bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinction of early complement classical and lectin pathway activation via quantification of C1s/C1-INH and MASP-1/C1-INH complexes using novel ELISAs
Authors: Hurler Lisa , Toonen Erik J. M. , Kajdácsi Erika , van Bree Bregje , Brandwijk Ricardo J. M. G. E. , de Bruin Wieke , Lyons Paul A. , Bergamaschi Laura ,   Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration, Sinkovits György , Cervenak László , Würzner Reinhard , Prohászka Zoltán
Published: November 2022

The most commonly used markers to assess complement activation are split products that are produced through activation of all three pathways and are located downstream of C3. In contrast, C4d derives from the cleavage of C4 and indicates either classical (CP) or lectin pathway (LP) activation. Although C4d is perfectly able to distinguish between CP/LP and alternative pathway (AP) activation, no well-established markers are available to differentiate between early CP and LP activation. Active enzymes of both pathways (C1s/C1r for the CP, MASP-1/MASP-2 for the LP) are regulated by C1 esterase inhibitor (C1-INH) through the formation of covalent complexes. Aim of this study was to develop validated immunoassays detecting C1s/C1-INH and MASP-1/C1-INH complex levels. Measurement of the complexes reveals information about the involvement of the respective pathways in complement-mediated diseases. Two sandwich ELISAs detecting C1s/C1-INH and MASP-1/C1-INH complex were developed and tested thoroughly, and it was investigated whether C1s/C1-INH and MASP-1/C1-INH complexes could serve as markers for either early CP or LP activation. In addition, a reference range for these complexes in healthy adults was defined, and the assays were clinically validated utilizing samples of 414 COVID-19 patients and 96 healthy controls. The immunoassays can reliably measure C1s/C1-INH and MASP-1/C1-INH complex concentrations in EDTA plasma from healthy and diseased individuals. Both complex levels are increased in serum when activated with zymosan, making them suitable markers for early classical and early lectin pathway activation. Furthermore, measurements of C1-INH complexes in 96 healthy adults showed normally distributed C1s/C1-INH complex levels with a physiological concentration of 1846 ± 1060 ng/mL (mean ± 2SD) and right-skewed distribution of MASP-1/C1-INH complex levels with a median concentration of 36.9 (13.18 - 87.89) ng/mL (2.5-97.5 percentile range), while levels of both complexes were increased in COVID-19 patients (p<0.0001). The newly developed assays measure C1-INH complex levels in an accurate way. C1s/C1-INH and MASP-1/C1-INH complexes are suitable markers to assess early classical and lectin pathway activation. An initial reference range was set and first studies showed that these markers have added value for investigating and unraveling complement activation in human disease.
The predictive value of peripheral blood cells and lymphocyte subsets in oesophageal squamous cell cancer patients with neoadjuvant chemoradiotherapy
Authors: Zhou Jin , Lin Hai-Ping , Xu Xin , Wang Xiao-Hang , Rong Ling , Zhang Yao , Shen Lei , Xu Lei , Qin Wei-Ting , Ye Qing , Ma Xiu-Mei , Bai Yong-Rui
Published: November 2022

Purpose

Neoadjuvant chemoradiotherapy (nCRT) is a standard treatment option for patients with stage III oesophageal cancer. Approximately 30% of oesophageal cancer patients will have a pathological complete response (pCR) after nCRT. However, available clinical methods cannot accurately predict pCR for patients. We aimed to find more indicators that could be used to predict the pathological response to nCRT.

Method

A total of 84 patients with stage III oesophageal squamous cell cancer were enrolled in this study. Ten patients failed to have surgery as a result of progressive disease (PD). Among the patients who underwent surgery, 32 patients had a pathologic complete response (pCR), whereas 42 patients showed no or partial response (npCR) after nCRT. Routine blood test results and lymphocyte subset assessments before and after nCRT were retrospectively analysed. Univariate and multivariate analyses were used to identify independent predictors of the clinical curative effect of nCRT. Eventually, nomograms were established for predicting the PD and pCR rates.

Results

The numbers of lymphocytes, B lymphocytes, T lymphocytes, Th lymphocytes, Ts lymphocytes, and NK cells and the percentages of B lymphocytes and NK cells were decreased significantly after nCRT (P < 0.0001), whereas the percentages of T lymphocytes and Ts lymphocytes increased (P < 0.0001). Univariate analysis showed that age, the length of the lesion, the level of haemoglobin before nCRT, and the amount of change in haemoglobin were related to PD, and the percentage of NK cells after nCRT was related to pCR. Multivariate logistic analysis demonstrated that the length of the lesion, the neutrophil-to-lymphocyte ratio (NLR) before nCRT, and the amount of change in haemoglobin were independent predictors of PD, whereas the percentage of NK cells after nCRT was an independent predictor of pCR.

Conclusion

Lymphocyte subsets changed dramatically during nCRT, and these changes together with baseline and posttreatment lymphocyte subsets have predictive value in determining the response to nCRT for oesophageal cancer.
Cytokine expression in rhinovirus- vs. respiratory syncytial virus-induced first wheezing episode and its relation to clinical course
Authors: Hurme Pekka , Komulainen Miisa , Tulkki Marleena , Leino Annamari , Rückert Beate , Turunen Riitta , Vuorinen Tytti , Akdis Mübeccel , Akdis Cezmi A. , Jartti Tuomas
Published: November 2022

Rhinovirus (RV) and respiratory syncytial virus (RSV) are common causes of bronchiolitis. Unlike an RSV etiology, an RV etiology is associated with a markedly increased risk of asthma. We investigated the cytokine profiles of RV- and RSV-induced first wheezing episode and their correlation with prognosis. We recruited 52 sole RV- and 11 sole RSV-affected children with a severe first wheezing episode. Peripheral blood mononuclear cells (PBMCs) were isolated during acute illness and 2 weeks later and stimulated in vitro with anti-CD3/anti-CD28. Culture medium samples were analyzed for 56 different cytokines by multiplex ELISA. Recurrences were prospectively followed for 4 years. In adjusted analyses, the cytokine response from PBMCs in the RV group was characterized by decreased expression of interleukin 1 receptor antagonist (IL-1RA), interleukin 1 beta (IL-1β), and monocyte chemoattractant protein-1 (MCP-1) and increased expression of eosinophil chemotactic protein 2 (eotaxin-2), thymus- and activation-regulated chemokine (TARC), and epithelial-derived neutrophil-activating peptide 78 (ENA-78) in the acute phase and increased expression of fractalkine in the convalescent phase compared to those in the RSV group. An analysis of the change in cytokine expression between study points revealed an increased expression of fractalkine and IL-1β and decreased expression of I-309 (CCL1) and TARC in the RV group compared to those in the RSV group.. Considering hospitalization time, a significant non-adjusted group × cytokine interaction was observed in the levels of interferon gamma (IFN-γ), macrophage-derived chemokine (MDC), IL-1RA, and vascular endothelial growth factor (VEGF), indicating that a higher expression of cytokine was associated with shorter hospitalization time in the RSV group but not in the RV group. A significant interaction was also found in interleukin 6 (IL-6), but the cytokine response was not associated with hospitalization time in the RSV or RV group. In the RV group, increased expression of I-309 (CCL1) and TARC was associated with fewer relapses within 2 months, and decreased expression of interleukin 13 (IL-13) and increased expression of I-309 (CCL1) were associated with less relapses within 12 months. Differences in cytokine response from PBMCs were observed between RV- and RSV-induced first severe wheezing episode. Our findings also reveal new biomarkers for short- and medium-term prognosis in first-time wheezing children infected with RV or RSV.
Complex interaction and heterogeneity among cancer stem cells in head and neck squamous cell carcinoma revealed by single-cell sequencing
Authors: Xiao Mintao , Zhang Xinyi , Zhang Duoli , Deng Shuai , Zheng Anfu , Du Fukuan , Shen Jing , Yue Lin , Yi Tao , Xiao Zhangang , Zhao Yueshui
Published: November 2022

Background

Cancer stem cells (CSCs) have been characterized to be responsible for multidrug resistance, metastasis, recurrence, and immunosuppressive in head and neck squamous cell carcinoma (HNSCC). However, the diversity of CSCs remains to be investigated. In this study, we aimed to determine the heterogeneity of CSCs and its effect on the formation of tumor microenvironment (TME).

Methods

We depicted the landscape of HNSCC transcriptome profile by single-cell RNA-sequencing analysis of 20 HNSCC tissues from public databases, to reveal the Cell components, trajectory changes, signaling network, malignancy status and functional enrichment of CSCs within tumors.

Results

Immune checkpoint molecules CD276, LILRB2, CD47 were significantly upregulated in CSCs, enabling host antitumor response to be weakened or damaged. Notably, naive CSCs were divided to 2 different types of cells with different functions, exhibiting functional diversity. In addition, CSCs underwent self-renewal and tumor metastasis activity through WNT and ncWNT signaling. Among them, Regulon regulators (IRF1_394g, IRF7_160g, NFKB1_12g, NFKB2_33g and STAT1_356g) were activated in subgroups 2 and 3, suggesting their pivotal roles in the inflammatory response process in tumors. Among all CSCs, naive CSCs appear to be the most malignant resulting in a worse prognosis.

Conclusions

Our study reveals the major signal transduction and biological function of CSCs during HNSCC progression, highlighting the heterogeneity of CSCs and their underlying mechanisms in the formation of an immunosuppressive TME. Therefore, our study about heterogeneity of CSCs in HNSCC can bring new insights for the treatment of HNSCC.
Pilot genome-wide association study of antibody response to inactivated SARS-CoV-2 vaccines
Authors: Li Ping , Shi Dawei , Shen Wenlong , Shi Shu , Guo Xinjie , Li Jia , Xu Sihong , Zhang Yan , Zhao Zhihu
Published: November 2022

Vaccines are a key weapon against the COVID-19 pandemic caused by SARS-CoV-2. However, there are inter-individual differences in immune response to SARS-CoV-2 vaccines and genetic contributions to these differences have barely been investigated. Here, we performed genome-wide association study (GWAS) of antibody levels in 168 inactivated SARS-CoV-2 vaccine recipients. A total of 177 SNPs, corresponding to 41 independent loci, were identified to be associated with IgG, total antibodies or neutral antibodies. Specifically, the rs4543780, the intronic variant of FAM89A gene, was associated with total antibodies level and was annotated as a potential regulatory variant affecting gene expression of FAM89A, a biomarker differentiating bacterial from viral infections in febrile children. These findings might advance our knowledge of the molecular mechanisms driving immunity to SARS-CoV-2 vaccine.
Anti-inflammatory effects of Chaishi Tuire Granules on influenza A treatment by mediating TRAF6/MAPK14 axis
Authors: Wang Lili , Guo Jiamei , Wang Yingying , Zhao Pengcheng , Liu Bin , Zhang Yan , Xiong Yibai , Chen Qing , Lin Lin , Li Li , He Xiaojuan , Tan Yong , Cao Mengmeng , Yi Jianfeng , Deng Tao , Lu Cheng
Published: November 2022

Objectives

Influenza is an infectious respiratory disease that can cause severe inflammatory reactions and threaten human life. Chaishi Tuire Granules (CSTRG), a Chinese patent medicine widely used clinically in the treatment of respiratory diseases in China, has a definite anti-inflammatory effect. However, the mechanism of CSTRG in the treatment of influenza is still unclear. This study aimed to demonstrate the anti-inflammatory effect of CSTRG on influenza A treatment and potential mechanisms.

Methods

Influenza-associated mice pneumonia model was used to explore the antiviral and anti-inflammatory effects of CSTRG in vivo. Bioinformatics analysis methods such as network pharmacology and molecular docking were carried out to predict the main active components and potential anti-inflammatory targets of CSTRG. The anti-inflammatory activity of CSTRG was determined using the lipopolysaccharide (LPS)-induced macrophages RAW264.7 cells in vitro.

Results

In vivo results showed that CSTRG can reduce the viral load in the lung tissue of infected mice, reduce the expression of TNF-α and IL-6 in lung tissue and serum, and regulate the host inflammatory response. Additionally, CSTRG treatment markedly improves the sick signs, weight loss, lung index, and lung pathological changes. Bioinformatics analysis predicted that six active compounds of CSTRG including quercetin, kaempferol, luteolin, beta-sitosterol, sitosterol, and stigmasterol could contribute to the anti-influenza activity through regulating the TRAF6/MAPK14 axis. The following research confirmed that CSTRG significantly inhibited pro-inflammatory cytokines (TNF-α and IL-6) by suppressing the expression of TRAF6 and MAPK14 in LPS-stimulated macrophages RAW264.7 cells.

Conclusion

CSTRG might inhibit the inflammatory response by mediating the TRAF6/MAPK14 axis. In the future, in-depth research is still needed to verify the mechanism of CSTRG in the treatment of influenza.
Salinity and hydraulic retention time induce membrane phospholipid acyl chain remodeling in Halanaerobium congolense WG10 and mixed cultures from hydraulically fractured shale wells
Authors: Ugwuodo Chika Jude , Colosimo Fabrizio , Adhikari Jishnu , Shen Yuxiang , Badireddy Appala Raju , Mouser Paula J.
Published: November 2022

Bacteria remodel their plasma membrane lipidome to maintain key biophysical attributes in response to ecological disturbances. For Halanaerobium and other anaerobic halotolerant taxa that persist in hydraulically fractured deep subsurface shale reservoirs, salinity, and hydraulic retention time (HRT) are important perturbants of cell membrane structure, yet their effects remain poorly understood. Membrane-linked activities underlie in situ microbial growth kinetics and physiologies which drive biogeochemical reactions in engineered subsurface systems. Hence, we used gas chromatography–mass spectrometry (GC–MS) to investigate the effects of salinity and HRT on the phospholipid fatty acid composition of H. congolense WG10 and mixed enrichment cultures from hydraulically fractured shale wells. We also coupled acyl chain remodeling to membrane mechanics by measuring bilayer elasticity using atomic force microscopy (AFM). For these experiments, cultures were grown in a chemostat vessel operated in continuous flow mode under strict anoxia and constant stirring. Our findings show that salinity and HRT induce significant changes in membrane fatty acid chemistry of H. congolense WG10 in distinct and complementary ways. Notably, under nonoptimal salt concentrations (7% and 20% NaCl), H. congolense WG10 elevates the portion of polyunsaturated fatty acids (PUFAs) in its membrane, and this results in an apparent increase in fluidity (homeoviscous adaptation principle) and thickness. Double bond index (DBI) and mean chain length (MCL) were used as proxies for membrane fluidity and thickness, respectively. These results provide new insight into our understanding of how environmental and engineered factors might disrupt the physical and biogeochemical equilibria of fractured shale by inducing physiologically relevant changes in the membrane fatty acid chemistry of persistent microbial taxa.

GRAPHICAL ABSTRACT

Salinity significantly alters membrane bilayer fluidity and thickness in Halanaerobium congolense WG10.
Linking bacterial and fungal assemblages to soil nutrient cycling within different aggregate sizes in agroecosystem
Authors: Zhang Shan , Hu Wanjin , Xu Yue , Zhong Hui , Kong Zhaoyu , Wu Lan
Published: November 2022

Soil aggregates provide spatially heterogeneous microhabitats that support the coexistence of soil microbes. However, there remains a lack of detailed assessment of the mechanism underlying aggregate-microbiome formation and impact on soil function. Here, the microbial assemblages within four different aggregate sizes and their correlation with microbial activities related to nutrient cycling were studied in rice fields in Southern China. The results show that deterministic and stochastic processes govern bacterial and fungal assemblages in agricultural soil, respectively. The contribution of determinism to bacterial assemblage improved as aggregate size decreased. In contrast, the importance of stochasticity to fungal assemblage was higher in macroaggregates (>0.25 mm in diameter) than in microaggregates (<0.25 mm). The association between microbial assemblages and nutrient cycling was aggregate-specific. Compared with microaggregates, the impacts of bacterial and fungal assemblages on carbon, nitrogen, and phosphorus cycling within macroaggregates were more easily regulated by soil properties (i.e., soil organic carbon and total phosphorus). Additionally, soil nutrient cycling was positively correlated with deterministic bacterial assemblage but negatively correlated with stochastic fungal assemblage in microaggregates, implying that bacterial community may accelerate soil functions when deterministic selection increases. Overall, our study illustrates the ecological mechanisms underlying the association between microbial assemblages and soil functions in aggregates and highlights that the assembly of aggregate microbes should be explicitly considered for revealing the ecological interactions between agricultural soil and microbial communities.
The role of pathogens in diabetes pathogenesis and the potential of immunoproteomics as a diagnostic and prognostic tool
Authors: Sohail Muhammad Umar , Mashood Fathima , Oberbach Andreas , Chennakkandathil Sareena , Schmidt Frank
Published: November 2022

Diabetes mellitus (DM) is a group of metabolic diseases marked by hyperglycemia, which increases the risk of systemic infections. DM patients are at greater risk of hospitalization and mortality from bacterial, viral, and fungal infections. Poor glycemic control can result in skin, blood, bone, urinary, gastrointestinal, and respiratory tract infections and recurrent infections. Therefore, the evidence that infections play a critical role in DM progression and the hazard ratio for a person with DM dying from any infection is higher. Early diagnosis and better glycemic control can help prevent infections and improve treatment outcomes. Perhaps, half (49.7%) of the people living with DM are undiagnosed, resulting in a higher frequency of infections induced by the hyperglycemic milieu that favors immune dysfunction. Novel diagnostic and therapeutic markers for glycemic control and infection prevention are desirable. High-throughput blood-based immunoassays that screen infections and hyperglycemia are required to guide timely interventions and efficiently monitor treatment responses. The present review aims to collect information on the most common infections associated with DM, their origin, pathogenesis, and the potential of immunoproteomics assays in the early diagnosis of the infections. While infections are common in DM, their role in glycemic control and disease pathogenesis is poorly described. Nevertheless, more research is required to identify novel diagnostic and prognostic markers to understand DM pathogenesis and management of infections. Precise monitoring of diabetic infections by immunoproteomics may provide novel insights into disease pathogenesis and healthy prognosis.
Antibacterial spirooxindole alkaloids from Penicillium brefeldianum inhibit dimorphism of pathogenic smut fungi
Authors: Shi Huajun , Jiang Jinyan , Zhang Hang , Jiang Haimei , Su Zijie , Liu Dandan , Jie Ligang , He Fei
Published: November 2022

Three new antibacterial spirooxindole alkaloids, spirobrefeldins A–C (1–3), together with four known analogs, spirotryprostatin M (4), spirotryprostatin G (5), 12β-hydroxyverruculogen TR-2 (6), and 12α-hydroxyverruculogen TR-2 (7), were isolated from terrestrial fungus Penicillium brefeldianum. All the new compounds were elucidated extensively by the interpretation of their NMR (1D and 2D) spectra and high-resolution mass data, and their absolute configurations were determined by computational chemistry and CD spectra. The absolute configurations of spiro carbon C-2 in spirotryprostatin G (5) and spirotryprostatin C in literature were reported as S, which were revised to R based on experimental and calculated CD spectra. All the compounds were evaluated for their antimicrobial activities toward Pseudomonas aeruginosa PAO1, Dickeya zeae EC1, Staphylococcus epidermidis, Escherichia coli, and Sporisorium scitamineum. Compound 7 displayed moderate inhibitory activity toward dimorphic switch of pathogenic smut fungi Sporisorium scitamineum at 25 μM. Compounds 3 and 6 showed weak antibacterial activities against phytopathogenic bacterial Dickeya zeae EC1 at 100 μM.
Moderate ethanol exposure during early ontogeny of the rat alters respiratory plasticity, ultrasonic distress vocalizations, increases brain catalase activity, and acetaldehyde-mediated ethanol intake
Authors: D’aloisio Genesis , Acevedo María Belén , Angulo-Alcalde Asier , Trujillo Verónica , Molina Juan Carlos
Published: November 2022

Early ontogeny of the rat (late gestation and postnatal first week) is a sensitive period to ethanol’s positive reinforcing effects and its detrimental effects on respiratory plasticity. Recent studies show that acetaldehyde, the first ethanol metabolite, plays a key role in the modulation of ethanol motivational effects. Ethanol brain metabolization into acetaldehyde via the catalase system appears critical in modulating ethanol positive reinforcing consequences. Catalase system activity peak levels occur early in the ontogeny. Yet, the role of ethanol-derived acetaldehyde during the late gestational period on respiration response, ultrasonic vocalizations (USVs), and ethanol intake during the first week of the rat remains poorly explored. In the present study, pregnant rats were given a subcutaneous injection of an acetaldehyde-sequestering agent (D-penicillamine, 50 mg/kg) or saline (0.9% NaCl), 30 min prior to an intragastric administration of ethanol (2.0 g/kg) or water (vehicle) on gestational days 17–20. Respiration rates (breaths/min) and apneic episodes in a whole-body plethysmograph were registered on postnatal days (PDs) 2 and 4, while simultaneously pups received milk or ethanol infusions for 40-min in an artificial lactation test. Each intake test was followed by a 5-min long USVs emission record. On PD 8, immediately after pups completed a 15-min ethanol intake test, brain samples were collected and kept frozen for catalase activity determination. Results indicated that a moderate experience with ethanol during the late gestational period disrupted breathing plasticity, increased ethanol intake, as well brain catalase activity. Animals postnatally exposed to ethanol increased their ethanol intake and exerted differential affective reactions on USVs and apneic episodes depending on whether the experience with ethanol occur prenatal or postnatally. Under the present experimental conditions, we failed to observe, a clear role of acetaldehyde mediating ethanol’s effects on respiratory plasticity or affective states, nevertheless gestational acetaldehyde was of crucial importance in determining subsequent ethanol intake affinity. As a whole, results emphasize the importance of considering the participation of acetaldehyde in fetal programming processes derived from a brief moderate ethanol experience early in development, which in turn, argues against “safe or harmless” ethanol levels of exposure.
Analyses on safety and efficacy of non-standard dose of r-tPA in intravenous thrombolysis-treated AIS patients
Authors: Yuan Jiawen , Wu Ruxing , Xiang Jingyan , Deng Jiangshan , Zhang Xiaojie , Lu Kaili , Cao Fengya , Zhao Fei , Zhao Yuwu , Wang Feng
Published: November 2022

Background

Intravenous 0.9 mg/kg recombinant tissue plasminogen activator (r-tPA) is one of the most effective treatments in acute ischemic stroke patients. Practically, the dose of r-tPA is still a topic that is constantly being discussed.

Methods

For this observational study, data were obtained from 537 patients who received r-tPA thrombolysis at Shanghai Sixth People's Hospital stroke center over 5 years (2014–2019). Patients were divided into two groups: a non-standard dose group (0.6 mg/kg ≤ dose < 0.9 mg/kg) and a standard dose group (0.9 mg/kg). Different outcomes were observed: efficacy: 3 months mRS 0-1 (3m-mRS0-1); safety: symptomatic intracranial hemorrhage within 24 h (24h-sICH) and 3 months mortality (3m-death). We also observed the effect of r-tPA dose coefficient on outcomes in different age groups and baseline National Institute of Health stroke scale (NIHSS) score subgroups.

Results

There were 265 patients who gave the standard dose treatment and 272 gave the nonstandard dose. There was no significant difference between the non-standard dose group and the standard dose group in 3m-mRS0-1, 3m-death, and 24h-sICH (p = 0.567, 0.327, and 0.415, respectively). The dose coefficient presents a significant negative correlation (p = 0.034, B = −4.290) with 3m-death in NIHSS < 16 sub-group. Door-to-needle time (DNT) is the most important independent outcome-influential factor (MIOIF) in the NIHSS ≥16 sub-group. The diabetes history and baseline NIHSS score were the MIOIF in the age ≥80-year sub-group.

Conclusions

The non-standard dose group (0.6 mg/kg ≤ dose < 0.9 mg/kg) shows no difference in safety and effectiveness than the standard dose group (0.9 mg/kg) in our study. The standard dose should be considered first according to current evidence and Guidelines, but the non-standard dose (0.6 mg/kg ≤ dose < 0.9 mg/kg) might be an option in the actual diagnosis and treatment process considering the patient's clinical profile and financial condition.
Neuromuscular electrical stimulation improves swallowing initiation in patients with post-stroke dysphagia
Authors: Zhang Yao-Wen , Dou Zu-Lin , Zhao Fei , Xie Chun-Qing , Shi Jing , Yang Chen , Wan Gui-Fang , Wen Hong-Mei , Chen Pei-Rong , Tang Zhi-Ming
Published: November 2022

Objective

More than half of post-stroke patients develop dysphagia, which manifests as delayed swallowing and is associated with a high risk of aspiration. In this study, we aimed to investigate the immediate effect of neuromuscular electrical stimulation (NMES) on swallowing initiation in post-stroke patients using videofluoroscopic swallowing study (VFSS) data.

Materials and methods

This randomized, self-controlled crossover study included 35 patients with post-stroke dysphagia. All selected patients received real and sham NMES while swallowing 5 ml of thin liquid. Participants completed the conditions in random order, with a 10-min interval between conditions. The primary evaluation indicators included the Modified Barium Swallow Impairment Profile-6 (MBSImp-6) and Penetration-Aspiration Scale (PAS). Secondary indicators included oral transit time (OTT), pharyngeal transit time (PTT), and laryngeal closure duration (LCD).

Results

Modified Barium Swallow Impairment Profile-6 (P= 0.008) and PAS (P< 0.001) scores were significantly lower in the Real-NMES condition than in the Sham-NMES condition. OTT (P< 0.001) was also significantly shorter during Real-NMES than during Sham-NMES. However, LCD (P= 0.225) and PTT (P= 0.161) did not significantly differ between the two conditions.

Conclusion

Neuromuscular electrical stimulation may represent a supplementary approach for promoting early feeding training in patients with post-stroke dysphagia.

Clinical trial registration

[https://clinicaltrials.gov/], identifier [ChiCTR2100052464].
Book review of the adaptable mind: What neuroplasticity and neural reuse tells us about language and cognition
Authors: Pan Xueyao , Li Xi
Published: November 2022

From the works of Noam Chomsky to Jerry Fodor, the modularity of mind has been deeply rooted in cognitive science. From the “modular” perspective, cognition consists of functionally and anatomically isolable subsystems. Therefore, it is reasonable to assume a language module or a hardwired language organ that is functionally and anatomically different from the other cognitive modules (e.g., vision, olfaction, motor). However, evidence from neuroscience casts doubt on this modular hypothesis. It has been shown that many brain regions are likely to be reused and recycled by various neural communities in order to serve various cognitive functions. If this is the case, language and other cognitive faculties should not be considered modules, since they cannot be realized in special-purpose, special-structure regions. Therefore, it is time to change our understanding of our brains.
Cool and warm ionotropic receptors control multiple thermotaxes in Drosophila larvae
Authors: Omelchenko Alisa A. , Bai Hua , Spina Emma C. , Tyrrell Jordan J. , Wilbourne Jackson T. , Ni Lina
Published: November 2022

Animals are continuously confronted with different rates of temperature variation. The mechanism underlying how temperature-sensing systems detect and respond to fast and slow temperature changes is not fully understood in fly larvae. Here, we applied two-choice behavioral assays to mimic fast temperature variations and a gradient assay to model slow temperature changes. Previous research indicates that Rhodopsin 1 (Rh1) and its phospholipase C (PLC) cascade regulate fast and slow temperature responses. We focused on the ionotropic receptors (IRs) expressed in dorsal organ ganglions (DOG), in which dorsal organ cool-activated cells (DOCCs) and warm-activated cells (DOWCs) rely on IR-formed cool and warm receptors to respond to temperature changes. In two-choice assays, both cool and warm IRs are sufficient for selecting 18°C between 18°C and 25°C but neither function in cool preferences between 25°C and 32°C. The Rh1 pathway, on the other hand, contributes to choosing preferred temperatures in both assays. In a gradient assay, cool and warm IR receptors exert opposite effects to guide animals to ∼25°C. Cool IRs drive animals to avoid cool temperatures, whereas warm IRs guide them to leave warm regions. The Rh1 cascade and warm IRs may function in the same pathway to drive warm avoidance in gradient assays. Moreover, IR92a is not expressed in temperature-responsive neurons but regulates the activation of DOWCs and the deactivation of DOCCs. Together with previous studies, we conclude that multiple thermosensory systems, in various collaborative ways, help larvae to make their optimal choices in response to different rates of temperature change.
Disrupting PTPRJ transmembrane-mediated oligomerization counteracts oncogenic receptor tyrosine kinase FLT3 ITD
Authors: Schwarz Marie , Rizzo Sophie , Paz Walter Espinoza , Kresinsky Anne , Thévenin Damien , Müller Jörg P.
Published: November 2022

The receptor protein tyrosine phosphatase (RPTP) PTPRJ (also known as DEP-1) has been identified as a negative regulator of the receptor tyrosine kinase FLT3 signalling in vitro. The inactivation of the PTPRJ gene in mice expressing the constitutively active, oncogenic receptor tyrosine kinase FLT3 ITD aggravated known features of leukaemogenesis, revealing PTPRJ’s antagonistic role. FLT3 ITD mutations resulting in constitutively kinase activity and cell transformation frequently occur in patients with acute myeloid leukaemia (AML). Thus, in situ activation of PTPRJ could be used to abrogate oncogenic FLT3 signalling. The activity of PTPRJ is suppressed by homodimerization, which is mediated by transmembrane domain (TMD) interactions. Specific Glycine-to-Leucine mutations in the TMD disrupt oligomerization and inhibit the Epidermal Growth Factor Receptor (EGFR) and EGFR-driven cancer cell phenotypes. To study the effects of PTPRJ TMD mutant proteins on FLT3 ITD activity in cell lines, endogenous PTPRJ was inactivated and replaced by stable expression of PTPRJ TMD mutants. Autophosphorylation of wild-type and ITD-mutated FLT3 was diminished in AML cell lines expressing the PTPRJ TMD mutants compared to wild-type-expressing cells. This was accompanied by reduced FLT3-mediated global protein tyrosine phosphorylation and downstream signalling. Further, PTPRJ TMD mutant proteins impaired the proliferation and in vitro transformation of leukemic cells. Although PTPRJ’s TMD mutant proteins showed impaired self-association, the specific phosphatase activity of immunoprecipitated proteins remained unchanged. In conclusion, this study demonstrates that the destabilization of PTPRJ TMD–mediated self-association increases the activity of PTPRJ in situ and impairs FLT3 activity and FLT3-driven cell phenotypes of AML cells. Thus, disrupting the oligomerization of PTPRJ in situ could prove a valuable therapeutic strategy to restrict oncogenic FLT3 activity in leukemic cells.
Case report: Unique FLT4 variants associated with differential response to anlotinib in angiosarcoma
Authors: Gu Yuanyuan , Meng Jing , Ju Yongzhi , You Xia , Sun Tingting , Lu Jun , Guan Yin
Published: November 2022

Angiosarcoma (AS) is a rare, clinically aggressive tumor with limited treatment options and a poor prognosis. Mutations involving the angiogenesis-related genesTP53, PTPRB, PLCG1, KDR as well as FLT4 amplification have been observed in AS. There is a potential therapeutic value of inhibition of the VEGF pathway against angiosarcoma. Our case first described a patient with two sites of cutaneous angiosarcomas (cASs) that responded differently to anlotinib. And genetic analysis revealed that those two sites had different FLT4 variants, suggesting that FLT4 amplification could be the cause of anlotinib non-response.
Practice-oriented solutions integrating intraoperative electron irradiation and personalized proton therapy for recurrent or unresectable cancers: Proof of concept and potential for dual FLASH effect
Authors: Calvo Felipe A. , Ayestaran Adriana , Serrano Javier , Cambeiro Mauricio , Palma Jacobo , Meiriño Rosa , Morcillo Miguel A. , Lapuente Fernando , Chiva Luis , Aguilar Borja , Azcona Diego , Pedrero Diego , Pascau Javier , Delgado José Miguel , Aristu Javier , Alonso Alberto , Prezado Yolanda
Published: November 2022

Background

Oligo-recurrent disease has a consolidated evidence of long-term surviving patients due to the use of intense local cancer therapy. The latter combines real-time surgical exploration/resection with high-energy electron beam single dose of irradiation. This results in a very precise radiation dose deposit, which is an essential element of contemporary multidisciplinary individualized oncology.

Methods

Patient candidates to proton therapy were evaluated in Multidisciplinary Tumor Board to consider improved treatment options based on the institutional resources and expertise. Proton therapy was delivered by a synchrotron-based pencil beam scanning technology with energy levels from 70.2 to 228.7 MeV, whereas intraoperative electrons were generated in a miniaturized linear accelerator with dose rates ranging from 22 to 36 Gy/min (at Dmax) and energies from 6 to 12 MeV.

Results

In a period of 24 months, 327 patients were treated with proton therapy: 218 were adults, 97 had recurrent cancer, and 54 required re-irradiation. The specific radiation modalities selected in five cases included an integral strategy to optimize the local disease management by the combination of surgery, intraoperative electron boost, and external pencil beam proton therapy as components of the radiotherapy management. Recurrent cancer was present in four cases (cervix, sarcoma, melanoma, and rectum), and one patient had a primary unresectable locally advanced pancreatic adenocarcinoma. In re-irradiated patients (cervix and rectum), a tentative radical total dose was achieved by integrating beams of electrons (ranging from 10- to 20-Gy single dose) and protons (30 to 54-Gy Relative Biological Effectiveness (RBE), in 10–25 fractions).

Conclusions

Individual case solution strategies combining intraoperative electron radiation therapy and proton therapy for patients with oligo-recurrent or unresectable localized cancer are feasible. The potential of this combination can be clinically explored with electron and proton FLASH beams.
KRAS G12 isoforms exert influence over up-front treatments: A retrospective, multicenter, Italian analysis of the impact of first-line immune checkpoint inhibitors in an NSCLC real-life population
Authors: Fancelli Sara , Caliman Enrico , Mazzoni Francesca , Paglialunga Luca , Gatta Michelet Marta Rita , Lavacchi Daniele , Berardi Rossana , Mentrasti Giulia , Metro Giulio , Birocchi Ilaria , Delmonte Angelo , Priano Ilaria , Comin Camilla Eva , Castiglione Francesca , Bartoli Caterina , Voltolini Luca , Pillozzi Serena , Antonuzzo Lorenzo
Published: November 2022

Background

KRAS is commonly mutated in non-small cell lung cancer (NSCLC); however, the prognostic and predictive impact of each G12 substitution has not been fully elucidated. The approval of specific G12C inhibitors has modified the idea of KRAS “undruggability”, and although the first-line standard consists of immune checkpoint inhibitors (ICIs) with or without chemotherapy, as suggested at ASCO 2022, the outcome in KRAS-mutated population is still controversial.

Methods

We retrospectively described the clinical and pathological characteristics of a homogeneous G12 mutated cohort of 219 patients treated in four Italian oncologic units. We evaluated the outcome (PFS at 18 months and OS at 30 months) of those who underwent standard first-line treatment according to PD-L1 status, focusing on differences across single mutations.

Results

In the study population, 47.9% of patients harbor the KRAS G12C mutation; 20.5%, G12V; 17.4%, G12D; and 8.2%, G12A. Smoking was a common behavior of patients harboring transversions and transition mutations. PD-L1 expression does not show particular distribution in the case series, although we recorded a prevalence of PD-L1 <1% in G12V (51.4%) compared to G12A (26.7%). ICIs alone was the clinician’s choice in 32.7% of patients, and the chemo-immune combination in 17.3% of patients. We described the independent prognostic role of young age (p = 0.007), female gender (p = 0.016), and an ICI-based regimen (p = 0.034) regardless of mutations. Overall, our data confirm the worst prognostic value of G12V mutation apart from treatment choice unlike the other major mutations (C, D, and A) that showed a favorable trend in PFS.

Conclusions

KRAS G12 mutations are confirmed to have different characteristics, and the outcome is influenced by ICI first-line regimen. This study provides valuable information for further analysis in the future.
Assessment of exocrine pancreatic function in children and adolescents with direct and indirect testing
Authors: Hopson Puanani , Smadi Yamen , Mehta Vijay , Patel Samit , Mehta Devendra , Horvath Karoly
Published: November 2022

The exocrine pancreas plays an important role in digestion. Understanding of the physiology and regulation of exocrine function provides insight into disease processes and basis of functional testing. Specifically, exocrine pancreatic insufficiency (EPI) can cause maldigestion and thus a proper assessment of exocrine pancreatic function is important. There are indirect and direct methods for evaluating pancreatic function. Indirect methods are varied and include stool, serum, urine, and breath tests. Fecal elastase is a commonly used indirect test today. Direct methods involve stimulated release of pancreatic fluid that is collected from the duodenum and analyzed for enzyme activity. The most used direct test today is the endoscopic pancreatic function test. Indirect pancreatic function testing is limited in identifying cases of mild to moderate EPI, and as such in these cases, direct testing has higher sensitivity and specificity in diagnosing EPI. This review provides a comprehensive guide to indirect and direct pancreatic function tests as well as an in-depth look at exocrine pancreatic function including anatomy, physiology, and regulatory mechanisms.
Sports activity and changes in physical fitness of Polish children and adolescents: OSF study
Authors: Baj-Korpak Joanna , Zaworski Kamil , Stelmach Marian J. , Lichograj Piotr , Wochna Marek
Published: November 2022

Background

Physical activity promotion programs for children and adolescents should constitute the basis of any national health policy aiming to improve physical fitness, which is a significant health indicator in children, adolescents, adults as well as elderly persons.

Methods

The study included 1,230 children and adolescents aged 8–16 years (60.1% of girls) from Poland. Five hundred and twenty-seven persons covered by the survey (42.8%) participated in physical activity promotion called “Athletics for All!” (AFA) as an experimental group and 703 peers not participating in any forms of physical extra-curricular activities as a control group. Participants were measured for basic anthropometric parameters and body mass indices were calculated: Body Mass Index (BMI) and Ponderal Index (PI). Evaluation of physical fitness was made using the OSF Test (3 × 10 m shuttle run, standing broad jump, 1 kg medicine ball overhead throw, 4-min run). Comparative analysis between the experimental and control groups was carried out using the T-test for independent samples. Analysis of correlations between quantitative variables was performed with Pearson's r coefficient.

Results

Statistically significant differences in all the tests were noted between the experimental group (AFA) and the control group in favor of the former one. Taking into account reference ranges of BMI created according to the latest Polish norms, statistically significant differences were noted between the subgroups in all physical fitness tests. As far as PI is concerned, in the AFA group significant differences were noted in all physical fitness tests between subgroups created in accordance with the aforementioned norms.

Conclusion

The findings of our study show that it is necessary to introduce physical activity promotion programs for children and adolescents. Such programs should constitute the basis of national health policy aiming at improving physical fitness among young people.
Efficacy and safety of Shexiang Baoxin Pill for stable coronary artery disease: A systematic review and meta-analysis of 42 randomized controlled trials
Authors: Wei Jingjing , Ma Teng , Zhou Cheng , Hao Pengle , Li Bin , Wang Xinlu , Yu Rui , Zhu Mingjun , Wang Yongxia
Published: November 2022

Objective: Patients with stable coronary artery disease (SCAD) still have a higher risk of adverse cardiovascular events. Shexiang Baoxin Pill (SBP) is widely used as a complementary and alternative treatment for SCAD. This study aimed to further verify the therapeutic effect and safety of SBP on SCAD.

Methods: Seven databases were involved in this meta-analysis as of 1 June 2022. Data was collected from all the randomized controlled trials (RCTs) of the combination of SBP and conventional western medicine (CWM) in treating SCAD which was conducted by two independent authors. Risk of bias was assessed using the Cochrane risk-of-bias 2.0 (RoB2.0) tool, and the meta-analysis was accomplished with Review Manager 5.3. Furthermore, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) profiler 3.2.2 software was selected to grade the current evidence in our findings.

Results: 42 articles, involving 6,694 patients were screened among all the 1,374 records in the analysis. The results demonstrated that the combination therapy was more efficient than CWM alone in lowering the incidence of major adverse cardiovascular events (MACE, RR = 0.50, 95% CI: 0.37 to 0.68, p < 0.00001) and ameliorating the total effective rate of angina symptom improvement (RR = 1.23, 95% CI: 1.19 to 1.28, p < 0.00001), the effective rate of electrocardiogram improvement (RR = 1.34, 95% CI: 1.26 to 1.43, p < 0.00001), the frequency of angina pectoris (MD = −2.83, 95% CI: −3.62 to −2.05, p < 0.00001), and the duration of angina pectoris (MD = −1.32, 95% CI: −2.04 to −0.61, p = 0.0003). We also found that, after SBP treatment, a more positive blood lipid level and left ventricular ejection fraction without the increase in adverse cases were calculated in our meta-analysis. What’s more, Subgroup analysis indicated that treatment duration may be the source of heterogeneity. The certainty of the evidence for MACE, and electrocardiogram improvement exhibited moderate certainty, and the certainty of the evidence for the remaining outcomes was judged as low certainty. The trial sequential analysis further affirmed the clinical efficacy of SBP.

Conclusion: The available evidence indicates that SBP may be an effective therapeutic option in patients with SCAD. However, considering the inferior quality and inconsistent results in the included trials, further rigorous RCTs are required.

Systematic Review Registration:https://www.crd.york.ac.uk/prospero, identifier [CRD42022334529].
Systemic and brain delivery of antidiabetic peptides through nasal administration using cell-penetrating peptides
Authors: Maeng Jeehye , Lee Kyunglim
Published: November 2022

The intranasal route has emerged as a promising strategy that can direct delivery of drugs into the systemic circulation because the high-vascularized nasal cavity, among other advantages, avoids the hepatic first-pass metabolism. The nose-to-brain pathway provides a non-invasive alternative to other routes for the delivery of macromolecular therapeutics. A great variety of methodologies has been developed to enhance the efficiency of transepithelial translocation of macromolecules. Among these, the use of cell-penetrating peptides (CPPs), short protein transduction domains (PTDs) that facilitate the intracellular transport of various bioactive molecules, has become an area of extensive research in the intranasal delivery of peptides and proteins either to systemic or to brain compartments. Some CPPs have been applied for the delivery of peptide antidiabetics, including insulin and exendin-4, for treating diabetes and Alzheimer’s disease. This review highlights the current status of CPP-driven intranasal delivery of peptide drugs and its potential applicability as a universal vehicle in the nasal drug delivery.