bluuebunny/crossref_metadata_2025 huggingface dataset:
Machine Learning-Based Personalized Risk Prediction Model for Mortality of Patients Undergoing Mitral Valve Surgery: The PRIME Score
Authors: Zhou Ning , Ji Zhili , Li Fengjuan , Qiao Bokang , Lin Rui , Jiang Wenxi , Zhu Yuexin , Lin Yuwei , Zhang Kui , Li Shuanglei , You Bin , Gao Pei , Dong Ran , Wang Yuan , Du Jie
Published: April 2022

Background

Mitral valve surgery (MVS) is an effective treatment for mitral valve diseases. There is a lack of reliable personalized risk prediction models for mortality in patients undergoing mitral valve surgery. Our aim was to develop a risk stratification system to predict all-cause mortality in patients after mitral valve surgery.

Methods

Different machine learning models for the prediction of all-cause mortality were trained on a derivation cohort of 1,883 patients undergoing mitral valve surgery [split into a training cohort (70%) and internal validation cohort (30%)] to predict all-cause mortality. Forty-five clinical variables routinely evaluated at discharge were used to train the models. The best performance model (PRIME score) was tested in an externally validated cohort of 220 patients undergoing mitral valve surgery. The model performance was evaluated according to the area under the curve (AUC). Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were compared with existing risk strategies.

Results

After a median follow-up of 2 years, there were 133 (7.063%) deaths in the derivation cohort and 17 (7.727%) deaths in the validation cohort. The PRIME score showed an AUC of 0.902 (95% confidence interval [CI], 0.849–0.956) in the internal validation cohort and 0.873 (95% CI: 0.769–0.977) in the external validation cohort. In the external validation cohort, the performance of the PRIME score was significantly improved compared with that of the existing EuroSCORE II (NRI = 0.550, [95% CI 0.001–1.099], P = 0.049, IDI = 0.485, [95% CI 0.230–0.741], P < 0.001).

Conclusion

Machine learning-based model (the PRIME score) that integrate clinical, demographic, imaging, and laboratory features demonstrated superior performance for the prediction of mortality patients after mitral valve surgery compared with the traditional risk model EuroSCORE II.

Clinical Trial Registration

[http://www.clinicaltrials.gov], identifier [NCT05141292].
Creating Multicultural Opportunities in Music Teacher Education: Sharing Diversity Through Online Competitions
Authors: Karkina Svetlana , Singh Balwant , Batyrshina Gulnara , Nurgayanova Nelya
Published: April 2022

Facing the emergency of the COVID19 pandemic, Higher Education faced new challenges which required the design and implementation of new types of multicultural interaction by the means of online tools. Online competition is the new form of international interaction popularity of which is growing rapidly at present. This study aimed to assess the advantages of online competitions in promoting multicultural opportunities in the education of music teachers. The research work was organized in two stages at Kazan Federal University (Russia) in the collaboration with Partap College of Education (India) where two online competitions—an international competition of students’ research works, and a vocal singing competition—were organized. The jury committee included nine members who represented three countries (Russia, India, and Armenia). During the competitions, 95 students’ research reports and 75 vocal performance records were collected. The results were analyzed by using the average rating method. The most significant criteria to assess the research work included the knowledge in the field of cultural diversity and the research scope demonstrating global experience. The vocal records were compared by the criteria such as art and technical level of performance, artistic style, expressive performance, and others. The comparative analysis was used for studying cultural diversity in the vocal records which presented more than fifteen different cultures delivering Western and Eastern musical traditions and featured differences in genres, fret-harmonic structure, performance style, and national instruments. The obtained results showed a high level of sharing of musical cultural diversity through these two online competitions. It was concluded that online competition demonstrates advantages in sharing the diversity of music cultures. The criteria based on multiculturality allows evaluating competitive works objectively while focusing at the same time on their diversity. The implementation of a multicultural approach in online competitions will promote sharing in the world of music, allowing participants to experience diversities in order to preserve each artistic tradition in the context of its original cultural heritage.
Induction of Collagen I by CXCL10 in Ovarian Theca–Stroma Cells via the JNK Pathway
Authors: Wang Chaojun , Sun Yun
Published: April 2022

Premature ovarian insufficiency (POI) poses a great threat to reproductive-age women. Ovarian fibrogenesis is a basic histologic feature of POI. Ovarian theca–stroma cells are responsible for ovarian fibrosis, but few studies have focused on the ovarian microenvironment. The role and mechanism of chemokines in the development of POI remain unclear. Here, we evaluated C-X-C motif chemokine ligand 10 (CXCL10) in biochemical POI patients, POI patients, and a POI mouse model. CXCL10 levels in serum and follicular fluid were higher in both bPOI and POI patients than in controls. An increased level of CXCL10 was also observed in a POI mouse model. CXCL10 concentrations in serum and follicular fluid were positively associated with follicle-stimulating hormone and negatively associated with antral follicle count. Our study for the first time found that CXCL10 induced COL1A1 and COL1A2 production, two subunits of collagen I in mouse theca–stroma cells by activating the JNK/c-Jun pathway. Inhibition of JNK and c-Jun attenuated the increases of COL1A1 and COL1A2 caused by CXCL10. Moreover, CXCL10 had no effects on hormone synthesis, proliferation, and apoptosis in human luteinized granulosa (hGL) cells. Our findings revealed a potential diagnostic value of CXCL10 in the early stage of POI and shed new insights into the biological function of CXCL10 in ovarian fibrosis.
MiRKAT-MC: A Distance-Based Microbiome Kernel Association Test With Multi-Categorical Outcomes
Authors: Jiang Zhiwen , He Mengyu , Chen Jun , Zhao Ni , Zhan Xiang
Published: April 2022

Increasing evidence has elucidated that the microbiome plays a critical role in many human diseases. Apart from continuous and binary traits that measure the extent or presence of a disease, multi-categorical outcomes including variations/subtypes of a disease or ordinal levels of disease severity are commonly seen in clinical studies. On top of that, studies with clustered design (i.e., family-based and longitudinal studies) are popular alternatives to population-based ones as they are able to identify characteristics on both individual and population levels and to investigate the trajectory of traits of interest over time. However, existing methods for microbiome association analysis are inadequate to handle multi-categorical outcomes, neither independent nor clustered data. We propose a microbiome kernel association test with multi-categorical outcomes (MiRKAT-MC). Our method is versatile to deal with both nominal and ordinal outcomes for independent and clustered data. In addition, it incorporates multiple ecological distances to allow for different association patterns between outcomes and microbiome compositions to be incorporated. A computationally efficient pseudo-permutation strategy is used to evaluate the statistical significance. Comprehensive simulations show that MiRKAT-MC preserves the nominal type I error and increases statistical powers under various scenarios and data types. We also apply MiRKAT-MC to real data sets with nominal and ordinal outcomes to gain biological insights. MiRKAT-MC is easy to implement, and freely available via an R package at https://github.com/Zhiwen-Owen-Jiang/MiRKATMC with a Graphical User Interface through R Shinny also available.
Chronically Elevated O-GlcNAcylation Limits Nitric Oxide Production and Deregulates Specific Pro-Inflammatory Cytokines
Authors: Abramowitz Lara K. , Hanover John A.
Published: April 2022

Inflammation is the immune response to harmful stimuli, including pathogens, damaged cells and toxic compounds. However, uncontrolled inflammation can be detrimental and contribute to numerous chronic inflammatory diseases, such as insulin resistance. At the forefront of this response are macrophages, which sense the local microenvironment to respond with a pro-inflammatory, M1-polarized phenotype, or anti-inflammatory, M2-polarized phenotype. M1 macrophages upregulate factors like pro-inflammatory cytokines, to promote inflammatory signaling, and inducible Nitric Oxide Synthase (iNOS), to produce nitric oxide (NO). The generated NO can kill microorganisms to protect the body, but also signal back to the macrophage to limit pro-inflammatory cytokine production to maintain macrophage homeostasis. Thus, the tight regulation of iNOS in macrophages is critical for the immune system. Here, we investigated how elevation of the nutrient-sensitive posttranslational modification, O-GlcNAc, impacts M1 polarized macrophages. We identified increased gene expression of specific pro-inflammatory cytokines (Il-6, Il-1β, Il-12) when O-GlcNAc cycling was blocked. We further uncovered an interaction between O-GlcNAc and iNOS, with iNOS being an OGT target in vitro. Analysis of M1 polarized bone marrow derived macrophages deficient in the enzyme that removes O-GlcNAc, O-GlcNAcase (OGA), revealed decreased iNOS activity as measured by a reduction in NO release. Further, elevated O-GlcNAc acted on Il-6 expression through the iNOS pathway, as iNOS inhibitior L-NIL raised wildtype Il-6 expression similar to OGA deficient cells but had no further effect on the hyper-O-GlcNAcylated cells. Thus O-GlcNAc contributes to macrophage homeostasis through modulation of iNOS activity.
Donor–Recipient Non-HLA Variants, Mismatches and Renal Allograft Outcomes: Evolving Paradigms
Authors: Jethwani Priyanka , Rao Arundati , Bow Laurine , Menon Madhav C.
Published: April 2022

Despite significant improvement in the rates of acute allograft rejection, proportionate improvements in kidney allograft longevity have not been realized, and are a source of intense research efforts. Emerging translational data and natural history studies suggest a role for anti-donor immune mechanisms in a majority of cases of allograft loss without patient death, even when overt evidence of acute rejection is not identified. At the level of the donor and recipient genome, differences in highly polymorphic HLA genes are routinely evaluated between donor and recipient pairs as part of organ allocation process, and utilized for patient-tailored induction and maintenance immunosuppression. However, a growing body of data have characterized specific variants in donor and recipient genes, outside of HLA loci, that induce phenotypic changes in donor organs or the recipient immune system, impacting transplant outcomes. Newer mechanisms for “mismatches” in these non-HLA loci have also been proposed during donor–recipient genome interactions with transplantation. Here, we review important recent data evaluating the role of non-HLA genetic loci and genome-wide donor-recipient mismatches in kidney allograft outcomes.
IL-6 and IL-10 Are Associated With Gram-Negative and Gram-Positive Bacteria Infection in Lymphoma
Authors: Zhu Qiuhua , Li Huan , Zheng Shanshan , Wang Bin , Li Mingjie , Zeng Wenbin , Zhou Lanlan , Guan Zebing , Wang Hong , Liu Yanan , Gao Yanmin , Qiu Shiqiu , Chen Chaolun , Yang Shimei , Yuan Yuemei , Zhang Hanling , Ruan Guanqiao , Pan Xueyi
Published: April 2022

To investigate the Th1/Th2 cytokine profile in patients with lymphoma during the myelosuppression stage of infection. 52 patients with gram-negative bacterial infection (G- group), 49 patients with gram-positive bacterial infection (G+ group), 51 uninfected patients with lymphoma (uninfected group) and 20 healthy controls (healthy group) were enrolled in this study. We evaluated the quantification of Th1/Th2 cytokines with flow cytometry bead assay (CBA) in the sera to explore a rapid diagnostic method to determine the type of infection and anti-infective effect. The levels of procalcitonin (PCT) were also detected simultaneously. The four groups did not differ with regard to IL-2 and IL-4 (P>0.05). The IFN-γ and TNF-α levels of patients with lymphoma were higher than those of healthy controls (P<0.05). There was significantly upregulated IL-6 and IL-10 expression in the G- group (P<0.001). A similar trend was reflected in the IL-6 of the G+ group, which was significantly increased (P<0.001). However, no significant upregulation was observed for IL-10 in the G+ group. According to the different degrees of increased IL-6 and IL-10 levels, We proposed to use the G- Bacterial Infection Cytokine Profile (G- BICP) and the G+ Bacterial Infection Cytokine Profile (G+ BICP) for the first time to differentiate between Gram-negative and Gram-positive (G-/G+) bacterial infection in adults with lymphoma in the myelosuppression stage after chemotherapy. The IL-6, IL-10 and PCT in the G- group and the IL-6, PCT in the G+ group were significantly decreased at day 4 and day 8 compared with those at day 1. IL-6 and IL-10 are closely associated with the severity and treatment efficacy in adults with lymphomas who develop infections after chemotherapy and can help distinguish between G- and G+ bacterial infections at an early stage.
Reflections on Some of the Exceptional Features of HTLV-1 and HTLV-1 Research: A Perspective
Authors: Gallo Robert C. , Tagaya Yutaka
Published: April 2022

The report is not a review or a summary. In a manner, it is a perspective but an unusual one. It looks back to the years my colleagues and I (RG) began preparing for human retroviruses (beginning in 1970), how they evolved, and attempts to bring to light or simply to emphasize many exceptional characteristics of a retrovirus known as HTLV-1 and some fortuitous coincidences, with emphasis on the needs of the field. These events cover over one half a century. We have had many reviews on HTLV-1 disease, epidemiology, and basic aspects of its replication, genome, gene functions, structure, and pathogenesis, though continued updates are needed. However, some of its truly exceptional features have not been highlighted, or at least not in a comprehensive manner. This article attempts to do so.
Expression of Constitutive Fusion of Ubiquitin to PCNA Restores the Level of Immunoglobulin A/T Mutations During Somatic Hypermutation in the Ramos Cell Line
Authors: Lerner Leticia K. , Bonte Dorine , Le Guillou Morwenna , Mohammad Mahwish Mian , Kasraian Zeinab , Sarasin Alain , Despras Emmanuelle , Aoufouchi Said
Published: April 2022

Somatic hypermutation (SHM) of immunoglobulin (Ig) genes is a B cell specific process required for the generation of specific and high affinity antibodies during the maturation of the immune response against foreign antigens. This process depends on the activity of both activation-induced cytidine deaminase (AID) and several DNA repair factors. AID-dependent SHM creates the full spectrum of mutations in Ig variable (V) regions equally distributed at G/C and A/T bases. In most mammalian cells, deamination of deoxycytidine into uracil during S phase induces targeted G/C mutagenesis using either direct replication of uracils or TLS mediated bypass, however only the machinery of activated B lymphocytes can generate A/T mutagenesis around AID-created uracils. The molecular mechanism behind the latter remains incompletely understood to date. However, the lack of a cellular model that reproduces both G/C and A/T mutation spectra constitutes the major hurdle to elucidating it. The few available B cell lines used thus far to study Ig SHM indeed undergo mainly G/C mutations, that make them inappropriate or of limited use. In this report, we show that in the Ramos cell line that undergoes constitutive G/C-biased SHM in culture, the low rate of A/T mutations is due to an imbalance in the ubiquitination/deubiquitination reaction of PCNA, with the deubiquitination reaction being predominant. The inhibition of the deubiquitinase complex USP1-UAF1 or the expression of constitutive fusion of ubiquitin to PCNA provides the missing clue required for DNA polymerase η recruitment and thereafter the introduction of A/T base pair (bp) mutations during the process of IgV gene diversification. This study reports the establishment of the first modified human B cell line that recapitulates the mechanism of SHM of Ig genes in vitro.
Temperature-Induced Environmental Chain Reaction in Marine Sedimentation and Its Impact on Manila Clam Ruditapes philippinarum
Authors: Liu Yi , Zhang Jihong , Wang Xinmeng , Wu Wenguang , Kang Qinzi , Li Chaolun
Published: April 2022

Marine Heatwaves (MHWs) events have been increasing, causing severe impacts on marine ecosystems and aquaculture. In this study, the effects of temperature on changes in sediment dissolved oxygen (DO) and hydrogen sulfide (H2S) concentrations and their effects on the behavioral and physiological responses of a bivalve were investigated by simulating different sudden summer temperature change conditions. The results showed that temperature was an important factor affecting DO consumption and H2S release in sediments, and sediment type also played a key role. At higher temperatures, DO was consumed more rapidly and H2S release increased in sediments, and the DO was consumed and H2S released in sandy sediments was less than in silty sand sediments. The response of Manila clam’s exercise behavior under environmental pressure was also rapid. The excavation index of the Manila clam decreased with the DO consumption, indicating that the Manila clam could alter its burial depth and move toward the sediment-water interface when stressed. Compared with phenol oxidases (PO) activity being activated under experimental conditions, succinate concentrations only increased slightly at 32°C, and did not surpass the threshold indicative of anaerobic metabolism. However, when toxic substances such as H2S start to accumulate, they may damage the immune system and tissues of the Manila clam, thereby affecting its future survival. Therefore, when temperatures are high for long periods in summer, it is necessary to take timely action to prevent and guard against harm caused by DO and H2S to aquaculture organisms.
Reduction in Volume of Nucleus Basalis of Meynert Is Specific to Parkinson’s Disease and Progressive Supranuclear Palsy but Not to Multiple System Atrophy
Authors: Rogozinski Sophia , Klietz Martin , Respondek Gesine , Oertel Wolfgang H. , Grothe Michel J. , Pereira Joana B. , Höglinger Günter U.
Published: April 2022

Objectives

To study in vivo gray matter (GM) volumes of the nucleus basalis of Meynert (nbM) in different parkinsonian syndromes and assess their relationship with clinical variables.

Methods

T1-weighted magnetic resonance images from patients with progressive supranuclear palsy (PSP, N = 43), multiple system atrophy (MSA, N = 23), Parkinson’s disease (PD, N = 26), and healthy controls (HC, N = 29) were included. T1-weighted images were analyzed using a voxel-based morphometry approach implemented in the VBM8 toolbox, and nbM volumes were extracted from the spatially normalized GM images using a cyto-architectonically-defined nbM mask in stereotactic standard space. NbM volumes were compared between groups, while controlling for intracranial volume. Further, within each group correlation analyses between nbM volumes and the Mini Mental Status Examination (MMSE), Hoehn and Yahr stage, PSP Rating Scale, Unified Parkinson’s Disease Rating Scale part III and Frontal Assessment Battery scores were performed.

Results

Significantly lower nbM volumes in patients with PSP and PD compared to HC or patients with MSA were found. No significant correlations between MMSE and nbM volumes were detected in any of the subgroups. No significant correlations were found between clinical scores and nbM volumes in PSP or other groups.

Conclusion

nbM volumes were reduced both in PD and PSP but not in MSA. The lack of significant correlations between nbM and cognitive measures suggests that other factors, such as frontal atrophy, may play a more important role than subcortical cholinergic atrophy in PSP patients. These results may indicate that other drug-targets are needed to improve cognitive function in PSP patients.
A Dynamic Efficient Sensory Encoding Approach to Adaptive Tuning in Neural Models of Optic Flow Processing
Authors: Steinmetz Scott T. , Layton Oliver W. , Powell Nathaniel V. , Fajen Brett R.
Published: April 2022

This paper introduces a self-tuning mechanism for capturing rapid adaptation to changing visual stimuli by a population of neurons. Building upon the principles of efficient sensory encoding, we show how neural tuning curve parameters can be continually updated to optimally encode a time-varying distribution of recently detected stimulus values. We implemented this mechanism in a neural model that produces human-like estimates of self-motion direction (i.e., heading) based on optic flow. The parameters of speed-sensitive units were dynamically tuned in accordance with efficient sensory encoding such that the network remained sensitive as the distribution of optic flow speeds varied. In two simulation experiments, we found that model performance with dynamic tuning yielded more accurate, shorter latency heading estimates compared to the model with static tuning. We conclude that dynamic efficient sensory encoding offers a plausible approach for capturing adaptation to varying visual environments in biological visual systems and neural models alike.
SARM1 Promotes Photoreceptor Degeneration in an Oxidative Stress Model of Retinal Degeneration
Authors: Gibbons Luke , Ozaki Ema , Greene Chris , Trappe Anne , Carty Michael , Coppinger Judith A. , Bowie Andrew G. , Campbell Matthew , Doyle Sarah L.
Published: April 2022

SARM1 (sterile alpha and armadillo motif-containing protein) is a highly conserved Toll/IL-1 Receptor (TIR) adaptor with important roles in mediating immune responses. Studies in the brain have shown that SARM1 plays a role in induction of neuronal axon degeneration in response to a variety of injuries. We recently demonstrated that SARM1 is pro-degenerative in a genetic model of inherited retinopathy. This current study aimed to characterise the effect of SARM1 deletion in an alternative model of retinal degeneration (RD) in which the retinal pigment epithelium (RPE) fragments following administration of oxidising agent, sodium iodate (NaIO3), leading to subsequent photoreceptor cell death. Following administration of NaIO3, we observed no apparent difference in rate of loss of RPE integrity in SARM1 deficient mice compared to WT counterparts. However, despite no differences in RPE degeneration, photoreceptor cell number and retinal thickness were increased in Sarm1–/– mice compared to WT counterparts. This apparent protection of the photoreceptors in SARM1 deficient mice is supported by an observed decrease in pro-apoptotic caspase-3 in the photoreceptor layer of Sarm1–/– mice compared to WT. Together these data indicate a pro-degenerative role for SARM1 in the photoreceptors, but not in the RPE, in an oxidative stress induced model of retinal degeneration consistent with its known degenerative role in neurons in a range of neurodegenerative settings.
From a Demand-Based to a Supply-Limited Framework of Brain Metabolism
Authors: Herculano-Houzel Suzana , Rothman Douglas L.
Published: April 2022

What defines the rate of energy use by the brain, as well as per neurons of different sizes in different structures and animals, is one fundamental aspect of neuroscience for which much has been theorized, but very little data are available. The prevalent theories and models consider that energy supply from the vascular system to different brain regions is adjusted both dynamically and in the course of development and evolution to meet thedemandsof neuronal activity. In this perspective, we offer an alternative view: that regional rates of energy use might be mostly constrained bysupply, given the properties of the brain capillary network, the highly stable rate of oxygen delivery to the whole brain under physiological conditions, and homeostatic constraints. We present evidence that these constraints, based on capillary density and tissue oxygen homeostasis, are similar between brain regions and mammalian species, suggesting they derive from fundamental biophysical limitations. The same constraints also determine the relationship between regional rates of brain oxygen supply and usage over the full physiological range of brain activity, from deep sleep to intense sensory stimulation, during which the apparent uncoupling of blood flow and oxygen use is still a predicted consequence of supply limitation. By carefully separating “energy cost” into energy supply and energy use, and doing away with the problematic concept of energetic “demands,” our new framework should help shine a new light on the neurovascular bases of metabolic support of brain function and brain functional imaging. We speculate that the trade-offs between functional systems and even the limitation to a single attentional spot at a time might be consequences of a strongly supply-limited brain economy. We propose that a deeper understanding of brain energy supply constraints will provide a new evolutionary understanding of constraints on brain function due to energetics; offer new diagnostic insight to disturbances of brain metabolism; lead to clear, testable predictions on the scaling of brain metabolic cost and the evolution of brains of different sizes; and open new lines of investigation into the microvascular bases of progressive cognitive loss in normal aging as well as metabolic diseases.
Inter-Observer and Intra-Observer Variability in Gross Tumor Volume Delineation of Primary Esophageal Carcinomas Based on Different Combinations of Diagnostic Multimodal Images
Authors: Li Fengxiang , Li Yankang , Wang Xue , Zhang Yingjie , Liu Xijun , Liu Shanshan , Wang Wei , Wang Jinzhi , Guo Yanluan , Xu Min , Li Jianbin
Published: April 2022

Background and Purpose

This study aimed to investigate inter-/intra-observer delineation variability in GTVs of primary esophageal carcinomas (ECs) based on planning CT with reference to different combinations of diagnostic multimodal images from endoscopy/EUS, esophagography and FDG-PET/CT.

Materials and Methods

Fifty patients with pathologically proven thoracic EC who underwent diagnostic multimodal images before concurrent chemoradiotherapy were enrolled. Five radiation oncologist independently delineated the GTVs based on planning CT only (GTVC), CT combined with endoscopy/EUS (GTVCE), CT combined with endoscopy/EUS and esophagography (X-ray) (GTVCEX), and CT combined with endoscopy/EUS, esophagography, and FDG-PET/CT (GTVCEXP). The intra-/inter-observer variability in the volume, longitudinal length, generalized CI (CIgen), and position of the GTVs were assessed.

Results

The intra-/inter-observer variability in the volume and longitudinal length of the GTVs showed no significant differences (p>0.05). The mean intra-observer CIgen values for all observers was 0.73 ± 0.15. The mean inter-observer CIgen values for the four multimodal image combinations was 0.67 ± 0.11. The inter-observer CIgen for the four combined images was the largest, showing significant differences with those for the other three combinations. The intra-observer CIgen among different observers and inter-observer CIgen among different combinations of multimodal images showed significant differences (p<0.001). The intra-observer CIgen for the senior radiotherapists was larger than that for the junior radiotherapists (p<0.001).

Conclusion

For radiation oncologists with advanced medical imaging training and clinical experience, using diagnostic multimodal images from endoscopy/EUS, esophagography, and FDG-PET/CT could reduce the intra-/inter-observer variability and increase the accuracy of target delineation in primary esophageal carcinomas.
Treatment of Retinoblastoma: What Is the Latest and What Is the Future
Authors: Schaiquevich Paula , Francis Jasmine H. , Cancela María Belén , Carcaboso Angel Montero , Chantada Guillermo L. , Abramson David H.
Published: April 2022

The management of retinoblastoma, the most common intraocular malignancy in children, has changed drastically over the last decade. Landmark developments in local drug delivery, namely, safer techniques for intravitreal chemotherapy injection and ophthalmic artery chemosurgery, have resulted in eye globe salvages that were not previously attainable using systemic chemotherapy or external beam irradiation. Novel drugs, oncolytic viruses, and immunotherapy are promising approaches in the treatment of intraocular retinoblastoma. Importantly, emerging studies of the pattern of tumor dissemination and local drug delivery may provide the first steps toward new treatments for metastatic disease. Here, we review recent advances in retinoblastoma treatment, especially with regard to local drug delivery, that have enabled successful conservative management of intraocular retinoblastoma. We also review emerging data from preclinical and clinical studies on innovative approaches that promise to lead to further improvement in outcomes, namely, the mechanisms and potential uses of new and repurposed drugs and non-chemotherapy treatments, and discuss future directions for therapeutic development.
Icaritin Inhibits Migration and Invasion of Human Ovarian Cancer Cells via the Akt/mTOR Signaling Pathway
Authors: Gao Lvfen , Ouyang Yuan , Li Ruobin , Zhang Xian , Gao Xuesong , Lin Shaoqiang , Wang Xiaoyu
Published: April 2022

Ovarian cancer (OC) is the most lethal of all gynecologic malignancies with poor survival rates. Although surgical treatment and chemotherapy had advanced to improve survival, platinum-based chemoresistance remains a major hurdle in the clinical treatment of OC. The search for novel active ingredients for the treatment of drug-resistant OC is urgently needed. Here, we demonstrated that icaritin, the main active ingredient derived from the traditional Chinese herb Epimedium genus, significantly suppressed the proliferation, migration, and invasion of both drug-susceptible and cisplatin-resistant OC cells in vitro. Mechanistically, icaritin at 20 μM significantly inhibited the phosphorylation of Akt and mTOR, as well as decreased the expression of vimentin and increased the expression of E-cadherin. Our data indicate that icaritin, a prenylated flavonoid natural product, could serve as a potential inhibitor of cisplatin-resistant OC by inhibiting the Akt/mTOR signaling pathway.
Prognostic Impact of Platelet-Large Cell Ratio In Myelodysplastic Syndromes
Authors: Chen Qiuni , Chen Yue , Zhang Yijing , Zhang Lijuan , Chen Kankan , He Zhengmei , Wang Chunling , Yu Liang
Published: April 2022

Background

Myelodysplastic syndromes (MDSs) are a very heterogeneous group of myeloid disorders with high prevalence and risk of developing acute myeloid leukemia. The more accurate risk stratification can provide a better guidance of treatment. The platelet–large cell ratio (P-LCR) is a parameter reported in complete blood cell count tests, and was associated with many diseases, but its role in MDS is not clear.

Purpose

This study aims to explore the impact of the P-LCR on the prognosis of patients with MDS, which is of great significance for clinical treatment.

Methods

In the retrospective study, 122 newly diagnosed MDS patients were enrolled. We used the bioinformatics tool X-tile to define a P-LCR threshold of 36.7% to predict prognosis. Patients were divided into P-LCRlow and P-LCRhigh groups, and their characteristics were compared between the two groups.

Results

Results show that the P-LCRlow was associated with worse overall survival (OS) than the P-LCRhigh patients (median OS, 18.53 months versus 25.77 months, p=0.0057), but there were no statistical differences in progression-free survival (PFS) between the two groups (p=0.2001). The results of univariate and multivariate Cox proportional hazard analyses adjusted for gender, bone marrow blast level, platelet count, and International Prognostic Scoring System scores showed that the P-LCR was useful in the evaluation of PFS [hazard ratio (HR) 0.212, 95%CI 0.064–0.702, p=0.011] and OS of MDS (HR 0.464, 95%CI 0.284–0.757, p=0.002).

Conclusion

This study is the first report showing that the P-LCR would be a simple and immediately available biomarker for predicting the prognosis of MDS.
Tongxinluo May Alleviate Inflammation and Improve the Stability of Atherosclerotic Plaques by Changing the Intestinal Flora
Authors: Qi Yan , Liu Wenzhao , Yan Xuefang , Zhang Chen , Zhang Chunmei , Liu Lingxin , Zheng Xuehui , Suo Mengying , Ti Yun , Ni Mei , Zhang Meng , Bu Peili
Published: April 2022

Intestinal flora plays an important role in atherosclerosis. Tongxinluo, as a multi-target Chinese medicine to improve atherosclerosis, whether it can improve atherosclerosis by affecting the intestinal flora is worth exploring. We established a vulnerable plaque model of atherosclerosis in New Zealand white rabbits by high cholesterol diet and balloon injury (HCB), and performed Tongxinluo intervention. We detected the level of inflammation by immunohistochemistry, Western Blot, and ELISA, analyzed plaque characteristics by calculating the vulnerability index, and analyzed the changes of gut microbiota and metabolites by 16S rRNA gene sequencing and untargeted metabolomic sequencing. The results showed that Tongxinluo intervention improved plaque stability, reduced inflammatory response, inhibited NLRP3 inflammatory pathway, increased the relative abundance of beneficial bacteria such as Alistipes which reduced by HCB, and increased the content of beneficial metabolites such as trans-ferulic acid in feces. Through correlation analysis, we found that some metabolites were significantly correlated with some bacteria and some inflammatory factors. In particular, the metabolite trans-ferulic acid was also significantly positively correlated with plaque stability. Our further studies showed that trans-ferulic acid could also inhibit the NLRP3 inflammatory pathway. In conclusion, Tongxinluo can improve plaque stability and reduce inflammation in atherosclerotic rabbits, which may be achieved by modulating intestinal flora and intestinal metabolism. Our study provides new views for the role of Tongxinluo in improving atherosclerotic vulnerable plaque, which has important clinical significance.
Tyrosine Phosphatase PTPRO Deficiency in ERBB2-Positive Breast Cancer Contributes to Poor Prognosis and Lapatinib Resistance
Authors: Dong Hongmei , Du Liang , Cai Songwang , Lin Wan , Chen Chaoying , Still Matthew , Yao Zhimeng , Coppes Robert P. , Pan Yunlong , Zhang Dianzheng , Gao Shegan , Zhang Hao
Published: April 2022

Despite the initial benefit from treating ERBB2-positive breast cancer with tyrosine kinase inhibitor lapatinib, resistance develops inevitably. Since the expression of protein tyrosine phosphatase receptor-type O (PTPRO), a member of the R3 subfamily of receptor protein tyrosine phosphatases (PTPs), is inversely correlated with the aggressiveness of multiple malignancies, we decided to explore the correlation between PTPRO and lapatinib resistance in ERBB2-positive breast cancer. Results of immunohistochemical (IHC) staining and the correlation analysis between the expression levels of PTPRO and the clinicopathological parameters indicate that PTPRO is downregulated in cancer tissues as compared with normal tissues and negatively associated with differentiation, tumor size, tumor depth, as well as the expression of ERBB2 and Ki67. Results from Kaplan–Meier analyses indicate that lower expression of PTPRO is correlated with shorter relapse-free survival for patients with ERBB2-positive breast cancer, and multivariable Cox regression analysis found that PTPRO can potentially serve as an independent prognostic indicator for ERBB2-positive breast cancer. Results from both human breast cancer cells with PTPRO knockdown or overexpression and mouse embryonic fibroblasts (MEFs) which derived from Ptpro+/+ and Ptpro−/− mice with then stably transfected plasmid FUGW-Erbb2 consistently demonstrated the essentiality of PTPRO in the lapatinib-mediated anticancer process. Our findings suggest that PTPRO is not only able to serve as an independent prognostic indicator, but upregulating PTPRO can also reverse the lapatinib resistance of ERBB2-positive breast cancer.
Ginsenoside Compound K Enhances Fracture Healing via Promoting Osteogenesis and Angiogenesis
Authors: Ding Lingli , Gu Song , Zhou Bingyu , Wang Min , Zhang Yage , Wu Siluo , Zou Hong , Zhao Guoping , Gao Zhao , Xu Liangliang
Published: April 2022

Fractures have an extraordinarily negative impact on an individual’s quality of life and functional status, particularly delayed or non-union fractures. Osteogenesis and angiogenesis are closely related to bone growth and regeneration, and bone modeling and remodeling. Recently Chinese medicine has been extensively studied to promote osteogenic differentiation in MSCs. Studies have found that Ginseng can be used as an alternative for tissue regeneration and engineering. Ginseng is a commonly used herbal medicine in clinical practice, and one of its components, Ginsenoside Compound K (CK), has received much attention. Evidence indicates that CK has health-promoting effects in inflammation, atherosclerosis, diabetics, aging, etc. But relatively little is known about its effect on bone regeneration and the underlying cellular and molecular mechanisms. In this study, CK was found to promote osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) by RT-PCR and Alizarin Red S staining in vitro. Mechanistically, we found CK could promote osteogenesis through activating Wnt/β-catenin signaling pathway by immunofluorescence staining and luciferase reporter assay. And we also showed that the tube formation capacity of human umbilical vein endothelial cells (HUVECs) was increased by CK. Furthermore, using the rat open femoral fracture model, we found that CK could improve fracture repair as demonstrated by Micro-CT, biomechanical and histology staining analysis. The formation of H type vessel in the fracture callus was also increased by CK. These findings provide a scientific basis for treating fractures with CK, which may expand its application in clinical practice.
Paraquat Induces Lung Injury via miR-199-Mediated SET in a Mouse Model
Authors: Cai Quan , Jin Yan , Jia Ziyi , Liu Zhi
Published: April 2022

Objective: To explore the molecular mechanism of lung injury caused by paraquat (PQ) poisoning by investigating miR-199-mediated SET.

Methods: A paraquat poisoning model was established in C57BL/6 male mice via intraperitoneal injection of paraquat. The mice were transfected with miR-199 siRNA and or mimic. After 14 days of treatment, pathophysiological changes of the lung were observed and lung tissue was analyzed via Hematoxylin-Eosin staining. The levels of miR-199, SETs, surfactant protein SP-A and SP-B, and inflammatory and oxidative factors were analyzed by qPCR, Western Blot, and ELISA kits.

Results: A acute lung-injury (ALI) model was established using PQ treatment and confirmed with edema of pulmonary endothelium with low electronic density of endothelial cytoplasm, presence of protein-rich fluid, and numerous erythrocytes in alveolar space, concentric figures of damaged tubular myelin, alveolar destruction, and increase in inflammatory cell numbers. Compared with the control group, miR-199 and SET levels were reduced in the PQ-treated group. miR-199 siRNA increased the SET level, inflammatory and oxidative levels, and reduced the levels of SP-A and SP-B, and miR-199 mimic reduced the SET level, inflammatory and oxidative levels, and increased the levels of SP-A and SP-B. PQ treatment reduced miR-199 level.

Conclusion: Paraquat induces ALI by affecting miR-199-mediated SET.
Kaempferol From Penthorum chinense Pursh Attenuates Hepatic Ischemia/Reperfusion Injury by Suppressing Oxidative Stress and Inflammation Through Activation of the Nrf2/HO-1 Signaling Pathway
Authors: Chen Yifan , Li Tongxi , Tan Peng , Shi Hao , Cheng Yonglang , Cai Tianying , Bai Junjie , Du Yichao , Fu Wenguang
Published: April 2022

The purpose of this study is to investigate the protective effect of kaempferol (KAE), the main active monomer from Penthorum chinense Pursh, on hepatic ischemia/reperfusion injury (HI/RI) and its specific mechanism. HI/RI is a common complication closely related to the prognosis of liver surgery, and effective prevention and treatment methods are still unavailable. Ischemia/reperfusion (I/R) injury is caused by tissue damage during ischemia and sustained oxidative stress and inflammation during reperfusion. Penthorum chinense Pursh is a traditional Chinese medicine widely used to treat liver disease since ancient times. Kaempferol (KAE), a highly purified flavonoid active monomer isolated and extracted from Penthorum chinense Pursh, was investigated for its protective effect on HI/RI. Our study indicates that KAE pretreatment alleviated I/R-induced transaminase elevation and pathological changes. Further analysis revealed that KAE pretreatment attenuates I/R-induced oxidative stress (as measured by the content of MDA, SOD and GSH) in vivo and reduces hypoxia/reoxygenation (H/R) -induced reactive oxygen species (ROS) generation in vitro. Meanwhile, KAE inhibits activation of NF-κB/p65 and reduces the release of pro-inflammatory factors (TNF-α and IL-6) to protect the liver from I/R-induced inflammation. Nuclear erythroid 2-related factor 2 (Nrf2) is a crucial cytoprotection regulator because it induces anti-inflammatory, antioxidant, and cytoprotective genes. Therefore, we analyzed the protein levels of Nrf2 and its downstream heme oxygenase-1 (HO-1) in the liver of mice and hepatocytes of humankind, respectively, and discovered that KAE pretreatment activates the Nrf2/HO-1 signaling pathway. In summary, this study confirmed the hepatoprotective effect of KAE on HI/RI, which inhibits oxidative stress and inflammation by activating the Nrf2/HO-1 signaling pathway.
An Ayurgenomics Approach: Prakriti-Based Drug Discovery and Development for Personalized Care
Authors: Huang Zoufang , Chavda Vivek P. , Bezbaruah Rajashri , Uversky Vladimir N. , P. Sucharitha , Patel Aayushi B. , Chen Zhe-Sheng
Published: April 2022

Originating in ancient India, Ayurveda is an alternative medicinal approach that provides substantial evidence for a theoretical-level analysis of all aspects of life. Unlike modern medicine, Ayurveda is based upon tridoshas (Vata, pitta, and Kapha) and Prakriti. On the other hand, the research of all the genes involved at the proteomics, metabolomics, and transcriptome levels are referred to as genomics. Geoclimatic regions (deshanupatini), familial characteristics (kulanupatini), and ethnicity (jatiprasakta) have all been shown to affect phenotypic variability. The combination of genomics with Ayurveda known as ayurgenomics provided new insights into tridosha that may pave the way for precision medicine (personalized medicine). Through successful coordination of “omics,” Prakriti-based treatments can help change the existing situation in health care. Prakriti refers to an individual’s behavioral trait, which is established at the moment of birth and cannot be fully altered during one’s existence. Ayurvedic methodologies are based on three Prakriti aspects: aushadhi (medication), vihara (lifestyle), and ahara (diet). A foundation of Prakriti-based medicine, preventative medicine, and improvement of life quality with longevity can be accomplished through these ayurvedic characteristics. In this perspective, we try to understand prakriti’s use in personalized medicine, and how to integrate it with programs for drug development and discovery.
MMP9 Expression Correlates With Cisplatin Resistance in Small Cell Lung Cancer Patients
Authors: Wu Longqiu , Wang Xiangcai , He Xin , Li Qiang , Hua Qian , Liu Rongrong , Qiu Zhengang
Published: April 2022

Background: Cisplatin is the basis of the primary treatment for SCLC chemotherapy. However, the limited objective response rate and definite drug resistance greatly restrict the clinical potential and therapeutic benefits of cisplatin use. Therefore, it is essential to identify biomarkers that can discern the sensitivity of SCLC patients to cisplatin treatment.

Methods: We collected two SCLC cohorts treated with cisplatin that included mutation data, prognosis data and expression data. The sensitivity of cisplatin was evaluated by the pRRophetic algorithm. MCPcounter, quanTIseq, and xCell algorithms were used to evaluate immune cell score. GSEA and ssGSEA algorithms were used to calculate immune-related pathway scores. Univariate and multivariate Cox regression models were employed, and survival analysis was used to evaluate the prognostic value of the candidate genes.

Results: MMP9-High is related to improved clinical prognoses of patients with SCLC (HR = 0.425, p = 0.0085; HR = 0.365, p = 0.0219). Multivariate results showed that MMP-High could be used as an independent predictor of the prognosis of SCLC after cisplatin treatment (HR = 0.216, p = 0.00153; HR = 0.352; p = 0.0199). In addition, MMP9-High displayed a significantly lower IC50 value of cisplatin and higher immunogenicity than MMP9-Low SCLC. Compared with MMP9-Low SCLC, MMP9-High included significantly increased levels of T-cells, cytoxic lymphocytes, B-cells, NK-cells, and dense cells (DCS). Similarly, the activity of cytokine binding, B-cell, NK-cell mediated immune response chemokine binding, and antigen presentation pathways in MMP9-High was significantly higher than that in MMP9-Low.

Conclusion: In this study, we identified that MMP9-High could be potentially considered a novel biomarker used to ascertain the improved prognosis of SCLC patients after cisplatin treatment. Furthermore, we indicated that the tumor immune microenvironment of MMP9-High SCLC is mainly characterized by a large number of infiltrated activated immune cells as well as activated immune-related pathways.