bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural pathways of phonological and semantic processing and its relations to children’s reading skills
Authors: Wagley Neelima , Booth James R.
Published: October 2022

Behavioral research shows that children’s phonological ability is strongly associated with better word reading skills, whereas semantic knowledge is strongly related to better reading comprehension. However, most neuroscience research has investigated how brain activation during phonological and semantic processing is related to word reading skill. This study examines if connectivity during phonological processing in the dorsal inferior frontal gyrus (dIFG) to posterior superior temporal gyrus (pSTG) pathway is related to word reading skill, whereas connectivity during semantic processing in the ventral inferior frontal gyrus (vIFG) to posterior middle temporal gyrus (pMTG) pathway is related to reading comprehension skill. We used behavioral and functional magnetic resonance imaging (fMRI) data from a publicly accessible dataset on OpenNeuro.org. The research hypotheses and analytical plan were pre-registered on the Open Science Framework. Forty-six children ages 8–15 years old were included in the final analyses. Participants completed an in-scanner reading task tapping into phonology (i.e., word rhyming) and semantics (i.e., word meaning) as well as standardized measures of word reading and reading comprehension skill. In a series of registered and exploratory analyses, we correlated connectivity coefficients from generalized psychophysiological interactions (gPPI) with behavioral measures and used z-scores to test the equality of two correlation coefficients. Results from the preregistered and exploratory analyses indicated weak evidence that functional connectivity of dIFG to pSTG during phonological processing is positively correlated with better word reading skill, but no evidence that connectivity in the vIFG-pMTG pathway during semantic processing is related to better reading comprehension skill. Moreover, there was no evidence to support the differentiation between the dorsal pathway’s relation to word reading and the ventral pathway’s relation to reading comprehension skills. Our finding suggesting the importance of phonological processing to word reading is in line with prior behavioral and neurodevelopmental models.
Stroke mortality attributable to high red meat intake in China and South Korea: An age–period–cohort and joinpoint analysis
Authors: Chen Fangyao , Hu Weiwei , Chen Shiyu , Si Aima , Zhang Yuxiang , Ma Jiaojiao
Published: October 2022

The high intake of red meat is well recognized as a major health concern worldwide. It has been recognized as a risk factor for several non-communicable chronic diseases, including stroke. However, previously published studies have not performed a comprehensive analysis of the long-time trend of stroke mortality attributable to high red meat intake in China and South Korea, two countries with similar dietary patterns and changing trends. Therefore, this study aimed to reveal the influence of age, time period, and birth cohort on long-term trends of stroke mortality attributable to high red meat intake and relative gender differences in China and South Korea. Data were obtained from the Global Burden of Disease 2019 database. The age–period–cohort model was used to estimate the effect of age, time period, and birth cohort. The average and annual percent changes were estimated using the joinpoint regression analysis. Results indicated that the overall attributable age-standardized mortality rates of stroke in China decreased by 1.0% (P < 0.05) for female and 0.1% (P > 0.05) for male individuals, compared with a decrease of 4.9% for female and 3.7% for male individuals in South Korea (both P < 0.05). Age–period–cohort analysis revealed that the attributable stroke mortality decreased along with the time period, and increased along with age. Significant gender differences were observed, male individuals in both countries were at higher risk than their female counterparts, especially in China. Joinpoint analysis suggested that the attributable stroke mortality for both genders in South Korea and female individuals in China showed a decreasing trend, while it is stable for male individuals in China. Although prominent reductions were observed during the past decades, the attributable stroke mortality risk in China and South Korea is still high. Our findings indicate that controlling the intake of red meat may be a cost-effective strategy to reduce stroke mortality risk and the corresponding disease burden, especially for Chinese male individuals.
Targeting CD38 for acute leukemia
Authors: Zhong Xushu , Ma Hongbing
Published: October 2022

Acute leukemia (AL) is a hematological malignancy, and the prognosis of most AL patients hasn’t improved significantly, particularly for relapsed or refractory (R/R) AL. Therefore, new treatments for R/R adult acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are urgently necessary. Novel developments have been made in AL treatment, including target and immune therapies. CD38 is one of the targets due to its high expression in many hematological malignancies, including multiple myeloma, ALL and a subset of AML. Consequently, targeting CD38 therapies, including CD38 monoclonal antibodies (mAbs), bispecific antibodies, and CAR-T cell therapy, exhibit promising efficacy in treating multiple myeloma without significant toxicity and are being explored in other hematological malignancies and nonhematological diseases. Herein, this review focuses on targeting CD38 therapies in ALL and AML, which demonstrate sound antileukemic effects in acute leukemia and are expected to become effective treatment methods.
Development and validation of a novel prognosis prediction model for patients with myelodysplastic syndrome
Authors: Liang Haiping , Feng Yue , Guo Yuancheng , Jian Jinli , Zhao Long , Luo Xingchun , Tao Lili , Liu Bei
Published: October 2022

Background

Somatic mutations are widespread in patients with Myelodysplastic Syndrome (MDS) and are associated with prognosis. However, a practical prognostic model for MDS that incorporates somatic mutations urgently needs to be developed.

Methods

A cohort of 201 MDS patients from the Gene Expression Omnibus (GEO) database was used to develop the model, and a single-center cohort of 115 MDS cohorts from Northwest China was used for external validation. Kaplan-Meier analysis was performed to compare the effects of karyotype classifications and gene mutations on the prognosis of MDS patients. Univariate and multivariate Cox regression analyses and Lasso regression were used to screen for key prognostic factors. The shinyapps website was used to create dynamic nomograms with multiple variables. The time-dependent receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA) were used to evaluate the model’s discrimination, accuracy and clinical utility.

Results

Six risk factors (age, bone morrow blast percentage, ETV6, TP53, EZH2, and ASXL1) were considered as predictor variables in the nomogram. The nomogram showed excellent discrimination, with respective the area under the ROC curve (AUC) values of 0.850, 0.839, 0.933 for the training cohort at 1 year, 3 years and 5 years; 0.715, 0.802 and 0.750 for the testing cohort at 1 year, 3 years and 5 years; and 0.668, 0.646 and 0.731 for the external validation cohort at 1 year, 3 years and 5 years. The calibration curves and decision curve showed that the nomogram had good consistency and clinical practical benefit. Finally, a stratified analysis showed that MDS patients with high risk had worse survival outcomes than patients with low risk.

Conclusion

We developed a nomogram containing six risk factors, which provides reliable and objective predictions of prognosis for MDS patients.
Characterization of hotspot exonuclease domain mutations in the DNA polymerase ϵ gene in endometrial cancer
Authors: Tian Wenjuan , Ji Zhaodong , Wang Jingshu , Meng Jiao , Bi Rui , Ren Yulan , Shan Boer , Yang Gong , Wang Huaying
Published: October 2022

Objective

This study was aimed to profile hotspot exonuclease domain mutations (EDMs) of the DNA polymerase ϵ gene (POLE) in endometrial cancer (EC) and to investigate the effects of EDMs on tumor cell behavior and catalytic activities of Polϵ.

Methods

POLE sequencing was performed in tumor tissue samples from patients with EC to identify hotspot EDMs. Bioinformatics tools were used to select the potential pathogenic EDMs. The association of EDMs with the clinical outcomes of patients was assessed. EC cells were transfected with wildtype POLE or POLE variants to examine the effects of the EDMs on EC cell behavior, including cell cycle, migration, and invasion. Co-immunoprecipitation was employed to obtain FLAG-tagged wildtype and mutant catalytic subunits of Polϵ, followed by the assessment of polymerase and exonuclease activities.

Results

In addition to previously reported P286R and V411L, R375Q and P452L were identified as novel, and deleterious POLE hotspot EDMs of EC. Patients in EDM group had significantly better clinical outcomes than the rest of the cohort. Compared with wildtype POLE, overexpression of POLE variants promoted cisplatin resistance, G0/G1 cell cycle arrest, and cell migration and invasion in EC cells. Overexpression of POLE variants significantly increased the abundance of 3’-OH and upregulated the expression of DNA mismatch repair genes in HEK293T cells. Compared with wildtype Polϵ, Pol ϵ mutants exhibited undermined polymerase and exonuclease abilities in the presence of mismatched nucleotides in HEK293 cells.

Conclusion

We characterized the of hotspot exonuclease domain mutations in the DNA polymerase ϵ gene and identified P286R, V411L, R375Q, and P452L as pathogenic POLE hotspot EDMs in endometrial cancer. These hotspot EDMs are associated with the malignant behavior of endometrial cancer cells in vitro and favorable prognosis in patients, suggesting that POLE affects a wide range of cellular processes beyond DNA replication and proofreading.
Multilevel impacts of a pediatric early warning system in resource-limited pediatric oncology hospitals
Authors: Mirochnick Emily , Graetz Dylan E. , Ferrara Gia , Puerto-Torres Maria , Gillipelli Srinithya R. , Elish Paul , Muniz-Talavera Hilmarie  , Gonzalez-Ruiz Alejandra , Armenta Miriam , Barra Camila , Diaz-Coronado Rosdali , Hernandez Cinthia , Juarez Susana , Loeza Jose de Jesus , Mendez Alejandra , Montalvo Erika , Penafiel Eulalia , Pineda Estuardo , Agulnik Asya
Published: October 2022

Background

Pediatric Early Warning Systems (PEWS) reduce clinical deterioration, improve interdisciplinary communication, and provide cost savings; however, little is known about how these impacts are achieved or related. This study evaluates the multi-level impacts of PEWS in resource-limited pediatric oncology centers.

Methods

We conducted 71 semi-structured interviews including physicians (45%), nurses (45%), and administrators (10%) from 5 resource-limited pediatric oncology centers in 4 Latin American countries. Interviews were conducted in Spanish, transcribed, and translated into English. A code book was developed using a priori and inductively derived codes. Transcripts were independently coded by 2 coders, achieving a kappa of 0.8-0.9. Thematic content analysis explored perceived impacts of PEWS at the level of the patient, clinician, healthcare team, and institution.

Results

PEWS improved the quality of attention for patients, reducing morbidity and mortality. Clinicians felt more knowledgeable, confident, and empowered providing patient care, resulting in greater job satisfaction. PEWS affected team dynamics by improving interdisciplinary (ward and intensive care unit) and interprofessional (physicians and nurses) relationships and communication. This ultimately led to institutional culture change with emphasis on patient safety, collaboration with other centers, and receipt of institutional awards. Together, these impacts led to hospital-wide support of ongoing PEWS use.

Conclusions

In resource-limited hospitals, PEWS use results in multi-level positive impacts on patients, clinicians, teams, and institutions, creating a feedback loop that further supports ongoing PEWS use. These findings can guide advocacy for PEWS to various stakeholders, improve PEWS effectiveness, and inform assessment of other interventions to improve childhood cancer outcomes.
The role of neoadjuvant chemotherapy in patients with locally advanced colon cancer: A systematic review and meta-analysis
Authors: Liang Zongyu , Li Zhu , Yang Qingshui , Feng Jiahao , Xiang Deyu , Lyu Haina , Mai Guangzhi , Wang Wanchuan
Published: October 2022

Background

Controversy persists about neoadjuvant chemotherapy (NAC) within the field of locally advanced colon cancer (LACC). The purpose of this study was to assess the existing and latest literature with high quality to determine the role of NAC in various aspects.

Methods

A comprehensive literature search of the PubMed, Embase, Web of Science, and the Cochrane Library databases was conducted from inception to April 2022. Review Manager 5.3 was applied for meta-analyses with a random-effects model whenever possible.

Results

Overall, 8 studies were included in this systematic review and meta-analysis, comprising 4 randomized controlled trials (RCTs) and 4 retrospective studies involving 40,136 participants. The 3-year overall survival (OS) (HR: 0.90, 95% CI: 0.66-1.23, P = 0.51) and 5-year OS (HR: 0.89, 95% CI: 0.53-1.03, P = 0.53) were comparable between two groups. Mortality in 30 days was found less frequent in the NAC group (OR: 0.43, 95% CI: 0.20-0.91, P = 0.03), whereas no significant differences were detected concerning other perioperative complications, R0 resection, or adverse events. In terms of subgroup analyses for RCTs, less anastomotic leak (OR: 0.51, 95% CI: 0.31-0.86, P = 0.01) and higher R0 resection rate (OR: 2.35, 95% CI: 1.04-5.32, P = 0.04) were observed in the NAC group.

Conclusions

NAC is safe and feasible for patients with LACC, but no significant survival benefit could be demonstrated. The application of NAC still needs to be prudent until significant evidence supporting the oncological outcomes is presented.

Systematic review registration

https://www.crd.york.ac.uk/prospero, identifier (CRD42022333306).
Degradome-focused RNA interference screens to identify proteases important for breast cancer cell growth
Authors: Hölzen Lena , Syré Kerstin , Mitschke Jan , Brummer Tilman , Miething Cornelius , Reinheckel Thomas
Published: October 2022

Proteases are known to promote or impair breast cancer progression and metastasis. However, while a small number of the 588 human and 672 murine protease genes have been extensively studied, others were neglected. For an unbiased functional analysis of all genome-encoded proteases, i.e., the degradome, in breast cancer cell growth, we applied an inducible RNA interference library for protease-focused genetic screens. Importantly, these functional screens were performed in two phenotypically different murine breast cancer cell lines, including one stem cell-like cell line that showed phenotypic plasticity under changed nutrient and oxygen availability. Our unbiased genetic screens identified 252 protease genes involved in breast cancer cell growth that were further restricted to 100 hits by a selection process. Many of those hits were supported by literature, but some proteases were novel in their functional link to breast cancer. Interestingly, we discovered that the environmental conditions influence the degree of breast cancer cell dependency on certain proteases. For example, breast cancer stem cell-like cells were less susceptible to depletion of several mitochondrial proteases in hypoxic conditions. From the 100 hits, nine proteases were functionally validated in murine breast cancer cell lines using individual knockdown constructs, highlighting the high reliability of our screens. Specifically, we focused on mitochondrial processing peptidase (MPP) subunits alpha (Pmpca) and beta (Pmpcb) and discovered that MPP depletion led to a disadvantage in cell growth, which was linked to mitochondrial dysfunction.
Extracellular vesicles from gastric epithelial GES-1 cells infected with Helicobacter pylori promote changes in recipient cells associated with malignancy
Authors: González María Fernanda , Burgos-Ravanal Renato , Shao Baohai , Heinecke Jay , Valenzuela-Valderrama Manuel , Corvalán Alejandro H. , Quest Andrew F. G.
Published: October 2022

Chronic Helicobacter pylori (H. pylori) infection is considered the main risk factor for the development of gastric cancer. Pathophysiological changes in the gastric mucosa initiated by this bacterium can persist even after pharmacological eradication and are likely attributable also to changes induced in non-infected cells as a consequence of intercellular communication via extracellular vesicles (EVs). To better understand what such changes might entail, we isolated EVs from immortalized normal gastric GES-1 cells infected (EVHp+) or not with H. pylori (EVHp-) by ultracentrifugation and characterized them. Infection of GES-1 cells with H. pylori significantly increased the release of EVs and slightly decreased the EV mean size. Incubation with EVHp+ for 24 h decreased the viability of GES-1 cells, but increased the levels of IL-23 in GES-1 cells, as well as the migration of GES-1 and gastric cancer AGS cells. Furthermore, incubation of GES-1 and AGS cells with EVHp+, but not with EVHp-, promoted cell invasion and trans-endothelial migration in vitro. Moreover, stimulation of endothelial EA.hy926 cells for 16 h with EVHp+ promoted the formation of linked networks. Finally, analysis by mass spectrometry identified proteins uniquely present and others enriched in EVHp+ compared to EVHp-, several of which are known targets of hypoxia induced factor-1α (HIF-1α) that may promote the acquisition of traits important for the genesis/progression of gastric pre-neoplastic changes associated with H. pylori infection. In conclusion, the harmful effects of H. pylori infection associated with the development of gastric malignancies may spread via EVs to non-infected areas in the early and later stages of gastric carcinogenesis.
Drug resistance dependent on allostery: A P-loop rigor Eg5 mutant exhibits resistance to allosteric inhibition by STLC
Authors: Indorato Rose-Laure , DeBonis Salvatore , Garcia-Saez Isabel , Skoufias Dimitrios A.
Published: October 2022

The mitotic kinesin Eg5 has emerged as a potential anti-mitotic target for the purposes of cancer chemotherapy. Whether clinical resistance to these inhibitors can arise is unclear. We exploited HCT116 cancer cell line to select resistant clones to S-trityl-L-cysteine (STLC), an extensively studied Eg5 loop-L5 binding inhibitor. The STLC resistant clones differed in their resistance to other loop-L5 binding inhibitors but remained sensitive to the ATP class of competitive Eg5 specific inhibitors. Eg5 is still necessary for bipolar spindle formation in the resistant clones since the cells were sensitive to RNAi mediated depletion of Eg5. One clone expressing Eg5(T107N), a dominant point mutation in the P-loop of the ATP binding domain of the motor, appeared to be not only resistant but also dependent on the presence of STLC. Eg5(T107N) expression was associated also with resistance to the clinical relevant loop-L5 Eg5 inhibitors, Arry-520 and ispinesib. Ectopic expression of the Eg5(T107N) mutant in the absence of STLC was associated with strong non-exchangeable binding to microtubules causing them to bundle. Biochemical assays showed that in contrast to the wild type Eg5-STLC complex, the ATP binding site of the Eg5(T107N) is accessible for nucleotide exchange only when the inhibitor is present. We predict that resistance can be overcome by inhibitors that bind to other than the Eg5 loop-L5 binding site having different chemical scaffolds, and that allostery-dependent resistance to Eg5 inhibitors may also occur in cells and may have positive implications in chemotherapy since once diagnosed may be beneficial following cessation of the chemotherapeutic regimen.
Prognosis of clear cell renal cell carcinoma patients stratified by age: A research relied on SEER database
Authors: Liao Zhouning , Wang Dang , Song Ning , Xu Yang , Ge Heming , Peng Zhangzhe
Published: October 2022

Objective

Clear cell renal cell carcinoma may affect patients of any age. To date, there are only a limited number of large data studies on renal clear cell carcinoma in different age groups. This study assessed CCRCC risk factors in different age groups using the Surveillance Epidemiology and End Results (SEER) database.

Methods

We selected 58372 cases from the SEER database. These patients were divided into seven different age groups. Cox regression models were used to find independent risk factors for the survival of CCRCC patients. Based on independent risk factors, a nomogram was drawn with R software. Kaplan-Meier method for survival analysis and X-tile software were used to find the optimal age group for diagnosis.

Results

Univariate analysis revealed that patients’ age, sex, race, marital status, grade, TNM (tumor, node, metastasis) stage, surgery, WHO/ISUP grade were correlated with survival (P<0.01). Age was an independent risk factor for survival in patients with CCRCC according to multivariate Cox regression analysis (p<0.01). All-cause mortality and tumor-specific mortality increased according to the increasing age of the patients. The optimal cut-off values for age were defined as 58 and 76 years and 51 and 76 years, respectively, according to overall survival (OS) and cause-specific survival (CSS).

Conclusion

There is a negative correlation between age and survival of CCRCC patients. The difference in prognosis of patients in different age groups has important implications for clinical treatment. Therefore, the diagnosis and treatment plan should be based on more detailed age grouping, which is more beneficial to improving the prognosis and survival of patients.
Distal neuropathic pain in HIV is associated with functional connectivity patterns in default mode and salience networks
Authors: Hays Weeks Chelsea C. , Simmons Alan N. , Strigo Irina A. , Timtim Sara , Ellis Ronald J. , Keltner John R.
Published: October 2022

HIV-associated distal neuropathic pain (DNP) is one of the most prevalent, disabling, and treatment-resistant complications of HIV, but its biological underpinnings are incompletely understood. While data specific to mechanisms underlying HIV DNP are scarce, functional neuroimaging of chronic pain more broadly implicates the role of altered resting-state functional connectivity within and between salience network (SN) and default mode network (DMN) regions. However, it remains unclear the extent to which HIV DNP is associated with similar alterations in connectivity. The current study aimed to bridge this gap in the literature through examination of resting-state functional connectivity patterns within SN and DMN regions among people with HIV (PWH) with and without DNP. Resting state functional magnetic resonance imaging (rs-fMRI) scans were completed among 62 PWH with HIV-associated peripheral neuropathy, of whom 27 reported current DNP and 35 did not. Using subgrouping group iterative multiple estimation, we compared connectivity patterns in those with current DNP to those without. We observed weaker connectivity between the medial prefrontal cortex (MPFC) and posterior cingulate cortex (PCC) and stronger connectivity between the anterior cingulate cortex (ACC) and thalamus among those reporting DNP. Overall, these findings implicate altered within DMN (i.e., MPFC-PCC) and within SN (i.e., ACC-thalamus) connectivity as potential manifestations of adaptation to pain from neuropathy and/or mechanisms underlying the development/maintenance of DNP. Findings are discussed in the context of differential brain response to pain (i.e., mind wandering, pain aversion, pain facilitation/inhibition) and therapeutic implications.
Reconstruction of metatarsal bone after giant cell tumor resection with no vascularized fibular graft in a pediatric patient: Case report and review of literature
Authors: Florio M. , Careri S. , Zoccali C. , Aulisa A. G. , Falciglia F. , Toniolo R. M. , Giordano M.
Published: October 2022

The Giant Cell tumor (GCT) is a benign, locally aggressive lesion that cause bone destruction and shows a malignant potential. It is a relatively common skeletal tumor that is therefore typically seen in young adults. Few cases are described in literature of GCT in the immature skeleton, and the metatarsal is an unusual location for a primary bone GCT, especially in pediatric age. Therefore, there are very few data reported regarding the management protocol of GCT in metatarsal bones. We report a case about the use of no vascularized fibular graft for an original Y-shaped reconstruction of the metatarsal bone after Giant Cell Tumor resection in a 9 years-old patient, and performed a literature review about metatarsal bone reconstruction in skeletally immature patient.
Exosomes and mimics as novel delivery platform for cancer therapy
Authors: Yang Fuxu , Wang Mingyue , Guan Xingang
Published: October 2022

Exosomes are nano-sized biological extracellular vesicles transmitting information between cells and constituting a new intercellular communication mode. Exosomes have many advantages as an ideal drug delivery nanocarrier, including good biocompatibility, permeability, low toxicity, and low immunogenicity. Recently, exosomes have been used to deliver chemotherapeutic agents, natural drugs, nucleic acid drugs, and other antitumor drugs to treat many types of tumors. Due to the limited production of exosomes, synthetic exosome-mimics have been developed as an ideal platform for drug delivery. This review summarizes recent advances in the application of exosomes and exosome-mimics delivering therapeutic drugs in treating cancers.
Electroacupuncture induces weight loss by regulating tuberous sclerosis complex 1-mammalian target of rapamycin methylation and hypothalamic autophagy in high-fat diet-induced obese rats
Authors: Yao Junpeng , Yan Xiangyun , Xiao Xianjun , You Xi , Li Yanqiu , Yang Yuqing , Zhang Wei , Li Ying
Published: October 2022

Background: Obesity can be caused by abnormalities of hypothalamic autophagy, which is closely regulated by the epigenetic modification of TSC1-mTOR. However, whether the weight-reducing effect of EA may relate to the modification of TSC1-mTOR methylation and hypothalamic autophagy remain unclear. This study was conducted to reveal the possible mechanism by which EA reduces BW by measuring the levels of TSC1-mTOR methylation and hypothalamic autophagy-related components.

Methods: The weight-reducing effect of EA was investigated in high-fat diet (HFD)-induced obese (DIO) rats by monitoring the BW, food consumption, and epididymal white adipose tissue (eWAT)/BW ratio. Hematoxylin and eosin staining was performed for morphological evaluation of eWAT. Immunofluorescence was utilized to observe the localization of LC3 in the hypothalamus. The expressions of autophagy components (Beclin-1, LC3, and p62) and mTOR signaling (mTOR, p-mTOR, p70S6K, and p-p70S6K) were assessed by western blot. The methylation rate of the TSC1 promoter was detected by bisulfite genomic sequencing.

Results: Treatment with EA significantly reduced the BW, food consumption, and eWAT/BW ratio; attenuated the morphological alternations in the adipocytes of DIO rats. While HFD downregulated the expression levels of Beclin-1 and LC3 and upregulated those of p62, these changes were normalized by EA treatment. EA markedly decreased the methylation rate of the TSC1 gene promoter and suppressed the protein expressions of mTOR, p-mTOR, p70S6K, and p-p70S6K in the hypothalamus.

Conclusion: EA could reduce BW and fat accumulation in DIO rats. This ameliorative effect of EA may be associated with its demethylation effect on TSC1-mTOR and regulation of autophagy in the hypothalamus.
Integrated network pharmacology and experimental analysis unveil multi-targeted effect of 18α- glycyrrhetinic acid against non-small cell lung cancer
Authors: Irshad Rasha , Raj Nafis , Gabr Gamal A. , Manzoor Nikhat , Husain Mohammad
Published: October 2022

Non-small cell lung cancer (NSCLC) is one of the most malignant types of cancer with soaring incidence rates worldwide, attributed to its heterogeneity and complex etiology. Evidently, alternative anti-cancer therapies comprising traditional medicines and natural products have gained attention for their ability to act as chemopreventive agents with minimal toxicities, either alone or in combination. Accumulating studies have substantiated the inevitability of network pharmacology studies for effectively mapping molecular targets of natural products against multifaceted diseases, including cancer. The 18α-Glycyrrhetinic acid (18α-GA), a triterpenoid found in licorice plants, has shown promising medicinal properties, although, its mechanism of action against NSCLC yet remains elusive. The present study was conducted to explore the anti- NSCLC potential of 18α-GA, employing integrative network pharmacology, molecular docking, and experimental research. Initially, network analysis revealed 181 common targets of 18α-GA in NSCLC as shown in the “compound-target- disease” network employing Cytoscape 3.8.2. Further analyses identified EGFR, AKT1, PI3KR1, MAPK1, IGF1, and SRC as the most crucial hub targets of 18α-GA against NSCLC. Moreover, molecular docking simulations and functional enrichment analyses indicated the involvement of multiple signaling pathways in suppressing NSCLC. Subsequent in-vitro studies verified the antiproliferative effect of 18α-GA on two NSCLC cancer cell lines, H1299 and A549. Mechanistically, 18α-GA arrested cell cycle at the G1 phase, induced apoptosis, decreased migratory potential, and protein expression levels of EGFR-PI3K/AKT, as examined by flow cytometry, morphological assessment, RT-PCR, and western blot. In conclusion, this study delineates the therapeutic potential and underlying mechanism(s) of 18α-GA as a putative novel drug against NSCLC. However, further studies are warranted to elucidate the complete molecular mechanism(s) using animal models of NSCLC.
Based on network pharmacology and molecular docking to explore the protective effect of Epimedii Folium extract on cisplatin-induced intestinal injury in mice
Authors: Xia Juan , Hu Jun-Nan , Wang Zi , Cai En-Bo , Ren Shen , Wang Ying-Ping , Lei Xiu-Juan , Li Wei
Published: October 2022

Background: Epimedii Folium, as a natural botanical medicine, has been reported to have protective effects on intestinal diseases by modulating multiple signaling pathways. This study aimed to explore the potential targets and molecular mechanisms of Epimedii Folium extract (EFE) against cisplatin-induced intestinal injury through network pharmacology, molecular docking, and animal experiments.

Methods: Network pharmacology was used to predict potential candidate targets and related signaling pathways. Molecular docking was used to simulate the interactions between significant potential candidate targets and active components. For experimental validation, mice were intraperitoneally injected with cisplatin 20 mg/kg to establish an intestinal injury model. EFE (100, 200 mg/kg) was administered to mice by gavage for 10 days. The protective effect of EFE on intestinal injury was analyzed through biochemical index detection, histopathological staining, and western blotting.

Results: Network pharmacology analysis revealed that PI3K-Akt and apoptosis signaling pathways were thought to play critical roles in EFE treatment of the intestinal injury. Molecular docking results showed that the active constituents of Epimedii Folium, including Icariin, Epimedin A, Epimedin B, and Epimedin C, stably docked with the core AKT1, p53, TNF-α, and NF-κB. In verified experiments, EFE could protect the antioxidant defense system by increasing the levels of glutathione peroxidase (GSH-Px) and catalase (CAT) while reducing the content of malondialdehyde (MDA). EFE could also inhibit the expression of NF-κB and the secretion of inflammatory factors, including TNF-α, IL-1β, and IL-6, thereby relieving the inflammatory damage. Further mechanism studies confirmed that EFE had an excellent protective effect on cisplatin-induced intestinal injury by regulating PI3K-Akt, caspase, and NF-κB signaling pathways.

Conclusion: In summary, EFE could mitigate cisplatin-induced intestinal damage by modulating oxidative stress, inflammation, and apoptosis.
The effects of aqueous extract of Labisia Pumila (Blume) Fern.-Vill. Var. Alata on wound contraction, hydroxyproline content and histological assessments in superficial partial thickness of second-degree burn model
Authors: Ibrahim Nurul ‘Izzah , Mohamed Isa Naina , Mohamed Norazlina , Mohd Ramli Elvy Suhana , Shuid Ahmad Nazrun
Published: October 2022

Background: Burns are considered a critical care problem in emergency medicine, resulting in physical, psychological, and chronic disabilities. Silver sulfadiazine is the gold standard in topical burn treatment but was associated with toxicity to keratinocytes and fibroblasts, which may delay wound healing. In discovering potential alternative treatments for burn wound healing, this study was performed to determine the effect of Labisia Pumila (Blume) Fern.-Vill. Var. Alata (LPVa) extract on thermal-burn wounds in rats.

Methods: A total of 50 Sprague-Dawley male rats were categorized into five groups. There were three control groups; normal control (left untreated), negative control (given ointment base) and positive control (given silver sulfadiazine). Meanwhile, the two intervention groups were given with 2% LPVa leaf and root extracts, respectively. Burn wounds were inflicted on the loin region of the rat by applying a heated steel rod at 80°C for 10 s. On days 3, 7, 14, and 21, wounds were measured macroscopically using a digital calliper and one animals of each group were sacrificed, and the wounded skin were excised for histomorphological assessments. The wounds were excised for hydroxyproline content on Day 14 of treatment.

Result: For wound contraction percentage, both the leaf and root extracts of LPVa showed a significant reduction in burn wound size on Day 7 onwards, when compared to other groups. For hydroxyproline content, only the leaf extract of LPVa produced significantly higher content compared to both negative and normal control groups. In terms of histological examination, the leaf extract group demonstrated a superior healing effect than the root extract group.

Conclusion: Both leaf and root extracts of LPVa could promote wound healing in the thermal-burn wound rat model, with leaf extract being superior to root extract.
A network-based approach for isolating the chronic inflammation gene signatures underlying complex diseases towards finding new treatment opportunities
Authors: Hickey Stephanie L. , McKim Alexander , Mancuso Christopher A. , Krishnan Arjun
Published: October 2022

Complex diseases are associated with a wide range of cellular, physiological, and clinical phenotypes. To advance our understanding of disease mechanisms and our ability to treat these diseases, it is critical to delineate the molecular basis and therapeutic avenues of specific disease phenotypes, especially those that are associated with multiple diseases. Inflammatory processes constitute one such prominent phenotype, being involved in a wide range of health problems including ischemic heart disease, stroke, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease, and autoimmune and neurodegenerative conditions. While hundreds of genes might play a role in the etiology of each of these diseases, isolating the genes involved in the specific phenotype (e.g., inflammation “component”) could help us understand the genes and pathways underlying this phenotype across diseases and predict potential drugs to target the phenotype. Here, we present a computational approach that integrates gene interaction networks, disease-/trait-gene associations, and drug-target information to accomplish this goal. We apply this approach to isolate gene signatures of complex diseases that correspond to chronic inflammation and use SAveRUNNER to prioritize drugs to reveal new therapeutic opportunities.
Oscillating propagation and parametric instability of the partial Gaussian beam in graded-index multimode fibers
Authors: Yang Guangye , Wang Sandan , Yuan Jinpeng , Zhou Haitao , Wu Zhifang , Li Sijin
Published: October 2022

We investigate the input and propagation characteristics and geometric parametric instability of the partial Gaussian beam limited by the fiber face area in a graded-index multimode fiber. The theoretical simulation shows that the energy of the partial Gaussian beam and the coupling efficiency of the fiber face are restricted by the fiber face area for the different powers and spot sizes of the input Gaussian beam. The spot intensity pattern of the partial Gaussian beam exhibits a standard oscillating distribution in space as the beam undergoes periodic oscillations with propagation. Also, the dynamic evolution process from parametric sidebands to a supercontinuum is affected by the peak power, the spot size of the partial Gaussian beam, and the fiber length. Finally, the experimental output spectra with different powers of the partial Gaussian beam and fiber lengths in a graded-index multimode fiber confirm the prediction of theoretical simulations. This work provides practical guidance for optimizing supercontinuum source expansion and spectral power density.
Artificial intelligence analysis of the impact of fibrosis in arrhythmogenesis and drug response
Authors: Sánchez de la Nava Ana María , Gómez-Cid Lidia , Domínguez-Sobrino Alonso , Fernández-Avilés Francisco , Berenfeld Omer , Atienza Felipe
Published: October 2022

Background: Cardiac fibrosis has been identified as a major factor in conduction alterations leading to atrial arrhythmias and modification of drug treatment response.

Objective: To perform an in silico proof-of-concept study of Artificial Intelligence (AI) ability to identify susceptibility for conduction blocks in simulations on a population of models with diffused fibrotic atrial tissue and anti-arrhythmic drugs.

Methods: Activity in 2D cardiac tissue planes were simulated on a population of variable electrophysiological and anatomical profiles using the Koivumaki model for the atrial cardiomyocytes and the Maleckar model for the diffused fibroblasts (0%, 5% and 10% fibrosis area). Tissue sheets were of 2 cm side and the effect of amiodarone, dofetilide and sotalol was simulated to assess the conduction of the electrical impulse across the planes. Four different AI algorithms (Quadratic Support Vector Machine, QSVM, Cubic Support Vector Machine, CSVM, decision trees, DT, and K-Nearest Neighbors, KNN) were evaluated in predicting conduction of a stimulated electrical impulse.

Results: Overall, fibrosis implementation lowered conduction velocity (CV) for the conducting profiles (0% fibrosis: 67.52 ± 7.3 cm/s; 5%: 58.81 ± 14.04 cm/s; 10%: 57.56 ± 14.78 cm/s; p < 0.001) in combination with a reduced 90% action potential duration (0% fibrosis: 187.77 ± 37.62 ms; 5%: 93.29 ± 82.69 ms; 10%: 106.37 ± 85.15 ms; p < 0.001) and peak membrane potential (0% fibrosis: 89.16 ± 16.01 mV; 5%: 70.06 ± 17.08 mV; 10%: 82.21 ± 19.90 mV; p < 0.001). When the antiarrhythmic drugs were present, a total block was observed in most of the profiles. In those profiles in which electrical conduction was preserved, a decrease in CV was observed when simulations were performed in the 0% fibrosis tissue patch (Amiodarone ΔCV: −3.59 ± 1.52 cm/s; Dofetilide ΔCV: −13.43 ± 4.07 cm/s; Sotalol ΔCV: −0.023 ± 0.24 cm/s). This effect was preserved for amiodarone in the 5% fibrosis patch (Amiodarone ΔCV: −4.96 ± 2.15 cm/s; Dofetilide ΔCV: 0.14 ± 1.87 cm/s; Sotalol ΔCV: 0.30 ± 4.69 cm/s). 10% fibrosis simulations showed that part of the profiles increased CV while others showed a decrease in this variable (Amiodarone ΔCV: 0.62 ± 9.56 cm/s; Dofetilide ΔCV: 0.05 ± 1.16 cm/s; Sotalol ΔCV: 0.22 ± 1.39 cm/s). Finally, when the AI algorithms were tested for predicting conduction on input of variables from the population of modelled, Cubic SVM showed the best performance with AUC = 0.95.

Conclusion:In silico proof-of-concept study demonstrates that fibrosis can alter the expected behavior of antiarrhythmic drugs in a minority of atrial population models and AI can assist in revealing the profiles that will respond differently.
Rule-based definition of muscle bundles in patient-specific models of the left atrium
Authors: Rossi Simone , Abdala Laryssa , Woodward Andrew , Vavalle John P. , Henriquez Craig S. , Griffith Boyce E.
Published: October 2022

Atrial fibrillation (AF) is the most common arrhythmia encountered clinically, and as the population ages, its prevalence is increasing. Although the CHA2DS2−VASc score is the most used risk-stratification system for stroke risk in AF, it lacks personalization. Patient-specific computer models of the atria can facilitate personalized risk assessment and treatment planning. However, a challenge faced in creating such models is the complexity of the atrial muscle arrangement and its influence on the atrial fiber architecture. This work proposes a semi-automated rule-based algorithm to generate the local fiber orientation in the left atrium (LA). We use the solutions of several harmonic equations to decompose the LA anatomy into subregions. Solution gradients define a two-layer fiber field in each subregion. The robustness of our approach is demonstrated by recreating the fiber orientation on nine models of the LA obtained from AF patients who underwent WATCHMAN device implantation. This cohort of patients encompasses a variety of morphology variants of the left atrium, both in terms of the left atrial appendages (LAAs) and the number of pulmonary veins (PVs). We test the fiber construction algorithm by performing electrophysiology (EP) simulations. Furthermore, this study is the first to compare its results with other rule-based algorithms for the LA fiber architecture definition available in the literature. This analysis suggests that a multi-layer fiber architecture is important to capture complex electrical activation patterns. A notable advantage of our approach is the ability to reconstruct the main LA fiber bundles in a variety of morphologies while solving for a small number of harmonic fields, leading to a comparatively straightforward and reproducible approach.
Intrarenal Doppler approaches in hemodynamics: A major application in critical care
Authors: Qian Xiaoling , Zhen Junhai , Meng Qingxiang , Li Li , Yan Jing
Published: October 2022

The treatment of severe cases usually requires multimodality hemodynamic monitoring approaches, particularly for tissue and organ perfusion tracking. Currently, only a few studies have investigated renal perfusion status at the bedside. Ultrasound has become increasingly utilized to guide the hemodynamic management of severe patients. Similarly, intrarenal Doppler (IRD) is widely used to assess renal perfusion from both the intrarenal artery and vein perspectives. The renal resistive index (RRI), which reflects the renal arterial blood flow profile, is often applied to predict the reversibility of renal dysfunction and to titrate hemodynamic support. Intrarenal venous flow (IRVF) patterns and the renal venous stasis index (RVSI), which reflects the intrarenal vein blood flow profile, are now being used to assess intravenous congestion. They may also be useful in predicting the risk of acute kidney injury and avoiding fluid overload. IRD can provide diverse and supplemental information on renal perfusion and may help to establish the early diagnosis in severe patients. This review focused on the specific operational methods, influencing factors, and applications of IRD in hemodynamics.
Physiological factors affecting the mechanical performance of peripheral muscles: A perspective for long COVID patients through a systematic literature review
Authors: Suba Rao Harinivas Rao , Hamzaid Nur Azah , Ahmad Mohd Yazed , Hamzah Norhamizan
Published: October 2022

Background: Peripheral muscle weakness can be measured quantitatively in long COVID patients. Mechanomyography (MMG) is an alternative tool to measure muscle strength non-invasively.

Objective: This literature review aims to provide evidence on the efficacy of MMG in measuring muscle strength for long COVID patients and to determine the physiological factors that may affect the use of MMG in assessing muscle performance.

Methods: A systematic literature review was conducted using EBSCO’s MEDLINE Complete. A total of five out of 2,249 potential publications fulfilled the inclusion criteria.

Results: The selected studies addressed muscle performance based on the physiological effects of age, gender, and physical activity level. MMG is sensitive in measuring muscle strength for long COVID patients due to its higher signal-to-noise ratio and lightweight accelerometers. Its neglectable skin impedance and low risk of influences during the recording of surface motions make MMG a reliable tool.

Conclusion: Muscle performance is affected by age, gender, and physical activity level. Sensors, such as MMG, as well as the length of the muscle and the characteristics of the muscle activity, are important considerations when choosing a sensor for diagnostic evaluation. The efficacy of MMG in measuring muscle strength for long COVID patients and the physiological factors that may affect the use of MMG in assessing muscle performance are discussed.
Annexin A1 exerts renoprotective effects in experimental crescentic glomerulonephritis
Authors: Labes Robert , Dong Lei , Mrowka Ralf , Bachmann Sebastian , von Vietinghoff Sibylle , Paliege Alexander
Published: October 2022

Non-resolving inflammation plays a critical role during the transition from renal injury towards end-stage renal disease. The glucocorticoid-inducible protein annexin A1 has been shown to function as key regulator in the resolution phase of inflammation, but its role in immune-mediated crescentic glomerulonephritis has not been studied so far.

Methods: Acute crescentic glomerulonephritis was induced in annexin A1-deficient and wildtype mice using a sheep serum against rat glomerular basement membrane constituents. Animals were sacrificed at d5 and d10 after nephritis induction. Renal leukocyte abundance was studied by immunofluorescence and flow cytometry. Alterations in gene expression were determined by RNA-Seq and gene ontology analysis. Renal levels of eicosanoids and related lipid products were measured using lipid mass spectrometry.

Results: Histological analysis revealed an increased number of sclerotic glomeruli and aggravated tubulointerstitial damage in the kidneys of annexin A1-deficient mice compared to the wildtype controls. Flow cytometry analysis confirmed an increased number of CD45+ leukocytes and neutrophil granulocytes in the absence of annexin A1. Lipid mass spectrometry showed elevated levels of prostaglandins PGE2 and PGD2 and reduced levels of antiinflammatory epoxydocosapentaenoic acid regioisomers. RNA-Seq with subsequent gene ontology analysis revealed induction of gene products related to leukocyte activation and chemotaxis as well as regulation of cytokine production and secretion.

Conclusion: Intrinsic annexin A1 reduces proinflammatory signals and infiltration of neutrophil granulocytes and thereby protects the kidney during crescentic glomerulonephritis. The annexin A1 signaling cascade may therefore provide novel targets for the treatment of inflammatory kidney disease.