bluuebunny/crossref_metadata_2025 huggingface dataset:
Contaminants from a former Croatian coal sludge dictate the structure of microbiota in the estuarine (Raša Bay) sediment and soil
Authors: Zhang Weiting , Mo Qianyun , Huang Zaixing , Sabar Muhammad Adnan , Medunić Gordana , Ivošević Tatjana , He Huan , Urynowicz Michael , Liu Fang-Jing , Guo Hongguang , Haider Rizwan , Ali Muhammad Ishtiaq , Jamal Asif
Published: February 2023

Introduction

Croatian superhigh-organic-sulfur Raša coal had been mined for nearly 400 years. The release of hazardous trace elements (HTEs) and toxic organic pollutants (TOPs) into the local environment by coal mining, preparation, and combustion activities has resulted in pollution.

Methods

In this study, the diversity and composition of microbial communities in estuarine sediment and soil samples as well as community function responses to the pollutants were investigated.

Results

The results showed that PAH degradation does occur following 60 years of natural attenuation, the location is still heavily polluted by polycyclic aromatic hydrocarbons (PAHs) and HTEs. Microbial analyses have shown that high concentrations of PAHs have reduced the diversity and abundance of microbial communities. The pollution exerted an adverse, long-term impact on the microbial community structure and function in the brackish aquatic ecosystem. Microorganisms associated with the degradation of PAHs and sulfur-containing compounds have been enriched although the diversity and abundance of the microbial community have reduced. Fungi which are believed to be the main PAH degrader may play an important role initially, but the activity remains lower thereafter. It is the high concentrations of coal-derived PAHs, rather than HTEs, that have reduced the diversity and abundance of microbial communities and shaped the structure of the local microbiota.

Discussion

This study could provide a basis for the monitoring and restoration of ecosystems impacted by coal mining activities considering the expected decommission of a large number of coal plants on a global scale in the coming years due to growing global climate change concerns.
Detection of Klebsiella pneumonia DNA and ESBL positive strains by PCR-based CRISPR-LbCas12a system
Authors: Wang Shang , Wang Shan , Tang Ying , Peng Guoyu , Hao Tongyu , Wu Xincheng , Wei Jiehong , Qiu Xinying , Zhou Dewang , Zhu Shimao , Li Yuqing , Wu Song
Published: February 2023

Introduction

Klebsiella pneumonia (K. pneumonia) is a Gram-negative bacterium that opportunistically causes nosocomial infections in the lung, bloodstream, and urinary tract. Extended-spectrum β-Lactamases (ESBLs)-expressed K. pneumonia strains are widely reported to cause antibiotic resistance and therapy failure. Therefore, early identification of K. pneumonia, especially ESBL-positive strains, is essential in preventing severe infections. However, clinical detection of K. pneumonia requires a time-consuming process in agar disk diffusion. Nucleic acid detection, like qPCR, is precise but requires expensive equipment. Recent research reveals that collateral cleavage activity of CRISPR-LbCas12a has been applied in nucleic acid detection, and the unique testing model can accommodate various testing models.

Methods

This study established a system that combined PCR with CRISPR-LbCas12a targeting the K. pneumoniae system. Additionally, this study summarized the antibiotic-resistant information of the past five years’ K. pneumoniae clinic cases in Luohu Hospital and found that the ESBL-positive strains were growing. This study then designs a crRNA that targets SHV to detect ESBL-resistant K. pneumoniae. This work is to detect K. pneumoniae and ESBL-positive strains’ nucleic acid using CRISPR-Cas12 technology. We compared PCR-LbCas12 workflow with PCR and qPCR techniques.

Results and Discussion

This system showed excellent detection specificity and sensitivity in both bench work and clinical samples. Due to its advantages, its application can meet different detection requirements in health centers where qPCR is not accessible. The antibiotic-resistant information is valuable for further research.
Companion diagnostic requirements for spatial biology using multiplex immunofluorescence and multispectral imaging
Authors: Locke Darren , Hoyt Clifford C.
Published: February 2023

Immunohistochemistry has long been held as the gold standard for understanding the expression patterns of therapeutically relevant proteins to identify prognostic and predictive biomarkers. Patient selection for targeted therapy in oncology has successfully relied upon standard microscopy-based methodologies, such as single-marker brightfield chromogenic immunohistochemistry. As promising as these results are, the analysis of one protein, with few exceptions, no longer provides enough information to draw effective conclusions about the probability of treatment response. More multifaceted scientific queries have driven the development of high-throughput and high-order technologies to interrogate biomarker expression patterns and spatial interactions between cell phenotypes in the tumor microenvironment. Such multi-parameter data analysis has been historically reserved for technologies that lack the spatial context that is provided by immunohistochemistry. Over the past decade, technical developments in multiplex fluorescence immunohistochemistry and discoveries made with improving image data analysis platforms have highlighted the importance of spatial relationships between certain biomarkers in understanding a patient’s likelihood to respond to, typically, immune checkpoint inhibitors. At the same time, personalized medicine has instigated changes in both clinical trial design and its conduct in a push to make drug development and cancer treatment more efficient, precise, and economical. Precision medicine in immuno-oncology is being steered by data-driven approaches to gain insight into the tumor and its dynamic interaction with the immune system. This is particularly necessary given the rapid growth in the number of trials involving more than one immune checkpoint drug, and/or using those in combination with conventional cancer treatments. As multiplex methods, like immunofluorescence, push the boundaries of immunohistochemistry, it becomes critical to understand the foundation of this technology and how it can be deployed for use as a regulated test to identify the prospect of response from mono- and combination therapies. To that end, this work will focus on: 1) the scientific, clinical, and economic requirements for developing clinical multiplex immunofluorescence assays; 2) the attributes of the Akoya Phenoptics workflow to support predictive tests, including design principles, verification, and validation needs; 3) regulatory, safety and quality considerations; 4) application of multiplex immunohistochemistry through lab-developed-tests and regulated in vitro diagnostic devices.
Age of first exposure to soccer heading: Associations with cognitive, clinical, and imaging outcomes in the Einstein Soccer Study
Authors: Charney Molly F. , Ye Kenny Q. , Fleysher Roman , DeMessie Bluyé , Stewart Walter F. , Zimmerman Molly E. , Kim Mimi , Lipton Richard B. , Lipton Michael L.
Published: February 2023

Introduction

The objective of this study is to assess the role of age at first exposure (AFE) to soccer heading as a predictor of known adverse associations of recent and longer-term heading with brain microstructure, cognitive, and behavioral features among adult amateur soccer players.

Methods

The sample included 276 active amateur soccer players (196 male and 81 female) aged 18–53 years old. AFE to soccer heading was treated as a binary variable, dichotomized at ≤ 10 years vs. >10 years old, based on a recently promulgated US Soccer policy, which bans heading for athletes ages 10 and under.

Results

We found that soccer players who began heading at age 10 or younger performed better on tests of working memory (p = 0.03) and verbal learning (p = 0.02), while accounting for duration of heading exposure, education, sex, and verbal intelligence. No difference in brain microstructure or behavioral measures was observed between the two exposure groups.

Discussion

The findings indicate that, among adult amateur soccer players, AFE to heading before age 10 compared to later start of heading, is not associated with adverse outcomes, and may be associated with better cognitive performance in young adulthood. Cumulative heading exposure across the lifespan, rather than early life exposure, may drive risk for adverse effects and should be the focus of future longitudinal studies to inform approaches to enhance player safety.
Time course of recovery of different motor functions following a reproducible cortical infarction in non-human primates
Authors: Kosugi Akito , Saga Yosuke , Kudo Moeko , Koizumi Masashi , Umeda Tatsuya , Seki Kazuhiko
Published: February 2023

A major challenge in human stroke research is interpatient variability in the extent of sensorimotor deficits and determining the time course of recovery following stroke. Although the relationship between the extent of the lesion and the degree of sensorimotor deficits is well established, the factors determining the speed of recovery remain uncertain. To test these experimentally, we created a cortical lesion over the motor cortex using a reproducible approach in four common marmosets, and characterized the time course of recovery by systematically applying several behavioral tests before and up to 8 weeks after creation of the lesion. Evaluation of in-cage behavior and reach-to-grasp movement revealed consistent motor impairments across the animals. In particular, performance in reaching and grasping movements continued to deteriorate until 4 weeks after creation of the lesion. We also found consistent time courses of recovery across animals for in-cage and grasping movements. For example, in all animals, the score for in-cage behaviors showed full recovery at 3 weeks after creation of the lesion, and the performance of grasping movement partially recovered from 4 to 8 weeks. In addition, we observed longer time courses of recovery for reaching movement, which may rely more on cortically initiated control in this species. These results suggest that different recovery speeds for each movement could be influenced by what extent the cortical control is required to properly execute each movement.
Ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease: A systematic review and critical appraisal
Authors: Bohnen Jeffrey L. B. , Albin Roger L. , Bohnen Nicolaas I.
Published: February 2023

Background

There is increasing interest in therapeutic ketosis as a potential therapy for neurodegenerative disorders–in particular, mild cognitive impairment (MCI), Alzheimer's disease (AD), and Parkinson's disease (PD)–following a proof-of-concept study in Parkinson's disease published in 2005.

Methods

To provide an objective assessment of emerging clinical evidence and targeted recommendations for future research, we reviewed clinical trials involving ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease reported since 2005. Levels of clinical evidence were systematically reviewed using the American Academy of Neurology criteria for rating therapeutic trials.

Results

10 AD, 3 MCI, and 5 PD therapeutic ketogenic trials were identified. Respective grades of clinical evidence were objectively assessed using the American Academy of Neurology criteria for rating therapeutic trials. We found class “B” evidence (probably effective) for cognitive improvement in subjects with mild cognitive impairment and subjects with mild-to-moderate Alzheimer's disease negative for the apolipoprotein ε4 allele (APOε4-). We found class “U” evidence (unproven) for cognitive stabilization in individuals with mild-to-moderate Alzheimer's disease positive for the apolipoprotein ε4 allele (APOε4+). We found class “C” evidence (possibly effective) for improvement of non-motor features and class “U” evidence (unproven) for motor features in individuals with Parkinson's disease. The number of trials in Parkinson's disease is very small with best evidence that acute supplementation holds promise for improving exercise endurance.

Conclusions

Limitations of the literature to date include the range of ketogenic interventions currently assessed in the literature (i.e., primarily diet or medium-chain triglyceride interventions), with fewer studies using more potent formulations (e.g., exogenous ketone esters). Collectively, the strongest evidence to date exists for cognitive improvement in individuals with mild cognitive impairment and in individuals with mild-to-moderate Alzheimer's disease negative for the apolipoprotein ε4 allele. Larger-scale, pivotal trials are justified in these populations. Further research is required to optimize the utilization of ketogenic interventions in differing clinical contexts and to better characterize the response to therapeutic ketosis in patients who are positive for the apolipoprotein ε4 allele, as modified interventions may be necessary.
A lightweight attention deep learning method for human-vehicle recognition based on wireless sensing technology
Authors: Song Mingxin , Zhu Rensheng , Chen Xinquan , Zheng Chunlei , Lou Liangliang
Published: February 2023

Wireless sensing-based human-vehicle recognition (WiHVR) methods have become a hot spot for research due to its non-invasiveness and cost-effective advantages. However, existing WiHVR methods shows limited performance and slow execution time on human-vehicle classification task. To address this issue, a lightweight wireless sensing attention-based deep learning model (LW-WADL) is proposed, which consists of a CBAM module and several depthwise separable convolution blocks in series. LW-WADL takes raw channel state information (CSI) as input, and extracts the advanced features of CSI by jointly using depthwise separable convolution and convolutional block attention mechanism (CBAM). Experimental results show that the proposed model achieves 96.26% accuracy on the constructed CSI-based dataset, and the model size is only 5.89% of the state of the art (SOTA) model. The results demonstrate that the proposed model achieves better performance on WiHVR tasks while reducing the model size compared to SOTA model.
Targeting Shank3 deficiency and paresthesia in autism spectrum disorder: A brief review
Authors: Huang Min , Qi Qi , Xu Tao
Published: February 2023

Autism spectrum disorder (ASD) includes a group of multifactorial neurodevelopmental disorders characterized by impaired social communication, social interaction, and repetitive behaviors. Several studies have shown an association between cases of ASD and mutations in the genes of SH3 and multiple ankyrin repeat domain protein 3 (SHANK3). These genes encode many cell adhesion molecules, scaffold proteins, and proteins involved in synaptic transcription, protein synthesis, and degradation. They have a profound impact on all aspects of synaptic transmission and plasticity, including synapse formation and degeneration, suggesting that the pathogenesis of ASD may be partially attributable to synaptic dysfunction. In this review, we summarize the mechanism of synapses related to Shank3 in ASD. We also discuss the molecular, cellular, and functional studies of experimental models of ASD and current autism treatment methods targeting related proteins.
Association between dietary calcium and depression among American adults: National health and nutrition examination survey
Authors: Shen Xia , Gu Xue , Liu Yuan-Yuan , Yang Long , Zheng Meng , Jiang Lei
Published: February 2023

Background

There is only limited evidence for an association between calcium (Ca) and depression, and the relationship was inconsistent. Therefore, the aim of this study was to assess the relationship between dietary Ca and the risk of depressive symptoms in individuals over the age of 18 in the US.

Methods

We extracted 14,971 participants from the US National Health and Nutrition Examination Survey (NHANES) 2007–2016 to probe their associations. Dietary Ca intake was measured through 24 h dietary recall method. Patients with the Patient Health Questionnaire-9 (PHQ-9) ≥ 10 scores were believed to have depressive symptoms. The association between dietary Ca and depressive symptoms was investigated using multivariate logistic regression, sensitivity analysis, and restricted cubic spline regression.

Results

In this study, 7.6% (1,144/14,971) of them had depressive symptoms. After adjusting for sex, age, race, poverty to income ratio (PIR), marital status, education, body mass index (BMI), caffeine intake, carbohydrates intake, total energy intake, smoking status, alcohol consumption, physical activity, diabetes, hypertension, severe cardiovascular disease (CVD), cancer, serum vitamin D, serum Ca, and Ca supplement, the adjusted ORs value [95% confidence interval (CI)] of depression for the lowest category (Q1 ≤ 534 mg/day) vs. Q2–Q4 of Ca intake were 0.83 (0.69–0.99), 0.97 (0.65–0.95), and 0.80 (0.63–0.98) with the p for trend (p = 0.014). The relationship between dietary Ca intake and depressive symptoms was linear (non-linear p = 0.148). None of the interactions were significant except among races (p for interaction = 0.001).

Conclusion

Association between dietary Ca and the prevalence of depressive symptoms in US adults. And Ca intake was negatively associated with the risk of depressive symptoms. As Ca intake increased, the prevalence of depressive symptoms decreased.
Effect of octenyl succinic anhydride modified starch on soy protein-polyphenol binary covalently linked complexes
Authors: Dong Die , Geng Tenglong , Cui Bo , Yuan Chao , Guo Li , Zhao Meng , Zou Feixue , Liu Pengfei , Zhang Hongxia
Published: February 2023

The present study aimed to investigate the effects of octenyl succinic anhydride modified starch (OSAS) on soy protein (SP)-(-)-epigallocatechin-3-gallate (EGCG) binary covalently linked complexes. Mean diameters of OSAS-SP-EGCG complexes decreased from 379.6 ± 54.9 nm to 272.7 ± 47.7 nm as the OSAS-to-SP-EGCG ratio changed from 1:2 to 4:1, while ζ-potential decreased from -19.1 ± 0.8 mV to -13.7 ± 1.2 mV. Fourier transform infrared spectroscopy results revealed that the characteristic peaks at 1725 cm–1 and 1569 cm–1 for OSAS disappeared in the OSAS-SP-EGCG complexes, indicating an interaction between OSAS and SP-EGCG complexes. X-ray diffraction analysis showed that with the increase of OSAS content, the diffraction peak at approximately 8.0° decreased from 8.22° to 7.74°, implying that the structures of OSAS and SP-EGCG complexes were rearranged after forming into OSAS-SP-EGCG complexes. The contact angle of the OSAS-SP-EGCG complexes significantly increased from 59.1° to 72.1° with the addition of OSAS increased, revealing that the addition of OSAS improved hydrophobicity of the SP-EGCG complexes. Transmission electron microscopy images revealed that the individual OSAS-SP-EGCG complexes became smaller but stuck together to form large fragments, which was different from the morphology of OSAS and SP-EGCG complexes. Thus, the OSAS-SP-EGCG complexes developed in this study may be effective emulsifiers for improving the stability of emulsion systems in the food industry.
Acanthopanax trifoliatus (L.) Merr polysaccharides ameliorates hyperglycemia by regulating hepatic glycogen metabolism in type 2 diabetic mice
Authors: Lin Yuzi , Pan Jinghua , Liu Yue , Yang Huiwen , Wu Guoyu , Pan Yufang
Published: February 2023

Introduction

Drug monotherapy was inadequate in controlling blood glucose levels and other comorbidities. An agent that selectively tunes multiple targets was regarded as a new therapeutic strategy for type 2 diabetes. Acanthopanax trifoliatus (L.) Merr polysaccharide (ATMP) is a bio-macromolecule isolated from Acanthopanax trifoliatus (L.) Merr and has therapeutic potential for diabetes management due to its anti-hyperglycemia activity.

Methods

Type 2 diabetes mellitus was induced in mice using streptozotocin, and 40 and 80 mg/kg ATMP was administered daily via the intragastric route for 8 weeks. Food intake, water intake, and body weight were recorded. The fasting blood glucose (FBG), fasting insulin (FINS) and an oral glucose tolerance test (OGTT) were performed. Histological changes in the liver and pancreas were analyzed by H&E staining. The mRNA and the protein levels of key factors involved in glycogen synthesis, glycogenolysis, and gluconeogenesis were measured by quantitative real time PCR and Western blotting.

Results

In this study, we found that ATMP could effectively improve glucose tolerance and alleviate insulin resistance by promoting insulin secretion and inhibiting glucagon secretion. In addition, ATMP decreases glycogen synthesis by inhibiting PI3K/Akt/GSK3β signaling, reduces glycogenolysis via suppressing cAMP/PKA signaling, and suppresses liver gluconeogenesis by activating AMPK signaling.

Conclusion

Together, ATMP has the potential to be developed as a new multitargets therapeutics for type 2 diabetes.
On the modulation of TRPM channels: Current perspectives and anticancer therapeutic implications
Authors: Ciaglia Tania , Vestuto Vincenzo , Bertamino Alessia , González-Muñiz Rosario , Gómez-Monterrey Isabel
Published: February 2023

The transient melastatin receptor potential (TRPM) ion channel subfamily functions as cellular sensors and transducers of critical biological signal pathways by regulating ion homeostasis. Some members of TRPM have been cloned from cancerous tissues, and their abnormal expressions in various solid malignancies have been correlated with cancer cell growth, survival, or death. Recent evidence also highlights the mechanisms underlying the role of TRPMs in tumor epithelial-mesenchymal transition (EMT), autophagy, and cancer metabolic reprogramming. These implications support TRPM channels as potential molecular targets and their modulation as an innovative therapeutic approach against cancer. Here, we discuss the general characteristics of the different TRPMs, focusing on current knowledge about the connection between TRPM channels and critical features of cancer. We also cover TRPM modulators used as pharmaceutical tools in biological trials and an indication of the only clinical trial with a TRPM modulator about cancer. To conclude, the authors describe the prospects for TRPM channels in oncology.
Efficacy and safety of anti-PD-1 antibody plus chemoradiotherapy in locally advanced esophageal squamous cancer
Authors: Ma Ji , Yao Nan , Lu Jiaying , Qu Wanxi , Cui Li , Yuan Shiwang , Li Na , Tong Shaodong , Qin Zhaohui , Yao Yuanhu
Published: February 2023

Objective

To compare effects and adverse events of anti-programmed cell death protein 1 (anti-PD-1) antibody combined with chemoradiotherapy (CRT) and CRT alone as the initial treatment in locally advanced esophageal squamous cell carcinoma (ESCC).

Methods

We retrospectively reviewed locally advanced ESCC patients who received Anti-PD-1+CRT as initial treatment at 3 institutions. Primary outcomes of interest were progression-free survival (PFS) and overall survival (OS); secondary outcomes were objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and treatment-related adverse events (AEs) including immune-related adverse events (irAEs).

Results

At data cutoff, 81 patients were included (30 Anti-PD-1+CRT, 51 CRT). Median follow-up was 31.4 months. Anti-PD-1+CRT resulted in significant improvements in PFS (median, 18.6 vs. 11.8 months, HR 0.48 [95% CI, 0.29–0.80], P = 0.008), and OS (median, 27.7 vs. 17.4 months, HR 0.37 [95% CI, 0.22–0.63], P = 0.002), compared with CRT in ESCC. The ORR and DCR of patients treated with Anti-PD-1+CRT were also significantly higher than those treated with CRT (80.0% vs. 56.9%, P = 0.034), (100% vs. 82.4%, P = 0.023), respectively. Anti-PD-1+CRT had better durable response compared with CRT, with DoR (median,17.3 vs. 11.1 months, P = 0.022). Treatment-related adverse event incidence was similar between the two groups (any Grade, 93.3% vs. 92.2%; ≥Grade 3, 50.0% vs. 33.3%).

Conclusion

Anti-PD-1 plus chemoradiotherapy demonstrated promising antitumor activity and was well tolerated in locally advanced ESCC.
Metabolomic biomarkers for the diagnosis and post-transplant outcomes of AFP negative hepatocellular carcinoma
Authors: Lin Zuyuan , Li Huigang , He Chiyu , Yang Modan , Chen Hao , Yang Xinyu , Zhuo Jianyong , Shen Wei , Hu Zhihang , Pan Linhui , Wei Xuyong , Lu Di , Zheng Shusen , Xu Xiao
Published: February 2023

Background

Early diagnosis for α-fetoprotein (AFP) negative hepatocellular carcinoma (HCC) remains a critical problem. Metabolomics is prevalently involved in the identification of novel biomarkers. This study aims to identify new and effective markers for AFP negative HCC.

Methods

In total, 147 patients undergoing liver transplantation were enrolled from our hospital, including liver cirrhosis patients (LC, n=25), AFP negative HCC patients (NEG, n=44) and HCC patients with AFP over 20 ng/mL (POS, n=78). 52 Healthy volunteers (HC) were also recruited in this study. Metabolomic profiling was performed on the plasma of those patients and healthy volunteers to select candidate metabolomic biomarkers. A novel diagnostic model for AFP negative HCC was established based on Random forest analysis, and prognostic biomarkers were also identified.

Results

15 differential metabolites were identified being able to distinguish NEG group from both LC and HC group. Random forest analysis and subsequent Logistic regression analysis showed that PC(16:0/16:0), PC(18:2/18:2) and SM(d18:1/18:1) are independent risk factor for AFP negative HCC. A three-marker model of Metabolites-Score was established for the diagnosis of AFP negative HCC patients with an area under the time-dependent receiver operating characteristic curve (AUROC) of 0.913, and a nomogram was then established as well. When the cut-off value of the score was set at 1.2895, the sensitivity and specificity for the model were 0.727 and 0.92, respectively. This model was also applicable to distinguish HCC from cirrhosis. Notably, the Metabolites-Score was not correlated to tumor or body nutrition parameters, but difference of the score was statistically significant between different neutrophil-lymphocyte ratio (NLR) groups (≤5 vs. >5, P=0.012). Moreover, MG(18:2/0:0/0:0) was the only prognostic biomarker among 15 metabolites, which is significantly associated with tumor-free survival of AFP negative HCC patients (HR=1.160, 95%CI 1.012-1.330, P=0.033).

Conclusion

The established three-marker model and nomogram based on metabolomic profiling can be potential non-invasive tool for the diagnosis of AFP negative HCC. The level of MG(18:2/0:0/0:0) exhibits good prognosis prediction performance for AFP negative HCC.
Risk stratification of postoperative cardiopulmonary toxicity after trimodality therapy for esophageal cancer
Authors: Kowalchuk Roman O. , Spears Grant M. , Morris Lindsay K. , Owen Dawn , Yoon Harry H. , Jethwa Krishan , Chuong Michael D. , Ferris Matthew J. , Haddock Michael G. , Hallemeier Christopher L. , Wigle Dennis , Lin Steven H. , Merrell Kenneth W.
Published: February 2023

Purpose/objective

Postoperative toxicity for esophageal cancer impacts patient quality of life and potentially overall survival (OS). We studied whether patient and toxicity parameters post-chemoradiation therapy predict for post-surgical cardiopulmonary total toxicity burden (CPTTB) and whether CPTTB was associated with short and long-term outcomes.

Materials/methods

Patients had biopsy-proven esophageal cancer treated with neoadjuvant chemoradiation and esophagectomy. CPTTB was derived from total perioperative toxicity burden (Lin et al. JCO 2020). To develop a CPTTB risk score predictive for major CPTTB, recursive partitioning analysis was used.

Results

From 3 institutions, 571 patients were included. Patients were treated with 3D (37%), IMRT (44%), and proton therapy (19%). 61 patients had major CPTTB (score ≥ 70). Increasing CPTTB was predictive of decreased OS (p<0.001), lengthier post-esophagectomy length of stay (LOS, p<0.001), and death or readmission within 60 days of surgery (DR60, p<0.001). Major CPTTB was also predictive of decreased OS (hazard ratio = 1.70, 95% confidence interval: 1.17-2.47, p=0.005). The RPA-based risk score included: age ≥ 65, grade ≥ 2 nausea or esophagitis attributed to chemoradiation, and grade ≥ 3 hematologic toxicity attributed to chemoradiation. Patients treated with 3D radiotherapy had inferior OS (p=0.010) and increased major CPTTB (18.5% vs. 6.1%, p<0.001).

Conclusion

CPTTB predicts for OS, LOS, and DR60. Patients with 3D radiotherapy or age ≥ 65 years and chemoradiation toxicity are at highest risk for major CPTTB, predicting for higher short and long-term morbidity and mortality. Strategies to optimize medical management and reduce toxicity from chemoradiation should be strongly considered.
Cuproptosis-related genes score: A predictor for hepatocellular carcinoma prognosis, immunotherapy efficacy, and metabolic reprogramming
Authors: Nie Guilin , Peng Dingzhong , Wen Ningyuan , Wang Yaoqun , Lu Jiong , Li Bei
Published: February 2023

Background

Cuproptosis is a newly identified type of programmed cell death, characterized by aggregation of mitochondrial lipoylated proteins and the destabilization of Fe–S cluster proteins triggered by copper. However, its role in hepatocellular carcinoma (HCC) remains unclear.

Methods

We analyzed the expression and prognostic significance of cuproptosis-related genes using the data obtained from TCGA and ICGC datasets. A cuproptosis-related genes (CRG) score was constructed and validated via least absolute shrinkage and selection operator (LASSO) Cox regression, multivariate Cox regression and nomogram model. The metabolic features, immune profile and therapy guidance of CRG-classified HCC patients were processed via R packages. The role of kidney-type glutaminase (GLS) in cuproptosis and sorafenib treatment has been confirmed via GLS knockdown.

Results

The CRG score and its nomogram model performed well in predicting prognosis of HCC patients based on the TCGA cohort (training set), ICGC cohort and GEO cohort (validation set). The risk score was proved as an independent predictor for overall survival (OS) of HCC. The area under the curves (AUCs) of the model in the training and validation cohorts were all around 0.83 (TCGA, 1- year), 0.73 (TCGA, 3- year), 0.92 (ICGC, 1- year), 0.75 (ICGC, 3- year), 0.77 (GEO, 1- year), 0.76(GEO, 3- year). Expression levels of metabolic genes and subtypes of immune cells, and sorafenib sensitiveness varied significantly between the high-CRG group and low-CRG group. One of the model-included gene, GLS, might be involved in the process of cuproptosis and sorafenib treatment in HCC cell line.

Conclusion

The five cuproptosis-related genes model contributed to prognostic prediction and provided a new sight for cuproptosis-related therapy in HCC.
Different pathological response and histological features following neoadjuvant chemotherapy or chemo-immunotherapy in resected non-small cell lung cancer
Authors: Alì Greta , Poma Anello Marcello , Di Stefano Iosè , Zirafa Carmelina Cristina , Lenzini Alessandra , Martinelli Giulia , Romano Gaetano , Chella Antonio , Baldini Editta , Melfi Franca , Fontanini Gabriella
Published: February 2023

Introduction

Non-small cell lung cancer (NSCLC) is the leading cause of cancer incidence and mortality worldwide. Neoadjuvant chemo-immunotherapy has led to clinical benefits in resectable NSCLC in comparison to chemo-therapy alone. Major pathological response (MPR) and pathological complete response (pCR) have been used as surrogates of neoadjuvant therapy response and clinical outcomes. However, the factors affecting the pathological response are still controversial. Therefore, in this study we retrospectively examined MPR and pCR in two different cohorts of NSCLC patients, 14 treated by chemotherapy and 12 by chemo-immunotherapy in the neoadjuvant setting.

Methods

In resected tumor specimens, different histological characteristics were evaluated: necrosis, fibrosis, inflammation, presence of organizing pneumonia, granuloma, cholesterol cleft, and reactive epithelial alterations. In addition, we evaluated how MPR impacts on event-free survival (EFS) and overall survival (OS). In a small group of patients treated by chemo-immunotherapy, a gene expression analysis of the Hippo pathway was performed both in preoperative biopsies and matched post-surgical specimens.

Results

We observed a better pathological response in the chemo-immunotherapy treated cohort: 6/12 patients (50.0%) achieved a MPR ≤10% and 1/12 (8.3%) achieved pCR both on primary tumor and on lymph nodes. On the contrary, no patient treated with chemotherapy alone achieved pCR or MPR ≤10%. A higher amount of stroma in the neoplastic bed was observed in patients treated with immuno-chemotherapy. Moreover, patients achieving better MPR (including pCR) had significantly improved overall survival (OS) and event-free survival (EFS). After neoadjuvant chemo-immunotherapy, residual tumors showed a remarkable upregulation of genes consistent with the activation of YAP/TAZ. Also, alternative checkpoint, such as CTLA-4, were enhanced.

Discussion

Our findings showed that neoadjuvant chemo-immunotherapy treatment improves MPR and pCR thus resulting in better EFS and OS. Moreover, a combined treatment could induce different morphological and molecular changes in comparison to chemotherapy alone, thus giving new insights in the assessment of pathological response.
Risk factors for post-transplant relapse and survival in younger adult patients with t(8;21)(q22;q22) acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation: A multicenter retrospective study
Authors: Zhou Wei , Chen Guofeng , Gong Dan , Gao Yi , Yu Li
Published: February 2023

Background

Outcomes of patients with t(8;21)(q22;q22) acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain heterogeneous.

Methods

To identify the risk factors for relapse and survival after allo-HSCT in t(8;21) AML patients, we retrospectively evaluated the clinical and prognostic information of 142 patients with t(8;21) AML undergoing allo-HSCT between January 2002 and September 2018 at 15 hematology research centers in China.

Results

Twenty-nine patients (20%) relapsed after undergoing allo-HSCT. A > 1-log reduction in RUNX1/RUNX1T1-based minimal residual disease (MRD) directly before allo-HSCT and a > 3-log reduction within the first 3 months after allo-HSCT were associated with a significantly lower post-transplant 3-year cumulative incidence of relapse (CIR, 9% vs. 62% and 10% vs. 47%,all P < 0.001), whereas transplantation during the second complete remission (CR2, 39% vs. 17% during CR1, P = 0.022), during relapse (62% vs. 17% during CR1, P < 0.001) and KIT D816 mutations at diagnosis (49% vs. 18%, P = 0.039) were related to a significantly higher 3-year CIR. Multivariate analysis demonstrated that a > 1-log reduction in MRD directly before transplantation (CIR: hazard ratio(HR), 0.21 [0.03–0.71], P = 0.029; overall survival (OS): HR = 0.27 [0.08–0.93], P = 0.038) and a > 3-log reduction in post-transplant MRD within the first 3 months (CIR: HR = 0.25 [0.07–0.89], P = 0.019; OS: HR = 0.38 [0.15–0.96], P = 0.040) were independent favorable prognostic factors, and transplantation during relapse (CIR: HR = 5.55 [1.23–11.56], P = 0.041; OS: HR = 4.07 [1.82–20.12], P = 0.045) were independent adverse prognostic factors for post-transplant relapse and survival in patients with t(8;21) AML.

Conclusion

Our study suggests that for patients with t(8;21) AML undergoing allo-HSCT, it would be better to receive transplantation during CR1 with a MRD directly before transplantation achieving at least 1-log reduction. MRD monitoring in the first 3 months after allo-HSCT might be robust in predicting relapse and adverse survival after allo-HSCT.
The degeneration-pain relationship in the temporomandibular joint: Current understandings and rodent models
Authors: Chung Man-Kyo , Wang Sheng , Alshanqiti Ishraq , Hu Jiaxin , Ro Jin Y.
Published: February 2023

Temporomandibular disorders (TMD) represent a group of musculoskeletal conditions involving the temporomandibular joints (TMJ), the masticatory muscles and associated structures. Painful TMD are highly prevalent and conditions afflict 4% of US adults annually. TMD include heterogenous musculoskeletal pain conditions, such as myalgia, arthralgia, and myofascial pain. A subpopulations of TMD patients show structural changes in TMJ, including disc displacement or degenerative joint diseases (DJD). DJD is a slowly progressing, degenerative disease of the TMJ characterized by cartilage degradation and subchondral bone remodeling. Patients with DJD often develop pain (TMJ osteoarthritis; TMJ OA), but do not always have pain (TMJ osteoarthrosis). Therefore, pain symptoms are not always associated with altered TMJ structures, which suggests that a causal relationship between TMJ degeneration and pain is unclear. Multiple animal models have been developed for determining altered joint structure and pain phenotypes in response to various TMJ injuries. Rodent models of TMJOA and pain include injections to induce inflammation or cartilage destruction, sustained opening of the oral cavity, surgical resection of the articular disc, transgenic approaches to knockout or overexpress key genes, and an integrative approach with superimposed emotional stress or comorbidities. In rodents, TMJ pain and degeneration occur during partially overlapping time periods in these models, which suggests that common biological factors may mediate TMJ pain and degeneration over different time courses. While substances such as intra-articular pro-inflammatory cytokines commonly cause pain and joint degeneration, it remains unclear whether pain or nociceptive activities are causally associated with structural degeneration of TMJ and whether structural degeneration of TMJ is necessary for producing persistent pain. A thorough understanding of the determining factors of pain-structure relationships of TMJ during the onset, progression, and chronification by adopting novel approaches and models should improve the ability to simultaneously treat TMJ pain and TMJ degeneration.
Leishmanicidal and immunomodulatory properties of Brazilian green propolis extract (EPP-AF®) and a gel formulation in a pre-clinical model
Authors: Rebouças-Silva Jéssica , Amorim Nathaly Alcazar , Jesus-Santos Flávio Henrique , de Lima Jéssica Aparecida , Lima Jonilson Berlink , Berretta Andresa A. , Borges Valéria M.
Published: February 2023

Leishmaniasis is a widespread group of neglected vector-borne tropical diseases that possess serious therapeutic limitations. Propolis has been extensively used in traditional medical applications due to its range of biological effects, including activity against infectious agents. Here we evaluated the leishmanicidal and immunomodulatory properties of Brazilian green propolis extract (EPP-AF®) and a gel formulation incorporating EPP-AF®, in both in vitro and in vivo models of Leishmania amazonensis infection. Propolis extract, obtained from a standardized blend following hydroalcoholic extraction, showed the characteristic fingerprint of Brazilian green propolis as confirmed by HPLC/DAD. A carbopol 940 gel formulation was obtained containing propolis glycolic extract at 3.6% w/w. The release profile, assessed using the Franz diffusion cell protocol, demonstrated a gradual and prolonged release of p-coumaric acid and artepillin C from the carbomer gel matrix. Quantification of p-coumaric acid and artepillin C in the gel formulation over time revealed that p-coumaric acid followed the Higuchi model, dependent on the disintegration of the pharmaceutical preparation, while artepillin C followed a zero-order profile with sustained release. In vitro analysis revealed the ability of EPP-AF® to reduce the infection index of infected macrophages (p < 0.05), while also modulating the production of inflammatory biomarkers. Decreases in nitric oxide and prostaglandin E2 levels were observed (p < 0.01), suggesting low iNOS and COX-2 activity. Furthermore, EPP-AF® treatment was found to induce heme oxygenase-1 antioxidant enzyme expression in both uninfected and L. amazonensis-infected cells, as well as inhibit IL-1β production in infected cells (p < 0.01). ERK-1/2 phosphorylation was positively correlated with TNF-α production (p < 0.05), yet no impact on parasite load was detected. In vivo analysis indicated the effectiveness of topical treatment with EPP-AF® gel alone (p < 0.05 and p < 0.01), or in combination with pentavalent antimony (p < 0.05 and p < 0.001), in the reduction of lesion size in the ears of L. amazonensis-infected BALB/c mice after seven or 3 weeks of treatment, respectively. Taken together, the present results reinforce the leishmanicidal and immunomodulatory effects of Brazilian green propolis, and demonstrate promising potential for the EPP-AF® propolis gel formulation as a candidate for adjuvant therapy in the treatment of Cutaneous Leishmaniasis.
Nucleolin recognizing silica nanoparticles inhibit cell proliferation by activating the Bax/Bcl-2/caspase-3 signalling pathway to induce apoptosis in liver cancer
Authors: Xiang Liangliang , Li Yun , Gu Xinyu , Li Shujie , Li Junwei , Li Jinlong , Yi Yongxiang
Published: February 2023

Multifunctional nanocarrier platforms have shown great potential for the diagnosis and treatment of liver cancer. Here, a novel nucleolin-responsive nanoparticle platform was constructed for the concurrent detection of nucleolin and treatment of liver cancer. The incorporation of AS1411 aptamer, icaritin (ICT) and FITC into mesoporous silica nanoparticles, labelled as Atp-MSN (ICT@FITC) NPs, was the key to offer functionalities. The specific combination of the target nucleolin and AS1411 aptamer caused AS1411 to separate from mesoporous silica nanoparticles surface, allowing FITC and ICT to be released. Subsequently, nucleolin could be detected by monitoring the fluorescence intensity. In addition, Atp-MSN (ICT@FITC) NPs can not only inhibit cell proliferation but also improve the level of ROS while activating the Bax/Bcl-2/caspase-3 signalling pathway to induce apoptosis in vitro and in vivo. Moreover, our results demonstrated that Atp-MSN (ICT@FITC) NPs had low toxicity and could induce CD3+ T-cell infiltration. As a result, Atp-MSN (ICT@FITC) NPs may provide a reliable and secure platform for the simultaneous identification and treatment of liver cancer.
Integrated single-cell and transcriptome sequencing analyses develops a metastasis-based risk score system for prognosis and immunotherapy response in uveal melanoma
Authors: Meng Shuting , Zhu Tianye , Fan Zhiwei , Cheng Yulan , Dong Yefeng , Wang Fengxu , Wang Xuehai , Dong Deping , Yuan Songtao , Zhao Xinyuan
Published: February 2023

Background: Uveal melanoma (UM) is the most frequent ocular neoplasm with a strong metastatic ability. The prognostic value of metastasis-associated genes (MAGs) of UM remains unclear. It is urgent to develop a prognostic score system according to the MAGs of UM.

Methods: Unsupervised clustering was used to identify MAGs-based molecular subtypes. Cox methods were utilized to generate a prognostic score system. The prognostic ability of the score system was detected by plotting ROC and survival curves. The immune activity and underlying function were depicted by CIBERSORT GSEA algorithms.

Results: Gene cluster analysis determined two MAGs-based subclusters in UM, which were remarkably different in clinical outcomes. A risk score system containing six MAGs (COL11A1, AREG, TIMP3, ADAM12, PRRX1 and GAS1) was set up. We employed ssGSEA to compare immune activity and immunocyte infiltration between the two risk groups. Notch, JAK/STAT and mTOR pathways were greatly enriched in the high-risk group. Furthermore, we observed that knockdown of AREG could inhibit UM proliferation and metastasis by in vitro assays.

Conclusion: The MAGs-based subtype and score system in UM can enhance prognosis assessment, and the core system provides valuable reference for clinical decision-making.
Autophagy regulates plastid reorganization during spermatogenesis in the liverwort Marchantia polymorpha
Authors: Norizuki Takuya , Minamino Naoki , Sato Miyuki , Ueda Takashi
Published: February 2023

Autophagy is a highly conserved system that delivers cytoplasmic components to lysosomes/vacuoles. Plastids are also degraded through autophagy for nutrient recycling and quality control; however, the involvement of autophagic degradation of plastids in plant cellular differentiation remains unclear. Here, we investigated whether spermiogenesis, the differentiation of spermatids into spermatozoids, in the liverwort Marchantia polymorpha involves autophagic degradation of plastids. Spermatozoids of M. polymorpha possess one cylindrical plastid at the posterior end of the cell body. By fluorescently labeling and visualizing plastids, we detected dynamic morphological changes during spermiogenesis. We found that a portion of the plastid was degraded in the vacuole in an autophagy-dependent manner during spermiogenesis, and impaired autophagy resulted in defective morphological transformation and starch accumulation in the plastid. Furthermore, we found that autophagy was dispensable for the reduction in plastid number and plastid DNA elimination. These results demonstrate a critical but selective role of autophagy in plastid reorganization during spermiogenesis in M. polymorpha.
Instigating prevalent abiotic stress resilience in crop by exogenous application of phytohormones and nutrient
Authors: Swain Rinny , Sahoo Smrutishree , Behera Mamata , Rout Gyana Ranjan
Published: February 2023

In recent times, the demand for food and feed for the ever-increasing population has achieved unparalleled importance, which cannot afford crop yield loss. Now-a-days, the unpleasant situation of abiotic stress triggers crop improvement by affecting the different metabolic pathways of yield and quality advances worldwide. Abiotic stress like drought, salinity, cold, heat, flood, etc. in plants diverts the energy required for growth to prevent the plant from shock and maintain regular homeostasis. Hence, the plant yield is drastically reduced as the energy is utilized for overcoming the stress in plants. The application of phytohormones like the classical auxins, cytokinins, ethylene, and gibberellins, as well as more recent members including brassinosteroids, jasmonic acids, etc., along with both macro and micronutrients, have enhanced significant attention in creating key benefits such as reduction of ionic toxicity, improving oxidative stress, maintaining water-related balance, and gaseous exchange modification during abiotic stress conditions. Majority of phytohormones maintain homeostasis inside the cell by detoxifying the ROS and enhancing the antioxidant enzyme activities which can enhance tolerance in plants. At the molecular level, phytohormones activate stress signaling pathways or genes regulated by abscisic acid (ABA), salicylic acid (SA), Jasmonic acid (JA), and ethylene. The various stresses primarily cause nutrient deficiency and reduce the nutrient uptake of plants. The application of plant nutrients like N, K, Ca, and Mg are also involved in ROS scavenging activities through elevating antioxidants properties and finally decreasing cell membrane leakage and increasing the photosynthetic ability by resynthesizing the chlorophyll pigment. This present review highlighted the alteration of metabolic activities caused by abiotic stress in various crops, the changes of vital functions through the application of exogenous phytohormones and nutrition, as well as their interaction.