bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactions of heparin with key glycoproteins of human respiratory syncytial virus
Authors: Shi Deling , He Peng , Song Yuefan , Linhardt Robert J. , Dordick Jonathan S. , Chi Lianli , Zhang Fuming
Published: April 2023

Introduction: The unexpected surge of respiratory syncytial virus (RSV) cases following pandemic phase of COVID-19 has drawn much public attention. Drawing on the latest antiviral research, revisiting this heightened annual outbreak of respiratory disease could lead to new treatments. The ability of sulfated polysaccharides to compete for a variety of viruses binding to cell surface heparan sulfate, suggests several drugs that might have therapeutic potential for targeting RSV–glycosaminoglycan interactions.

Methods: In the current study, the binding affinity and kinetics of two RSV glycoproteins (RSV-G protein and RSV-F protein) to heparin were investigated by surface plasmon resonance. Furthermore, solution competition studies using heparin oligosaccharides of different lengths indicated that the binding of RSV-G protein to heparin is size-dependent, whereas RSV-F protein did not show any chain length preference.

Results and discussion: The two RSV glycoproteins have slightly different preferences for heparin sulfation patterns, but the N-sulfo group in heparin was most critical for the binding of heparin to both RSV-G protein and RSV-F protein. Finally, pentosan polysulfate and mucopolysaccharide polysulfate were evaluated for their inhibition of the RSV-G protein and RSV-F protein–heparin interaction, and both highly negative compounds showed strong inhibition.
Mosaic results after preimplantation genetic testing for aneuploidy may be accompanied by changes in global gene expression
Authors: Martin A. , Mercader A. , Dominguez F. , Quiñonero A. , Perez M. , Gonzalez-Martin R. , Delgado A. , Mifsud A. , Pellicer A. , De Los Santos M. J.
Published: April 2023

Aneuploidy in preimplantation embryos is a major cause of human reproductive failure. Unlike uniformly aneuploid embryos, embryos diagnosed as diploid-aneuploid mosaics after preimplantation genetic testing for aneuploidy (PGT-A) can develop into healthy infants. However, the reason why these embryos achieve full reproductive competence needs further research. Current RNA sequencing techniques allow for the investigation of the human preimplantation transcriptome, providing new insights into the molecular mechanisms of embryo development. In this prospective study, using euploid embryo gene expression as a control, we compared the transcriptome profiles of inner cell mass and trophectoderm samples from blastocysts with different levels of chromosomal mosaicism. A total of 25 samples were analyzed from 14 blastocysts with previous PGT-A diagnosis, including five low-level mosaic embryos and four high-level mosaic embryos. Global gene expression profiles visualized in cluster heatmaps were correlated with the original PGT-A diagnosis. In addition, gene expression distance based on the number of differentially expressed genes increased with the mosaic level, compared to euploid controls. Pathways involving apoptosis, mitosis, protein degradation, metabolism, and mitochondrial energy production were among the most deregulated within mosaic embryos. Retrospective analysis of the duration of blastomere cell cycles in mosaic embryos revealed several mitotic delays compared to euploid controls, providing additional evidence of the mosaic status. Overall, these findings suggest that embryos with mosaic results are not simply a misdiagnosis by-product, but may also have a genuine molecular identity that is compatible with their reproductive potential.
Aβ1-42-containing platelet-derived extracellular vesicle is associated with cognitive decline in Parkinson’s disease
Authors: Wang Ziyu , Zheng Yuanchu , Cai Huihui , Yang Chen , Li Siming , Lv Hong , Feng Tao , Yu Zhenwei
Published: April 2023

Background

Cortical amyloid deposition is a common observation in Parkinson’s disease dementia (PDD) patients. Aβ1-42 is linked to a more rapid progression of dementia. Platelets, which degranulate upon activation, are a primary source of Aβ. It has been repeatedly reported that peripheral extracellular vesicles (EVs) can partially reach the central nervous system. Thus, we speculate that activated platelet-derived Aβ1-42-containing EVs (PEV-Aβ1-42) play a crucial role in the cognitive decline of PD patients.

Methods

The study included 189 participants: 66 with non-dementia PD, 73 with PDD, and 50 healthy controls. All participants underwent blood collection and clinical assessments. Twenty PD patients underwent re-examination and repeated blood collection 14 months later. A nano-scale flow cytometry assay was used to detect PEVs and PEV-Aβ1-42 using fluorescence-labeled CD62P and Aβ1-42 antibodies.

Results

Parkinson’s disease dementia patients had higher PEV-Aβ1-42 concentrations than healthy controls (p = 0.028). The ratio of PEV-Aβ1-42 to PEV was significantly higher in PDD patients compared to those in non-dementia PD and healthy controls (pPD-ND < 0.001, pHC = 0.041). The PEV-Aβ1-42/PEV ratio appears to influence the odds of developing dementia (OR = 1.76, p < 0.001). The change in the PEV-Aβ1-42/PEV ratio was also correlated with cognitive decline over 14 months (r = −0.447, p < 0.05).

Conclusion

The plasma PEV-Aβ1-42/PEV ratio may serve as a diagnostic and prognostic biomarker for PDD patients.
Prediction of long-term mortality in patients with ischemic stroke based on clinical characteristics on the first day of ICU admission: An easy-to-use nomogram
Authors: Jin Guangyong , Hu Wei , Zeng Longhuan , Ma Buqing , Zhou Menglu
Published: April 2023

Background

This study aimed to establish and validate an easy-to-use nomogram for predicting long-term mortality among ischemic stroke patients.

Methods

All raw data were obtained from the Medical Information Mart for Intensive Care IV database. Clinical features associated with long-term mortality (1-year mortality) among ischemic stroke patients were identified using least absolute shrinkage and selection operator regression. Then, binary logistic regression was used to construct a nomogram, the discrimination of which was evaluated by the concordance index (C-index), integrated discrimination improvement (IDI), and net reclassification index (NRI). Finally, a calibration curve and decision curve analysis (DCA) were employed to study calibration and net clinical benefit, compared to the Glasgow Coma Scale (GCS) and the commonly used disease severity scoring system.

Results

Patients who were identified with ischemic stroke were randomly assigned into developing (n = 1,443) and verification (n = 646) cohorts. The following factors were associated with 1-year mortality among ischemic stroke patients, including age on ICU admission, marital status, underlying dementia, underlying malignant cancer, underlying metastatic solid tumor, heart rate, respiratory rate, oxygen saturation, white blood cells, anion gap, mannitol injection, invasive mechanical ventilation, and GCS. The construction of the nomogram was based on the abovementioned features. The C-index of the nomogram in the developing and verification cohorts was 0.820 and 0.816, respectively. Compared with GCS and the commonly used disease severity scoring system, the IDI and NRI of the constructed nomogram had a statistically positive improvement in predicting long-term mortality in both developing and verification cohorts (all with p < 0.001). The actual mortality was consistent with the predicted mortality in the developing (p = 0.862) and verification (p = 0.568) cohorts. Our nomogram exhibited greater net clinical benefit than GCS and the commonly used disease severity scoring system.

Conclusion

This proposed nomogram has good performance in predicting long-term mortality among ischemic stroke patients.
Targeted metabolomics reveals serum changes of amino acids in mild to moderate ischemic stroke and stroke mimics
Authors: Tao Shuxin , Xiao Xinxing , Li Xin , Na Fan , Na Guo , Wang Shuang , Zhang Pin , Hao Fang , Zhao Peiran , Guo Dong , Liu Xuewu , Yang Dawei
Published: April 2023

Background

The pathophysiological processes linked to an acute ischemic stroke (IS) can be reflected in the circulating metabolome. Amino acids (AAs) have been demonstrated to be one of the most significant metabolites that can undergo significant alteration after a stroke.

Methods

We sought to identify the potential biomarkers for the early detection of IS using an extensive targeted technique for reliable quantification of 27 different AAs based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). A cohort with 216 participants was enrolled, including 70 mild to moderate ischemic stroke patients (National Institutes of Health Stroke Scale < 15, MB group), 76 stroke mimics (MM group) and 70 healthy controls (NC group).

Results

It was found that upon comparing MB and MM to control patients, AAs shifts were detected via partial least squares discrimination analysis (PLS-DA) and pathway analysis. Interestingly, MB and MM exhibited similar AAs pattern. Moreover, ornithine, asparagine, valine, citrulline, and cysteine were identified for inclusion in a biomarker panel for early-stage stroke detection based upon an AUC of 0.968 (95% CI 0.924–0.998). Levels of ornithine were positively associated with infract volume, 3 months mRS score, and National Institutes of Health Stroke Scale (NIHSS) score in MB. In addition, a metabolites biomarker panel, including ornithine, taurine, phenylalanine, citrulline, cysteine, yielded an AUC of 0.99 (95% CI 0.966–1) which can be employed to effectively discriminate MM patients from control.

Conclusion

Overall, alternations in serum AAs are characteristic metabolic features of MB and MM. AAs could serve as promising biomarkers for the early diagnosis of MB patients since mild to moderate IS patients were enrolled in the study. The metabolism of AAs can be considered as a key indicator for both the prevention and treatment of IS.
Does stochastic resonance improve performance for individuals with higher autism-spectrum quotient?
Authors: Raul Pratik , McNally Kate , Ward Lawrence M. , van Boxtel Jeroen J. A.
Published: April 2023

While noise is generally believed to impair performance, the detection of weak stimuli can sometimes be enhanced by introducing optimum noise levels. This phenomenon is termed ‘Stochastic Resonance’ (SR). Past evidence suggests that autistic individuals exhibit higher neural noise than neurotypical individuals. It has been proposed that the enhanced performance in Autism Spectrum Disorder (ASD) on some tasks could be due to SR. Here we present a computational model, lab-based, and online visual identification experiments to find corroborating evidence for this hypothesis in individuals without a formal ASD diagnosis. Our modeling predicts that artificially increasing noise results in SR for individuals with low internal noise (e.g., neurotypical), however not for those with higher internal noise (e.g., autistic, or neurotypical individuals with higher autistic traits). It also predicts that at low stimulus noise, individuals with higher internal noise outperform those with lower internal noise. We tested these predictions using visual identification tasks among participants from the general population with autistic traits measured by the Autism-Spectrum Quotient (AQ). While all participants showed SR in the lab-based experiment, this did not support our model strongly. In the online experiment, significant SR was not found, however participants with higher AQ scores outperformed those with lower AQ scores at low stimulus noise levels, which is consistent with our modeling. In conclusion, our study is the first to investigate the link between SR and superior performance by those with ASD-related traits, and reports limited evidence to support the high neural noise/SR hypothesis.
The cholinergic anti-inflammatory pathway inhibits inflammation without lymphocyte relay
Authors: Simon Thomas , Kirk Joseph , Dolezalova Nikola , Guyot Mélanie , Panzolini Clara , Bondue Alexandre , Lavergne Julien , Hugues Sandrine , Hypolite Nicolas , Saeb-Parsy Kourosh , Perkins Justin , Macia Eric , Sridhar Arun , Vervoordeldonk Margriet J. , Glaichenhaus Nicolas , Donegá Matteo , Blancou Philippe
Published: April 2023

The magnitude of innate inflammatory immune responses is dependent on interactions between peripheral neural and immune cells. In particular, a cholinergic anti-inflammatory pathway (CAP) has been identified in the spleen whereby noradrenaline (NA) released by splenic nerves binds to ß2-adrenergic receptors (β2-AR) on CD4+ T cells which, in turn, release acetylcholine (ACh). The binding of ACh to α7 acetylcholine receptors (α7-AChR) expressed by splenic macrophages inhibits the production of inflammatory cytokines, including tumor necrosis factor (TNF). However, the role of ACh-secreting CD4+ T-cells in the CAP is still controversial and largely based on the absence of this anti-inflammatory pathway in mice lacking T-cells (nude, FoxN1−/−). Using four conscious, non-lymphopenic transgenic mouse models, we found that, rather than acting on CD4+ T-cells, NA released by splenic nerve terminals acts directly onto β2-AR on splenic myeloid cells to exert this anti-inflammatory effect. We also show that, while larger doses of LPS are needed to trigger CAP in nude mouse strain compared to other strains, TNF production can be inhibited in these animals lacking CD4+ T-cell by stimulating either the vagus or the splenic nerve. We demonstrate that CD4+ T-cells are dispensable for the CAP after antibody-mediated CD4+ T-cell depletion in wild type mice. Furthermore, we found that NA-mediated inhibition of in vitro LPS-induced TNF secretion by human or porcine splenocytes does not require α7-AChR signaling. Altogether our data demonstrate that activation of the CAP by stimulation of vagus or splenic nerves in mice is mainly mediated by direct binding of NA to β2-AR on splenic macrophages, and suggest that the same mechanism is at play in larger species.
Anti-hypoxic Effect of Polysaccharide Extract of Brown Seaweed Sargassum dentifolium in Tongue Squamous Cell Carcinoma
Authors: Gamal-Eldeen Amira M. , Raafat Bassem M. , Alrehaili Amani A. , El-Daly Sherien M. , Hawsawi Nahed , Banjer Hamsa J. , Raafat Eman M. , Almehmadi Mazen M.
Published: April 2023

Graphical Abstract

Anti-hypoxic activity of S. dentifolium through multiple mediators.
Clinical nutrition in surgical oncology: Young AIOM-AIRO-SICO multidisciplinary national survey on behalf of NutriOnc research group
Authors: Marano Luigi , Marmorino Federica , Desideri Isacco , Carbone Ludovico , Rizzo Alessandro , Salvestrini Viola , Roviello Franco , Cinieri Saverio , Donato Vittorio , De Luca Raffaele ,   NutriOnc Research Group
Published: April 2023

Malnutrition is a common condition in cancer patients which is usually associated with functional limitations, as well as increased morbidity and mortality. Based on the support of the young sections of Italian Association of Medical Oncology (AIOM), Italian Association of Radiotherapy and Clinical Oncology (AIRO) and Italian Society of Surgical Oncology (SICO) merged into the NutriOnc Research Group, we performed a multidisciplinary national survey with the aim to define the awareness of nutritional issues among healthcare professionals delivering anticancer care. The questionnaire was organized in four sections, as follows: Knowledge and practices regarding Nutritional Management of cancer patients; Timing of screening and assessment of Nutritional Status; Nutritional Treatment and prescription criteria; Immunonutrition and educational topics. The modules focused on esophagogastric, hepato-bilio-pancreatic and colorectal malignancies. Overall, 215 physicians completed the survey. As regards the management of Nutritional Status of cancer patients, many responders adopted the ERAS program (49.3%), while a consistent number of professionals did not follow a specific validated nutritional care protocol (41.8%), mainly due to lack of educational courses (14.5%) and financial support (15.3%). Nearly all the included institutions had a multidisciplinary team (92%) to finalize the treatment decision-making. Cancer patients routinely underwent nutritional screening according to 57.2% of interviewed physicians. The timing of nutritional assessment was at diagnosis (37.8%), before surgery (25.9%), after surgery (16.7%), before radiochemotherapy (13.5%) and after radiochemotherapy (7%). Most of the responders reported that nutritional status was assessed throughout the duration of cancer treatments (55.6%). An important gap between current delivery and need of nutritional assessment persists. The development of specific and defined care protocols and the adherence to these tools may be the key to improving nutritional support management in clinical practice.
The relationship between vitamin K and metabolic dysfunction-associated fatty liver disease among the United States population: National Health and Nutrition Examination Survey 2017–2018
Authors: Wang Xinyue , Zhang Wei , Huang Jiale , Li Hongwei , Gao Jian
Published: April 2023

Background

The effect of vitamin K is associated with several pathological processes in fatty liver. However, the association between vitamin K levels and metabolic dysfunction-associated fatty liver disease (MAFLD) remains unclear.

Objective

Here, we investigated the relationship between vitamin K intake and MAFLD risk by employing the American National Health and Nutrition Examination Surveys (NHANES) including 3,571 participants.

Methods

MAFLD was defined as hepatic steatosis with one or more of the following: overweight or obesity, type 2 diabetes, or >2 other metabolic risk abnormalities. The total vitamin K was the sum of dietary and supplement dietary intake. The relationship of between log10(vitamin K) and MAFLD was investigated using survey-weighted logistic regression and stratified analysis, with or without dietary supplementation.

Results

The MAFLD population had a lower vitamin K intake than the non-MAFLD population (p = 0.024). Vitamin K levels were inversely associated with MAFLD in the fully adjusted model (OR = 0.488, 95% CI: 0.302–0.787, p = 0.006). Consistent results were seen in the group without dietary supplements (OR = 0.373, 95% CI: 0.186–0.751, p = 0.009) but not in the group consuming dietary supplements (OR = 0.489, 95% CI: 0.238–1.001, p = 0.050).

Conclusion

Vitamin K intake may be a protective factor for MAFLD, especially for individual not using dietary supplements. Nevertheless, more high-quality prospective studies are needed to clarify the causal relationship between them.
Comprehensive analysis of metabolomics on flesh quality of yellow catfish (Pelteobagrus fulvidraco) fed plant-based protein diet
Authors: Li Xue , Wang Shidong , Zhang Muzi , Jiang Haibo , Qian Yunxia , Wang Rixin , Li Ming
Published: April 2023

Background

To investigate the mechanism of plant protein components on nutritional value, growth performance, flesh quality, flavor, and proliferation of myocytes of yellow catfish (Pelteobagrus fulvidraco).

Methods

A total of 540 yellow catfish were randomly allotted into six experimental groups with three replicates and fed six different diets for 8 weeks.

Results and Conclusions

The replacement of fish meal with cottonseed meal (CM), sesame meal (SEM), and corn gluten meal (CGM) in the diet significantly reduced growth performance, crude protein, and crude lipid, but the flesh texture (hardness and chewiness) was observably increased. Moreover, the flavor-related amino acid (glutamic acid, glycine, and proline) contents in the CM, SEM, and CGM groups of yellow catfish muscle were significantly increased compared with the fish meal group. The results of metabolomics showed that soybean meal (SBM), peanut meal (PM), CM, SEM, and CGM mainly regulated muscle protein biosynthesis by the variations in the content of vitamin B6, proline, glutamic acid, phenylalanine, and tyrosine in muscle, respectively. In addition, Pearson correlation analysis suggested that the increased glutamic acid content and the decreased tyrosine content were significantly correlated with the inhibition of myocyte proliferation genes. This study provides necessary insights into the mechanism of plant proteins on the dynamic changes of muscle protein, flesh quality, and myocyte proliferation in yellow catfish.
Development and evaluation of novel artemisinin-isatin hybrids with potential anti-leukemic cytotoxicity
Authors: Wang Peng , Zhang Zhe , Cao Wei , Zhang Xuan
Published: April 2023

Twenty-one novel ester tethered artemisinin-isatin hybrids were designed, synthesized and screened against human myeloid leukemia cell lines (K562 and K562/ADR), human acute lymphoblastic leukemia cell line (CCRF-CEM) as well as normal human peripheral blood mononuclear cells (PBMCs) for their cytotoxicity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The structure-activity relationships (SARs) were also discussed to facilitate further rational design of more effective candidates. The preliminary results showed that most of the ester tethered artemisinin-isatin hybrids (IC50: 0.32-29.35 µM) exhibited promising activity against CCRF-CEM cells, and some of them (IC50: 1.23-49.84 µM) were also active against K562 and K562/ADR human myeloid leukemia cell lines. Among them, hybrid 7d (IC50: 0.32, 2.67 and 1.23 µM) not only possessed profound activity against the three tested leukemia cell lines and excellent safety and selectivity profiles, but also showed promising pharmacokinetic properties. Accordingly, hybrid 7d could be considered as a potential lead molecule for the development of novel anti-leukemic agents with minimal untoward events to normal human cells.
GD2 and GD3 gangliosides as diagnostic biomarkers for all stages and subtypes of epithelial ovarian cancer
Authors: Galan Alba , Papaluca Arturo , Nejatie Ali , Matanes Emad , Brahimi Fouad , Tong Wenyong , Hachim Ibrahim Yaseen , Yasmeen Amber , Carmona Euridice , Klein Kathleen Oros , Billes Sonja , Dawod Ahmed E. , Gawande Prasad , Jeter Anna Milik , Mes-Masson Anne-Marie , Greenwood Celia M. T. , Gotlieb Walter H. , Saragovi H. Uri
Published: April 2023

Background

Ovarian cancer (OC) is the deadliest gynecological cancer, often diagnosed at advanced stages. A fast and accurate diagnostic method for early-stage OC is needed. The tumor marker gangliosides, GD2 and GD3, exhibit properties that make them ideal potential diagnostic biomarkers, but they have never before been quantified in OC. We investigated the diagnostic utility of GD2 and GD3 for diagnosis of all subtypes and stages of OC.

Methods

This retrospective study evaluated GD2 and GD3 expression in biobanked tissue and serum samples from patients with invasive epithelial OC, healthy donors, non-malignant gynecological conditions, and other cancers. GD2 and GD3 levels were evaluated in tissue samples by immunohistochemistry (n=299) and in two cohorts of serum samples by quantitative ELISA. A discovery cohort (n=379) showed feasibility of GD2 and GD3 quantitative ELISA for diagnosing OC, and a subsequent model cohort (n=200) was used to train and cross-validate a diagnostic model.

Results

GD2 and GD3 were expressed in tissues of all OC subtypes and FIGO stages but not in surrounding healthy tissue or other controls. In serum, GD2 and GD3 were elevated in patients with OC. A diagnostic model that included serum levels of GD2+GD3+age was superior to the standard of care (CA125, p<0.001) in diagnosing OC and early-stage (I/II) OC.

Conclusion

GD2 and GD3 expression was associated with high rates of selectivity and specificity for OC. A diagnostic model combining GD2 and GD3 quantification in serum had diagnostic power for all subtypes and all stages of OC, including early stage. Further research exploring the utility of GD2 and GD3 for diagnosis of OC is warranted.
Pre- to postoperative alpha-fetoprotein ratio-based nomogram to predict tumor recurrence in patients with hepatocellular carcinoma
Authors: Yang Chengkai , Wang Huaxiang , Liu Jianyong , Yang Fang , Lv Lizhi , Jiang Yi , Cai Qiucheng
Published: April 2023

Background

This study aimed to investigate the role of the alpha fetoprotein (AFP) ratio before and after curative resection in the prognosis of patients with hepatocellular carcinoma (HCC) and to develop a novel pre- to postoperative AFP ratio nomogram to predict recurrence free survival (RFS) for HCC patients after curative resection.

Methods

A total of 485 pathologically confirmed HCC patients who underwent radical hepatectomy from January 2010 to December 2018 were retrospectively analyzed. The independent prognostic factors of hepatocellular carcinoma were identified by multivariate COX proportional model analysis, and the nomogram model was constructed. The receiver operating characteristic and the C-index were used to evaluate the accuracy and efficacy of the model prediction, the correction curve was used to assess the calibration of the prediction model, and decision curve analysis was used to evaluate the clinical application value of the nomogram model.

Results

A total of 485 HCC patients were divided into the training cohort (n = 340) and the validation cohort (n = 145) by random sampling at a ratio of 7:3. Using X-tile software, it was found that the optimal cut-off value of the AFP ratio in the training cohort was 0.8. In both cohorts, the relapse-free survival of patients with an AFP ratio <0.8 (high-risk group) was significantly shorter than in those with an AFP ratio ≥0.8 (low-risk group) (P < 0.05). An AFP ratio <0.8 was an independent risk factor for recurrence of HCC after curative resection. Based on the AFP ratio, BCLC stage and cirrhosis diagnosis, a satisfactory nomogram was developed. The AUC of our nomogram for predicting 1-, 3-, and 5-year RFS was 0.719, 0.690, and 0.708 in the training cohort and 0.721, 0.682, and 0.681 in the validation cohort, respectively. Furthermore, our model demonstrated excellent stratification as well as clinical applicability.

Conclusion

The AFP ratio was a reliable biomarker for tumor recurrence. This easy-to-use AFP ratio-based nomogram precisely predicted tumor recurrence in HCC patients after curative resection.
BRAF-mediated brain tumors in adults and children: A review and the Australian and New Zealand experience
Authors: Trinder Sarah M. , McKay Campbell , Power Phoebe , Topp Monique , Chan Bosco , Valvi Santosh , McCowage Geoffrey , Govender Dinisha , Kirby Maria , Ziegler David S. , Manoharan Neevika , Hassall Tim , Kellie Stewart , Heath John , Alvaro Frank , Wood Paul , Laughton Stephen , Tsui Karen , Dodgshun Andrew , Eisenstat David D. , Endersby Raelene , Luen Stephen J. , Koh Eng-Siew , Sim Hao-Wen , Kong Benjamin , Gottardo Nicholas G. , Whittle James R. , Khuong-Quang Dong-Anh , Hansford Jordan R.
Published: April 2023

The mitogen-activated protein kinase (MAPK) pathway signaling pathway is one of the most commonly mutated pathways in human cancers. In particular, BRAF alterations result in constitutive activation of the rapidly accelerating fibrosarcoma–extracellular signal–regulated kinase–MAPK significant pathway, leading to cellular proliferation, survival, and dedifferentiation. The role of BRAF mutations in oncogenesis and tumorigenesis has spurred the development of targeted agents, which have been successful in treating many adult cancers. Despite advances in other cancer types, the morbidity and survival outcomes of patients with glioma have remained relatively stagnant. Recently, there has been recognition that MAPK dysregulation is almost universally present in paediatric and adult gliomas. These findings, accompanying broad molecular characterization of gliomas, has aided prognostication and offered opportunities for clinical trials testing targeted agents. The use of targeted therapies in this disease represents a paradigm shift, although the biochemical complexities has resulted in unexpected challenges in the development of effective BRAF inhibitors. Despite these challenges, there are promising data to support the use of BRAF inhibitors alone and in combination with MEK inhibitors for patients with both low-grade and high-grade glioma across age groups. Safety and efficacy data demonstrate that many of the toxicities of these targeted agents are tolerable while offering objective responses. Newer clinical trials will examine the use of these therapies in the upfront setting. Appropriate duration of therapy and durability of response remains unclear in the glioma patient cohort. Longitudinal efficacy and toxicity data are needed. Furthermore, access to these medications remains challenging outside of clinical trials in Australia and New Zealand. Compassionate access is limited, and advocacy for mechanism of action-based drug approval is ongoing.
Eastern India Collaboration on Multisystem Inflammatory Syndrome in Children (EICOMISC): A Multicenter Observational Study of 134 Cases
Authors: Nayak Snehamayee , Panda Prakash Chandra , Biswal Basudev , Agarwalla Sunil Kumar , Satapathy Amit Kumar , Jena Pradeep Kumar , Gulla Krishna Mohan , Rath Debasmita , Mahapatra Anuspandana , Mishra Pravakar , Priyadarshini Debashree , Mahapatro Samarendra , Nayak Saurav , Das Rashmi Ranjan ,   EICOMISC Study Group
Published: April 2023

Background

Few single center studies from resource-poor settings have reported about the epidemiology, clinical feature and outcome of multisystem inflammatory syndrome in children (MIS-C). However, larger data from multi-center studies on the same is lacking including from Indian setting.

Methods

This retrospective collaborative study constituted of data collected on MIS-C from five tertiary care teaching hospitals from Eastern India. Children ≤ 15 years of age with MIS-C as per the WHO criteria were included. Primary outcome was mortality.

Results

A total of 134 MIS-C cases were included (median age, 84 months; males constituted 66.7%). Fever was a universal finding. Rash was present in 40%, and conjunctivitis in 71% cases. Gastro-intestinal and respiratory symptoms were observed in 50.7% and 39.6% cases, respectively. Co-morbidity was present in 23.9% cases. Shock at admission was noted in 35%, and 27.38% required mechanical ventilation. Fifteen (11.2%) children died. The coronary abnormalities got normalized during follow-up in all except in one child. Initial choice of immunomodulation had no effect on the outcomes. Presence of underlying co-morbidity, lymphopenia, thrombocytosis, hyponatremia, increased LDH (>300 U/L), and hypoalbuminemia were the factors significantly associated an increased mortality.

Conclusions

MIS-C has myriad of manifestations. Underlying co-morbidity, lymphopenia, thrombocytosis, hyponatremia, increased LDH (>300 U/L), and hypoalbuminemia were associated with an increased mortality. No difference in outcome was noted with either steroid or IVIg or both. Coronary artery abnormalities resolved in nearly all cases.
Prevention Effect of Protopanaxadiol-Type Saponins Saponins and Protopanaxatriol-Type Saponins on Myelosuppression Mice Induced by Cyclophosphamide
Authors: Zhang He , Zhang Lancao , Yang Chunhui , Zhang Yuyao , Li Jing , Zhang Xu , Chen Jinjin , Huang Baotai , Zhao Daqing , Li Xiangyan , Zhang Wei , Qi Bin
Published: April 2023

Ginsenosides from ginseng are used as a therapeutic agent for various diseases. They enhance the immunomodulatory effect in cyclophosphamide (CP)-treated tumor disease. The structural characteristics of steroidal saponins are mainly divided into protopanaxadiol-type saponin (PDS) and protopanaxatriol-type saponin (PTS). At present, few researchers have studied which kind of saponin plays a more important role, thus, we compared the prevention effect of PDS and PTS on myelosuppression mice induced by CP. The components and contents of saponin and monosaccharide were analyzed by using ultra high performance liquid chromatography-charged aerosol detector (UPLC-CAD) and reversed phase-high performance liquid chromatography (RP-HPLC), respectively. Thirty-two mice were randomly divided into four groups, including control, model (CP), CP+PDS, and CP+PTS. The mice were orally administered with PDS or PTS for 28 days and then injected with CP saline solution on 25, 26, 27, and 28 days at a dose of 50 mg × kg−1. After the end of modeling, the whole blood of mice from the ophthalmic venous plexus was collected to detect routine blood tests, inflammatory cytokines, and hematopoiesis-related cytokines. Cell cycle and the apoptosis of bone marrow in the right femur were detected. The spleen and thymus were used to calculate the organ index and histological examination, and splenocytes were used to detect the percentage of CD4+ and CD25+ T cells. In the saponins analysis, PDS mainly included the Rb1, Rc, Rb2, and Rd of protopanaxadiol-type ginsenosides (accounted for 91.64%), and PTS mainly included the Re, Rg1, and Rf of protopanaxatriol-type ginsenosides (accounted for 75.46%). The animal results showed that both PDS and PTS improved the most indicators of myelosuppression mice induced by CP, including increased weight, blood cell numbers, hematopoiesis-related cytokines, and inflammatory cytokines; promoted the cell cycle of bone marrow and inhibited the apoptosis of bone marrow; elevated the spleen and thymus indexes and CD4+ count of splenocytes. The prevention effect of PDS was better than PTS in some indicators, such as red blood cells, hemoglobin, interleukin (IL)-1β, IL-4, IL-10, tumor necrosis factor-α, CD4+, and thymus index. These results suggest both PDS and PTS can prevent myelosuppression of mice induced by CP. Meanwhile, PDS and its metabolite showed higher bioavailability and bioactivity compared with PTS.
Health-related quality of life in Her2-positive early breast cancer woman using trastuzumab: A systematic review and meta-analysis
Authors: Khoirunnisa Sudewi Mukaromah , Suryanegara Fithria Dyah Ayu , Setiawan Didik , Postma Maarten Jacobus
Published: April 2023

Background: Despite the benefits of trastuzumab in many trials, evidence of its impact on health-related quality of life (HRQoL) in early treatment has not been summarized. This study explored the effects of trastuzumab treatment on HRQoL, including pooled meta-analysis, in an effort to provide an integrated assessment of HRQoL for Her2-positive early breast cancer patients.

Methods: A comprehensive literature review to February 2023 using three databases, focusing on treatment using trastuzumab during the early stage, was performed. The mean changes from baseline during and after treatment were extracted from the included randomized control trials (RCTs) papers and total HRQoL scores were obtained from cross-sectional studies included. Mean difference (MD) and 95% confidence intervals were assessed by a random effect or fixed effect model based on heterogeneity (I2).

Results: A total of ten studies were identified and reviewed, consisting of seven RCTs and three cross-sectional studies. The pooled analysis of the mean change from baseline during treatment resulted in an MD of 1.92 (95% CI = 1.59 to 2.25, p < 0.05, I2 = 0%), favoring the trastuzumab group. A non-significant result of the mean change from baseline after treatment appeared in the analysis of 12-month follow-up. In the cross-sectional studies, pooled analyses of HRQoL showed that trastuzumab meaningfully demonstrated an improved HRQoL profile (MD = 9.29, 95% CI = 1.31 to 17.27, p = 0.02, I2 = 0%).

Conclusion: Trastuzumab as a targeted therapy resulted in a favorable effect on HRQoL in the early stages of Her2-positive breast cancer. The findings of significant improvements in patients’ HRQoL and less clinically meaningful deterioration in side effects of trastuzumab-containing regimen during treatment were supported by prolonged survival.
Safety, tolerance, and pharmacokinetics of salvianolic acid B in healthy Chinese volunteers: A randomized, double-blind, placebo-controlled phase 1 clinical trial
Authors: Cheng Junlin , Long Jun , Zhang Jingjing , Han Le , Hu Yunfang , Liu Jianghui , Qiu Runze , Zhu Zhibin , Fan Hongwei
Published: April 2023

Background: Salvianolic acid B (Sal B) is one of the main active ingredients of Salvia miltiorrhiza Bunge. In China, many traditional Chinese medicines have been modified into injections for higher bioavailability and better efficacy. Salvianolic acid injection has been widely used in the clinic.

Objective: This phase 1, randomized, double-blind, placebo-controlled, single-center study aimed to evaluate the safety, tolerance, and pharmacokinetics of Sal B injection in healthy Chinese volunteers.

Methods: For the single-ascending-dose study, forty-seven healthy volunteers were randomly divided into 25, 75, 150, 200, 250, and 300 mg groups. For the multiple-ascending-dose study, sixteen healthy volunteers were randomly divided into 150 and 300 mg groups. In each group, volunteers were treated with Sal B or placebo randomly. Their safety was evaluated by a skin test, physical examination, vital sign, laboratory examination, 12-lead electrocardiogram, Holter, and clinical symptoms and signs. Blood samples were collected in 75, 150, and 300 mg single-ascending-dose study groups and 150 mg multiple-ascending-dose study groups to determine the concentration of salvianolic acid B.

Results: In single-ascending-dose study groups, there were 41 adverse events in 24 cases (51.1%, 24/47). In multiple-ascending-dose study groups, there were 13 adverse events in eight cases (50.0%, 8/16). Sixty-six volunteers received the skin test, and three of them were excluded because of the positive result. Adverse events related to the treatment included increased alanine aminotransferase (4.0%), increased bilirubin (2.0%), increased creatinine kinase-MB (2.0%), increased brain natriuretic peptide (8.0%), increased urine N-acetyl-β-D-glucosidase (4.0%), dizziness (2.0%), and chest discomfort (2.0%). No serious adverse events occurred. No volunteers withdrew from the trial. Peak plasma concentration and the area under the plasma concentration–time curve of salvianolic acid B progressively increased in a dose-dependent manner in 75, 150, and 300 mg single-ascending-dose study groups. There was no accumulation after 5 consecutive days of administration of 150 mg salvianolic acid B.

Conclusion: Salvianolic acid B injections administered up to 300 mg in a single dose and 250 mg for 5 consecutive days showed excellent safety and tolerability in healthy Chinese volunteers.

Clinical Trial Registration:www.chinadrugtrials.org.cn, identifier CTR20192236
Resolving sub-cycle signatures: A perspective on hallmarks of terahertz metrology
Authors: Benea-Chelmus Ileana-Cristina , Tomasino Alessandro
Published: April 2023

Frequency up-conversion has become amongst the most prevalent techniques for detection of terahertz waves in metrology systems. State-of-the-art up-conversion techniques rely on the coherent transferring of the information encoded in all degrees of freedom of a terahertz wave to either the near-infrared or visible domain, where detectors are readily accessible. This allows for an indirect reconstruction of the terahertz wave. However, unlike most up-conversion methods employed in photonics which are concentrating on narrowband tones (at both terahertz and near-infrared frequencies), a broadband, hence temporally constrained, terahertz transient is sampled on time-scales shorter than its oscillation period. Here, femtosecond laser pules serve as temporal gates. In this perspective, we highlight several hallmarks of terahertz metrology that originate from these sub-cycle measurement capabilities and elaborate why this enables studies in fundamental and applied science, with a particular focus on novel measurement concepts in classical and quantum. We focus on so-far demonstrated detection performance in bulk non-linear crystals. Finally, we discuss current challenges and the most pressing questions ahead.
Effects of whole-body vibration training with different frequencies on the balance ability of the older adults: a network meta-analysis
Authors: Liu Peirong , Li Yongjie , Xiao Yajun , Li Duo , Liu Lin , Ma Yong , Zheng Weitao
Published: April 2023

Purpose: To compare the effects of whole-body vibration training (WBVT) with different frequencies on the balance ability of older adults.

Methods: Randomized controlled trials (RCTs) on the WBVT interventions on balance ability in older adults were searched through PubMed, Web of Science, The Cochrane Library, ProQuest, Embase, Opengrey, China National Knowledge Infrastructure (CNKI), Wanfang, and China Science and Technology Journal Database (CSTJ) databases from the establishment of the database to August 2022, and all literature that met the PICOS (Participants, Intervention, Comparison, Outcomes, Study design) criteria were enrolled. Two reviewers screened and assessed the methodological quality of the included literature according to the physiotherapy evidence database (PEDro) scale criteria. Statistical analysis was performed using Stata 14.0 software after data extraction.

Results: Twenty-five RCTs with a total of 1267 subjects were finally included. The results of the pairwise comparison of the Network Meta-analysis showed that the Timed Up and Go Test (TUGT) values of Low-frequency whole-body vibration training (LF-WBVT) was lower than the placebo and traditional rehabilitation groups, and the difference was statistically significant [WMD = −1.37, 95% CI (−2.53, −0.20)] [WMD = −1.84, 95% CI(-3.17,-0.51)]. The Five-repetition Sit-to-Stand Test (5STS) values of LF-WBVT, Medium-frequency whole-body vibration training (MF-WBVT), and High-frequency whole-body vibration training (HF-WBVT) were lower than the placebo and traditional rehabilitation groups, but none of them were statistically significant. In addition, the TUGT and 5STS values of HF-WBVT had a tendency to be lower than those of LF-WBVT and MF-WBVT, but neither of them was statistically different. The cumulative probability ranking results of both TUGT and 5STS showed that HF-WBVT was the best protocol.

Conclusion: Current evidence shows that HF-WBVT may be the best protocol for improving balance in older adults. Due to the study’s limitations, the conclusion obtained in this study still needs to be further confirmed by more high-quality studies.

Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021250405].
Conserved hierarchical gene regulatory networks for drought and cold stress response in Myrica rubra
Authors: Xu Weijie , Ren Haiying , Qi Xingjiang , Zhang Shuwen , Yu Zheping , Xie Jianbo
Published: April 2023

Stress response in plant is regulated by a large number of genes co-operating in diverse networks that serve multiple adaptive process. To understand how gene regulatory networks (GRNs) modulating abiotic stress responses, we compare the GRNs underlying drought and cold stresses using samples collected at 4 or 6 h intervals within 48 h in Chinese bayberry (Myrica rubra). We detected 7,583 and 8,840 differentially expressed genes (DEGs) under drought and cold stress respectively, which might be responsive to environmental stresses. Drought- and cold-responsive GRNs, which have been built according to the timing of transcription under both abiotic stresses, have a conserved trans-regulator and a common regulatory network. In both GRNs, basic helix-loop-helix family transcription factor (bHLH) serve as central nodes.MrbHLHp10transcripts exhibited continuous increase in the two abiotic stresses and acts upstream regulator ofASCORBATE PEROXIDASE(APX) gene. To examine the potential biological functions ofMrbHLH10, we generated a transgenicArabidopsisplant that constitutively overexpresses theMrbHLH10gene. Compared to wild-type (WT) plants, overexpressing transgenicArabidopsisplants maintained higher APX activity and biomass accumulation under drought and cold stress. Consistently, RNAi plants had elevated susceptibility to both stresses. Taken together, these results suggested thatMrbHLH10mitigates abiotic stresses through the modulation of ROS scavenging.
TasselLFANet: a novel lightweight multi-branch feature aggregation neural network for high-throughput image-based maize tassels detection and counting
Authors: Yu Zhenghong , Ye Jianxiong , Li Cuina , Zhou Huabing , Li Xun
Published: April 2023

Accurately and rapidly counting the number of maize tassels is critical for maize breeding, management, and monitoring the growth stage of maize plants. With the advent of high-throughput phenotyping platforms and the availability of large-scale datasets, there is a pressing need to automate this task for genotype and phenotype analysis. Computer vision technology has been increasingly applied in plant science, offering a promising solution for automated monitoring of a large number of plants. However, the current state-of-the-art image algorithms are hindered by hardware limitations, which compromise the balance between algorithmic capacity, running speed, and overall performance, making it difficult to apply them in real-time sensing field environments. Thus, we propose a novel lightweight neural network, named TasselLFANet, with an efficient and powerful structure for accurately and efficiently detecting and counting maize tassels in high spatiotemporal image sequences. Our proposed approach improves the feature-learning ability of TasselLFANet by adopting a cross-stage fusion strategy that balances the variability of different layers. Additionally, TasselLFANet utilizes multiple receptive fields to capture diverse feature representations, and incorporates an innovative visual channel attention module to detect and capture features more flexibly and precisely. We conducted a series of comparative experiments on a new, highly informative dataset called MrMT, which demonstrate that TasselLFANet outperforms the latest batch of lightweight networks in terms of performance, flexibility, and adaptability, achieving an F1 measure value of 94.4%, a mAP.@5 value of 96.8%, and having only 6.0M parameters. Moreover, compared with the regression-based TasselNetV3-Seg† model, our proposed model achieves superior counting performance, with a mean absolute error (MAE) of 1.80, a root mean square error (RMSE) of 2.68, and a R2 of 0.99. The proposed model meets the accuracy and speed requirements of the vision system in maize tassel detection. Furthermore, our proposed method is reliable and unaffected by geographical changes, providing essential technical support for computerized counting in the field.