Integrative proteome and metabolome unveil the central role of IAA alteration in axillary bud development following topping in tobacco.

Axillary bud is an important aspect of plant morphology, contributing to the final tobacco yield. However, the mechanisms of axillary bud development in tobacco remain largely unknown. To investigate this aspect of tobacco biology, the metabolome and proteome of the axillary buds before and after topping were compared. A total of 569 metabolites were differentially abundant before and 1, 3, and 5 days after topping. KEGG analyses further revealed that the axillary bud was characterized by a striking enrichment of metabolites involved in flavonoid metabolism, suggesting a strong flavonoid biosynthesis activity in the tobacco axillary bud after topping. Additionally, 9035 differentially expressed proteins (DEPs) were identified before and 1, 3, and 5 days after topping. Subsequent GO and KEGG analyses revealed that the DEPs in the axillary bud were enriched in oxidative stress, hormone signal transduction, MAPK signaling pathway, and starch and sucrose metabolism. The integrated proteome and metabolome analysis revealed that the indole-3-acetic acid (IAA) alteration in buds control dormancy release and sustained growth of axillary bud by regulating proteins involved in carbohydrate metabolism, amino acid metabolism, and lipid metabolism. Notably, the proteins related to reactive oxygen species (ROS) scavenging and flavonoid biosynthesis were strongly negatively correlated with IAA content. These findings shed light on a critical role of IAA alteration in regulating axillary bud outgrowth, and implied a potential crosstalk among IAA alteration, ROS homeostasis, and flavonoid biosynthesis in tobacco axillary bud under topping stress, which could improve our understanding of the IAA alteration in axillary bud as an important regulator of axillary bud development.

LncRNA PCGEM1 facilitates cervical cancer progression via miR-642a-5p/KIF5B axis.

At present, the role of many long non-coding RNAs (lncRNAs) as tumor suppressors in the formation and development of cervical cancer (CC) has been studied. However, lncRNA prostate cancer gene expression marker 1 (PCGEM1), whose high expression not only aggravates ovarian cancer but also can induce tumorigenesis and endometrial cancer progression, has not been studied in CC. The objective of this study was to investigate the expression and the underlying role of PCGEM1 in CC. The relative expression of PCGEM1 in CC cells was detected by real-time PCR. After the suppression of PCGEM1 expression by shRNA, the changes in the proliferation, migration, and invasion capacities were detected via CCK-8 assay, EdU assay, and colony formation assay wound healing assay. Transwell assay and the changes in expressions of epithelial-to-mesenchymal transition (EMT) markers were determined by western blot and immunofluorescence. The interplay among PCGEM1, miR-642a-5p, and kinesin family member 5B (KIF5B) was confirmed by bioinformatics analyses and luciferase reporter assay. Results showed that PCGEM1 expressions were up-regulated within CC cells. Cell viabilities, migration, and invasion were remarkably reduced after the suppression of PCGEM1 expression by shRNA in Hela and SiHa cells. N-cadherin was silenced, but E-cadherin expression was elevated by sh-PCGEM1. Moreover, by sponging miR-642a-5p in CC, PCGEM1 was verified as a competitive endogenous RNA (ceRNA) that modulates KIF5B levels. MiR-642a-5p down-regulation partially rescued sh-PCGEM1's inhibitory effects on cell proliferation, migration, invasion, and EMT process. In conclusion, the PCGEM1/miR-642a-5p/KIF5B signaling axis might be a novel therapeutic target in CC. This study provides a research basis and new direction for targeted therapy of CC.

Eudragit S100 coated iron oxide-chitosan nanocomposites for colon targeting of 5-aminosalicylic acid ameliorate ulcerative colitis by improving intestinal barrier function and inhibiting NLRP3 inflammasome.

The therapeutic effect of 5-amino salicylic acid (5-ASA), a first-line therapeutic agent for the treatment of ulcerative colitis (UC), is limited by the modest bioavailability afforded by its oral administration. In this study, a 5-ASA oral delivery system was developed using Eudragit S100-coated iron oxide-chitosan nanocomposites (ES-IOCS/5-ASA) to address this issue. According to drug release studies in vitro, ES-IOCS/5-ASA only released a small amount of drug in simulated gastric fluid with a pH of 1.2. However, in a medium with a pH of 7.5, a relatively rapid and complete release was noted. 5-ASA-loaded iron oxide-chitosan nanocomposites (IOCS/5-ASA) could be effectively taken up by NCM460 cells and performed better anti-inflammatory effects than free 5-ASA. At the same time, IOCS/5-ASA improved barrier damage in DSS-induced NCM460 cells. In vivo models of dextran sulphate sodium (DSS)-induced colitis were used to assess the therapeutic efficacy of oral administration of ES-IOCS/5-ASA. ES-IOCS/5-ASA significantly relieved DSS-induced colitis and enhanced the integrity of the intestinal epithelial barrier. ES-IOCS/5-ASA also reduced the expression of NLRP3, ASC and IL-1ß. Additionally, iron oxide nanoparticles used as nanozymes could alleviate inflammation. In summary, this study indicates that ES-IOCS/5-ASA exert anti-inflammatory effects on DSS-induced colitis by improving intestinal barrier function and inhibiting NLRP3 inflammasome expression, presenting a viable therapeutic choice for the treatment of UC.

Microglial circ-UBE2K exacerbates depression by regulating parental gene UBE2K via targeting HNRNPU.

Background: Knowledge about the pathogenesis of depression and treatments for this disease are lacking. Epigenetics-related circRNAs are likely involved in the mechanism of depression and have great potential as treatment targets, but their mechanism of action is still unclear. Methods: Circular RNA UBE2K (circ-UBE2K) was screened from peripheral blood of patients with major depressive disorder (MDD) and brain of depression model mice through high-throughput sequencing. Microinjection of circ-UBE2K overexpression lentivirus and adeno-associated virus for interfering with microglial circ-UBE2K into the mouse hippocampus was used to observe the role of circ-UBE2K in MDD. Sucrose preference, forced swim, tail suspension and open filed tests were performed to evaluate the depressive-like behaviors of mice. Immunofluorescence and Western blotting analysis of the effects of circ-UBE2K on microglial activation and immune inflammation. Pull-down-mass spectrometry assay, RNA immunoprecipitation (RIP) test and fluorescence in situ hybridization (FISH) were used to identify downstream targets of circ-UBE2K/ HNRNPU (heterogeneous nuclear ribonucleoprotein U) axis. Results: In this study, through high-throughput sequencing and large-scale screening, we found that circ-UBE2K levels were significantly elevated both in the peripheral blood of patients with MDD and in the brains of depression model mice. Functionally, circ-UBE2K-overexpressing mice exhibited worsened depression-like symptoms, elevated brain inflammatory factor levels, and abnormal microglial activation. Knocking down circ-UBE2K mitigated these changes. Mechanistically, we found that circ-UBE2K binds to heterogeneous nuclear ribonucleoprotein U (HNRNPU) to form a complex that upregulates the expression of the parental gene ubiquitin conjugating enzyme E2 K (UBE2K), leading to abnormal microglial activation and neuroinflammation and promoting the occurrence and development of depression. Conclusions: The findings of the present study revealed that the expression of circUBE2K, which combines with HNRNPU to form the circUBE2K/HNRNPU complex, is increased in microglia after external stress, thus regulating the expression of the parental gene UBE2K and mediating the abnormal activation of microglia to induce neuroinflammation, promoting the development of MDD. These results indicate that circ-UBE2K plays a newly discovered role in the pathogenesis of depression.

Global changes of miRNA expression indicates an increased reprogramming efficiency of induced mammary epithelial cells by repression of miR-222-3p in fibroblasts.

Background: Our previous studies have successfully reported the reprogramming of fibroblasts into induced mammary epithelial cells (iMECs). However, the regulatory relationships and functional roles of MicroRNAs (miRNAs) in the progression of fibroblasts achieving the cell fate of iMECs are insufficiently understood. Methods: First, we performed pre-and post-induction miRNAs sequencing analysis by using high-throughput sequencing. Following that, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment studies were used to determine the primary roles of the significantly distinct miRNAs and targeted genes. Finally, the effect of miR-222-3p on iMECs fate reprogramming in vitro by transfecting. Results: As a result goat ear fibroblasts (GEFs) reprogramming into iMECs activates a regulatory program, involving 79 differentially expressed miRNAs. Besides, the programming process involved changes in multiple signaling pathways such as adherens junction, TGF-ß signaling pathway, GnRH secretion and the prolactin signaling pathway, etc. Furthermore, it was discovered that the expression of miR-222-3p downregulation by miR-222-3p inhibitor significantly increase the reprogramming efficiency and promoted lipid accumulation of iMECs.

The potential of Burkholderia gladioli KRS027 in plant growth promotion and biocontrol against Verticillium dahliae revealed by dual transcriptome of pathogen and host.

Verticillium dahliae is a destructive, soil-borne pathogen that causes significant losses on numerous important dicots. Recently, beneficial microbes inhabiting the rhizosphere have been exploited and used to control plant diseases. In the present study, Burkholderia gladioli KRS027 demonstrated excellent inhibitory effects against Verticillium wilt in cotton seedlings. Plant growth and development was promoted by affecting the biosynthesis and signaling pathways of brassinosteroids (BRs), gibberellins (GAs), and auxins, consequently promoting stem elongation, shoot apical meristem, and root apical tissue division in cotton. Furthermore, based on the host transcriptional response to V. dahliae infection, it was found that KRS027 modulates the plants to maintain cell homeostasis and respond to other pathogen stress. Moreover, KRS027 induced disruption of V. dahliae cellular structures, as evidenced by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses. Based on the comparative transcriptomic analysis between KRS027 treated and control group of V. dahliae, KRS027 induced substantial alterations in the transcriptome, particularly affecting genes encoding secreted proteins, small cysteine-rich proteins (SCRPs), and protein kinases. In addition, KRS027 suppressed the growth of different clonal lineages of V. dahliae strains through metabolites, and volatile organic compounds (VOCs) released by KRS027 inhibited melanin biosynthesis and microsclerotia development. These findings provide valuable insights into an alternative biocontrol strategy for Verticillium wilt, demonstrating that the antagonistic bacterium KRS027 holds promise as a biocontrol agent for promoting plant growth and managing disease occurrence.

Characteristics of atypical Pulmonary Tuberculosis without typical clinical features diagnosed by pathology.

PURPOSE: Some patients with pulmonary tuberculosis (PTB) do not display typical clinical features, leading to delays in diagnosis and treatment. METHODS: We retrospectively analyzed PTB patients admitted to the Second Affiliated Hospital of Chongqing Medical University between 2017 and 2020. They are divided into pathological group (diagnosed through pathological biopsy) and control group (diagnosed via sputum or lavage fluid). Clinical data of both groups were compared. Based on radiographic features, the pathological group was further divided into the inflammation group, peripheral nodule group, and central occupancy group. We then statistically analyzed the computed tomography (CT) signs, bronchoscopic manifestations and results of pathological biopsy for each subgroup. RESULTS: The pathological group consisted of 75 patients, while the control group had 338 patients. Multivariate logistic regression analysis showed that the pathological group had more diabetes (OR = 3.266, 95% CI = 1.609-6.630, P = 0.001), lower ESR (OR = 0.984, 95% CI = 0.971-0.998, P = 0.022), and lower CRP (OR = 0.990, 95% CI = 0.980-0.999, P = 0.036). In the three subgroups, the exudative lesions in the inflammation group were mostly located in atypical areas of PTB. The lobulation sign and spiculation sign were frequently observed in the peripheral nodule group. All presented with significant hilar mediastinal lymphadenopathy in the central occupancy group. In the pathological group, bronchoscopic manifestations typically included mucosal edema and bronchial stenosis. CONCLUSION: Diabetes is an independent risk factor for atypical PTB. Expression of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in atypical PTB is low. Radiologically, it is most easily misdiagnosed when presented as peripheral solid nodules or masses, so a biopsy is recommended.

Jingangteng capsules ameliorate liver lipid disorders in diabetic rats by regulating microflora imbalances, metabolic disorders, and farnesoid X receptor.

BACKGROUND: The plant Smilax china L., also known as Jingangteng, is suspected of regulating glucose and lipid metabolism. Jingangteng capsules (JGTCs) are commonly used to treat gynecological inflammation in clinical practice. However, it is not clear whether JGTCs can regulate glucose and lipid metabolism, and the mechanism is unclear. PURPOSE: To investigate the impact and mechanism of action of JGTCs on diabetes and liver lipid disorders in rats. METHODS: The chemical constituents of JGTCs were examined using ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry. A high-fat diet and streptozotocin-induced diabetes model was used to evaluate anti-diabetic effects by assessing blood glucose and lipid levels and liver function. The mechanism was explored using fecal 16S rRNA gene sequencing and metabolomics profiling, reverse transcription-quantiative polymerase chain reaction (RT-qPCR), and Western blot analysis. RESULTS: Thirty-three components were identified in JGTCs. The serological and histomorphological assays revealed that JGTC treatment reduced levels of blood glucose and lipids, aspartate aminotransferase, alanine aminotransferase, and lipid accumulation in the liver of diabetic rats. According to 16S rDNA sequencing, JGTCs improved species richness and diversity in diabetic rats' intestinal flora and restored 22 dysregulated bacteria to control levels. Fecal metabolomics analysis showed that the altered fecal metabolites were rich in metabolites, such as histidine, taurine, low taurine, tryptophan, glycerophospholipid, and arginine. Serum metabolomics analysis indicated that serum metabolites were enriched in the metabolism of glycerophospholipids, fructose and mannose, galactose, linoleic acid, sphingolipids, histidine, valine, leucine and isoleucine biosynthesis, and tryptophan metabolism. Heatmaps revealed a strong correlation between metabolic parameters and gut microbial phylotypes. Molecular biology assays showed that JGTC treatment reversed the decreased expression of farnesoid X receptor (FXR) in the liver of diabetic rats and inhibited the expression of lipogenic genes (Srebp1c and FAS) as well as inflammation-related genes (interleukin (IL)-ß, tumor necrosis factor (TNF)-α, and IL-6). Liver metabolomics analysis indicated that JGTC could significantly regulate a significant number of bile acid metabolites associated with FXR, such as glyco-beta-muricholic acid, glycocholic acid, tauro-beta-muricholic acid, and tauro-gamma-muricholic acid. CONCLUSIONS: This was the first study to investigate the mechanisms of JGTCs' effects on liver lipid disorders in diabetic rats. JGTCs inhibited liver lipid accumulation and inflammatory responses in diabetic rats by affecting intestinal flora and metabolic disorders and regulating FXR-fat synthesis-related pathways to alleviate diabetic lipid disorders.

Mg-Cross-Linked Alginate Hydrogel Induces BMSC/Macrophage Crosstalk to Enhance Bone Tissue Regeneration via Dual Promotion of the Ligand-Receptor Pairing of the OSM/miR-370-3p-gp130 Signaling Pathway.

Macrophages play a pivotal role in the crosstalk between the immune and skeletal systems, while Mg-based biomaterials demonstrate immunomodulatory capabilities in this procedure. However, the mechanism of how Mg2+ promotes osteogenesis through the interplay of bone marrow-derived mesenchymal stem cells (BMSCs) and macrophages remains undescribed. Here, we demonstrated that a Mg-cross-linked alginate hydrogel exerted a dual enhancement of BMSCs osteogenic differentiation through the ligand-receptor pairing of the OSM/miR-370-3p-gp130 axis. On the one hand, Mg2+, released from the Mg-cross-linked hydrogel, stimulates bone marrow-derived macrophages to produce and secrete more OSM. On the other hand, Mg2+ lowers the miR-370-3p level in BMSCs and in turn, reverses its suppression on gp130. Then, the OSM binds to the gp130 heterodimer receptor and activates intracellular osteogenic programs in BMSCs. Taken together, this study reveals a novel cross-talk pattern between the skeletal and immune systems under Mg2+ stimulation. This study not only brings new insights into the immunomodulatory properties of Mg-based biomaterials for orthopedic applications but also enriches the miRNA regulatory network and provides a promising target to facilitate bone regeneration in large bone defects.

Ocular biometric characteristics of Han ethnicity in Tianjin and Uyghur ethnicity in Xinjiang undergoing cataract surgery.

AIM: To analyze and compare the differences among ocular biometric parameters in Han and Uyghur populations undergoing cataract surgery. METHODS: In this hospital-based prospective study, 410 patients undergoing cataract surgery (226 Han patients in Tianjin and 184 Uyghur patients in Xinjiang) were enrolled. The differences in axial length (AL), anterior chamber depth (ACD), keratometry [steep K (Ks) and flat K (Kf)], and corneal astigmatism (CA) measured using IOL Master 700 were compared between Han and Uyghur patients. RESULTS: The average age of Han patients was higher than that of Uyghur patients (70.22±8.54 vs 63.04±9.56y, P<0.001). After adjusting for age factors, Han patients had longer AL (23.51±1.05 vs 22.86±0.92 mm, P<0.001), deeper ACD (3.06±0.44 vs 2.97±0.37 mm, P=0.001), greater Kf (43.95±1.40 vs 43.42±1.69 D, P=0.001), steeper Ks (45.00±1.47 vs 44.26±1.71 D, P=0.001), and higher CA (1.04±0.68 vs 0.79±0.65, P=0.025) than Uyghur patients. Intra-ethnic male patients had longer AL, deeper ACD, and lower keratometry than female patients; however, CA between the sexes was almost similar. In the correlation analysis, we observed a positive correlation between AL and ACD in patients of both ethnicities (rHan =0.48, rUyghur =0.44, P<0.001), while AL was negatively correlated with Kf (rHan =-0.42, rUyghur =-0.64, P<0.001) and Ks (rHan =-0.38, rUyghur =-0.66, P<0.001). Additionally, Kf was positively correlated with Ks (rHan =0.89, rUyghur =0.93, P<0.001). CONCLUSION: There are differences in ocular biometric parameters between individuals of Han ethnicity in Tianjin and those of Uyghur ethnicity in Xinjiang undergoing cataract surgery. These ethnic variances can enhance our understanding of ocular diseases related to these parameters and provide guidance for surgical procedures.

A biomimetic spore nanoplatform for boosting chemodynamic therapy and bacteria-mediated antitumor immunity for synergistic cancer treatment.

Bacterial-based antitumor immunity has become a promising strategy to activate the immune system for fighting cancer. However, the potential application of bacterial therapy is hindered by the presence of instability and susceptibility to infections within bacterial populations. Furthermore, monotherapy is ineffective in completely eliminating complex cancer with multiple contributing factors. In this study, based on our discovery that spore shell (SS) of Bacillus coagulans exhibits excellent tumor-targeting ability and adjuvant activity, we develop a biomimetic spore nanoplatform to boost bacteria-mediated antitumor therapy, chemodynamic therapy and antitumor immunity for synergistic cancer treatment. In detail, SS is separated from probiotic spores and then attached to the surface of liposome (Lipo) that was loaded with hemoglobin (Hb), glucose oxidase (GOx) and JQ1 to construct SS@Lipo/Hb/GOx/JQ1. In tumor tissue, highly toxic hydroxyl radicals (•OH) are generated via sequential catalytic reactions: GOx catalyzing glucose into H2O2 and Fe2+ in Hb decomposing H2O2 into •OH. The combination of •OH and SS adjuvant can improve tumor immunogenicity and activate immune system. Meanwhile, JQ1-mediated down-regulation of PD-L1 and Hb-induced hypoxia alleviation synergistically reshape immunosuppressive tumor microenvironment and potentiate immune response. In this manner, SS@Lipo/Hb/GOx/JQ1 significantly suppresses tumor growth and metastasis. To summarize, the nanoplatform represents an optimum strategy to potentiate bacteria-based cancer immunotherapy.

Reactive oxygen species produced by photodynamic therapy enhance docosahexaenoic acid lipid peroxidation and induce the death of breast cancer cells.

Breast cancer remains a serious threat to women's physical and emotional health. The combination therapies can overcome the deficiency of single therapy, enhance the therapeutic effects and reduce the side effects at the same time. In this study, we synthesize a novel nanomedicine that enhanced the therapeutic effects of breast cancer treatment by combining photodynamic therapy and chemotherapy. The doxorubicin (DOX) and photosensitizer methyl pyropheophorbide-a (MPPa) are loaded into the nano-drug delivery system as DPSPFA/MPPa/DOX. In response to near-infrared (NIR) laser, the drugs were quickly released to the cancer cells. The MPPa produces reactive oxygen species (ROS) under the action of photodynamics. Unsaturated fatty acids with ROS promotes lipid peroxidation and the combination of chemotherapy and photodynamic therapy. The data shows that the DPSPFA/MPPa/DOX has a spherical shape, good dispersibility and stability, and the particle size is roughly 200 nm. The drug loading capability of DOX is about 13 %. Both of MCF7 cell model in vitro and breast cancer model in vivo, DPSPFA/MPPa/DOX showed an excellent anti-tumor effect of 86.9 % and without any obvious side effects. These findings might offer potential for a new approach for breast cancer treatment.

Comprehensive prognostic and immunological analysis of Cullin2 in pan-cancer and its identification in hepatocellular carcinoma.

BACKGROUND: As a member of the Cullin family, Cullin2 (CUL2) is involved in the development and spread of different types of cancers. However, the precise role of CUL2 in human cancer remains largely elusive. METHODS: In this study, various databases were applied to observe the CUL2 expression. Kaplan-Meier and Spearman correlation analyses were employed to investigate the potential links between CUL2 level, patient prognosis, and the infiltration of immune cells. In addition, the association between CUL2 and the efficacy of immunotherapy in an immunotherapy cohort was investigated. Moreover, the expression and distribution of CUL2 in cells were observed using the Human Protein Atlas (THPA) database. Finally, clinical tissue specimens and in vitro function assays were conducted to validate the expressions and effects of CUL2 on the biological functions in hepatocellular carcinoma (HCC) cells. RESULTS: While there are variations in CUL2 expression across different organs and cell types, it is notably upregulated in a majority of tumor tissues. In addition, CUL2 gene mutations are common in multiple cancers with low mutation rates and CUL2 is closely related to the prognosis of some cancer's patients, some immune regulatory factors, TMB, MSI, MMR genes, and DNA methylation. Further, our results found that downregulating CUL2 inhibits the proliferation, and migration abilities. CONCLUSIONS: The expression of CUL2 has an impact on the prognosis of various tumors, and this correlation is particularly noteworthy due to its significant association with the infiltration of immune cells within tumors. CUL2 was an oncogene contributing to the progression of HCC.

HLA-A+ tertiary lymphoid structures with reactivated tumor infiltrating lymphocytes are associated with a positive immunotherapy response in esophageal squamous cell carcinoma.

BACKGROUND: Immune checkpoint blockade (ICB) therapy provides remarkable clinical benefits for multiple cancer types. However, the overall response rate to ICB therapy remains low in esophageal squamous cell carcinoma (ESCC). This study aimed to identify biomarkers of ICB therapy for ESCC and interrogate its potential clinical relevance. METHODS: We investigated gene expression in 42 treatment-naïve ESCC tumor tissues and identified differentially expressed genes, tumor-infiltrating lymphocytes and immune-related genes signatures associated with differential immunotherapy responses. We systematically assessed the tumor microenvironment using the NanoString GeoMx digital spatial profiler, single-cell RNA-seq and multiplex immunohistochemistry in ESCC. Finally, we evaluated the associations between HLA-A-positive tertiary lymphoid structures (TLSs) and patients' responses to ICB in 60 ESCC patients. RESULTS: Tumor infiltrating B lymphocytes and several immune-related gene signatures, such as the antigen presenting machinery (APM) signature, are significantly elevated in ICB treatment responders. Multiplex immunohistochemistry identified the presence of HLA-A+ TLSs and showed that TLS-resident cells increasingly express HLA-A as TLSs mature. Most TLS-resident HLA-A+ cells are tumor-infiltrating T (TIL-T) or tumor-infiltrating B (TIL-B) lymphocytes. Digital spatial profiling of spatially distinct TIL-T lymphocytes and single-cell RNA-seq data from 60 ESCC tumor tissues revealed that CXCL13-expressing exhausted TIL-Ts inside TLSs are reactivated with elevated expression of the APM signature as TLSs mature. Finally, we demonstrated that HLA-A+ TLSs and their major cellular components, TIL-Ts and TIL-Bs, are associated with a clinical benefit from ICB treatment for ESCC. CONCLUSIONS: HLA-A+ TLSs are present in ESCC tumor tissues. TLS-resident TIL-Ts with elevated expression of the APM signature may be reactivated. HLA-A+ TLSs and their major cellular components, TIL-Ts and TIL-Bs, may serve as biomarkers for ICB-treated ESCC patients.

Deep Learning-Based Prediction of Radiation Therapy Dose Distributions in Nasopharyngeal Carcinomas: A Preliminary Study Incorporating Multiple Features Including Images, Structures, and Dosimetry.

Purpose: Intensity-modulated radiotherapy (IMRT) is currently the most important treatment method for nasopharyngeal carcinoma (NPC). This study aimed to enhance prediction accuracy by incorporating dose information into a deep convolutional neural network (CNN) using a multichannel input method. Methods: A target conformal plan (TCP) was created based on the maximum planning target volume (PTV). Input data included TCP dose distribution, images, target structures, and organ-at-risk (OAR) information. The role of target conformal plan dose (TCPD) was assessed by comparing the TCPD-CNN (with dose information) and NonTCPD-CNN models (without dose information) using statistical analyses with the ranked Wilcoxon test (P < .05 considered significant). Results: The TCPD-CNN model showed no statistical differences in predicted target indices, except for PTV60, where differences in the D98% indicator were < 0.5%. For OARs, there were no significant differences in predicted results, except for some small-volume or closely located OARs. On comparing TCPD-CNN and NonTCPD-CNN models, TCPD-CNN's dose-volume histograms closely resembled clinical plans with higher similarity index. Mean dose differences for target structures (predicted TCPD-CNN and NonTCPD-CNN results) were within 3% of the maximum prescription dose for both models. TCPD-CNN and NonTCPD-CNN outcomes were 67.9% and 54.2%, respectively. 3D gamma pass rates of the target structures and the entire body were higher in TCPD-CNN than in the NonTCPD-CNN models (P < .05). Additional evaluation on previously unseen volumetric modulated arc therapy plans revealed that average 3D gamma pass rates of the target structures were larger than 90%. Conclusions: This study presents a novel framework for dose distribution prediction using deep learning and multichannel input, specifically incorporating TCPD information, enhancing prediction accuracy for IMRT in NPC treatment.

Changing trends in the disease burden of uterine cancer globally from 1990 to 2019 and its predicted level in 25 years.

Background: We aim to evaluate the global, regional, and national burden of Uterine Cancer (UC) from 1990 to 2019. Methods: We gathered UC data across 204 countries and regions for the period 1990-2019, utilizing the Global Burden of Disease Database (GBD) 2019 public dataset. Joinpoint regression analysis was employed to pinpoint the year of the most significant changes in global trends. To project the UC trajectory from 2020 to 2044, we applied the Nordpred analysis, extrapolating based on the average trend observed in the data. Furthermore, the Bayesian Age-Period-Cohort (BAPC) model with integrated nested Laplace approximations was implemented to confirm the stability of the Nordpred analysis predictions. Results: Globally, the age-standardized rate (ASR) of incidence for UC has increased from 1990 to 2019 with an Average Annual Percentage Change (AAPC) of 0.50%. The ASR for death has declined within the same period (AAPC: -0.8%). An increase in the ASR of incidence was observed across all Socio-demographic Index (SDI) regions, particularly in High SDI regions (AAPC: 1.12%), while the ASR for death decreased in all but the Low SDI regions. Over the past 30 years, the highest incidence rate was observed in individuals aged 55-59 (AAPC: 0.76%). Among 204 countries and regions, there was an increase in the ASR of incidence in 165 countries and an increase in the ASR of deaths in 77 countries. Our projections suggest that both the incidence and death rates for UC are likely to continue their decline from 2020 to 2044. Conclusions: UC has significantly impacted global health negatively, with its influence stemming from a range of factors including geographical location, age-related and racial disparities, and SDI.

Aromatic Rules of C22H122+/2•/2-: Flexibility in Electronic Structures of 2D Superatomic Molecules.

Triangulene (C22H122•), a nonclassic non-Kekulé polycyclic aromatic hydrocarbon, is identified to be aromatic by structural and magnetic criteria. However, its aromatic origin remains confusing. Herein, the aromatic rules of C22H122• and its two charged counterparts C22H122+/2- were investigated on the basis of a recently developed two-dimensional (2D) superatomic-molecule theory. [C22H12]2+/2•/2- exhibit obvious local aromatic characters and can be regarded as [◊N3◊O3]+, [◊N3◊O3]-, and ◊N3◊F3 superatomic molecules, respectively, where ◊N, ◊O, and ◊F denote 2D superatoms bearing 3π, 4π, and 5π electrons. [C22H12]2+/2- realize electronic shell closure via superatomic lone pairs and covalent bonds, mimicking simple molecules, whereas the α-π and ß-π electrons in C22H122• follow the superatomic bonding patterns of C22H122- and C22H122+, respectively. Furthermore, based on the local character in 2D superatomic molecules, a doped nanoporous graphene, namely, C9N12B monolayer, was predicted. The material possesses excellent dynamical and thermodynamical stability, as well as a wide band gap of 2.77 eV, positioning it as a promising 2D material for future electronic applications.

FAT10 mediates the sorafenib-resistance of hepatocellular carcinoma cells by stabilizing E3 ligase NEDD4 to enhance PTEN/AKT pathway-induced autophagy.

Although sorafenib is the first-line therapeutic agent for advanced hepatocellular carcinoma (HCC), the development of drug resistance in HCC cells limits its clinical efficacy. However, the key factors involved in mediating the sorafenib resistance of HCC cells and the underlying mechanisms have not been elucidated. In this study, we generated sorafenib-resistant HCC cell lines, and our data demonstrate that HLA-F locus-adjacent transcript 10 (FAT10), a ubiquitin-like protein, is markedly upregulated in sorafenib-resistant HCC cells and that reducing the expression of FAT10 in sorafenib-resistant HCC cells increases sensitivity to sorafenib. Mechanistically, FAT10 stabilizes the expression of the PTEN-specific E3 ubiquitin ligase NEDD4 that causes downregulation of PTEN, thereby inducing AKT-mediated autophagy and promoting the resistance of HCC cells to sorafenib. Moreover, we screened the small molecule Compound 7695-0983, which increases the sensitivity of sorafenib-resistant HCC cells to sorafenib by inhibiting the expression of FAT10 to inhibit NEDD4-PTEN/AKT axis-mediated autophagy. Collectively, our preclinical findings identify FAT10 as a key factor in the sorafenib resistance of HCC cells and elucidate its underlying mechanism. This study provides new mechanistic insight for the exploitation of novel sorafenib-based tyrosine kinase inhibitor (TKI)-targeted drugs for treating advanced HCC.

Fused in sarcoma (FUS) inhibits milk production efficiency in mammals.

Efficient milk production in mammals confers evolutionary advantages by facilitating the transmission of energy from mother to offspring. However, the regulatory mechanism responsible for the gradual establishment of milk production efficiency in mammals, from marsupials to eutherians, remains elusive. Here, we find that mammary gland of the marsupial sugar glider contained milk components during adolescence, and that mammary gland development is less dynamically cyclic compared to that in placental mammals. Furthermore, fused in sarcoma (FUS) is found to be partially responsible for this establishment of low efficiency. In mouse model, FUS inhibit mammary epithelial cell differentiation through the cyclin-dependent kinase inhibitor p57Kip2, leading to lactation failure and pup starvation. Clinically, FUS levels are negatively correlated with milk production in lactating women. Overall, our results shed light on FUS as a negative regulator of milk production, providing a potential mechanism for the establishment of milk production from marsupial to eutherian mammals.

A Lightweight and Affordable Wearable Haptic Controller for Robot-Assisted Microsurgery.

In robot-assisted microsurgery (RAMS), surgeons often face the challenge of operating with minimal feedback, particularly lacking in haptic feedback. However, most traditional desktop haptic devices have restricted operational areas and limited dexterity. This report describes a novel, lightweight, and low-budget wearable haptic controller for teleoperated microsurgical robotic systems. We designed a wearable haptic interface entirely made using off-the-shelf material-PolyJet Photopolymer, fabricated using liquid and solid hybrid 3D co-printing technology. This interface was designed to resemble human soft tissues and can be wrapped around the fingertips, offering direct contact feedback to the operator. We also demonstrated that the device can be easily integrated with our motion tracking system for remote microsurgery. Two motion tracking methods, marker-based and marker-less, were compared in trajectory-tracking experiments at different depths to find the most effective motion tracking method for our RAMS system. The results indicate that within the 4 to 8 cm tracking range, the marker-based method achieved exceptional detection rates. Furthermore, the performance of three fusion algorithms was compared to establish the unscented Kalman filter as the most accurate and reliable. The effectiveness of the wearable haptic controller was evaluated through user studies focusing on the usefulness of haptic feedback. The results revealed that haptic feedback significantly enhances depth perception for operators during teleoperated RAMS.