Transcriptome analysis of differential sugar accumulation in the developing embryo of contrasting two Castanea mollissima cultivars.

Chinese chestnut (Castanea mollissima) is an important nut tree species, and its embryo is rich in sugar. We combined metabolomic and transcriptomic data to analyze metabolites and genes related to sugar in two Chinese chestnut cultivars at 60, 70, 80, 90 and 100 days after flowering (DAF). The soluble sugar content of high-sugar cultivar at maturity is 1.5 times that of low-sugar cultivar. Thirty sugar metabolites were identified in embryo, with the most dominant being sucrose. Analysis of the gene expression patterns revealed that the high-sugar cultivar promoted the conversion of starch to sucrose by up-regulating genes related to starch degradation and sucrose synthesis at 90-100 DAF. It also strongly increased the enzyme activity of SUS-synthetic, which may promote sucrose synthesis. Gene co-expression network analysis showed that ABA and peroxide were related to starch decomposition during Chinese chestnut ripening. Our study analyzed the composition and molecular synthesis mechanism of sugar in Chinese chestnut embryos, and provided a new insight into the regulation pattern of high sugar accumulation in Chinese chestnut nuts.

MiR-552-3p Regulates Multiple Fibrotic and Inflammatory genes Concurrently in Hepatic Stellate Cells Improving NASH-associated Phenotypes.

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by hepatic steatosis, inflammation, and progressive fibrosis. Our previous study demonstrated that microRNA-552-3p (miR-552-3p) was down-regulated in the livers of patients with NASH and alleviated hepatic glycolipid metabolic disorders. However, whether miR-552-3p affects NASH progression remains unclear. In this current study, we found that hepatic miR-552-3p expression was negatively correlated with the degree of liver fibrosis and inflammation of NASH patients. Interestingly, the level of miR-552-3p was decreased during hepatic stellate cell (HSC) activation in vitro. Overexpression of miR-552-3p could not only inhibit the expression of fibrotic and inflammatory genes, but also restrain the activation of TGF-ß1/Smad3 signaling pathway by down-regulating the expression of TGFBR2 and SMAD3 in HSCs, finally suppressing HSC activation. More importantly, overexpression of miR-552-3p ameliorated liver fibrosis and inflammation in two murine models: high fat/high fructose/high cholesterol diet-induced NASH model and carbon tetrachloride (CCl4)-treated liver fibrosis model. In conclusion, miR-552-3p plays a crucial role in the pathogenesis of NASH by limiting multiple fibrotic and inflammatory pathways in HSCs, which may shed light on its therapeutic potential in NASH.

Deficit irrigation combined with nitrogen application in the early growth stage of sugar beet increases the production capacity of canopy and avoids yield loss.

BACKGROUND: Properly reduced irrigation combined with nitrogen (N) application can be used to improve crop water use efficiency (WUE) in arid regions, but its effect on sugar beet is unknown at present. A two-year field experiment was conducted to evaluate the effects of N application (N0, 0; N1, 150; N2, 225 kg N ha-1 ) on the canopy production capacity (CPC), yield and WUE of sugar beet under normal irrigation (W1, 70% of field capacity (FC)) and deficit irrigation (DI) (W2, 50% FC) in the early growth stage (EGS). RESULTS: The results showed that the W2 treatment reduced the CPC by reducing gas exchange, leaf area index (LAI) and chlorophyll content (SPAD value) of sugar beet leaves compared to the W1 treatment. However, DI combined with N application increased these parameters. Specifically, N application increased the net photosynthetic rate by 40.7% by increased gas exchange, SPAD and LAI compared to the N0 treatment. In addition, N application increased WUE by 12.5% by increasing thickness of upper surface, stomatal aperture and cross-sectional area of petiole. This ultimately led to a significant increase in taproot yield (TY; 19.7%) and sugar yield (SY; 57.6%). Although the TY of the N2 treatment was higher than that of the N1 treatment, the SY and WUE did not increase significantly and the harvest index decreased significantly by 9.3%. CONCLUSION: DI combined with 150 kg N ha-1 in the EGS of sugar beet increases the WUE in arid areas while avoiding yield loss by improving the CPC. © 2023 Society of Chemical Industry.

Integrative analysis of the ST6GALNAC family identifies GATA2-upregulated ST6GALNAC5 as an adverse prognostic biomarker promoting prostate cancer cell invasion.

BACKGROUND: ST6GALNAC family members function as sialyltransferases and have been implicated in cancer progression. However, their aberrant expression levels, prognostic values and specific roles in metastatic prostate cancer (PCa) remain largely unclear. METHODS: Two independent public datasets (TCGA-PRAD and GSE21032), containing 648 PCa samples in total, were employed to comprehensively examine the mRNA expression changes of ST6GALNAC family members in PCa, as well as their associations with clinicopathological parameters and prognosis. The dysregulation of ST6GALNAC5 was further validated in a mouse PCa model and human PCa samples from our cohort (n = 64) by immunohistochemistry (IHC). Gene Set Enrichment Analysis, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and drug sensitivity analyses were performed to enrich the biological processes most related to ST6GALNAC5. Sulforhodamine B, transwell, luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to examine the PCa cell proliferation, invasion and transcriptional regulation, respectively. RESULTS: Systematical investigation of six ST6GALNAC family members in public datasets revealed that ST6GALNAC5 was the only gene consistently and significantly upregulated in metastatic PCa, and ST6GALNAC5 overexpression was also positively associated with Gleason score and predicted poor prognosis in PCa patients. IHC results showed that (1) ST6GALNAC5 protein expression was increased in prostatic intraepithelial neoplasia and further elevated in PCa from a PbCre;PtenF/F mouse model; (2) overexpressed ST6GALNAC5 protein was confirmed in human PCa samples comparing with benign prostatic hyperplasia samples from our cohort (p < 0.001); (3) ST6GALNAC5 overexpression was significantly correlated with perineural invasion of PCa. Moreover, we first found transcription factor GATA2 positively and directly regulated ST6GALNAC5 expression at transcriptional level. ST6GALNAC5 overexpression could partially reverse GATA2-depletion-induced inhibition of PCa cell invasion. The GATA2-ST6GALNAC5 signature exhibited better prediction on the poor prognosis in PCa patients than GATA2 or ST6GALNAC5 alone. CONCLUSIONS: Our results indicated that GATA2-upregulated ST6GALNAC5 might serve as an adverse prognostic biomarker promoting prostate cancer cell invasion.

Perfluoro-tert-butyl Group-Derived Capmatinib: Synthesis, Biological Evaluation and Its Application in 19 F Magnetic Resonance Imaging.

Capmatinib is an FDA-approved drug to treat metastatic non-small cell lung cancer with MET-exon 14 skipping. Herein, the perfluoro-tert-butyl group, which possesses nine chemically identical fluorine atoms, was introduced on Capmatinib to afford a targeted 19 F magnetic resonance imaging (MRI) probe, perfluoro-tert-butyl group-derived Capmatinib (9F-CAP). The 19 F MRI concentration limit was found to be 25 mM in FLASH sequence. Molecular docking simulation, surface plasmon resonance (SPR) (with a Kd of 40.7 µM), half-inhibitory concentration (with a IC50 of 168 nM), Annexin V, and cytotoxicity assays jointly demonstrated that the 9F-CAP targeted cMET protein specifically. Therefore, the targeted imaging capability of 9F-CAP is of great significance for the preoperative diagnosis of specific cancers.

Genome-wide identification, evolution and expression profiles analysis of bHLH gene family in Castanea mollissima.

The basic helix-loop-helix (bHLH) transcription factors (TFs) gene family is an important gene family in plants, and participates in regulation of plant apical meristem growth, metabolic regulation and stress resistance. However, its characteristics and potential functions have not been studied in chestnut (Castanea mollissima), an important nut with high ecological and economic value. In the present study, 94 CmbHLHs were identified in chestnut genome, of which 88 were unevenly distributed on chromosomes, and other six were located on five unanchored scaffolds. Almost all CmbHLH proteins were predicted in the nucleus, and subcellular localization demonstrated the correctness of the above predictions. Based on the phylogenetic analysis, all of the CmbHLH genes were divided into 19 subgroups with distinct features. Abundant cis-acting regulatory elements related to endosperm expression, meristem expression, and responses to gibberellin (GA) and auxin were identified in the upstream sequences of CmbHLH genes. This indicates that these genes may have potential functions in the morphogenesis of chestnut. Comparative genome analysis showed that dispersed duplication was the main driving force for the expansion of the CmbHLH gene family inferred to have evolved through purifying selection. Transcriptome analysis and qRT-PCR experiments showed that the expression patterns of CmbHLHs were different in different chestnut tissues, and revealed some members may have potential functions in chestnut buds, nuts, fertile/abortive ovules development. The results from this study will be helpful to understand the characteristics and potential functions of the bHLH gene family in chestnut.

Cancer-Associated Fibroblast-Derived miR-146a-5p Generates a Niche That Promotes Bladder Cancer Stemness and Chemoresistance.

Cancer stem-like cells (CSC) play pivotal roles in both chemoresistance and recurrence of many cancer types, including urothelial bladder cancer (UBC). In addition to intrinsic signaling pathways, extracellular cues from the tumor microenvironment (TME) are indispensable for the maintenance of CSCs. To better understand the mechanisms involved in TME-mediated generation and support of UBC CSCs, we focused on the role of cancer-associated fibroblasts (CAF) in this study. Overexpression of miR-146a-5p in CAFs promoted CAF-to-UBC cell interactions, cancer stemness, and chemoresistance to treatment with gemcitabine and cisplatin. Mechanistically, miR-146-5p upregulated SVEP1 in CAFs by enhancing the recruitment of transcriptional factor YY1. Meanwhile, by targeting the 3'UTR of mRNAs of ARID1A and PRKAA2 (also known as AMPKα2) in UBC cells, CAF-secreted miR-146a-5p promoted cancer stemness and chemoresistance. Downregulation of ARID1A resulted in the inhibition of SOCS1 and subsequent STAT3 activation, and downregulated PRKAA2 led to the activation of mTOR signaling. Elevated levels of exosomal miR-146a-5p in the serum of patients with UBC were correlated with both tumor stage and relapse risk. These findings altogether indicate that CAF-derived miR-146a-5p can promote stemness and enhance chemoresistance in UBC. Exosomal miR-146a-5p may be a biomarker of UBC recurrence and a potential therapeutic target. SIGNIFICANCE: The tumor-stromal cross-talk mediated by cancer-associated fibroblast-derived miR-146a-5p fosters cancer stem cell niche formation and cancer stemness to drive chemoresistance in urothelial bladder cancer.

Modulation of MRSA virulence gene expression by the wall teichoic acid enzyme TarO.

Phenol-soluble modulins (PSMs) and Staphylococcal protein A (SpA) are key virulence determinants for community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), an important human pathogen that causes a wide range of diseases. Here, using chemical and genetic approaches, we show that inhibition of TarO, the first enzyme in the wall teichoic acid (WTA) biosynthetic pathway, decreases the expression of genes encoding PSMs and SpA in the prototypical CA-MRSA strain USA300 LAC. Mechanistically, these effects are linked to the activation of VraRS two-component system that directly represses the expression of accessory gene regulator (agr) locus and spa. The activation of VraRS was due in part to the loss of the functional integrity of penicillin-binding protein 2 (PBP2) in a PBP2a-dependent manner. TarO inhibition can also activate VraRS in a manner independent of PBP2a. We provide multiple lines of evidence that accumulation of lipid-linked peptidoglycan precursors is a trigger for the activation of VraRS. In sum, our results reveal that WTA biosynthesis plays an important role in the regulation of virulence gene expression in CA-MRSA, underlining TarO as an attractive target for anti-virulence therapy. Our data also suggest that acquisition of PBP2a-encoding mecA gene can impart an additional regulatory layer for the modulation of key signaling pathways in S. aureus.

A Systematic Review of the Need for Guideline Recommendations; Slow Tapering vs. Maintenance Dose in Long-Term Antipsychotic Treatment: 2022.

The act of discontinuing the antipsychotic medication may be directly associated with relapse. This relationship might be due to adaptations that continue to exist after treatment is stopped, such as dopaminergic hypersensitivity. Therefore, more progressive weaning off antipsychotic medication may help reduce the likelihood of relapse when the medication is stopped. As there is a need to gradually reduce or stop using antipsychotic medication, our team tried to conduct a more in-depth search to give further answers to the suggested recommendations. Around 192 articles were gathered for our research, but we could only narrow our search to 36, which were further filtered, and eight were used. We went through all of the pertinent information available until May 2022 and reviewed it to determine the risks associated with prolonged antipsychotic usage and abrupt cessation in the psychotic spectrum of diseases. PubMed, Google Scholar, and Psychiatry Online were the databases used, and the keywords that were looked for and utilized were antipsychotics, tapering, relapse, maintenance dosage, schizophrenia, and psychosis. The recurrence incidence was high in patients in whom antipsychotics were stopped and in whom the dosage was quickly lowered. Patients who were gradually weaned off their antipsychotic medication and kept on the lowest effective dose had a much lower risk of experiencing a relapse. We suggest more studies, including randomized clinical trials and monitoring, considering the enhancement of guidelines for the total cessation of antipsychotic medication use.

Identification of Key Lipogenesis Stages and Proteins Involved in Walnut Kernel Development.

Walnuts are abundant in oil content, especially for polyunsaturated fatty acids, but the understanding of their formation is limited. We collected walnut (Juglans regia L.) kernels at 60, 74, 88, 102, 116, 130, and 144 days after pollination (designated S1-S7). The ultrastructure and accumulation of oil bodies (OBs) were observed using transmission electron microscopy (TEM), and the oil content, fatty acid composition, and proteomic changes in walnut kernels were determined. The oil content and OB accumulation increased during the development and rose sharply from S1 to S3 stages, which are considered the key lipogenesis stage. A total of 5442 proteins were identified and determined as differentially expressed proteins (DEPs) using label-free proteomic analysis. Fatty acid desaturases (FAD) 2, FAD3, oleosin, and caleosin were essential and upregulated from the S1 to S3 stages. Furthermore, the highly expressed oleosin gene JrOLE14.7 from walnuts was cloned and overexpressed in transgenic Brassica napus. The overexpression of JrOLE14.7 increased the oil content, diameter, hundred weight of seeds and changed the fatty acid composition and OB size of Brassica napus seeds. These findings provide insights into the molecular mechanism of oil biosynthesis and the basis for the genetic improvement of walnuts.

A c-MET-Targeted Topical Fluorescent Probe cMBP-ICG Improves Oral Squamous Cell Carcinoma Detection in Humans.

INTRODUCTION: The postoperative survival of oral squamous cell carcinoma (SCC) relies on precise detection and complete resection of original tumors. The mucosal extension of the tumor is evaluated visually during surgery, but small and flat foci are difficult to detect. Real-time fluorescence imaging may improve detection of tumor margins. MATERIALS AND METHODS: In the current study, a peptide-based near-infrared (NIR) fluorescence dye, c-MET-binding peptide-indocyanine green (cMBP-ICG), which specifically targets tumor via c-MET binding, was synthetized. A prospective pilot clinical trial then was conducted with oral SCC patients and intraoperatively to assess the feasibility of cMBP-ICG used to detect tumors margins. Fluorescence was histologically correlated to determine sensitivity and specificity. RESULTS: The immunohistochemistry (IHC) results demonstrated increased c-Met expression in oral SCC compared with normal mucosa. Tumor-to-background ratios ranged from 2.71 ± 0.7 to 3.11 ± 1.2 in different concentration groups. From 10 patients with oral SCC, 60 specimens were collected from tumor margins. The sensitivity and specificity of discriminative value derived from cMBP-ICG application in humans were respectively 100% and 75%. CONCLUSIONS: Topical application of cMBP-ICG is feasible and safe for optimizing intraoperative visualization and tumor margin detection in oral SCC patients, which could clinically increase the probability of complete resections and improve oncologic outcomes.

New-Onset Diabetes Mellitus in Post-renal Transplant Patients on Tacrolimus and Mycophenolate: A Systematic Review.

A frequent complication in kidney transplantation is post-transplant diabetes mellitus (PTDM). The primary goal of this study is to review the risk factors and preventive methods and compare the different available anti-diabetic medications for the management of PTDM. We searched databases like Pubmed and Google Scholar for related articles using specific terms and phrases. Following a thorough investigation, we applied the inclusion and exclusion criteria and completed a quality assessment. Modifiable risk factors have a significant role in the development of PTDM. The combinations of immunosuppressive treatment tacrolimus (TAC), cyclosporine A (CYC), and everolimus (EVL), steroids increase the incidence of PTDM significantly. Insulin is the most effective treatment for PTDM in the early transplant period; however, oral anti-diabetic medications look promising. Further clinical trials are required to determine the optimum treatment method for reducing the occurrence of PTDM and treating the existing condition with novel anti-hyperglycemic medications.

The Clinical Implications of the Academic Performance of the Siblings of Individuals With Autism Spectrum Disorder.

We all know that autism spectrum disorder (ASD) can affect academic performance. Many children with autism face different challenges at school. However, less attention is paid to the siblings of autistic children, who are at a high risk of ASD or the broad autism phenotype (BAP). Recent data also shows that many siblings of ASD children suffer from neurodevelopmental disorders, mental health problems as well as poor academic performance. This review will look at the possible etiologies of the poor school performance of autistic children's siblings, with an emphasis on the challenges they face. We will also highlight the clinical implications of these findings, and the possible solutions that can help this vulnerable group.

The Risk of Fatal Arrhythmias in Post-Myocardial Infarction Depression in Association With Venlafaxine.

Venlafaxine is a second line anti-depressant and the most commonly used in the treatment of selective serotonin reuptake inhibitor nonresponders in major depression; due to its effects on the noradrenergic and serotonergic systems as a serotonin and norepinephrine reuptake inhibitor, there has been considerable apprehension regarding its use in patients with cardiovascular diseases, particularly post-myocardial infarction depression, some of the feared adverse effects include QT prolongation, arrhythmias including torsades de pointes and sudden cardiac death. We tried to resolve the facts regarding the risks associated with venlafaxine use in cardiac patients. We have reviewed all the relevant information up to May 2022 regarding the risks of venlafaxine use in cardiovascular disease, particularly with a focus on post-myocardial infarction depression, and gathered around 350 articles in our research and narrowed it down to 49 articles. The database used was PubMed and the keywords used were venlafaxine, arrhythmia, major depression, post-myocardial infarction, and ventricular tachycardia. We carefully screened all relevant articles and found articles supporting and refuting the effects of venlafaxine in increasing cardiovascular morbidity and mortality. We have concluded that there is a significant variability due to confounding factors affecting individual cases. Overall there is no increased arrhythmia risk in comparison with other anti-depressants except in high-risk cases such as with pre-existing cardiovascular disease, certain genotypes, and other co-morbidities. Any patient with a high risk of arrhythmias due to any etiology should receive a screening electrocardiogram before venlafaxine prescription for baseline QT interval and periodically while on therapy to check for changes. We encourage further research, including randomized clinical trials and post-marketing surveillance regarding the use of venlafaxine in high-risk cases such as patients with multiple co-morbidities, elderly patients, or patients with certain genotypes.

Potential Benefits of Sodium-Glucose Transporter-2 Inhibitors in the Symptomatic and Functional Status of Patients With Heart Failure: A Systematic Review and Meta-Analysis.

This review evaluates the potential benefits of sodium-glucose transporter-2 (SGLT-2) inhibitors on symptom burden/health-related quality of life (HRQoL), functional improvement, hospitalization for heart failure (HHF), cardiovascular mortality (CVM), and all-cause mortality (ACM) in patients with heart failure (HF) with reduced or preserved ejection fraction (EF). We analyzed 12 randomized clinical trials (RCTs) accessed through 11 records and three secondary analyses from PubMed and Scopus following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines. These studies evaluated 23,389 patients treated with either an SGLT-2 inhibitor or placebo in addition to the standard of care. Four studies recruited diabetic patients, some of whom had HF at the baseline and were evaluated as a subgroup. One study had diabetes and HF present in all patients at the baseline. Ten studies recruited patients with HF at their baseline irrespective of diabetic status. Eight studies evaluated the SGLT-2 inhibitors for a composite of hospitalization for heart failure or cardiovascular mortality (HHF/CVM) and ACM. Five of these studies showed a decreased risk for HHF/CVM, and two showed a reduced risk for ACM. One trial showed benefits in patients with heart failure with reduced ejection fraction (HFrEF) only and not in heart failure with preserved ejection fraction (HFpEF). Other studies revealed benefits but did not reach statistical significance. Ten studies assessed the SGLT-2 inhibitors for improvement in symptoms and HRQoL; four demonstrated a significant improvement, three showed a slight improvement, and three did not find any benefit. Five trials evaluated participants' functional progress by assessing for a six-minute walk test (6MWT). Two studies showed a significant increase in the distance walked by the patient, while three others did not. The SGLT-2 inhibitors reduce the risk of HHF/CVM irrespective of ejection fraction and result in a symptomatic improvement.

The Relationship between Vitamin D and Basal Cell Carcinoma: A Systematic Review.

This systematic review studies the relationship between vitamin D serum levels and basal cell carcinoma (BCC). The primary source of vitamin D is sunlight exposure. Recently, an increase in the intake of vitamin D supplements has been noticed. The protective value of vitamin D is well established and has been studied several times for the health of the bones, cartilage, growth, various dermatological diseases, and also as a chemoprotective agent against several cancers. On the scientific front, it has yet to be established that increasing serum vitamin D levels increase the incidence of BCC. We included reports that investigated this relationship in this review. We applied keywords in published papers in PubMed, ScienceDirect, Cochrane, and Google Scholar to find relevant studies. After applying the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist and the quality appraisal for 68 records, we included only ten studies. In these studies, serum levels of vitamin D were measured. Five of them supported the link between BCC incidence and development and high serum vitamin D levels (e.g., Mahamat-Saleh Y, et al.), while the other five did not (e.g., Tang JY, et al.). We included only two studies that investigated the vitamin D receptor (VDR) polymorphism. Experts debate adding a high dose of vitamin D supplements to our daily routine. After studying most of the reports, it was ascertained that the literature supports keeping vitamin D serum levels below 30-60 nmol/L. However, further studies should be done to help find a healthy balance of vitamin D serum levels, especially when it comes to increasing the risk of cancer like BCC.

Evaluation and Treatment of Depression in Stroke Patients: A Systematic Review.

Those who received early diagnosis and treatment for poststroke depression had lower mortality rates, cognitive impairments, improved long-term disability, a higher quality of life, and lower rates of suicidal thoughts than those who did not. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 standards were used to conduct this systematic review. Until May 1, 2022, a systematic search was conducted utilizing ScienceDirect, Cochrane, PubMed, Google Scholar, and PubMed central databases, which have been used during the previous 10 years. Randomized controlled trials (RCTs), observational studies, systematic reviews, review articles, case reports, clinical studies, and meta-analyses were included in the research, which covered post-stroke depression patients and how to identify and treat them. There were 545 possibly related titles found in the database search. Finally, each publication was given a quality rating, and 10 studies with a score of higher than 70% were allowed into the review. Because of their brevity and ease of use, they employed the Patient Health Questionnaire-9 (PHQ-9) and PHQ-2 screening instruments in stroke patients. According to pooled studies, the risk of acquiring post-stroke depression (PSD) was lower in participants undergoing pharmacological therapy with selective serotonin reuptake inhibitors (SSRIs), especially after a year. Identifying further features of the PSD process, we believe, is the most pressing need for future study since it might lead to a more precise treatment strategy.

18F-FDG PET as an imaging biomarker for the response to FGFR-targeted therapy of cancer cells via FGFR-initiated mTOR/HK2 axis.

Rationale: The overall clinical response to FGFR inhibitor (FGFRi) is far from satisfactory in cancer patients stratified by FGFR aberration, the current biomarker in clinical practice. A novel biomarker to evaluate the therapeutic response to FGFRi in a non-invasive and dynamic manner is thus greatly desired. Methods: Six FGFR-aberrant cancer cell lines were used, including four FGFRi-sensitive ones (NCI-H1581, NCI-H716, RT112 and Hep3B) and two FGFRi-resistant ones (primary for NCI-H2444 and acquired for NCI-H1581/AR). Cell viability and tumor xenograft growth analyses were performed to evaluate FGFRi sensitivities, accompanied by corresponding 18F-fluorodeoxyglucose (18F-FDG) uptake assay. mTOR/PLCγ/MEK-ERK signaling blockade by specific inhibitors or siRNAs was applied to determine the regulation mechanism. Results: FGFR inhibition decreased the in vitro accumulation of 18F-FDG only in four FGFRi-sensitive cell lines, but in neither of FGFRi-resistant ones. We then demonstrated that FGFRi-induced transcriptional downregulation of hexokinase 2 (HK2), a key factor of glucose metabolism and FDG trapping, via mTOR pathway leading to this decrease. Moreover, 18F-FDG PET imaging successfully differentiated the FGFRi-sensitive tumor xenografts from primary or acquired resistant ones by the tumor 18F-FDG accumulation change upon FGFRi treatment. Of note, both 18F-FDG tumor accumulation and HK2 expression could respond the administration/withdrawal of FGFRi in NCI-H1581 xenografts correspondingly. Conclusion: The novel association between the molecular mechanism (FGFR/mTOR/HK2 axis) and radiological phenotype (18F-FDG PET uptake) of FGFR-targeted therapy was demonstrated in multiple preclinical models. The adoption of 18F-FDG PET biomarker-based imaging strategy to assess response/resistance to FGFR inhibition may benefit treatment selection for cancer patients.

Physical Activity Status and Diabetic Retinopathy: A Review.

Substantial evidence highlights the association between physical inactivity and diabetes onset and complications. Little is known regarding the link between physical inactivity and diabetic retinopathy in terms of onset, progression, and severity. This review aims to investigate these associations and understand the underlying mechanisms behind these associations. Decreased sedentary times and the inclusion of more physical activity have been linked to the delayed onset and progression of diabetic retinopathy and less severe forms of said condition. Physical activity provides both protective and anti-inflammatory effects on the retina. Further research is needed to understand and elucidate the exact mechanisms by which lack of physical activity affects retinal health and the onset, progression, and severity of diabetic retinopathy.

Identification of hexosamine biosynthesis pathway as a novel prognostic signature and its correlation with immune infiltration in bladder cancer.

Background: Urinary bladder cancer (UBC) is one of the common urological malignancies, lacking reliable biomarkers to predict clinical outcomes in UBC patients. Thus, it is needed to identify the novel diagnostic/prognostic biomarkers to stratify the high-risk UBC patients. As a shunt pathway of glycolysis, the hexosamine biosynthesis pathway (HBP) has been implicated in carcinogenesis. However, its prognostic value in UBC remains unclear. Methods: The RNA sequencing and mRNA microarray datasets were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus databases. The expression levels of five HBP genes were analyzed in normal and UBC samples, and their associations with stage, grade and survival were plotted. The performance of HBP risk group was evaluated by receiver-operating characteristics (ROC) curve. The HBP signature was generated by Gene Set Variation Analysis (GSVA) and its association with clinicopathological parameters and survival were analyzed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out to examine the potential biological functions of HBP using DAVID online tool. The infiltration estimation fraction of immune cells was performed using CIBERSORT-ABS algorithm. Gene set enrichment analysis (GSEA) was used to explore the potential function of HBP in tumor immunoregulation. Results: Four HBP genes were upregulated in UBCs compared to normal tissues in TCGA-BLCA dataset. The upregulation of all five HBP genes was significantly associated with tumor grade and stage of UBC in three independent UBC datasets. The expression of HBP genes predicted poor clinical outcomes in UBC patients in both TCGA-BLCA and GSE13507 datasets. The high-risk group based on HBP genes showed a poor prognosis. Furthermore, HBP signature was positively associated with tumor grade and stage in TCGA-BLCA dataset and with tumor grade, stage, distal metastasis and poor survival in GSE13507 dataset. Interestingly, high-HBP signature group exhibited a high infiltration of immune cells, particularly the macrophage population. Conclusion: We identified that HBP was a promising prognostic biomarker in UBC patients and strongly associated with immune infiltration.