bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor Macroscopic Morphology Is an Important Prognostic Factor in Predicting Chemotherapeutic Efficacy and Clinical Outcomes of Patients With Colorectal Neuroendocrine Neoplasms, One Multicenter Retrospective Cohort Study
Authors: Wang Zhijie , An Ke , Li Rui , Liu Qian
Published: December 2021

Background and Aims

Locally advanced and metastatic colorectal neuroendocrine neoplasm (NEN) is a rare disease with a dismal prognosis. We aimed to explore the value of the macroscopic morphology of NENs in the management of TNM stage II-IV colorectal NENs, which has not been fully elucidated in previous reports.

Methods

We retrospectively enrolled 125 eligible patients with TNM stage II-IV colorectal NENs who were diagnosed between 2000 and 2020 from three Chinese hospitals. All were categorized into either protruding or ulcerative NEN groups through endoscopic evaluation of their macroscopic morphology. Clinicopathological data were collected and compared between the two groups. Survival analysis was performed to assess the survival outcomes between the two groups.

Results

A total of 77 and 48 patients had protruding and ulcerative NENs, respectively. Patients with ulcerative NENs had a larger median tumor size (P<0.001) and higher median Ki-67 index (P<0.001), and a larger proportion of these patients had grade G3 disease (P=0.001) and poorly differentiated neoplasms (P=0.001), as well as higher frequencies of T3 and T4 tumors (P=0.006) than patients with protruding NENs. In addition, patients with ulcerative NENs showed a much lower response to first-line chemotherapy [50% (95% CI: 27.3% - 72.7%) versus 20% (95% CI: 3.1% - 36.9%), P=0.03] and a worse 3-year progression-free survival (PFS) rate [19.7% (95% CI: 7.2% - 32.2%) versus 49.5% (95% CI: 37.5% - 61.5%), P=0.001] and 3-year overall survival (OS) rate [30.7% (95% CI: 15.6% - 45.8%) versus 76.9% (95% CI: 66.5% - 87.3%), P<0.001] than those with protruding NENs. The multivariate analysis results indicated that the macroscopic shape of NENs was an independent prognostic factor affecting both PFS (HR = 1.760, 95% CI: 1.024 – 3.026, P = 0.04) and OS (HR = 2.280, 95% CI: 1.123 – 4.628, P = 0.02).

Conclusions

Ulcerative NENs were more malignant and chemotherapy resistant than protruding NENs. Tumor macroscopic morphology is a valuable prognostic factor for stage II-IV colorectal NENs.
Network Pharmacology and Inflammatory Microenvironment Strategy Approach to Finding the Potential Target of Siraitia grosvenorii (Luo Han Guo) for Glioblastoma
Authors: Li Juan , Bi De , Zhang Xin , Cao Yunpeng , Lv Kun , Jiang Lan
Published: December 2021

Background: Glioblastoma (GBM) is the most common and aggressive primary intracranial tumor of the central nervous system, and the prognosis of GBM remains a challenge using the standard methods of treatment—TMZ, radiation, and surgical resection. Traditional Chinese medicine (TCM) is a helpful complementary and alternative medicine. However, there are relatively few studies on TCM for GBM.

Purpose: We aimed to find the connection between TCM and anti-GBM.

Study design: Network pharmacology and inflammatory microenvironment strategy were used to predict Siraitia grosvenorii (Luo Han Guo) target for treating glioblastoma.

Methods: We mainly used network pharmacology and bioinformatics.

Results: CCL5 was significantly highly expressed in GBM with poor prognostics. Uni-cox and randomForest were used to determine that CCL5 was especially a biomarker in GBM. CCL5 was also the target for SG and TMZ. The active ingredient of Luo Han Guo — squalene and CCL5 —showed high binding efficiency. CCL5, a chemotactic ligand, was enriched and positively correlated in eosinophils. CCL5 was also the target of Luo Han Guo, and its effective active integrate compound –— squalene — might act on CCL5.

Conclusion: SG might be a new complementary therapy of the same medicine and food, working on the target CCL5 and playing an anti-GBM effect. CCL5 might affect the immune microenvironment of GBM.
Case Report: Meningoencephalitis With Thrombotic Occlusive Vasculopathy in a Young EBV-Naïve Boy Is Associated With a Novel SH2D1A Mutation
Authors: Steininger Jolanda , Rossmanith Raphael , Geier Christoph B. , Leiss-Piller Alexander , Thonhauser Lukas , Weiss Simone , Hainfellner Johannes A. , Freilinger Michael , Schmidt Wolfgang M. , Eibl Martha M. , Wolf Hermann M.
Published: December 2021

X-linked lymphoproliferative disease (XLP1) is a combined immunodeficiency characterized by severe immune dysregulation caused by mutations in the SH2D1A/SAP gene. Loss or dysfunction of SH2D1A is associated with the inability in clearing Epstein-Barr-Virus (EBV) infections. Clinical manifestation is diverse and ranges from life-threatening hemophagocytic lymphohistiocytosis (HLH) and fulminant infectious mononucleosis (FIM) to lymphoma and antibody deficiency. Rare manifestations include aplastic anemia, chronic gastritis and vasculitis. Herein, we describe the case of a previously healthy eight-year old boy diagnosed with XLP1 presenting with acute non-EBV acute meningoencephalitis with thrombotic occlusive vasculopathy. The patient developed multiple cerebral aneurysms leading to repeated intracerebral hemorrhage and severe cerebral damage. Immunological examination was initiated after development of a susceptibility to infections with recurrent bronchitis and one episode of severe pneumonia and showed antibody deficiency with pronounced IgG1-3-4 subclass deficiency. We could identify a novel hemizygous SH2D1A point mutation affecting the start codon. Basal levels of SAP protein seemed to be detectable in CD8+ and CD4+ T- and CD56+ NK-cells of the patient what indicated an incomplete absence of SAP. In conclusion, we could demonstrate a novel SH2D1A mutation leading to deficient SAP protein expression and a rare clinical phenotype of non-EBV associated acute meningoencephalitis with thrombotic occlusive vasculopathy.
mtROS Induced via TLR-2-SOCE Signaling Plays Proapoptotic and Bactericidal Role in Mycobacterium fortuitum-Infected Head Kidney Macrophages of Clarias gariepinus
Authors: Dahiya Priyanka , Hussain Md. Arafat , Mazumder Shibnath
Published: December 2021

The mechanisms underlying Mycobacterium fortuitum-induced mycobacteriosis remain unexplored. Using head kidney macrophages (HKM) from catfish (Clarias gariepinus), we report that Ca2+ surge across mitochondrial-Ca2+ uniporter (MICU), and consequent mitochondrial ROS (mtROS) production, is imperative for mycobactericidal activity. Inhibition of mtROS alleviated HKM apoptosis and enhanced bacterial survival. Based on RNA interference (RNAi) and inhibitor studies, we demonstrate that the Toll-like receptor (TLR)-2–endoplasmic reticulum (ER) stress–store-operated calcium entry (SOCE) axis is instrumental for activating the mt-Ca2+/mtROS cascade in M. fortuitum-infected HKM. Additionally, pharmacological inhibition of mtROS attenuated the expression of CHOP, STIM1, and Orai1, which suggests a positive feedback loop between ER-stress-induced SOCE and mtROS production. Elevated tumor necrosis factor alpha (TNF-α) levels and caspase-8 activity were observed in HKM consequent to M. fortuitum infection, and our results implicate that mtROS is crucial in activating the TNF-mediated caspase-8 activation. Our results for the first time demonstrate mitochondria as an innate immune signaling center regulating mycobacteriosis in fish. We conclude that M. fortuitum-induced persistent SOCE signaling leads to mtROS production, which in turn activates the TNF-α/caspase-8 axis culminating in HKM apoptosis and bacterial clearance.
Recent Progress on the Applications of Carbonaceous and Metal-Organic Framework Nanomaterials for Supercapacitors
Authors: Zheng Sheng Qiang , Lim Siew Shee , Foo Chuan Yi , Haw Choon Yian , Chiu Wee Siong , Chia Chin Hua , Khiew Poi Sim
Published: December 2021

Supercapacitors (SCs) have been widely investigated in the realm of energy resulting from their superior long lifespan and remarkable power density. However, their practical usage is limited because of the high effective resistance and relatively low energy density. Electrode material is crucial for determining the performance of SCs, so the innovation and development of advanced electrode materials is particularly important. Metal-organic frameworks (MOFs) and carbonaceous materials, including MOF-derived carbons and carbon nanotubes (CNTs), are befitting as electrode active materials for SCs on the strength of the unique features of high porosity, tunable structures, and easy formation of composites with other compounds. Hence, great efforts were devoted on the synthesis strategies and structural modifications of electrodes to enhance the performance of SCs. In this review, the recent innovations in the realm of SCs, including the application of pristine and derivatives of MOFs as SC electrode materials, were extensively studied. Furthermore, the functions and electrochemical performance of various MOFs and their derivatives (e.g., MOF-derived carbons) were analyzed accordingly. Lastly, the innovations and application of CNTs as SC electrode active materials are systematically summarized. This review highlights the electrochemical performance of some advanced MOF- and carbon-based materials, and the critical factors for SC electrode active materials to achieve excellent electrochemical performance in the application of energy storage systems.
Occurrence and Molecular Characterization of Abundant tet(X) Variants Among Diverse Bacterial Species of Chicken Origin in Jiangsu, China
Authors: Li Yingshan , Peng Kai , Yin Yi , Sun Xinran , Zhang Wenhui , Li Ruichao , Wang Zhiqiang
Published: December 2021

Many novel tigecycline-inactivating enzymes encoded by tet(X) variants from different bacteria were discovered since the plasmid-mediated tet(X3) and tet(X4) genes conferring high-level resistance to tigecycline in Enterobacterales and Acinetobacter were reported. However, there have been no comprehensive studies of the prevalence of different tet(X) variants in poultry farms. In this study, we collected 45 chicken fecal samples, isolated tet(X)-positive strains, and performed antimicrobial susceptibility testing, conjugation assay, whole-genome sequencing, and bioinformatics analysis. A total of 15 tet(X)-bearing strains were isolated from 13 samples. Species identification and tet(X) subtyping analysis found that the 15 strains belonged to eight different species and harbored four different tet(X) variants. Genomic investigation showed that transmission of tet(X) variants was associated with various mobile genetic elements, and tet(X4) was the most prevalent variant transferred by conjugative plasmids. Meanwhile, we characterized a plasmid co-harboring tet(X6) and blaOXA–58 in Acinetobacter baumannii. In summary, we demonstrated that different tet(X) variants were widely disseminated in the chicken farming environment and dominated by tet(X4). This finding expands the understanding of the prevalence of tet(X) among different animal sources, and it was advocated to reduce the usage of antibiotics to limit the emergence and transmission of novel tet(X) variants in the poultry industry.
Evaluating the Genetic Capacity of Mycoplasmas for Coenzyme A Biosynthesis in a Search for New Anti-mycoplasma Targets
Authors: Ras Tertius Alwyn , Strauss Erick , Botes Annelise
Published: December 2021

Mycoplasmas are responsible for a wide range of disease states in both humans and animals, in which their parasitic lifestyle has allowed them to reduce their genome sizes and curtail their biosynthetic capabilities. The subsequent dependence on their host offers a unique opportunity to explore pathways for obtaining and producing cofactors – such as coenzyme A (CoA) – as possible targets for the development of new anti-mycoplasma agents. CoA plays an essential role in energy and fatty acid metabolism and is required for membrane synthesis. However, our current lack of knowledge of the relevance and importance of the CoA biosynthesis pathway in mycoplasmas, and whether it could be bypassed within their pathogenic context, prevents further exploration of the potential of this pathway. In the universal, canonical CoA biosynthesis pathway, five enzymes are responsible for the production of CoA. Given the inconsistent presence of the genes that code for these enzymes across Mycoplasma genomes, this study set out to establish the genetic capacity of mycoplasmas to synthesize their own CoA de novo. Existing functional annotations and sequence, family, motif, and domain analysis of protein products were used to determine the existence of relevant genes in Mycoplasma genomes. We found that most Mycoplasma species do have the genetic capacity to synthesize CoA, but there was a differentiated prevalence of these genes across species. Phylogenetic analysis indicated that the phylogenetic position of a species could not be used to predict its enzyme-encoding gene combinations. Despite this, the final enzyme in the biosynthesis pathway – dephospho-coenzyme A kinase (DPCK) – was found to be the most common among the studied species, suggesting that it has the most potential as a target in the search for new broad-spectrum anti-mycoplasma agents.
Several Isoforms for Each Subunit Shared by RNA Polymerases are Differentially Expressed in the Cultivated Olive Tree (Olea europaea L.)
Authors: Fernández-Parras Isabel , Ramírez-Tejero Jorge Antolín , Luque Francisco , Navarro Francisco
Published: December 2021

Plants contain five nuclear RNA polymerases, with RNA pols IV and V in addition to conserved eukaryotic RNA pols I, II, and III. These transcriptional complexes share five common subunits, which have been extensively analyzed only in yeasts. By taking advantage of the recently published olive tree cultivar (Olea europaea L. cv. Picual) genome, we performed a genome-wide analysis of the genomic composition corresponding to subunits common to RNA pols. The cultivated olive tree genome is quite complex and contains many genes with several copies. We also investigated, for the first time, gene expression patterns for subunits common to RNA pols using RNA-Seq under different economically and biologically relevant conditions for the cultivar “Picual”: tissues/organs, biotic and abiotic stresses, and early development from seeds. Our results demonstrated the existence of a multigene family of subunits common to RNA pols, and a variable number of paralogs for each subunit in the olive cultivar “Picual.” Furthermore, these isoforms display specific and differentiated expression profiles depending on the isoform and growth conditions, which may be relevant for their role in olive tree biology.
Social Stress Increases Anxiety-Like Behavior Equally in Male and Female Zebrafish
Authors: Bozi Brenno , Rodrigues Jeane , Lima-Maximino Monica , de Siqueira-Silva Diógenes Henrique , Soares Marta Candeias , Maximino Caio
Published: December 2021

Zebrafish anxiety-like behavior was assessed in the novel tank test after the formation of dominant-subordinate hierarchies. Ten pairs of animals were subjected to dyadic interactions for 5 days, and compared with control animals. After this period, a clear dominance hierarchy was established across all dyads, irrespective of sex. Social status affected parameters of anxiety-like behavior in the novel tank test, with subordinate males and females displaying more bottom-dwelling, absolute turn angle, and freezing than dominant animals and controls. The results suggest that subordinate male and female zebrafish show higher anxiety-like behavior, which together with previous literature suggests that subordination stress is conserved across vertebrates.
A Novel Clinical-Driven Design for Robotic Hand Rehabilitation: Combining Sensory Training, Effortless Setup, and Large Range of Motion in a Palmar Device
Authors: Rätz Raphael , Conti François , Müri René M. , Marchal-Crespo Laura
Published: December 2021

Neurorehabilitation research suggests that not only high training intensity, but also somatosensory information plays a fundamental role in the recovery of stroke patients. Yet, there is currently a lack of easy-to-use robotic solutions for sensorimotor hand rehabilitation. We addressed this shortcoming by developing a novel clinical-driven robotic hand rehabilitation device, which is capable of fine haptic rendering, and that supports physiological full flexion/extension of the fingers while offering an effortless setup. Our palmar design, based on a parallelogram coupled to a principal revolute joint, introduces the following novelties: (1) While allowing for an effortless installation of the user's hand, it offers large range of motion of the fingers (full extension to 180° flexion). (2) The kinematic design ensures that all fingers are supported through the full range of motion and that the little finger does not lose contact with the finger support in extension. (3) We took into consideration that a handle is usually comfortably grasped such that its longitudinal axis runs obliquely from the metacarpophalangeal joint of the index finger to the base of the hypothenar eminence. (4) The fingertip path was optimized to guarantee physiologically correct finger movements for a large variety of hand sizes. Moreover, the device possesses a high mechanical transparency, which was achieved using a backdrivable cable transmission. The transparency was further improved with the implementation of friction and gravity compensation. In a test with six healthy participants, the root mean square of the human-robot interaction force was found to remain as low as 1.37 N in a dynamic task. With its clinical-driven design and easy-to-use setup, our robotic device for hand sensorimotor rehabilitation has the potential for high clinical acceptance, applicability and effectiveness.
Prognostic Significance of Prolonged Corrected QT Interval in Acute Ischemic Stroke
Authors: Ahn Sung-Ho , Lee Ji-Sung , Kim Young-Hak , Yun Mi-Sook , Han Jung-Hee , Kim Soo-Young , Park Min-Gyu , Park Kyung-Pil , Kang Dong-Wha , Kim Jong S. , Kwon Sun U.
Published: December 2021

Background and Purpose: The aim of this study was to determine the relationship between the heart rate-corrected QT (QTc) interval and the risk of incident long-term mortality in patients with acute ischemic stroke (AIS), considering the impact of sex differences on clinical characteristics, outcomes, and QTc intervals.

Methods: We analyzed prospectively registered data included patients with AIS who visited the emergency room within 24 h of stroke onset and underwent routine cardiac testing, such as measurements of cardiac enzymes and 12-lead ECG. QTc interval was corrected for heart rate using Fridericia's formula and was stratified by sex-specific quartiles. Cox proportional hazards models were used to examine the association between baseline QTc interval and incident all-cause death.

Results: A total of 1,668 patients with 1,018 (61.0%) men and mean age 66.0 ± 12.4 years were deemed eligible. Based on the categorized quartiles of the QTc interval, cardiovascular risk profile, and stroke severity increased with prolonged QTc interval, and the risk of long-term mortality increased over a median follow-up of 33 months. Cox proportional hazard model analysis showed that the highest quartile of QTc interval (≥479 msec in men and ≥498 msec in women; hazard ratio [HR]: 1.49, 95% confidence interval [CI]: 1.07–2.08) was associated with all-cause death. Furthermore, dichotomized QTc interval prolongation, defined by the highest septile of the QTc interval (≥501 ms in men and ≥517 m in women: HR: 1.33, 95% CI: 1.00–1.80) was significantly associated with all-cause mortality after adjusting for all clinically relevant variables, such as stroke severity.

Conclusions: Prolonged QTc interval was associated with increased risk of long-term mortality, in parallel with the increasing trend of prevalence of cardiovascular risk profiles and stroke severity, across sex differences in AIS patients.
The Salvinorin Analogue, Ethoxymethyl Ether Salvinorin B, Promotes Remyelination in Preclinical Models of Multiple Sclerosis
Authors: Paton Kelly F. , Robichon Katharina , Templeton Nikki , Denny Lisa , Al Abadey Afnan , Luo Dan , Prisinzano Thomas E. , La Flamme Anne C. , Kivell Bronwyn M.
Published: December 2021

Multiple sclerosis is a neurodegenerative disease associated with demyelination and neuroinflammation in the central nervous system. There is an urgent need to develop remyelinating therapies to better treat multiple sclerosis and other demyelinating diseases. The kappa opioid receptor (KOR) has been identified as a potential target for the development of remyelinating therapies; however, prototypical KOR agonists, such as U50,488 have side effects, which limit clinical use. In the current study, we investigated a Salvinorin A analog, ethoxymethyl ether Salvinorin B (EOM SalB) in two preclinical models of demyelination in C57BL/6J mice. We showed that in cellular assays EOM SalB was G-protein biased, an effect often correlated with fewer KOR-mediated side effects. In the experimental autoimmune encephalomyelitis model, we found that EOM SalB (0.1–0.3 mg/kg) effectively decreased disease severity in a KOR-dependent manner and led to a greater number of animals in recovery compared to U50,488 treatment. Furthermore, EOM SalB treatment decreased immune cell infiltration and increased myelin levels in the central nervous system. In the cuprizone-induced demyelination model, we showed that EOM SalB (0.3 mg/kg) administration led to an increase in the number of mature oligodendrocytes, the number of myelinated axons and the myelin thickness in the corpus callosum. Overall, EOM SalB was effective in two preclinical models of multiple sclerosis and demyelination, adding further evidence to show KOR agonists are a promising target for remyelinating therapies.
Transcriptome Analysis Reveals the Anti-cancerous Mechanism of Licochalcone A on Human Hepatoma Cell HepG2
Authors: Wang Jun , Wei Bo , Thakur Kiran , Wang Chu-Yan , Li Ke-Xin , Wei Zhao-Jun
Published: December 2021

Hepatocellular carcinoma is a malignancy with a low survival rate globally, and there is imperative to unearth novel natural phytochemicals as effective therapeutic strategies. Licochalcone A is a chalcone from Glycyrrhiza that displayed various pharmacological efficacy. A globally transcriptome analysis was carried out to reveal the gene expression profiling to explore Licochalcone A's function as an anti-cancer phytochemical on HepG2 cells and investigate its potential mechanisms. Altogether, 6,061 dysregulated genes were detected (3,414 up-regulated and 2,647 down-regulated). SP1 was expected as the transcription factor that regulates the functions of most screened genes. GO and KEGG analysis was conducted, and the MAPK signaling pathway and the FoxO signaling pathway were two critical signal pathways. Protein-protein interaction (PPI) network analysis based on STRING platform to discover the hub genes (MAPK1, ATF4, BDNF, CASP3, etc.) in the MAPK signaling pathway and (AKT3, GADD45A, IL6, CDK2, CDKN1A, etc.) the FoxO signaling pathway. The protein level of essential genes that participated in significant pathways was consistent with the transcriptome data. This study will provide an inclusive understanding of the potential anti-cancer mechanism of Licochalcone A on hepatocellular, signifying Licochalcone A as a promising candidate for cancer therapy.
Chronic Stress Effects on Tumor: Pathway and Mechanism
Authors: Hong Hanqing , Ji Min , Lai Dongmei
Published: December 2021

Chronic stress is an emotional experience that occurs when people encounter something they cannot adapt to. Repeated chronic stress increases the risk of a variety of diseases, such as cardiovascular disease, depression, endocrine disease, inflammation and cancer. A growing body of research has shown that there is a link between chronic stress and tumor occurrence in both animal studies and clinical studies. Chronic stress activates the neuroendocrine system (hypothalamic-pituitary-adrenal axis) and sympathetic nervous system. Stress hormones promote the occurrence and development of tumors through various mechanisms. In addition, chronic stress also affects the immune function of the body, leading to the decline of immune monitoring ability and promote the occurrence of tumors. The mechanisms of chronic stress leading to tumor include inflammation, autophagy and epigenetics. These factors increase the proliferation and invasion capacity of tumor cells and alter the tumor microenvironment. Antagonists targeting adrenergic receptors have played a beneficial role in improving antitumor activity, as well as chemotherapy resistance and radiation resistance. Here, we review how these mechanisms contribute to tumor initiation and progression, and discuss whether these molecular mechanisms might be an ideal target to treat tumor.
Patient-Derived Explants as a Precision Medicine Patient-Proximal Testing Platform Informing Cancer Management
Authors: Templeton Abby R. , Jeffery Penny L. , Thomas Patrick B. , Perera Mahasha P. J. , Ng Gary , Calabrese Alivia R. , Nicholls Clarissa , Mackenzie Nathan J. , Wood Jack , Bray Laura J. , Vela Ian , Thompson Erik W. , Williams Elizabeth D.
Published: December 2021

Precision medicine approaches that inform clinical management of individuals with cancer are progressively advancing. Patient-derived explants (PDEs) provide a patient-proximal ex vivo platform that can be used to assess sensitivity to standard of care (SOC) therapies and novel agents. PDEs have several advantages as a patient-proximal model compared to current preclinical models, as they maintain the phenotype and microenvironment of the individual tumor. However, the longevity of PDEs is not compatible with the timeframe required to incorporate candidate therapeutic options identified by whole exome sequencing (WES) of the patient’s tumor. This review investigates how PDE longevity varies across tumor streams and how this is influenced by tissue preparation. Improving longevity of PDEs will enable individualized therapeutics testing, and thus contribute to improving outcomes for people with cancer.
Prognostic Value and Outcome for ETV6/RUNX1-Positive Pediatric Acute Lymphoblastic Leukemia: A Report From the South China Children’s Leukemia Group
Authors: Qiu Kun-yin , Xu Hong-gui , Luo Xue-qun , Mai Hui-rong , Liao Ning , Yang Li-hua , Zheng Min-cui , Wan Wu-qing , Wu Xue-dong , Liu Ri-yang , Chen Qi-wen , Chen Hui-qin , Sun Xiao-fei , Jiang Hua , Long Xing-jiang , Chen Guo-hua , Li Xin-yu , Li Chang-gang , Huang Li-bin , Ling Ya-yun , Lin Dan-na , Wen Chuan , Kuang Wen-yong , Feng Xiao-qin , Ye Zhong-lv , Wu Bei-yan , He Xiang-lin , Li Qiao-ru , Wang Li-na , Kong Xian-ling , Xu Lu-hong , Li Chi-kong , Fang Jian-pei
Published: December 2021

Purpose

To analyzed the outcome of ETV6/RUNX1-positive pediatric acute B lymphoblastic leukemia (B-ALL) with the aim of identifying prognostic value.

Method

A total of 2,530 pediatric patients who were diagnosed with B-ALL were classified into two groups based on the ETV6/RUNX1 status by using a retrospective cohort study method from February 28, 2008, to June 30, 2020, at 22 participating ALL centers.

Results

In total, 461 (18.2%) cases were ETV6/RUNX1-positive. The proportion of patients with risk factors (age <1 year or ≥10 years, WB≥50×109/L) in ETV6/RUNX1-positive group was significantly lower than that in negative group (P<0.001), while the proportion of patients with good early response (good response to prednisone, D15 MRD < 0.1%, and D33 MRD < 0.01%) in ETV6/RUNX1-positive group was higher than that in the negative group (P<0.001, 0.788 and 0.004, respectively). Multivariate analysis of 2,530 patients found that age <1 or ≥10 years, SCCLG-ALL-2016 protocol, and MLL were independent predictor of outcome but not ETV6/RUNX1. The EFS and OS of the ETV6/RUNX1-positive group were significantly higher than those of the negative group (3-year EFS: 90.11 ± 4.21%vs82 ± 2.36%,P<0.0001, 3-year OS: 91.99 ± 3.92%vs88.79 ± 1.87%,P=0.017). Subgroup analysis showed that chemotherapy protocol, age, prednisone response, and D15 MRD were important factors affecting the prognosis of ETV6/RUNX1-positive children.

Conclusions

ETV6/RUNX1-positive pediatric ALL showed an excellent outcome but lack of independent prognostic significance in South China. However, for older patients who have the ETV6/RUNX1 fusion and slow response to therapy, to opt for more intensive treatment.
Pediatric Chronic Orofacial Pain: A Narrative Review of Biopsychosocial Associations and Treatment Approaches
Authors: Sangalli Linda , Gibler Robert , Boggero Ian
Published: December 2021

Pediatric chronic orofacial pain (OFP) is an umbrella term which refers to pain associated with the hard and soft tissues of the head, face, and neck lasting >3 months in patients younger than 18 years of age. Common chronic pediatric OFP diagnoses include temporomandibular disorder, headaches, and neuropathic pain. Chronic OFP can adversely affect youth's daily functioning and development in many areas of well-being, and may be associated with emotional stress, depression, functional avoidance, and poor sleep, among other negative outcomes. In this mini-review, we will discuss common psychological comorbidities and familial factors that often accompany chronic pediatric OFP conditions. We will also discuss traditional management approaches for pediatric orofacial pain including education, occlusal appliances, and psychological treatments such as relaxation, mindfulness-based interventions, and cognitive-behavioral treatments. Finally, we highlight avenues for future research, as a better understanding of chronic OFP comorbidities in childhood has the potential to prevent long-term pain-related disability in adulthood.
Safety of SGLT2 Inhibitors: A Pharmacovigilance Study from 2013 to 2021 Based on FAERS
Authors: Zhou Xiang , Ye Xiaofei , Guo Xiaojing , Liu Dongxu , Xu Jinfang , Hu Fangyuan , Zhai Yinghong , Gao Yongqing , Xu Xiao , Dong Ziwei , He Jia
Published: December 2021

Background: Sodium-glucose co-transporter-2 inhibitors (SGLT2is) are widely used in clinical practice for their demonstrated cardiorenal benefits, but multiple adverse events (AEs) have been reported. We aimed to describe the distribution of SGLT2i-related AEs in different systems and identify important medical event (IME) signals for SGLT2i.

Methods: Data from the first quarter (Q1) of 2013–2021 Q2 in FAERS were selected to conduct disproportionality analysis. The definition of AEs and IMEs relied on the system organ classes (SOCs) and preferred terms (PTs) by the Medical Dictionary for Regulatory Activities (MedDRA-version 24.0). Two signal indicators, the reported odds ratio (ROR) and information component (IC), were used to estimate the association between SGLT2is and IMEs.

Results: A total of 57,818 records related to SGLT2i, with 22,537 SGLT2i-IME pairs. Most SGLT2i-related IMEs occurred in monotherapy (N = 21,408, 94.99%). Significant signals emerged at the following SOCs: “metabolism and nutrition disorders” (N = 9,103; IC025 = 4.26), “renal and urinary disorders” (3886; 1.20), “infections and infestations” (3457; 0.85). The common strong signals were observed in diabetic ketoacidosis, ketoacidosis, euglycaemic diabetic ketoacidosis and Fournier’s gangrene. Unexpected safety signals such as cellulitis, osteomyelitis, cerebral infarction and nephrolithiasis were detected.

Conclusion: Our pharmacovigilance analysis showed that a high frequency was reported for IMEs triggered by SGLT2i monotherapy. Different SGLT2is caused different types and the association strengths of IMEs, while they also shared some specific PTs. Most of the results are generally consistent with previous studies, and more pharmacoepidemiological studies are needed to validate for unexpected AEs. Based on risk-benefit considerations, clinicians should be well informed about important medical events that may be aggravated by SGLT2is.
RETRACTED: Potamogeton perfoliatus L. Extract Attenuates Neuroinflammation and Neuropathic Pain in Sciatic Nerve Chronic Constriction Injury-Induced Peripheral Neuropathy in Rats
Authors: Mahmoud Mona F. , Rezq Samar , Alsemeh Amira E. , Abdelfattah Mohamed A. O. , El-Shazly Assem M. , Daoud Rachid , El Raey Mohamed A. , Sobeh Mansour
Published: December 2021

Sciatic nerve injury is often associated with neuropathic pain and neuroinflammation in the central and peripheral nervous systems. In our previous work, Potamogeton perfoliatus L. displayed anti-inflammatory, antipyretic and analgesic properties, predominantly via the inhibition of COX-2 enzyme and attenuation of oxidative stress. Herein, we extended our investigations to study the effects of the plant’s extract on pain-related behaviors, oxidative stress, apoptosis markers, GFAP, CD68 and neuro-inflammation in sciatic nerve chronic constriction injury (CCI) rat model. The levels of the pro-inflammatory marker proteins in sciatic nerve and brainstem were measured with ELISA 14 days after CCI induction. Pretreatment with the extract significantly attenuated mechanical and cold allodynia and heat hyperalgesia with better potential than the reference drug, pregabalin. In addition, CCI lead to the overexpression of prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), tumor necrosis alpha (TNFα), nuclear factor κB (NF-κB), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and NADPH oxidase-1 (NOX-1) and decreased the catalase level in sciatic nerve and brainstem. The observed neuro-inflammatory changes were accompanied with glial cells activation (increased GFAP and CD68 positive cells), apoptosis (increased Bax) and structural changes in both brainstem and sciatic nerve. The studied extract attenuated the CCI-induced neuro-inflammatory changes, oxidative stress, and apoptosis while it induced the expression of Bcl-2 and catalase in a dose dependent manner. It also decreased the brainstem expression of CD68 and GFAP indicating a possible neuroprotection effect. Taking together, P. perfoliatus may be considered as a novel therapy for neuropathic pain patients after performing the required clinical trials.
Network Robustness Analysis Based on Maximum Flow
Authors: Cai Meng , Liu Jiaqi , Cui Ying
Published: December 2021

Network robustness is the ability of a network to maintain a certain level of structural integrity and its original functions after being attacked, and it is the key to whether the damaged network can continue to operate normally. We define two types of robustness evaluation indicators based on network maximum flow: flow capacity robustness, which assesses the ability of the network to resist attack, and flow recovery robustness, which assesses the ability to rebuild the network after an attack on the network. To verify the effectiveness of the robustness indicators proposed in this study, we simulate four typical networks and analyze their robustness, and the results show that a high-density random network is stronger than a low-density network in terms of connectivity and resilience; the growth rate parameter of scale-free network does not have a significant impact on robustness changes in most cases; the greater the average degree of a regular network, the greater the robustness; the robustness of small-world network increases with the increase in the average degree. In addition, there is a critical damage rate (when the node damage rate is less than this critical value, the damaged nodes and edges can almost be completely recovered) when examining flow recovery robustness, and the critical damage rate is around 20%. Flow capacity robustness and flow recovery robustness enrich the network structure indicator system and more comprehensively describe the structural stability of real networks.
Identification of Abscisic Acid-Dependent Phosphorylated Basic Helix-Loop-Helix Transcription Factors in Guard Cells of Vicia faba by Mass Spectrometry
Authors: Hayashi Yuki , Takahashi Yohei , Fukatsu Kohei , Tada Yasuomi , Takahashi Koji , Kuwata Keiko , Suzuki Takamasa , Kinoshita Toshinori
Published: December 2021

An unknown 61 kDa protein is phosphorylated by abscisic acid (ABA)-activated protein kinase in response to ABA and binds to 14-3-3 protein in a phosphorylation-dependent manner in guard-cell protoplasts (GCPs) from Vicia faba. Subsequently, ABA-dependent phosphorylated proteins were identified as basic helix–loop–helix transcription factors, named ABA-responsive kinase substrates (AKSs) in GCPs from Arabidopsis thaliana. However, whether the 61 kDa protein in Vicia GCPs is an AKS is unclear. We performed immunoprecipitation of ABA-treated Vicia GCPs using anti-14-3-3 protein antibodies and identified several AKS isoforms in V. faba (VfAKSs) by mass spectrometry. The 61 kDa protein was identified as VfAKS1. Phosphoproteomic analysis revealed that VfAKSs are phosphorylated at Ser residues, which are important for 14-3-3 protein binding and monomerisation, in response to ABA in GCPs. Orthologs of AtABCG40, an ABA importer in guard cells, and CHC1, a clathrin heavy chain and a regulator of stomatal movement, also co-immunoprecipitated with 14-3-3 protein from guard cells.
Metric Goodness and Measurement Invariance of the Italian Brief Version of Interpersonal Reactivity Index: A Study With Young Adults
Authors: Diotaiuti Pierluigi , Valente Giuseppe , Mancone Stefania , Grambone Angela , Chirico Andrea
Published: December 2021

The Interpersonal Reactivity Index (IRI) is a widely used multidimensional measure to assess empathy across four main dimensions: perspective taking (PT) empathic concern (EC) personal distress (PD) fantasy (F). This study aimed to replicate the Italian validation process of the shortened IRI (Interpersonal Reactivity Index) scale in order to confirm its psychometric properties with a sample of young adults. The Gender Measurement Invariance of empathy in this age group was also an objective of the work in order to increase the data on this aspect. A total of 683 Italian university students participated in a non-probabilistic sampling. The 16-item version was confirmed in its four-factor structure but with changes to some items. The model showed good fits with both the CFA and the gender Measurement Invariance. The internal consistency measures were found to be fully satisfactory. Convergent validity was tested by the correlations with the Prosocialness Scale for Adults and The Toronto Alexithymia Scale-20. As hypothesized the measure proved good convergent validity with Prosocialness, i.e., the willingness to assist, help, share, care and empathy with others, and a relevant inverse association with the External Oriented Thinking, characterizing individuals with emotionally poor thinking. This research provided additional evidence for a link between alexithymia and poor empathic abilities in young adults.
Financial Performance Under the Influence of the Coronavirus Disease 2019: Effects of Strategic Flexibility and Environmental Dynamics in Big Data Capability
Authors: Chen Limei , Zhai Liping , Zhu Weiwei , Luo Gongzhi , Zhang Jing , Zhang Yaozhen
Published: December 2021

This study draws on the dynamic capabilities view and the firm’s big data capability (BDC) in the new economic environment. It constructs an adjusted intermediary model to study the mechanism of BDC, strategic flexibility, and environmental dynamic affecting financial performance. We find that strategic flexibility plays an intermediary role in the “Converse-U” relationship between BDC and financial performance. Environmental dynamics adjust the relationship between BDC and financial performance positively and smooth the “Converse-U” relationship. The findings suggest building and managing BDC, combining BDC with the management process, and achieving continuous financial performance improvement in a dynamic environment. The paper also puts forward the nonlinear hypothesis, discusses the “Converse-U” relationship between BDC and enterprise financial performance in the Chinese context of digital economy explosion and growth, and considers the intermediary mechanism of strategic flexibility and the regulatory effect of environmental dynamics.
Effects of Low-Load Blood-Flow Restricted Resistance Training on Functional Capacity and Patient-Reported Outcome in a Young Male Suffering From Reactive Arthritis
Authors: Jørgensen Stian Langgård , Mechlenburg Inger
Published: December 2021

Introduction: Reactive arthritis (ReA) is a chronic inflammatory disease usually caused by a preceding gastrointestinal or genitourinary bacterial infection. ReA usually occurs in the lower limbs causing joint pain and joint swelling. Physiotherapy-led exercise is recommended to prevent muscle atrophy. The purpose of this case report is to describe the outcome after 12 weeks of low-load blood flow restricted resistance training (BFR-RT) as a rehabilitation method for a young male suffering from ReA.

Methods and materials: A 17-year-old male suffered from ReA in the both knee joints and the left hip joint. 36 months after the incident, he suffered from another ReA incident in his right knee. Non-steroid anti-inflammatory drugs and a new arthrocentesis added with corticosteroid injection was unsuccessful in treating the ReA. The patient performed 12 weeks of BFR-RT on the right lower limb with a low amount of supervision after the first week of training. Assessment of unilateral 30-sec chair stand test (u30-sec CST), low-thigh circumference above apex patella, The Knee Injury and Osteoarthritis Outcome Score (KOOS), The Forgotten Knee Joint Score (FJS), and Numeric Ranking Scale for pain (NRS) was performed at baseline and after 3,6,9, and 12 weeks of BFR-RT.

Results: The patient completed all planned exercise sessions. u30-sec CST improved with 7 repetitions (reps) on the right limb and 5 reps on the left leg. Low-thigh circumference decreased 1.1 cm on the right leg and 1.0 on the left leg. KOOS symptoms, ADL, quality of life and FJS demonstrated a clinically relevant change on 10, 14 and 23 points.

Conclusion: The present case study indicates that even with low amounts of supervision BFR-RT could increase functional performance, reduce knee joint swelling and improve key patient-reported outcome.
A 20-Year Journey Through an Orphan African Baobab (Adansonia digitata L.) Towards Improved Food and Nutrition Security in Africa
Authors: Assogbadjo Achille E. , Chadare Flora Josiane , Manda Leonard , Sinsin Brice
Published: December 2021

The African baobab (Adansonia digitata L.) is a multipurpose orphan tree species of the semi-arid and sub-humid Sub-Saharan Africa where it plays an important role in rural livelihoods. Its wide distribution and dense nutrition properties make it an important species for food and nutrition security in Africa. However, despite the increasing interest in the species over the past two decades, the full potential of baobab remains underexploited. This review highlights strides made over the past 20 years (2001–2020) towards harnessing and unlocking the potential values of baobab in Benin, West Africa, to contribute to food and nutrition security. Challenges and threats are identified, and next steps suggested to guide research and development initiatives for orphan tree fruit species like baobab to address hunger and malnutrition in Africa.
Uptake of Climate Smart Agriculture in Peri-Urban Areas of South Africa's Economic Hub Requires Up-Scaling
Authors: Chitakira Munyaradzi , Ngcobo Nombuso Z. P.
Published: December 2021

Climate variability and change impact significantly on food security and the livelihoods of smallholder farmers making it necessary for the farmers to prioritize investment in adaptation and mitigation approaches, such as climate smart agriculture, to enhance resilience. Climate smart agriculture approaches have been adopted in many countries around the world to address the adverse impacts of climate change on agricultural production. There is limited information about climate smart agriculture adoption by peri-urban farmers in developing countries. The present study aimed to assess the extent to which agricultural activities by smallholder crop farmers in the City of Tshwane Metropolitan Municipality in Gauteng province of South Africa are climate smart, and to establish the sustainable measures to be put in place to enhance the adoption of climate smart agriculture. The study made use of a mixed method design combining qualitative and quantitative approaches. A combination of simple random and non-probability sampling techniques was employed to select the study locations and identify respondents. A sample of thirty-six farmers were selected for the study. The main findings revealed overwhelming awareness of climate change and the impacts thereof on crop productivity and yields. However, the respondents' level of awareness of climate smart agriculture technologies was generally low. Despite the lack of knowledge of climate smart agriculture practices, the farmers were, to an extent, utilizing adaptation mechanisms acquired from indigenous systems or scientific knowledge. Examples of these practices include mulching, cover cropping, crop rotation and use of crop varieties. The study concludes that much more can be done to scale up the uptake of climate smart agriculture in the Gauteng province. The study recommends formal and informal strategies including one-on-one extension programs to raise the awareness of climate smart agriculture technologies appropriate to the unique conditions of the farmers.
A Pathfinding Problem for Fork-Join Directed Acyclic Graphs with Unknown Edge Length
Authors: Hiraishi Kunihiko
Published: December 2021

In a previous paper by the author, a pathfinding problem for directed trees is studied under the following situation: each edge has a nonnegative integer length, but the length is unknown in advance and should be found by a procedure whose computational cost becomes exponentially larger as the length increases. In this paper, the same problem is studied for a more general class of graphs called fork-join directed acyclic graphs. The problem for the new class of graphs contains the previous one. In addition, the optimality criterion used in this paper is stronger than that in the previous paper and is more appropriate for real applications.
In Vitro Synergism of Azithromycin Combination with Antibiotics against OXA-48-Producing Klebsiella pneumoniae Clinical Isolates
Authors: Singkham-in Uthaibhorn , Muhummudaree Netchanok , Chatsuwan Tanittha
Published: December 2021

Carbapenem-resistant Klebsiella pneumoniae has globally emerged as an urgent threat leading to the limitation for treatment. K. pneumoniae carrying blaOXA-48, which plays a broad magnitude of carbapenem susceptibility, is widely concerned. This study aimed to characterize related carbapenem resistance mechanisms and forage for new antibiotic combinations to combat blaOXA-48-carrying K. pneumoniae. Among nine isolates, there were two major clones and a singleton identified by ERIC-PCR. Most isolates were resistant to ertapenem (MIC range: 2–>256 mg/L), but two isolates were susceptible to imipenem and meropenem (MIC range: 0.5–1 mg/L). All blaOXA-48-carrying plasmids conferred carbapenem resistance in Escherichia coli transformants. Two ertapenem-susceptible isolates carried both outer membrane proteins (OMPs), OmpK35 and OmpK36. Lack of at least an OMP was present in imipenem-resistant isolates. We evaluated the in vitro activity of an overlooked antibiotic, azithromycin, in combination with other antibiotics. Remarkably, azithromycin exhibited synergism with colistin and fosfomycin by 88.89% and 77.78%, respectively. Bacterial regrowth occurred after exposure to colistin or azithromycin alone. Interestingly, most isolates were killed, reaching synergism by this combination. In conclusion, the combination of azithromycin and colistin may be an alternative strategy in dealing with blaOXA-48-carrying K. pneumoniae infection during a recent shortage of newly effective antibiotic development.