bluuebunny/crossref_metadata_2025 huggingface dataset:
Ligninolytic characteristics of Pleurotus ostreatus cultivated in cotton stalk media
Authors: Li Guoqing , Wang Yahui , Yu Deshui , Zhu Peilei , Zhao Guiyun , Liu Caiyu , Zhao Hongyuan
Published: November 2022

Biodelignification is widely regarded as a low-efficiency process because it is usually slow and difficult to control. To improve its efficiency and understand its mechanism, the present study analyzed the delignification characteristics of Pleurotus ostreatus grown on a cotton stalk medium. The results demonstrated that all strains of P. ostreatus can selectively degrade the cotton stalk lignin. When cultured in a cotton stalk medium for 60 days, P. ostreatus degraded lignin primarily during its mycelium growth with up to 54.04% lignin degradation and produced laccase and manganese dependent peroxidase with high activity levels at the peaks of 70.17 U/ml and 62.39 U/ml, respectively, but no detectable lignin peroxidase. The results of nuclear magnetic resonance spectroscopy and Fourier transform infrared spectroscopy analyses of significant changes in lignin structure revealed that syringyl (S) lignin units were more degraded than guaiacyl (G) lignin units, with a significantly elevated G/S ratio. The Gas Chromatography-Mass Spectrometer analysis of low-molecular-weight compounds revealed that the delignification resulted in the formation of alcohols, organic acids, benzodiazepines, and alkanes. Identified benzodiazepines implied the degradation of G and S units of lignin. These findings will help to improve the efficiency of biodelignification and expand our understanding of its mechanism.
Microbial detoxification of mycotoxins in food
Authors: Abraham Nadine , Chan Edicon Tze Shun , Zhou Ting , Seah Stephen Y. K.
Published: November 2022

Mycotoxins are toxic secondary metabolites produced by certain genera of fungi including but not limited to Fusarium, Aspergillus, and Penicillium. Their persistence in agricultural commodities poses a significant food safety issue owing to their carcinogenic, teratogenic, and immunosuppressive effects. Due to their inherent stability, mycotoxin levels in contaminated food often exceed the prescribed regulatory thresholds posing a risk to both humans and livestock. Although physical and chemical methods have been applied to remove mycotoxins, these approaches may reduce the nutrient quality and organoleptic properties of food. Microbial transformation of mycotoxins is a promising alternative for mycotoxin detoxification as it is more specific and environmentally friendly compared to physical/chemical methods. Here we review the biological detoxification of the major mycotoxins with a focus on microbial enzymes.
Effects of early postnatal life nutritional interventions on immune-microbiome interactions in the gastrointestinal tract and implications for brain development and function
Authors: Mullaney Jane A. , Roy Nicole C. , Halliday Christine , Young Wayne , Altermann Eric , Kruger Marlena C. , Dilger Ryan N. , McNabb Warren C.
Published: November 2022

The gastrointestinal (GI) microbiota has co-evolved with the host in an intricate relationship for mutual benefit, however, inappropriate development of this relationship can have detrimental effects. The developing GI microbiota plays a vital role during the first 1,000 days of postnatal life, during which occurs parallel development and maturation of the GI tract, immune system, and brain. Several factors such as mode of delivery, gestational age at birth, exposure to antibiotics, host genetics, and nutrition affect the establishment and resultant composition of the GI microbiota, and therefore play a role in shaping host development. Nutrition during the first 1,000 days is considered to have the most potential in shaping microbiota structure and function, influencing its interactions with the immune system in the GI tract and consequent impact on brain development. The importance of the microbiota-GI-brain (MGB) axis is also increasingly recognized for its importance in these developmental changes. This narrative review focuses on the importance of the GI microbiota and the impact of nutrition on MGB axis during the immune system and brain developmental period in early postnatal life of infants.
How to survive pig farming: Mechanism of SCCmec element deletion and metabolic stress adaptation in livestock-associated MRSA
Authors: Huber Charlotte , Wolf Silver A. , Ziebuhr Wilma , Holmes Mark A. , Assmann Julia , Lübke-Becker Antina , Thürmer Andrea , Semmler Torsten , Brombach Julian , Bethe Astrid , Bischoff Markus , Wieler Lothar H. , Epping Lennard , Walther Birgit
Published: November 2022

Previous research on methicillin susceptible Staphylococcus aureus (MSSA) belonging to livestock-associated (LA-) sequence type (ST) 398, isolated from pigs and their local surroundings, indicated that differences between these MSSA and their methicillin resistant predecessors (MRSA) are often limited to the absence of the staphylococcal cassette chromosome mec (SCCmec) and few single nucleotide polymorphisms. So far, our understanding on how LA-MRSA endure the environmental conditions associated with pig-farming as well as the putative impact of this particular environment on the mobilisation of SCCmec elements is limited. Thus, we performed in-depth genomic and transcriptomic analyses using the LA-MRSA ST398 strain IMT38951 and its methicillin susceptible descendant. We identified a mosaic-structured SCCmec region including a putative replicative SCCmecVc which is absent from the MSSA chromosome through homologous recombination. Based on our data, such events occur between short repetitive sequences identified within and adjacent to two distinct alleles of the large cassette recombinase genes C (ccrC). We further evaluated the global transcriptomic response of MRSA ST398 to particular pig-farm associated conditions, i.e., contact with host proteins (porcine serum) and a high ammonia concentration. Differential expression of global regulators involved in stress response control were identified, i.e., ammonia-induced alternative sigma factor B-depending activation of genes for the alkaline shock protein 23, the heat shock response and the accessory gene regulator (agr)-controlled transcription of virulence factors. Exposure to serum transiently induced the transcription of distinct virulence factor encoding genes. Transcription of genes reported for mediating the loss of methicillin resistance, especially ccrC, was not significantly different compared to the unchallenged controls. We concluded that, from an evolutionary perspective, bacteria may save energy by incidentally dismissing a fully replicative SCCmec element in contrast to the induction of ccr genes on a population scale. Since the genomic SCCmec integration site is a hot-spot of recombination, occasional losses of elements of 16 kb size may restore capacities for the uptake of foreign genetic material. Subsequent spread of resistance, on the other hand, might depend on the autonomous replication machinery of the deleted SCCmec elements that probably enhance chances for reintegration of SCCmec into susceptible genomes by mere multiplication.
Novel therapeutic approach to slow down the inflammatory cascade in acute/subacute spinal cord injury: Early immune therapy with lipopolysaccharide enhanced neuroprotective effect of combinational therapy of granulocyte colony-stimulating factor and bone-marrow mesenchymal stem cell in spinal cord injury
Authors: Hashemizadeh Shiva , Hosseindoost Saereh , Omidi Ameneh , Aminianfar Hossein , Ebrahimi-Barough Somayeh , Ai Jafar , Arjmand Babak , Hadjighassem Mahmoudreza
Published: November 2022

Bone-marrow mesenchymal stem cells (BM-MSCs) have not yet proven any significant therapeutic efficacy in spinal cord injury (SCI) clinical trials, due to the hostile microenvironment of the injured spinal cord at the acute phase. This study aims to modulate the inflammatory milieu by lipopolysaccharide (LPS) and granulocyte colony-stimulating factor (G-CSF) to improve the BM-MSCs therapy. For this purpose, we determined the optimum injection time and sub-toxic dosage of LPS following a T10 contusion injury. Medium-dose LPS administration may result in a local anti-inflammatory beneficial role. This regulatory role is associated with an increase in NF-200-positive cells, significant tissue sparing, and improvement in functional recovery compared to the SCI control group. The second aim was to examine the potential ability of LPS and LPS + G-CSF combination therapy to modulate the lesion site before BM-MSC (1 × 105 cells) intra-spinal injection. Our results demonstrated combination therapy increased potency to enhance the anti-inflammatory response (IL-10 and Arg-1) and decrease inflammatory markers (TNF-α and CD86) and caspase-3 compared to BM-MSC monotherapy. Histological analysis revealed that combination groups displayed better structural remodeling than BM-MSC monotherapy. In addition, Basso–Beattie–Bresnahan (BBB) scores show an increase in motor recovery in all treatment groups. Moreover, drug therapy shows faster recovery than BM-MSC monotherapy. Our results suggest that a sub-toxic dose of LPS provides neuroprotection to SCI and can promote the beneficial effect of BM-MSC in SCI. These findings suggest that a combination of LPS or LPS + G-CSF prior BM-MSC transplantation is a promising approach for optimizing BM-MSC-based strategies to treat SCI. However, because of the lack of some methodological limitations to examine the survival rate and ultimate fate of transplanted BM-MSCs followed by LPS administration in this study, further research needs to be done in this area. The presence of only one-time point for evaluating the inflammatory response (1 week) after SCI can be considered as one of the limitations of this study. We believed that the inclusion of additional time points would provide more information about the effect of our combination therapy on the microglia/macrophage polarization dynamic at the injured spinal cord.
Dystonia and the pedunculopontine nucleus: Current evidences and potential mechanisms
Authors: Su Jun-hui , Hu Yao-wen , Yang Yi , Li Ruo-yu , Teng Fei , Li Li-xi , Jin Ling-jing
Published: November 2022

Being a major component of the midbrain locomotion region, the pedunculopontine nucleus (PPN) is known to have various connections with the basal ganglia, the cerebral cortex, thalamus, and motor regions of the brainstem and spinal cord. Functionally, the PPN is associated with muscle tone control and locomotion modulation, including motor initiation, rhythm and speed. In addition to its motor functions, the PPN also contribute to level of arousal, attention, memory and learning. Recent studies have revealed neuropathologic deficits in the PPN in both patients and animal models of dystonia, and deep brain stimulation of the PPN also showed alleviation of axial dystonia in patients of Parkinson's disease. These findings indicate that the PPN might play an important role in the development of dystonia. Moreover, with increasing preclinical evidences showed presence of dystonia-like behaviors, muscle tone changes, impaired cognitive functions and sleep following lesion or neuromodulation of the PPN, it is assumed that the pathological changes of the PPN might contribute to both motor and non-motor manifestations of dystonia. In this review, we aim to summarize the involvement of the PPN in dystonia based on the current preclinical and clinical evidences. Moreover, potential mechanisms for its contributions to the manifestation of dystonia is also discussed base on the dystonia-related basal ganglia-cerebello-thalamo-cortical circuit, providing fundamental insight into the targeting of the PPN for the treatment of dystonia in the future.
Impaired sustained attention in groups at high risk for antisocial personality disorder: A contingent negative variation and standardized low-resolution tomographic analysis study
Authors: Guan Muzhen , Ma Lifang , Zhu Yifang , Liao Yang , Zeng Lingwei , Wu Shengjun , Men Ke , Liu Xufeng
Published: November 2022

Objective

This study aimed to explore the characteristics of contingent negative variation (CNV) in groups at high risk for antisocial personality disorder.

Materials and methods

A classic CNV paradigm was used to compare the characteristics of attention maintenance among a group of individuals with conduct disorder (CD group; n = 27), a group of individuals with antisocial personality traits (AP; n = 29), a group of individuals with conduct disorder and antisocial personality traits (CD + AP group; n = 25), and a group of healthy controls (CG group; n = 30), to examine the characteristics of the amplitude and latency of CNV in different processing stages.

Results

Results of the event-related potential analysis were as follows: The mean amplitude analysis between 500 and 1,000 ms revealed that the mean CNV amplitudes in the CD + AP group (-1.388 ± 0.449 μV, P < 0.001) were significantly lower than that in the CG group (-4.937 ± 0.409 μV). The mean amplitude analysis between 1,000 and 1,500 ms revealed that the mean CNV amplitude in the CD + AP group (-0.931 ± 0.646 μV) was significantly lower than that in the CG group (4.809 ± 0.589 μV, P < 0.001). The mean amplitude analysis between 1,500 and 2,000 ms revealed that the mean CNV amplitude in the CG group (3.121 ± 0.725 μV) was significantly higher than that in the CD + AP group (-0.277 ± 0.795 μV, P = 0.012), whereas the mean CNV amplitude in the CD + AP group was not significantly different in the AP group (P = 0.168) and CD group (P > 0.05). Source localization results indicated altered activity in frontal-temporal regions.

Conclusion

The CNV amplitude characteristics in the CD + AP group and AP group were more consistent and fluctuated around the baseline, indicating the absence of attention maintenance resulted in impairments in attention allocation and motor preparation in the CD + AP group and AP group.
Cervical alignment and clinical outcome of anterior decompression with fusion vs. posterior decompression with fixation in kyphotic cervical spondylotic myelopathy
Authors: Du Wei , Wang Hai-Xu , Zhang Jing-Tao , Wang Feng , Zhang Xu , Shen Yong , Chen Rong , Zhang Li
Published: November 2022

Background context

Cervical kyphosis is a common but potentially debilitating and challenging condition. There is controversy on the optimal surgical strategy for the treatment of kyphotic cervical spondylotic myelopathy (KCSM) using either anterior approach or posterior approach.

Introduction

The purpose of this study was to investigate the surgical efficacy of anterior decompression with fusion (ADF) vs. posterior decompression with fixation (PDF) for the treatment of KCSM, and to further analyze the changes of cervical spinal alignment parameters and axial symptoms (AS) severity after kyphotic correction.

Materials and methods

We retrospectively reviewed 117 patients with KCSM who had undergone ADF (58 patients) and PDF (59 patients) between January 2016 and December 2020. Cervical spinal alignment parameters, including curvature index (CI) and C2-7 Cobb angle, were measured on the PreOP and PostOP lateral radiographs. Recovery rate was calculated based on the Japanese Orthopedic Association (JOA) score. AS severity was quantified by Neck Disability Index (NDI). A P-value less than 0.05 was considered to be significant.

Results

The patient mean age, gender, presenting symptoms and follow-up time were similar between the two groups (P > 0.05). However, there were statistically significant differences (P < 0.001) between the two groups regarding the operation levels, operating time and intraoperative blood loss. Analysis of PostOP follow-up data showed significant differences (P < 0.001) in CI, correction of CI, C2-7 Cobb angle, and NDI between the two groups, whereas no significant differences in JOA score (P = 0.16) and recovery rate (P = 0.14). There were significant differences (P < 0.001) in CI, C2-7 Cobb angle, JOA score, and NDI between PreOP and PostOP follow-up in each group. Correction of CI showed positive correlation with recovery of NDI in Group ADF (r = 0.51, P < 0.001), and in Group PDF (r = 0.45, P < 0.001).

Conclusion

Satisfied neurological improvement was obtained by ADF and PDF for patients with KCSM. Cervical kyphotic correction caused significant improvement of AS, and was more favorable with ADF than with PDF. Surgeons should pay full consideration of the merits and shortcomings of each approach when deciding on a surgical plan.
Encapsulation of bioactive compounds extracted from date palm seeds (Phoenix dactylifera L.) and their use in functional food
Authors: Hashim Mahmood A. , Huang Xin , Nadtochii Liudmila A. , Baranenko Denis A. , Boulkrane Mohamed Said , El-Messery Tamer M.
Published: November 2022

Liposomes have been used as a novel phytoconstituent delivery system to encapsulate lyophilized palm seed phenolic extract (PSPE) and incorporate it into yogurt as a food model to enhance the bioavailability of PSPE. Phenolic compounds were extracted with aqueous ethanol from palm seed powder using the solvent-maceration approach assisted by ultrasonication. Lyophilized PSPE (0.2–1% w/v) was enclosed in a liposome structure coated with or without chitosan (primary/secondary liposome). Particle size, zeta potential, encapsulation efficiency (EE), Fourier transform infrared spectroscopy (FTIR), and transmission electron microscopy (TEM) were applied to investigate the primary and secondary liposomes. To assess the in vitro bioaccessibility of PSPE and primary/secondary liposomes, the total phenolic content (TPC) and the antioxidant activity were studied during the oral, gastric, and intestinal digestion stages. Three concentrations of lyophilized secondary liposomes (1.25, 2.5, and 3.75% w/v) were added to the yogurt food model. During the 14 days of storage, the physical, chemical, and sensory properties were assessed. Compared to the primary liposomes (87%), the secondary liposomes (91%) showed a higher encapsulation efficiency. Comparing the secondary liposomes to the original liposomes and the non-encapsulated PSPE, the bioaccessibility of phenolic compounds was improved. Fortified yogurt with secondary liposomes had a lower syneresis and viscosity than the reference yogurt. The encapsulated PSPE provided a good level of protection, and its release increased throughout the intestinal phase. Thus, PSPE in a microencapsulated form has been proven to be a rich and cost-effective source of phenolics that can be used successfully to produce functional yogurt.
SIRT1, a novel transcriptional downstream target of CD44, linking its deacetylase activity to tumor cell invasion/metastasis
Authors: Ahmad Salma M. S. , Al-Mansoob Maryam , Ouhtit Allal
Published: November 2022

Our tetracycline-off-inducible CD44 expression system previously established in mouse model, revealed that activation of CD44 with its major ligand hyaluronan (HA) promoted breast cancer (BC) metastasis to the liver. To identify the mechanisms that underpin CD44-promoted BC cell invasion, microarray gene expression profiling using RNA samples from (Tet)-Off-regulated expression system of CD44s in MCF7 cells, revealed a set of upregulated genes including, nuclear sirtuin-1 (SIRT1 also known as NAD-dependent deacetylase), an enzyme that requires NAD+ as a cofactor to deacetylate several histones and transcription factors. It stimulates various oncogenic pathways promoting tumorigenesis. This data suggests that SIRT1 is a potential novel transcriptional target of CD44-downstream signaling that promote BC cell invasion/metastasis. This review will discuss the evidence supporting this hypothesis as well as the mechanisms linking SIRT1 to cell proliferation and invasion.
ZNF24 regulates the progression of KRAS mutant lung adenocarcinoma by promoting SLC7A5 translation
Authors: Jia Daqi , Li Leilei , Wang Peng , Feng Qiang , Pan Xinyan , Lin Peng , Song Shuling , Yang Lilin , Yang Julun
Published: November 2022

Background

Clinical treatment of RAS mutant cancers is challenging because of the complexity of the Ras signaling pathway. SLC7A5 is a newly discovered downstream gene of the Ras signaling pathway, but the regulatory mechanism is unclear. We aimed to explore the molecular mechanism and role in KRAS mutant lung adenocarcinoma progression.

Methods

Key gene that regulated SLC7A5 in KRAS mutant lung adenocarcinoma was screened by RNA sequencing and bioinformatics analysis. The effect of this gene on the expression of SLC7A5 was studied by RNAi. The regulatory mechanism between the two genes was investigated by immunofluorescence, CoIP, pulldown and yeast two-hybrid assays. The location of the two genes was determined by inhibiting Ras and the downstream pathways PI3K-AKT and MEK-ERK. By in vivo and in vitro experiments, the effects of the key gene on the biological functions of KRAS mutant lung adenocarcinoma were explored.

Results

We found a novel gene, ZNF24, which upregulated SLC7A5 protein expression rather than mRNA expression in KRAS mutant lung adenocarcinoma. Endogenous protein interactions occurred between ZNF24 and SLC7A5. Ras inhibition reduced the expression of ZNF24 and SLC7A5. ZNF24 and SLC7A5 are located downstream of the MEK-ERK and PI3K-AKT pathways. In vivo and in vitro functional experiments confirmed that the ZNF24-SLC7A5 signaling axis promoted the proliferation, invasion and migration of KRAS mutant lung adenocarcinoma.

Conclusions

ZNF24 promoted the growth of KRAS mutant lung adenocarcinoma by upregulating SLC7A5 protein expression, which suggested that ZNF24 is a new biomarker of KRAS mutant tumors and could be a new potential therapeutic target for Ras-driven tumors.
Nomogram to predict postoperative complications after cytoreductive surgery for advanced epithelial ovarian cancer: A multicenter retrospective cohort study
Authors: Jiang Caixia , Liu Yingwei , Tang Junying , Li Zhengyu , Min Wenjiao
Published: November 2022

Objective

To establish nomograms to predict the risk of postoperative complications following cytoreductive surgery in patients with advanced epithelial ovarian cancer (AEOC).

Methods

A multicenter retrospective cohort study that included patients with FIGO stage IIIC-IV epithelial ovarian cancer who underwent cytoreductive surgery was designed. By using univariate and multivariate analyses, patient preoperative characteristics were used to predict the risk of postoperative complications. Multivariate modeling was used to develop Nomograms.

Results

Overall, 585 AEOC patients were included for analysis (training cohort = 426, extrapolation cohort = 159). According to the findings, the training cohort observed an incidence of postoperative overall and severe complications of 28.87% and 6.10%, respectively. Modified frailty index (mFI) (OR 1.96 and 2.18), FIGO stage (OR 2.31 and 3.22), and Surgical Complexity Score (SCS) (OR 1.16 and 1.23) were the clinical factors that were most substantially associated to the incidence of overall and severe complications, respectively. The resulting nomograms demonstrated great internal discrimination, good consistency, and stable calibration, with C-index of 0.74 and 0.78 for overall and severe complications prediction, respectively. A satisfactory external discrimination was also indicated by the extrapolation cohort, with the C-index for predicting overall and severe complications being 0.92 and 0.91, respectively.

Conclusions

The risk of considerable postoperative morbidity exists after cytoreductive surgery for AEOC. These two nomograms with good discrimination and calibration might be useful to guide clinical decision-making and help doctors assess the probability of postoperative complications for AEOC patients.
Advances in CAR T cell immunotherapy for paediatric brain tumours
Authors: Rao Padmashree , Furst Liam , Meyran Deborah , Mayoh Chelsea , Neeson Paul J. , Terry Rachael , Khuong-Quang Dong-Anh , Mantamadiotis Theo , Ekert Paul G.
Published: November 2022

Brain tumours are the most common solid tumour in children and the leading cause of cancer related death in children. Current treatments include surgery, chemotherapy and radiotherapy. The need for aggressive treatment means many survivors are left with permanent severe disability, physical, intellectual and social. Recent progress in immunotherapy, including genetically engineered T cells with chimeric antigen receptors (CARs) for treating cancer, may provide new avenues to improved outcomes for patients with paediatric brain cancer. In this review we discuss advances in CAR T cell immunotherapy, the major CAR T cell targets that are in clinical and pre-clinical development with a focus on paediatric brain tumours, the paediatric brain tumour microenvironment and strategies used to improve CAR T cell therapy for paediatric tumours.
A novel prediction model for pathological complete response based on clinical and blood parameters in locally advanced rectal cancer
Authors: Lu Siyi , Liu Zhenzhen , Wang Yuxia , Meng Yan , Peng Ran , Qu Ruize , Zhang Zhipeng , Fu Wei , Wang Hao
Published: November 2022

Background

The aim of this study was to investigate whether clinical and blood parameters can be used for predicting pathological complete response (pCR) to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC).

Methods

We retrospectively enrolled 226 patients with LARC [allocated in a 7:3 ratio to a training (n = 158) or validation (n = 68) cohort] who received nCRT before radical surgery. Backward stepwise logistic regression was performed to identify clinical and blood parameters associated with achieving pCR. Models based on clinical parameters (CP), blood parameters (BP), and clinical-blood parameters (CBP) were constructed for comparison with previously reported Tan’s model. The performance of the four models was evaluated by receiver operating characteristic (ROC) curve analysis, calibration, and decision curve analysis (DCA) in both cohorts. A dynamic nomogram was constructed for the presentation of the best model.

Results

The CP and BP models based on multivariate logistic regression analysis showed that interval, Grade, CEA and fibrinogen–albumin ratio index (FARI), sodium-to-globulin ratio (SGR) were the independent clinical and blood predictors for achieving pCR, respectively. The area under the ROC curve of the CBP model achieved a score of 0.818 and 0.752 in both cohorts, better than CP (0.762 and 0.589), BP (0.695 and 0.718), Tan (0.738 and 0.552). CBP also showed better calibration and DCA than other models in both cohorts. Moreover, CBP revealed significant improvement compared with other models in training cohort (P < 0.05), and CBP showed significant improvement compared with CP and Tan’s model in validation cohort (P < 0.05).

Conclusion

We demonstrated that CBP predicting model have potential in predicting pCR to nCRT in patient with LARC.
Deep learning and radiomics to predict the mitotic index of gastrointestinal stromal tumors based on multiparametric MRI
Authors: Yang Linsha , Du Dan , Zheng Tao , Liu Lanxiang , Wang Zhanqiu , Du Juan , Yi Huiling , Cui Yujie , Liu Defeng , Fang Yuan
Published: November 2022

Introduction

Preoperative evaluation of the mitotic index (MI) of gastrointestinal stromal tumors (GISTs) represents the basis of individualized treatment of patients. However, the accuracy of conventional preoperative imaging methods is limited. The aim of this study was to develop a predictive model based on multiparametric MRI for preoperative MI prediction.

Methods

A total of 112 patients who were pathologically diagnosed with GIST were enrolled in this study. The dataset was subdivided into the development (n = 81) and test (n = 31) sets based on the time of diagnosis. With the use of T2-weighted imaging (T2WI) and apparent diffusion coefficient (ADC) map, a convolutional neural network (CNN)-based classifier was developed for MI prediction, which used a hybrid approach based on 2D tumor images and radiomics features from 3D tumor shape. The trained model was tested on an internal test set. Then, the hybrid model was comprehensively tested and compared with the conventional ResNet, shape radiomics classifier, and age plus diameter classifier.

Results

The hybrid model showed good MI prediction ability at the image level; the area under the receiver operating characteristic curve (AUROC), area under the precision–recall curve (AUPRC), and accuracy in the test set were 0.947 (95% confidence interval [CI]: 0.927–0.968), 0.964 (95% CI: 0.930–0.978), and 90.8 (95% CI: 88.0–93.0), respectively. With the average probabilities from multiple samples per patient, good performance was also achieved at the patient level, with AUROC, AUPRC, and accuracy of 0.930 (95% CI: 0.828–1.000), 0.941 (95% CI: 0.792–1.000), and 93.6% (95% CI: 79.3–98.2) in the test set, respectively.

Discussion

The deep learning-based hybrid model demonstrated the potential to be a good tool for the operative and non-invasive prediction of MI in GIST patients.
Ureteropelvic junction obstruction in infants: Open or minimally invasive surgery? A systematic review and meta-analysis
Authors: Cascini Valentina , Lauriti Giuseppe , Di Renzo Dacia , Miscia Maria Enrica , Lisi Gabriele
Published: November 2022

Introduction

The historical gold standard treatment for ureteropelvic junction obstruction (UPJO) was the open Anderson–Hynes dismembered pyeloplasty (OP). Minimally invasive surgery (MIS) procedures, including laparoscopic pyeloplasty (LP) and robot-assisted laparoscopic pyeloplasty (RALP), have been reported to achieve better outcomes (i.e., decreased morbidity, reduced postoperative pain, superior esthetic results, and shortened length of hospital stay, LOS), with a success rate similar to OP. The main limitation of the MIS approach is the age and weight of patients, limiting these procedures to children >1 year. This study aims to evaluate the feasibility and benefits of MIS pyeloplasty compared to OP to surgically treat UPJO in children <1 year of age.

Materials and methods

A systematic review was independently performed by two authors. Papers comparing both techniques (MIS pyeloplasty vs. OP) in infants were included in the meta-analysis. Data (mean ± DS or percentage) were analyzed using Rev.Man 5.4 A p < 0.05 was considered significant.

Results

Nine studies (eight retrospective and one prospective) meet the inclusion criteria. A total of 3,145 pyeloplasties have been included, with 2,859 (90.9%) OP and 286 (9.1%) MIS. Age at operation was 4.9 ± 1.4 months in OP vs. 5.8 ± 2.2 months in MIS, p = ns. Weight at surgery was 6.4 ± 1.4 kg in OP vs. 6.9 ± 1.4 kg in MIS, p = ns. Operative time was 129.4 ± 24.1 min for OP vs. 144.0 ± 32.3 min for MIS, p < 0.001. LOS was 3.2 ± 1.9 days for OP vs. 2.2 ± 0.9 days for MIS, p < 0.01. Postoperative complications were present in 10.0 ± 12.9% of OP vs. 10.9 ± 11.6% in MIS, p = ns. Failure of surgery was 5.2 ± 3.5% for OP vs. 4.2 ± 3.3% for MIS, p = ns.

Conclusion

The development of miniaturized instruments and technical modifications has made MIS feasible and safe in infants and small children. MIS presented a longer operative time than OP. However, MIS seemed effective for treating UPJO in infants, showing shortened LOS compared to OP. No differences have been reported with regard to the incidence of postoperative complications and failure of pyeloplasty. Given the low quality of evidence of the meta-analysis according to the GRADE methodology, we would suggest limiting MIS procedures in infants to only those high-volume centers with experienced surgeons.
Favorable outcome of empagliflozin treatment in two pediatric glycogen storage disease type 1b patients
Authors: Hexner-Erlichman Zufit , Veiga-da-Cunha Maria , Zehavi Yoav , Vadasz Zahava , Sabag Adi D. , Tatour Sameh , Spiegel Ronen
Published: November 2022

Background

Glycogen storage disease type 1b (GSD1b) is an ultra-rare autosomal recessive disorder, caused by mutations in SLC37A4 gene. Affected patients present with episodes of fasting hypoglycemia and lactic acidosis, hepatomegaly, growth retardation, hyperlipidemia and renal impairment. In addition, patients present neutropenia, neutrophil dysfunction and oral, and skin infections as well as a significant predisposition to develop inflammatory bowel disease (IBD). Low neutrophil counts and function is related to the toxic accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P). Recently, several reports have shown that off-label treatment with empagliflozin (EMPA), an inhibitor of the renal glucose transporter SGLT2, decreased blood 1,5-anhydroglucitol (1,5-AG), and neutrophil 1,5-AG6P, thus resulting in a new therapeutic option for neutropenia and neutrophil dysfunction in patients.

Methods

Off-label treatment with EMPA was established in two GSD1b patients after signed informed consent. The patients were followed clinically. We monitored neutrophil counts and function, 1,5-AG levels in plasma and its renal clearance before and during EMPA treatment.

Results

A 17 year-old girl who had long standing oral ulcers and developed IBD, requiring systemic steroid and regular granulocyte colony-stimulating factor (GCSF) therapy and an 8 year-old boy who had steady non healing oral lesions were treated with empagliflozin during 18–24 months. Treatment led to increase of neutrophil counts and function with substantial clinical improvement. This included remission of IBD in the first patient which allowed to discontinue both GCSF and steroid therapy and resolution of oral lesions in both patients. The concentration of 1,5-AG in blood was greatly decreased within two weeks of treatment and remained stable thereafter.

Conclusions

Repurposing of empagliflozin to treat neutropenia in two GSD1b patients was safe and resulted in the urinary excretion of 1,5-AG, the normalization of neutrophil function, and a remarkable improvement of neutropenia-related clinical traits. We showed for the first time that empagliflozin increases concomitantly the renal clearance of both 1,5-anhydroglucitol and glucose in GSD1b patients.
Metabolomics profiling of AKT/c-Met-induced hepatocellular carcinogenesis and the inhibitory effect of Cucurbitacin B in mice
Authors: Ji Xiangyu , Chen Xin , Sheng Lei , Deng Dongjie , Wang Qi , Meng Yan , Qiu Zhenpeng , Zhang Baohui , Zheng Guohua , Hu Junjie
Published: November 2022

Hepatocellular carcinoma (HCC), the most common kind of liver cancer, accounts for the majority of liver cancer diagnoses and fatalities. Clinical aggressiveness, resistance to traditional therapy, and a high mortality rate are all features of this disease. Our previous studies have shown that co-activation of AKT and c-Met induces HCC development, which is the malignant biological feature of human HCC. Cucurbitacin B (CuB), a naturally occurring tetracyclic triterpenoid compound with potential antitumor activity. However, the metabolic mechanism of AKT/c-Met-induced Hepatocellular Carcinogenesis and CuB in HCC remains unclear. In this study, we established an HCC mouse model by hydrodynamically transfecting active AKT and c-Met proto-oncogenes. Based on the results of hematoxylin-eosin (H&E), oil red O (ORO) staining, and immunohistochemistry (IHC), HCC progression was divided into two stages: the early stage of HCC (3 weeks after AKT/c-Met injection) and the formative stage of HCC (6 weeks after AKT/c-Met injection), and the therapeutic effect of CuB was evaluated. Through UPLC-Q-TOF-MS/MS metabolomics, a total of 26 distinct metabolites were found in the early stage of HCC for serum samples, while in the formative stage of HCC, 36 distinct metabolites were found in serum samples, and 13 different metabolites were detected in liver samples. 33 metabolites in serum samples and 11 in live samples were affected by CuB administration. Additionally, metabolic pathways and western blotting analysis revealed that CuB influences lipid metabolism, amino acid metabolism, and glucose metabolism by altering the AKT/mTORC1 signaling pathway, hence decreasing tumor progression. This study provides a metabolic basis for the early diagnosis, therapy, and prognosis of HCC and the clinical application of CuB in HCC.
Shuangyu Tiaozhi decoction alleviates non-alcoholic fatty liver disease by improving lipid deposition, insulin resistance, and inflammation in vitro and in vivo
Authors: Yin Guoliang , Liang Hongyi , Sun Wenxiu , Zhang Shizhao , Feng Yanan , Liang Pengpeng , Chen Suwen , Liu Xiangyi , Pan Wenchao , Zhang Fengxia
Published: November 2022

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. Our previous studies have found that Shuangyu Tiaozhi Decoction (SYTZD) could produce an improvement in NAFLD-related indicators, but the underlying mechanism associated with this improvement remains unclear. The study aimed to investigate the potential mechanism of SYTZD against NAFLD through network pharmacology and experimental verification. The components of SYTZD and SYTZD drug containing serum were analyzed using ultra-performance liquid chromatography to quadrupole/time-of-flight mass spectrometry (UPLC-Q/TOF-MS). Active components and targets of SYTZD were screened by the traditional Chinese medical systems pharmacology (TCMSP) and encyclopedia of traditional Chinese medicine (ETCM) databases. NAFLD-related targets were collected from the GeneCards and DisGeNET databases. The component-disease targets were mapped to identify the common targets of SYTZD against NAFLD. Protein–protein interaction (PPI) network of the common targets was constructed for selecting the core targets. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the core targets was performed using the database for annotation, visualization, and integrated discovery (DAVID) database. Furthermore, animal and cell models were constructed for validating the predictions of network pharmacology. Lipid accumulation, liver histopathology, insulin resistance, and core gene expression were measured by oil red O staining, hematoxylin and eosin staining, insulin tolerance test, real-time quantitative polymerase chain reaction, and Western blotting, respectively. Two components and 22 targets of SYTZD against NAFLD were identified by UPLC-Q/TOF-MS and relevant databases. PPI analysis found that ESR1, FASN, mTOR, HIF-1α, VEGFA, and GSK-3β might be the core targets of SYTZD against NAFLD, which were mainly enriched in the thyroid hormone pathway, insulin resistance pathway, HIF-1 pathway, mTOR pathway, and AMPK pathway. Experimental results revealed that SYTZD might exert multiple anti-NAFLD mechanisms, including improvements in lipid deposition, inflammation, and insulin resistance. SYTZD treatment led to decreases in the lipid profiles, hepatic enzyme levels, inflammatory cytokines, and homeostatic model assessment for insulin resistance (HOMA-IR). SYTZD treatment affected relative mRNA and protein levels associated with various pathways. Our findings reveal that SYTZD could alleviate NAFLD through a multi-component, multi-target, and multi-pathway mechanism of action.
AA147 ameliorates post-cardiac arrest cerebral ischemia/reperfusion injury through the co-regulation of the ATF6 and Nrf2 signaling pathways
Authors: Yuan Zhu , Lu Liping , Lian Yingtao , Zhao Yuanrui , Tang Tingting , Xu Song , Yao Zhun , Yu Zhui
Published: November 2022

Ischemia/reperfusion caused by cardiac arrest (CA) disturbs endoplasmic reticulum (ER) homeostasis and redox balance in neurons. AA147, originally developed as a pharmacologic activator of the activating transcription factor 6 (ATF6), can protect multiple tissues from ischemia/reperfusion injury (IRI) by decreasing reactive oxygen species (ROS) and restoring ER function. However, it is unclear whether pharmacologic treatment of AA147 could ameliorate post-CA cerebral IRI and whether it is associated with proteostasis regulation and anti-oxidative stress mechanism. In the present study, mice were subjected to 9 min-CA surgery followed by cardiopulmonary resuscitation (CPR). AA147 or vehicle was administered 1 day before the operation and 15 min after the return of spontaneous circulation. We found that AA147 restored neurological function and reduced dead neurons in mice suffering from CA. Moreover, AA147 inhibited CA/CPR-caused neuronal apoptosis and ER stress, indicated by reduced TUNEL-positive neurons, surged expression of Bcl-2/Bax, and down expression of cleaved caspase-3, caspase-12, C/EBP homologous protein (CHOP). The expression of ATF6 and its regulated gene glucose-regulated protein 78 (GRP78) increased significantly after the administration of AA147, suggesting the activation of the ATF6 pathway. In addition, AA147 also alleviated the upsurge of the ROS generation and MDA levels as well as increased SOD activity, accompanied by enhancement of the nuclear factor E2-related factor 2 (Nrf2) and its modulated heme-oxygenase-1 (HO-1) expressions. Cotreatment of AA147 with inhibitors of the ATF6 or Nrf2 significantly suppressed AA147-dependent reductions in ROS scavenging and neuronal death after CA/CPR. The results suggested that AA147 could confer neuroprotection against post-CA cerebral IRI through inhibition of oxidative stress along with ER stress-associated apoptosis, which is attributed to the coregulation of both ATF6 and Nrf2 signaling pathways activity. Our findings support the potential for AA147 as a therapeutic approach to improve post-CA brain injury.
NMI: a potential biomarker for tumor prognosis and immunotherapy
Authors: He Teng , Qiao Yinbiao , Yang Qi , Chen Jie , Chen Yongyuan , Chen Xiaoke , Hao Zhixing , Lin Mingjie , Shao Zheyu , Wu Pin , Xu Feng
Published: November 2022

N-Myc and STAT Interactor protein (NMI) is an interferon inducible protein participating in various cellular activities, and is widely involved in the process of tumorigenesis and progression. Studies have shown that the loss of NMI expression in breast cancer can promote its progression by inducing epithelial-mesenchymal transition (EMT). However, the expression level of NMI in other tumors and its impact on immune cell infiltration, patient prognosis, and drug treatment are still unclear. Here, we analyzed the role of NMI in pan-cancer through multiple omics data. We found that NMI was abnormally expressed in a variety of tumor tissues. The expression of NMI was closely related to the unique molecular and immunotyping, diagnosis and prognosis of various tumor tissues. In addition, we identified the main proteins that interact with NMI, and focused on the relationship between the clinical parameters of lower grade glioma (LGG) and NMI expression. Subsequently, we found that the expression of NMI was correlated with the infiltration of multiple immune cells and the expression of immune checkpoints. Finally, we also found that the expression of NMI was correlated with the sensitivity to multiple antitumor drugs. In conclusion, our comprehensive pan-cancer analysis of NMI revealed that it is a potential molecular marker for tumor diagnosis and treatment, plays an important role in tumor immunity, and is a promising molecular target for cancer treatment.
Acute and sub-acute toxicity evaluation of dihydro-p-coumaric acid isolated from leaves of Tithonia diversifolia Hemsl. A. Gray in BALB/c mice
Authors: Devi Thiyam B. , Jena Sarita , Patra Biswajit , Singh Kabrambam D. , Chawla Saurabh , Raina Vishakha , Koijam Arunkumar Singh , Parida Ajay , Rajashekar Yallappa
Published: November 2022

In present study, the acute and sub-acute toxicities of Dihydro-p-coumaric acid isolated from the leaves of Tithonia diversifolia (Hemsl.) A. Gray was studied for safety issues in mammals. For acute toxicity tests, isolated compound was administered orally in both male and female BALB/c mice at the doses of 200, 800, and 1,600 mg/kg body weight for 7 days. In sub-acute toxicity study 50 and 500 mg/kg bw of the compound was orally administered for 14 days. Toxicity induced behavioural changes, haematological parameters, biochemical markers and histopathological sections were studied after Dihydro-p-coumaric acid administration. The vital organs like heart, kidney, uterus and testis revealed no adverse effects at doses of upto 1,600 mg/kg bw and 500 mg/kg bw. Slight hepatotoxicity was however demonstrated by ALT and AST assay but histopathological section did not concur as much. The study demonstrated insignificant difference in the percentage of feed intake, water intake, weight gain, haematological parameters and histopathological changes, with no toxicity signs and mortality. Dihydro-p-coumaric acid can be regarded as safe in both acute and sub-acute toxicity assay in both sexes. This indicates Dihydro-p-coumaric acid as a viable alternative to synthetic pesticides.
Identification of pharmacokinetic markers for safflower injection using a combination of system pharmacology, multicomponent pharmacokinetics, and quantitative proteomics study
Authors: Shi Peiying , Ruan Yijun , Zhong Chenhui , Teng Linglin , Ke Liyuan , Yao Hong
Published: November 2022

Safflower injection (SI), a water-extract preparation from safflower (Carthamus tinctorius L.), has been widely used for the treatment of cardio-cerebrovascular diseases. This work aims to develop an approach for identifying PK markers of cardiovascular herbal medicines using SI as a case study. Firstly, qualitative and quantitative analyses were performed to reveal ingredients of the preparation via HPLC-MS. Subsequently, multiple PK ingredients and integrated PK investigations were carried out to ascertain ingredients with favorable PK properties (e.g., easily detected at conventional PK time points and high system exposure) for the whole preparation. Next, ingredients against cardiovascular diseases (CVDs) in the preparation were predicted with target fishing and system pharmacology studies. Finally, ingredients with favorable PK properties, satisfactory PK representativeness for the preparation, and high relevance to CVDs were considered as potential PK markers. Their therapeutic effect was further evaluated using the H2O2-induced H9c2 cardiomyocyte-injured model and a proteomics study to identify objective PK markers. As results, it disclosed that SI mainly contains 11 ingredients. Among them, five ingredients, namely, hydroxysafflor yellow A (HSYA), syringin (SYR), p-coumaric acid (p-CA), scutellarin (SCU), and p-hydroxybenzaldehyde (p-HBA), showed favorable PK properties. HSYA, SYR, and rutin (RU) were predicted to show high relevance to CVDs and screened as potential PK markers. However, only HSYA and SYR were confirmed as therapeutic ingredients against CVDs. Combined with these findings, only HSYA demonstrated satisfactory representativeness on PK properties and therapeutic effects of multiple ingredients of the preparation, thereby indicating that HSYA is a potential PK marker for the SI. The results of this study can provide a reference for the characterization of PK markers for traditional Chinese medicines.