose of ChAdOx1 nCoV-19 vaccine. A non-inferiority non-randomized controlled trial compared a half dose of ChAdOx1 nCoV-19 with the full dose, with an interval of 8 to 10 weeks, in individuals aged 18–49 years. The primary endpoints were the incidence rate of new cases/1,000 person-year at 90 days after 14 days of the second dose, confirmed by RT-PCR and new cases registered at SUS National Health Surveillance Database (e-SUS VS). The anti-SARS-CoV-2 spike (S) protein receptor binding domain (RBD) by chemiluminescence and the neutralizing antibodies by plaque reduction neutralization test (PRNT) were titrated. The soluble biomarkers were quantified with a multiplex immunoassay. Follow-up was 90 days after 14 days of the second dose. A total of 29,598 individuals were vaccinated. After exclusion, 16,570 individuals who received half a dose and 6,402 who received full doses were analyzed. The incidence of new cases confirmed by RT-PCR of half dose was non-inferior to full dose (23.7 vs. 25.7 cases per 1,000 persons-year [coefficient group -0.09 CI95%(-0.49 to 0.31)], even after adjusting for age and sex. There were no deaths or hospitalization after immunization of either group. Immunogenicity was evaluated in a subsample (N=558) compared to 154 healthcare workers who received a full dose. The seroconversion rate in seronegative individuals at baseline half dose was 99.8%, similar to that of the full dose (100%). Geometric mean concentration (95% CI; BAU/mL) were half dose = 188 (163-217) and full dose = 529 (423–663) (p < 0.001). In seropositive subjects at baseline (pre-immune individuals), the first dose induced very high and similar IgG-S in half dose 1,359 (1,245-1,483) and full dose 1,354 (1,048–1,749) BAU/mL. A half dose induced a high increase in plasma chemokines, pro-inflammatory/regulatory cytokines, and growth factors. The frequency of adverse events was similar. No serious adverse events or deaths were reported. A half dose of ChAdOx1 nCoV-19 is as effective, safe, and immunogenic as the full dose. The immune response in pre-immune (seropositive in the baseline) individuals indicates that the half dose may be a booster dose schedule.
Chimeric antigen receptor T cells applied to solid tumors
Authors: Zhou Zhongguo , Tao Can , Li Jianting , Tang Johnny Cheuk-on , Chan Albert Sun-chi , Zhou Yuanyuan
Published: October 2022

Chimeric antigen receptor T cell (CAR-T) therapy is novel tumor immunotherapy that enables autologous T to express synthetic receptors to specifically recognize the surface tumor-associated antigens for exerting subsequent antitumor effects, and eliminating the resistance, metastases and recurrence of cancer. Although CAR T cells have exhibited success in eradicating hematologic malignancies, their applications to solid tumors has not yet been achieved due to obstacles such as the immune-suppressor tumor microenvironment and lack of tumor specific target antigens. In this review, we presented advancements in the development of CAR T cell therapy in solid tumors, and offered a brief summary of the challenges, as well as novel engineering and pharmaceutical interventions to overcome these barriers. Looking forward, we discussed the latest studies which are expected to reach the clinicals in the next few years, including CRISPR screens-based CAR modification and CAR T cells driven from progenitor-like T cells. Collectively, this review may inspire researchers and clinicians to develop clinical available strategies of CAR T cell therapies in solid tumor.
Population dynamics of Capitella aff. teleta (Polychaeta, Capitellidae) in Gamo Lagoon, northeastern Japan, during a series of restoration works following the 2011 Great East Japan Earthquake and tsunami
Authors: Hashimoto Akane , Sato-Okoshi Waka
Published: October 2022

The population dynamics of the capitellid polychaete Capitella aff. teleta were studied in Gamo Lagoon, located in northeast Japan, for the subsequent 2 years from 2016, when a series of restoration works was conducted following the 2011 Great East Japan Earthquake and tsunami. Capitella aff. teleta was found to be widely distributed from the estuary side, where the levee was located, to the innermost part but was more abundant in the innermost part, which is rich in organic matter. In the lagoon, the daily maximum water level dropped from 2017 to 2018 during the reconstruction of a flow-conducting levee, which blocked water flow and isolated the inner part of the lagoon. Although the density decreased drastically for approximately 11 months under diurnal hypoxia and strongly reducing conditions, small-sized new recruits were observed and the population recovered quickly after the daily maximum water level increased. In Gamo Lagoon, C. aff. teleta inhabiting the innermost part and estuary side of the lagoon contributed to maintaining the population by dispersing planktonic larvae between them. Thus, the maximum water level had a significant effect on the maintenance of the C. aff. teleta population in the lagoon, and sufficiently high water levels enable the dispersion of planktonic larvae to help recover the population quickly, suggesting that it is important to keep the water area connected.
The role of benthic habitat mapping for science and managers: A multi-design approach in the Southeast Brazilian Shelf after a major man-induced disaster
Authors: Menandro Pedro S. , Lavagnino Ana Carolina , Vieira Fernanda V. , Boni Geandré C. , Franco Tarcila , Bastos Alex C.
Published: October 2022

Seabed mapping is currently the baseline information for ocean management and conservation, and is an indispensable item within research and Marine Spatial Planning. Here, we use a case study and published data along the southeast Brazilian continental shelf to illustrate the concepts and ideas of potential benthic habitat mapping and the importance of having maps on different scales and the potential for using a multi-design approach. The case analysis presented here uses a regional map and distinct criteria (seabed geodiversity and biodiversity, and potential influence of a tailings plume) to define three areas along the continental shelf to be mapped in a high-resolution, as part of a marine monitoring program. The background of the case study is a tailing dam failure disaster that led to the input of iron ore tailings in the ocean, leading to a major environmental disaster. Three areas were chosen, including: a Marine Protected Area (MPA Costa das Algas), a major fishing ground (the Doce River prodelta/depocenter), and an understudied reef area (Forgotten Reefs). Potential benthic habitat mapping was carried out using acoustic surveys (multibeam echosounder acquiring bathymetry and backscatter) and ground-truthing (sediment samples and seafloor image). Results detailed the potential habitats throughout the three areas, providing primary information for the study of benthic habitats and their distribution. The multi-design approach indicated that although a regional analysis can indicate potential vulnerability as a first assessment approach, high-resolution potential habitat mapping (herein, 20 m or finer) is beneficial to evaluate and produce a higher-confidence level for decision-makers. Having an overall view of what and where to collect new and finer data would be best to identify vulnerable areas that, in this case study, could be threatened by plume dispersion and tailings accumulation. Our results support the delineation of priority areas aiming for monitoring, protection and guiding for other studies, besides the consolidation of habitat importance and the integration of various datasets through a hierarchical classification scheme. Although Brazil has never produced a regional or national habitat map for the entire continental margin, there are already conditions to plan, execute and maintain a habitat mapping program, partnering with Universities, Government Institutions (e.g., the Brazilian Navy), and the private sector. In the context of the UN Decade of Ocean Science targets, it is urgent to plan and implement a national database capable of supporting a habitat classification effort on a broader national scale, with the flexibility to support a multi-design or a multi-scale approach.
Genetic variations affecting ACE2 protein stability in minority populations
Authors: Mahase Vidhyanand , Sobitan Adebiyi , Rhoades Raina , Zhang Fuquan , Baranova Ancha , Johnson Mark , Otolorin Abiodun , Tang Qiyi , Teng Shaolei
Published: October 2022

While worldwide efforts for improving COVID-19 vaccines are currently considered a top priority, the role of the genetic variants responsible for virus receptor protein stability is less studied. Angiotensin-converting enzyme-2 is the primary target of the SARS-CoV-1/SARS-CoV-2 spike (S) glycoprotein, enabling entry into the human body. Here, we applied computational saturation mutagenesis approaches to determine the folding energy caused by all possible mutations in ACE2 proteins within ACE2 - SARS-CoV-1-S/ACE2 - SARS-CoV-2-S complexes. We observed ACE2 mutations at residue D350 causing the most stabilizing effects on the protein. In addition, we identified ACE2 genetic variations in African Americans (rs73635825, rs766996587, and rs780574871), Latino Americans (rs924799658), and both groups (rs4646116 and rs138390800) affecting stability in the ACE2 - SARS-CoV-2-S complex. The findings in this study may aid in targeting the design of stable neutralizing peptides for treating minority patients.
Revealing the prognostic and clinicopathological significance of systemic immune-inflammation index in patients with different stage prostate cancer: A systematic review and meta-analysis
Authors: Qi Wenqiang , Zhou Yongheng , Liu Zhifeng , Wang Jian , Lv Guangda , Zhong Minglei , Wang Wenfu , Li Rongyang , Chen Shouzhen , Shi Benkang , Zhu Yaofeng
Published: October 2022

Background

A novel inflammatory marker called the systemic immune-inflammation index (SII) was applied to predict the prognosis of different cancers. However, the role of SII in prostate cancer (PCa) remains unclear. This systematic review aims to explore the prognostic role of SII in different stage PCa.

Methods

We comprehensively searched three public databases: PubMed, EMBASE, and the Cochrane Library. The hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were extracted to evaluate the association between SII and the prognosis and clinicopathological characteristics in different stage PCa patients.

Results

Ten studies and 7,986 patients were enrolled in our meta-analysis, 1,442 patients were diagnosed with metastatic-castration resistant prostate cancer (mCRPC), and 6544 patients were diagnosed with non-metastatic prostate cancer (nmPCa). According to the pooled results, we found that a high SII was associated with worse overall survival (OS) in mCRPC patients (HR = 1.94, 95% CI: 1.26–3.01, p = 0.003), and a high SII was associated with biochemical recurrence-free survival (BFS) in nmPCa patients (HR = 1.85, 95% CI: 1.06–3.24, p = 0.031). But there was no significant association observed between SII and progression-free survival (PFS) in mCRPC patients (HR = 1.90, 95% CI: 0.87–4.14, p = 0.107). And we found that the high SII was associated with advanced tumor stage of PCa (OR = 2.19, 95% CI: 1.11–4.33, p = 0.024), presence of lymph node involvement (OR = 2.72, 95% CI: 1.96–3.76, p < 0.001) and Gleason score (OR = 1.27, 95% CI: 1.13–1.44, p < 0.001).

Conclusion

High SII was associated with bad OS in mCRPC patients, and associated with bad BFS and some adverse pathological features in nmPCa patients. We think SII can be a prognostic predictor for PCa patients. The application of SII will advance the diagnosis and treatment of different stage prostate cancer.