Isolation of a more aggressive GVI-1 genotype strain HX of the avian infectious bronchitis virus.

The avian infectious bronchitis virus (IBV) poses a significant economic threat to the global poultry industry. Although in recent years, the GVI-1 lineage of IBV has proliferated throughout China, there is still a lack of comprehensive studies regarding the pathogenicity of this lineage, particularly with respect to infections of the digestive tract and the antigenic characteristics of the S1 gene. In this study, we investigated the effects of infecting 14-day-old chicks with the HX strain of the GVI-1 lineage over a 14-d period postinfection. Assessment of the pathogenicity of the HX strain included clinical observations; monitoring of body weight, organ viral load, viral shedding, and gross anatomy; histopathological analysis, and bioinformatics-based antigenic characterization of the S1 protein. The findings revealed that compared with previously reported GVI-1 lineage strains, the HX strain is characterized by greater virulence, with infection leading to approximately 26% mortality and extensive severe organ damage, including that of the proventriculus and kidneys. Moreover, at 14 d postinfection, 80% of oral swabs and 100% of cloacal swabs from chickens infected with the HX strain tested positive, indicating a prolonged period of viral shedding relative to that previously reported for GVI-1 lineage strains. Bioinformatic analysis of B-cell epitopes on the S1 protein revealed 7 potential antigenic epitopes. Collectively, our findings in this study provide clear evidence to indicate that compared previously reported GVI-1 lineage strains, chicks infected with the IBV GVI-1 lineage strain HX are characterized by heightened rates of mortality, more pronounced organ damage, and an extended period of viral shedding. This comprehensive characterization highlights the pathogenic potential of the GVI-1 lineage and its capacity to induce severe kidney and proventriculus damage, thereby emphasizing the imperative of early initiated preventive measures. Furthermore, on the basis of our analysis of the antigenic properties of the S1 protein, we have identified 7 potential linear B-cell epitopes, which will provide valuable insights for the development of epitope-based vaccines.

Ultrahigh electromechanical response from competing ferroic orders.

Materials with electromechanical coupling are essential for transducers and acoustic devices as reversible converters between mechanical and electrical energy1-6. High electromechanical responses are typically found in materials with strong structural instabilities, conventionally achieved by two strategies-morphotropic phase boundaries7 and nanoscale structural heterogeneity8. Here we demonstrate a different strategy to accomplish ultrahigh electromechanical response by inducing extreme structural instability from competing antiferroelectric and ferroelectric orders. Guided by the phase diagram and theoretical calculations, we designed the coexistence of antiferroelectric orthorhombic and ferroelectric rhombohedral phases in sodium niobate thin films. These films show effective piezoelectric coefficients above 5,000 pm V-1 because of electric-field-induced antiferroelectric-ferroelectric phase transitions. Our results provide a general approach to design and exploit antiferroelectric materials for electromechanical devices.

The Effect of Novel AI-based Cecum Recognition System on Adenoma Detection Metrics at Screening Colonoscopy Setting.

BACKGROUND AND AIMS: Cecal intubation of colonoscopy relies on self-reporting. We developed an artificial intelligence-based cecum recognition system (AI-CRS) for post hoc verification of cecal intubation and explored its impact on adenoma metrics. METHODS: Quality metrics, including cecal intubation rate (CIR), adenoma detection rate (ADR), and other ADR-related metrics were compared both before (2015-2018) and after (2019-2022) the implementation of AI-CRS. RESULTS: While CIR did not change significantly after the implementation of AI-CRS, ADR and AADR significantly increased. While ADR significantly increased in all segments, the most significant increase in AADR was observed in the proximal colon. Implementation of AI-CRS was associated with a higher likelihood of detecting adenoma (aOR=1.35, 95%CI=1.26-1.45) and advanced adenoma (aOR=1.23, 95%CI=1.07-1.41), respectively. CONCLUSIONS: Implementation of a post hoc verification of cecal intubation using an AI-CRS significantly improved various adenoma metrics in screening colonoscopy.

Impact of time period and birth cohort on the trend of advanced neoplasm prevalence in the 40-49 average-risk screening population.

BACKGROUND AND AIMS: Early-onset colorectal cancer (CRC) is increasing globally. While the United States have lowered the age of initiation of screening to 45, other countries still start screening at age 50. In Taiwan, the incidence of CRC has declined in 55-74 year-olds after the initiation of screening, but still increased in those 50-54, potentially due to rising precancerous lesion incidence in 40-49 year-olds. This study aimed to explore the chronological trend of the prevalence of colorectal advanced neoplasms (AN) in the screening population aged 40-54. METHODS: We retrospectively analyzed a screening colonoscopy cohort for prevalence of AN in average-risk subjects aged 40-54 from 2003 to 2019. Logistic regression was used to distinguish cohort effect from time-period effect on the prevalence of AN. RESULTS: In total, 27,805 subjects (52.1% male) men were enrolled. There were notable increases in prevalence of AN in all three age groups during the 17-year span, but these were more rapid in age 40-44 (0.99% to 3.22%) and 45-49 (2.50% to 4.19%). Age 50-54 had higher risk of AN [aOR=1.62(1.19-2.19)] in 2003-2008 but not in later periods [2009-2014: aOR=1.08(0.83-1.41)] and [2015-2019: aOR=0.76(0.56-1.03)] when compared with age 45-49. CONCLUSION: The prevalence of AN in age 40-54 increased in the Taiwanese population, with a later birth cohort having a higher prevalence of AN. However, the prevalence of AN in age 45-49 increased more remarkably and approximated that in age 50-54, which may justify earlier initiation of CRC screening at age 45.

The risk factor for adverse pregnancy outcomes and its impact on clinical effect in IgA nephropathy: A retrospective observational study.

AIM: IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. Pregnant IgAN patients are more susceptible to adverse pregnancy outcomes (APO). However, the risk factor for APO and its effects on the long-term renal outcome of pregnant IgAN patients remained unclear. METHODS: We performed a retrospective observational study covering 2003-2019 that included 44 female IgAN patients with pregnancy history to investigate the risk factor for APO and its impact on clinical outcome in IgAN. Renal function outcome and proteinuria remission were evaluated in pregnant IgAN women with and without APO. RESULTS: In this retrospective and observational study, we found that patients with APO exhibited higher levels of serum creatinine and IgM, and lower haemoglobin levels while other clinical characteristics, pathological characteristics and therapy protocol had no significant difference. We found that anaemia and a higher level of serum IgM were independent risk factors for APO. IgAN pregnant women without APO experienced a higher proportion of proteinuria remission than those with APO, but there is no difference in the renal function outcome. CONCLUSION: Pregnant IgAN patients with higher risks, including lower haemoglobin levels and higher IgM levels deserve intensive monitoring, and aggressive therapy to reduce proteinuria should be carried out in pregnant IgAN patients with APO.

Geniposidic Acid Attenuates Chronic Tubulointerstitial Nephropathy Through Regulation of the NF-ƙB/Nrf2 Pathway Via Aryl Hydrocarbon Receptor Signaling.

Renal fibrosis is an outcome of chronic kidney disease, independent of the underlying etiology. Renal fibrosis is caused primarily by oxidative stress and inflammation. We identified the components of Plantaginis semen and elucidated their anti-fibrotic and anti-inflammatory mechanisms. The renoprotective components and underlying molecular mechanisms of P. semen were investigated in rats with adenine-induced chronic tubulointerstitial nephropathy (TIN) and in idole-3-acetic acid (IAA)-stimulated NRK-52E cells. Acetate and n-butanol extracts were found to be the bioactive fractions of P. semen. A total of 65 compounds including geniposidic acid (GPA), apigenin (APG), and acteoside (ATS) were isolated and identified. Among the seven main extract components, treatment with GPA, APG, and ATS reduced the serum levels of creatinine and urea in TIN rats. Mechanistically, GPA ameliorated renal fibrosis through repressing aryl hydrocarbon receptor (AHR) signaling and regulating redox signaling including inhibiting proinflammatory nuclear factor kappa B (NF-ƙB) and its target gene products as well as activated antioxidative nuclear factor-erythroid-2-related factor 2 (Nrf2) and its downstream target gene products in both TIN rats and IAA-stimulated NRK-52E cells. The inhibitory effect of GPA on AHR, NF-Ƙb, and Nrf2 signaling were partially abolished in IAA-stimulated NRK-52E cells treated with CH223191 compared with untreated IAA-stimulated NRK-52E cells. These data demonstrated that GPA alleviates oxidative stress and inflammation partly by suppressing AHR signaling.

Predicting the T790M mutation in non-small cell lung cancer (NSCLC) using brain metastasis MR radiomics: a study with an imbalanced dataset.

BACKGROUND: Early detection of T790M mutation in exon 20 of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients with brain metastasis is crucial for optimizing treatment strategies. In this study, we developed radiomics models to distinguish NSCLC patients with T790M-positive mutations from those with T790M-negative mutations using multisequence MR images of brain metastasis despite an imbalanced dataset. Various resampling techniques and classifiers were employed to identify the most effective strategy. METHODS: Radiomic analyses were conducted on a dataset comprising 125 patients, consisting of 18 with EGFR T790M-positive mutations and 107 with T790M-negative mutations. Seventeen first- and second-order statistical features were selected from CET1WI, T2WI, T2FLAIR, and DWI images. Four classifiers (logistic regression, support vector machine, random forest [RF], and extreme gradient boosting [XGBoost]) were evaluated under 13 different resampling conditions. RESULTS: The area under the curve (AUC) value achieved was 0.89, using the SVM-SMOTE oversampling method in combination with the XGBoost classifier. This performance was measured against the AUC reported in the literature, serving as an upper-bound reference. Additionally, comparable results were observed with other oversampling methods paired with RF or XGBoost classifiers. CONCLUSIONS: Our study demonstrates that, even when dealing with an imbalanced EGFR T790M dataset, reasonable predictive outcomes can be achieved by employing an appropriate combination of resampling techniques and classifiers. This approach has significant potential for enhancing T790M mutation detection in NSCLC patients with brain metastasis.

Uncovering missing glycans and unexpected fragments with pGlycoNovo for site-specific glycosylation analysis across species.

Precision mapping of site-specific glycans using mass spectrometry is vital in glycoproteomics. However, the diversity of glycan compositions across species often exceeds database capacity, hindering the identification of rare glycans. Here, we introduce pGlycoNovo, a software within the pGlyco3 software environment, which employs a glycan first-based full-range Y-ion dynamic searching strategy. pGlycoNovo enables de novo identification of intact glycopeptides with rare glycans by considering all possible monosaccharide combinations, expanding the glycan search space to 16~1000 times compared to non-open search methods, while maintaining accuracy, sensitivity and speed. Reanalysis of SARS Covid-2 spike protein glycosylation data revealed 230 additional site-specific N-glycans and 30 previously unreported O-glycans. pGlycoNovo demonstrated high complementarity to six other tools and superior search speed. It enables characterization of site-specific N-glycosylation across five evolutionarily distant species, contributing to a dataset of 32,549 site-specific glycans on 4602 proteins, including 2409 site-specific rare glycans, and uncovering unexpected glycan fragments.

Chemical constituents from the endophytic fungus Aspergillus sp. S3 of Hibiscus tiliaceus.

A new sterol, aspersterol E (1), a newly discovered alkaloid, asperginine A (2), and five known compounds (3-7) were obtained from the endophytic fungus Aspergillus sp. S3 of Hibiscus tiliaceus Linn. The compounds were extracted from their fermentation products using silica gel, ODS C18, and semi-preparative HPLC. The structure of each compound was determined through spectroscopic analysis. All the obtained compounds (1-7) were evaluated for their cytotoxic activity against the mouse pre-gastric cancer cell line MFC by using the MTT assay. The IC50 values of compounds 1, 2, 3, and 5 were found to be 153.43 µM, 61.25 µM, 73.19 µM, and 181.69 µM respectively.

Birds as reservoirs: unraveling the global spread of Gamma- and Deltacoronaviruses.

Avian migration is a global phenomenon that transcends geographical boundaries. These migratory birds serve as unwitting carriers of diverse Gammacoronaviruses (γ-CoVs) and Deltacoronaviruses (δ-CoVs). While recombination events have been documented among γ-CoVs in avian species and ß-CoVs in mammals, evidence for recombination between CoVs of distinct genera remains limited. This minireview examines the prevalence of CoVs in both domestic waterfowl (ducks and geese) and wild bird populations inhabiting various regions. We investigate the dissemination patterns of γ-CoVs and δ-CoVs among these populations, highlighting their shared characteristics. Furthermore, the review explores the intricate web of cross-species transmission of δ-CoVs from wild birds to mammals, with a particular focus on pigs. Understanding the distinct features of CoVs harbored by waterfowl and wild birds and their potential for cross-species transmission is crucial for preparedness and response to future CoV epidemics.

Barleriside A, an aryl hydrocarbon receptor antagonist, ameliorates podocyte injury through inhibiting oxidative stress and inflammation.

Introduction: Increasing evidence shows that hyperactive aryl hydrocarbon receptor (AHR) signalling is involved in renal disease. However, no currently available intervention strategy is effective in halting disease progression by targeting the AHR signalling. Our previous study showed that barleriside A (BSA), a major component of Plantaginis semen, exhibits renoprotective effects. Methods: In this study, we determined the effects of BSA on AHR expression in 5/6 nephrectomized (NX) rats. We further determined the effect of BSA on AHR, nuclear factor kappa B (NF-ƙB), and the nuclear factor erythroid 2-related factor 2 (Nrf2) signalling cascade in zymosan-activated serum (ZAS)-stimulated MPC5 cells. Results: BSA treatment improved renal function and inhibited intrarenal nuclear AHR protein expression in NX-treated rats. BSA mitigated podocyte lesions and suppressed AHR mRNA and protein expression in ZAS-stimulated MPC5 cells. BSA inhibited inflammation by improving the NF-ƙB and Nrf2 pathways in ZAS-stimulated MPC5 cells. However, BSA did not markedly upregulate the expression of podocyte-specific proteins in the ZAS-mediated MPC5 cells treated with CH223191 or AHR siRNA compared to untreated ZAS-induced MPC5 cells. Similarly, the inhibitory effects of BSA on nuclear NF-ƙB p65, Nrf2, and AHR, as well as cytoplasmic cyclooxygenase-2, heme oxygenase-1, and AHR, were partially abolished in ZAS-induced MPC5 cells treated with CH223191 or AHRsiRNA compared with untreated ZAS-induced MPC5 cells. These results indicated that BSA attenuated the inflammatory response, partly by inhibiting AHR signalling. Discussion: Both pharmacological and siNRA findings suggested that BSA mitigated podocyte lesions by improving the NF-ƙB and Nrf2 pathways via inhibiting AHR signalling. Therefore, BSA is a high-affinity AHR antagonist that abolishes oxidative stress and inflammation.

Molecular surveillance based on anaplasmosis in domestic small ruminants: First report on zoonotic Anaplasma capra and phylogenetic insights from Faisalabad, Pakistan.

Anaplasma is an intracellular alphaproteobacteria that infects diverse blood cell types in animal hosts including small ruminants. Epidemiological and risk factors information on zoonotic anaplasmosis with respect to anaplasmosis in sheep and goats are scarce. Therefore, the objective of the current study was to estimate the prevalence, risk factors of anaplasmosis and phylogenetic investigation of A. capra in sheep and goats from Faisalabad district, Pakistan. Briefly, 384 blood samples were randomly collected from sheep and goats of Faisalabad district, Pakistan, during January to May 2022. The samples were processed for the detection of Anaplasma targeting 16S rRNA gene using PCR. The data regarding disease determinants were collected using a predesigned questionnaire. Out of 384 samples, 131 samples were found positive for Anaplasma spp. with a prevalence rate of 34.11%. The results indicated a significantly higher prevalence of anaplasmosis in goats (41.88%) compared to sheep (22.00%). In addition, the chi square indicated that housing type, tick infestation, gender, tick control practices, age, mix farming, and hygiene were significantly associated with the occurrence of disease. The analysis of multivariate logistic regression expressed gender as the significant risk factor (p = 0.0001, OR = 1.757, CI = 1.305-2.366). The acquired sequences revealed four novel isolates of A. capra (Genbank accession numbers ON834323, ON838209, ON838210, and ON838211). The phylogenetic analysis of the 16S rRNA gene of A. capra revealed three distinct clusters with 99-100% homology with other isolates from different countries. Our isolates showed higher similarity with isolates from China (KM206273, KP314237, MT799937), Pakistan (ON238129, ON238130, ON238131), Angola (MT898988), India (MZ558066), Iran (MW692362), and Turkey (MT632469) isolated from human, sheep, ticks, goats, cattle, Gaddi goat, Persian Onager (Equus hemionus onager), and Turkish goats, respectively. In conclusion, A. capra is endemic in Punjab, Pakistan, there is a need to conduct large scale surveillance studies to assess the status of this pathogen at human-animal interface as well as to develop effective preventive and control strategies to reduce the economic losses associated with anaplasmosis in small ruminants.

Novel mutations in acetolactate synthase confer high levels of resistance to tribenuron-methyl in Fagopyrum tataricum.

Tartary buckwheat (Fagopyrum tataricum) field weeds are rich in species, with many weeds causing reduced quality, yield, and crop failure. The selection of herbicide-resistant Tartary buckwheat varieties, while applying low-toxicity and efficient herbicides as a complementary weed control system, is one way to improve Tartary buckwheat yield and quality. Therefore, the development of herbicide-resistant varieties is important for the breeding of Tartary buckwheat. In this experiment, 50 mM ethyl methyl sulfonate solution was used to treat Tartary buckwheat seeds (M1) and then planted in the field. Harvested seeds (M2) were planted in the experiment field of Guizhou University, and when seedlings had 5-7 leaves, the seedlings were sprayed with 166 mg/L tribenuron-methyl (TBM). A total of 15 resistant plants were obtained, of which three were highly resistant. Using the homologous cloning method, an acetolactate synthase (ALS) gene encoding 547 amino acids was identified in Tartary buckwheat. A GTG (valine) to GGA (glycine) mutation (V409G) occurred at position 409 of the ALS gene in the high tribenuron-methyl resistant mutant sm113. The dm36 mutant harbored a double mutation, a deletion mutation at position 405, and a GTG (valine) to GGA (glycine) mutation (V411G) at position 411. The dm110 mutant underwent a double mutation: an ATG (methionine) to AGG (arginine) mutation (M333R) at position 333 and an insertion mutation at position 372. The synthesis of Chl a, Chl b, total Chl, and Car was significantly inhibited by TBM treatment. TBM was more efficient at suppressing the growth of wild-type plants than that of mutant plants. Antioxidant enzyme activities such as ascorbate peroxidase, peroxidase, and superoxide dismutase were significantly higher in resistant plants than in wild-type after spraying with TBM; malondialdehyde content was significantly lower than in wild-type plants after spraying with TBM. Plants with a single-site mutation in the ALS gene could survive, but their growth was affected by herbicide application. In contrast, plants with dual-site mutations in the ALS gene were not affected, indicating that plants with dual-site mutations in the ALS gene showed higher levels of resistance than plants with a single-site mutation in the ALS gene.

The importance of high total body water/fat free mass ratio and serial changes in body composition for predicting hospital mortality in patients with severe pneumonia: a prospective cohort study.

PURPOSE: This study aimed to investigate the impact of body composition variables on hospital mortality compared to other predictive factors among patients with severe pneumonia. Additionally, we aimed to monitor the dynamic changes in body composition variables over the course on days 1, 3, and 8 after intensive care unit (ICU) admission for each patient. METHODS: We conducted a prospective study, enrolling patients with severe pneumonia admitted to the medical intensive care unit at Kaohsiung Chang Gung Memorial Hospital from February 2020 to April 2022. We collected clinical data from all patients and assessed their body composition at 1, 3, and 8 days post-ICU admission. On day 1, we analyzed clinical and body composition variables to predict in-hospital mortality. RESULTS: Multivariate analysis identified the Modified Nutrition Risk in the Critically Ill (mNUTRIC) score and the ratio of total body water to fat-free mass (TBW/FFM) as independent factors associated with in-hospital mortality in severe pneumonia patients. Receiver operating characteristic analysis determined that the TBW/FFM ratio was the most reliable predictive parameter of in-hospital mortality, with a cutoff value of 0.74. General linear regression with repeated measures analysis showed that hospital non-survivors displayed notable fluctuations in body water, fat, and muscle variables over the course of days 1, 3, and 8 after ICU admission. CONCLUSIONS: The mNUTRIC score and TBW/FFM ratio emerged as independent factors for predicting hospital mortality, with the TBW/FFM ratio demonstrating the highest reliability as a predictive parameter.

Association between single and multiple cardiometabolic diseases and all-cause mortality among Chinese older adults: A prospective, nationwide cohort study.

BACKGROUND AND AIM: Cardiometabolic diseases (CMDs) are leading causes of death and disability, but little is known about the additive mortality effects of multiple CMDs. This study aimed to examine the association between single and multiple CMDs and all-cause mortality among older Chinese population. METHODS AND RESULTS: Using the Chinese Longitudinal Healthy Longevity Survey (CLHLS) database, we analyzed data from 2008 to 2018 to assess the relationship between CMDs and mortality. Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for single and multiple CMDs. At baseline, 11,351 participants (56.9% female) aged 60 years or older were included. 11.91% of participants had a single CMD, 1.51% had two CMDs, and 0.22% had three CMDs. Over a decade follow-up, 8992 deaths (79.2%) were recorded. A dose-response relationship was observed, with the mortality risk increasing by 17% for each additional disease. The fully-adjusted HRs for all-cause mortality were 1.16, 1.36, and 2.03 for one, two, and three CMDs, respectively. Larger effects of single and multiple CMDs were observed in the male group (P = 0.015) and the younger senior group (P < 0.001). CONCLUSIONS: This large-scale study found that CMDs multiply mortality risks, especially in younger seniors and males. The risk is highest when heart disease and stroke coexist, and diabetes further increases it. Public health efforts should prioritize evidence-based management and prevention of CMDs.

Study on the sensitizing effect of SM-1 combined with irradiation on head and neck squamous cell carcinoma.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is globally prevalent with high recurrence, low survival rate, and poor quality of life for patients. Derived from PAC-1, SM-1 can activate procaspase-3 and induce apoptosis in cancer cells to exert anti-tumor effects. However, the inhibitory effect of SM-1 on HNSCC after combination with radiation are unclear. This study aims to investigate the radiosensitizing effect of SM-1 on HNSCC in vitro and in vivo. METHODS: MTT method was used to detect the effect of SM-1 on the viability of HNSCC cell lines (HONE1, HSC-2, and CAL27). The effects of SM-1 combined with radiation on the survival index of HONE1, HSC-2, and CAL27 cell lines were determined by colony formation assay. Flow cytometry was used to investigate the effects of SM-1 and radiation combination on cell apoptosis and cell cycle, and western blot experiments were performed to detect the expression of apoptosis and cell cycle-related proteins. Finally, a xenograft tumor model of CAL27 was established to evaluate the anti-tumor effect of SM-1 combined with radiation in vivo. RESULTS: In vitro, SM-1 effectively inhibited the activity of HNSCC cell lines HONE1, HSC-2, and CAL27 cells, and synergistically showed anti-proliferation activity during combined irradiation. Meanwhile, anti-tumor effect of SM-1 on HNSCC was higher than that of Debio1143, and the radiosensitivity of cells was greatly increased. Flow cytometry and western blot analysis showed that SM-1 induced G2/M phase arrest of head and neck squamous cell carcinoma cells via inhibiting the expression of CyclinB1 and CDC2. Moreover, SM-1 activated caspase-3 activity and up-regulated the cleaved form of PARP1 to induce cell apoptosis. In vivo, SM-1 combined irradiation showed a good anti-tumor effect. CONCLUSION: SM-1 enhances HNSCC cell radiation sensitivity in vitro and in vivo, supporting its potential as a radiosensitizer for clinical trials in combination with radiotherapy.

LncRNA NPTN-IT1-201 Ameliorates Depressive-like Behavior by Targeting miR-142-5p and Regulating Inflammation and Apoptosis via BDNF.

OBJECTIVE: Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are widely expressed in the brain and are associated with the development of neurological and neurodegenerative diseases. However, their roles and molecular mechanisms in major depressive disorder (MDD) remain largely unknown. This study aimed to identify lncRNAs and miRNAs involved in the development of MDD and elucidate their molecular mechanisms. METHODS: Transcriptome and bioinformatic analyses were performed to identify miRNAs and lncRNAs related to MDD. C57 mice were subjected to chronic unpredictable mild stress (CUMS) to establish a depression model. Lentiviruses containing either lncRNA NPTN-IT1-201 or miR-142-5p were microinjected into the hippocampal region of these mice. Behavioral tests including the sucrose preference test (SPT), tail suspension test (TST), and forced swim test (FST) were conducted to evaluate depressive-like behaviors. RESULTS: The results revealed that overexpression of lncRNA NPTN-IT1-201 or inhibition of miR-142-5p significantly ameliorated depressive-like behaviors in CUMS-treated mice. Dual-luciferase reporter assays confirmed interactions between miR-142-5p with both brain-derived neurotrophic factor (BDNF) and NPTN-IT1-201. ELISA analysis revealed significant alterations in relevant biomarkers in the blood samples of MDD patients compared to healthy controls. Histological analyses, including HE and Nissl staining, showed marked structural changes in brain tissues following CUMS treatment, which were partially reversed by lncRNA NPTN-IT1-201 overexpression or miR-142-5p inhibition. Immunofluorescence imaging demonstrated significant differences in the levels of BAX, Bcl2, p65, Iba1 among different treatment groups. TUNEL assays confirmed reduced apoptosis in brain tissues following these interventions. Western blotting showed the significant differences in BDNF, BAX, and Bcl2 protein levels among different treatment groups. CONCLUSION: NPTN-IT1-201 regulates inflammation and apoptosis in MDD by targeting BDNF via miR-142-5p, making it a potential therapeutic target for MDD.

Deep learning based clinical target volumes contouring for prostate cancer: Easy and efficient application.

BACKGROUND: Radiotherapy has been crucial in prostate cancer treatment. However, manual segmentation is labor intensive and highly variable among radiation oncologists. In this study, a deep learning based automated contouring model is constructed for clinical target volumes (CTVs) of intact and postoperative prostate cancer. METHODS: Computed tomography (CT) data sets of 197 prostate cancer patients were collected. Two auto-delineation models were built for radical radiotherapy and postoperative radiotherapy of prostate cancer respectively, and each model included CTVn for pelvic lymph nodes and CTVp for prostate tumors or prostate tumor beds. RESULTS: In the radical radiotherapy model, the volumetric dice (VD) coefficient of CTVn calculated by AI, was higher than that of the one delineated by the junior physicians (0.85 vs. 0.82, p = 0.018); In the postoperative radiotherapy model, the quantitative parameter of CTVn and CTVp, counted by AI, was better than that of the junior physicians. The median delineation time for AI was 0.23 min in the postoperative model and 0.26 min in the radical model, which were significantly shorter than those of the physicians (50.40 and 45.43 min, respectively, p < 0.001). The correction time of the senior physician for AI was much shorter compared with that for the junior physicians in both models (p < 0.001). CONCLUSION: Using deep learning and attention mechanism, a highly consistent and time-saving contouring model was built for CTVs of pelvic lymph nodes and prostate tumors or prostate tumor beds for prostate cancer, which also might be a good approach to train junior radiation oncologists.

Current concepts of the crosstalk between lncRNA and E2F1: shedding light on the cancer therapy.

Long noncoding RNAs (lncRNAs) constitute a distinctive subset of RNA molecules with limited protein-coding potential, which exert crucial impacts on various biological activities. In the context of cancer, dysregulated lncRNAs function as essential regulators that affect tumor initiation and malignant progression. These lncRNAs serve as competitive endogenous RNAs (ceRNAs) through sponging microRNAs and regulating the expression of targeted genes. Moreover, they also directly bind to RNA-binding proteins, which can be integrated into a complex mechanistic network. E2F1, an extensively studied transcription factor, mediates multiple malignant behaviors by regulating cell cycle progression, tumor metastasis, and therapeutic response. Emerging evidence suggests that lncRNAs play a pivotal role in regulating the E2F1 pathway. This review aims to elucidate the intricate gene regulatory programs between lncRNAs and E2F1 in cancer progression. We elaborate on distinct mechanistic networks involved in cancer progression, emphasizing the potential of the lncRNAs/E2F1 axes as promising targets for cancer therapy. Additionally, we provide novel perspectives on current evidence, limitations, and future directions for targeting lncRNAs in human cancers. Fully deciphering the intricate network of lncRNA/E2F1-mediated regulatory mechanisms in cancer could facilitate the translation of current findings into clinical course, such efforts ultimately significantly improve the clinical prognosis of cancer patients.

Promising first-line immuno-combination therapies for unresectable hepatocellular carcinoma: A cost-effectiveness analysis.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death all over the world, and brings a heavy social economic burden especially in China. Several immuno-combination therapies have shown promising efficacy in the first-line treatment of unresectable HCC and are widely used in clinical practice. Nevertheless, which combination is the most affordable one is unknown. Our study assessed the cost-effectiveness of the immuno-combinations as first-line treatment for patients with unresectable HCC from the perspective of Chinese payers. METHODS: A Markov model was built according to five multicenter, phase III, open-label, randomized trials (Himalaya, IMbrave150, ORIENT-32, CARES-310, LEAP-002) to investigate the cost-effectiveness of tremelimumab plus durvalumab (STRIDE), atezolizumab plus bevacizumab (A + B), sintilimab plus bevacizumab biosimilar (IBI305) (S + B), camrelizumab plus rivoceranib (C + R), and pembrolizumab plus lenvatinib (P + L). Three disease states were included: progression free survival (PFS), progressive disease (PD) as well as death. Medical costs were searched from West China Hospital, published literatures or the Red Book. Cost-effectiveness ratios (CERs) and incremental cost-effectiveness ratios (ICERs) were evaluated to compare costs among different combinations. Sensitivity analyses were performed to assess the robust of the model. RESULTS: The total cost and quality-adjusted life years (QALYs) of C + R, S + B, P + L, A + B and STRIDE were $12,109.27 and 0.91, $26,961.60 and 1.12, $55,382.53 and 0.83, $70,985.06 and 0.90, $84,589.01 and 0.73, respectively, resulting in the most cost-effective strategy of C + R with CER of $13,306.89 per QALY followed by S + B with CER of $24,072.86 per QALY. Compared with C + R, the ICER of S + B strategy was $70,725.38 per QALY, which would become the most cost-effective when the willing-to-pay threshold exceeded $73,500/QALY. In the subgroup analysis, with the application of Asia results in Leap-002 trial, the model results were the same as global data. In the sensitivity analysis, with the variation of parameters, the results were robust. CONCLUSION: As one of the promising immuno-combination therapies in the first-line systemic treatment of HCC, camrelizumab plus rivoceranib demonstrated the potential to be the most cost-effective strategy, which warranted further studies to best inform the real-world clinical practices.