A fluorescence anisotropy-based competition assay to identify inhibitors against ricin and Shiga toxin ribosome interactions.

Ricin is one of the most toxic substances known and a type B biothreat agent. Shiga toxins (Stxs) produced by E. coli (STEC) and Shigella dysenteriae are foodborne pathogens. There is no effective therapy against ricin or STEC and there is an urgent need for inhibitors. Ricin toxin A subunit (RTA) and A1 subunit of Stx2a (Stx2A1) bind to the C-terminal domain (CTD) of the ribosomal P-stalk proteins to depurinate the sarcin/ricin loop. Modulation of toxin-ribosome interactions has not been explored as a strategy for inhibition. Therefore, development of assays that detect inhibitors of toxin-ribosome interactions remains a critical need. Here we describe a fluorescence anisotropy (FA)-based competitive binding assay using a BODIPY-TMR labeled 11-mer peptide (P11) derived from the P-stalk CTD to measure the binding affinity of peptides ranging from 3-11 amino acids for the P-stalk pocket of RTA and Stx2A1. Comparison of the affinity with the surface plasmon resonance (SPR) assay indicated that although the rank order was the same by both methods, the FA assay could differentiate better between peptides that show nonspecific interactions by SPR. The FA assay detects only interactions that compete with the labeled P11 and can validate inhibitor specificity and mechanism of action.

Matrix metalloproteinases targeting in prostate cancer.

Prostate cancer (PCa) is one of the most common tumors affecting men all over the world. PCa has brought a huge health burden to men around the world, especially for elderly men, but its pathogenesis is unclear. In prostate cancer, epigenetic inheritance plays an important role in the development, progression, and metastasis of the disease. An important role in cancer invasion and metastasis is played by matrix metalloproteinases (MMPs), zinc-dependent proteases that break down extracellular matrix. We review two important forms of epigenetic modification and the role of matrix metalloproteinases in tumor regulation, both of which may be of significant value as novel biomarkers for early diagnosis and prognosis monitoring. The author considers that both mechanisms have promising therapeutic applications for therapeutic agent research in prostate cancer, but that efforts should be made to mitigate or eliminate the side effects of drug therapy in order to maximize quality of life of patients. The understanding of epigenetic modification, MMPs, and their inhibitors in the functional regulation of prostate cancer is gradually advancing, it will provide a new technical means for the prevention of prostate cancer, early diagnosis, androgen-independent prostate cancer treatment, and drug research.

The bidirectional relationship between activities of daily living and frailty during short-and long-term follow-up period among the middle-aged and older population: findings from the Chinese nationwide cohort study.

Objective: Frailty and activities of daily living (ADL) disability are common conditions among older population. Studies on the bidirectional relationship between frailty and ADL are limited. The current study examined the cross-sectional and longitudinal associations between frailty and ADL in middle-aged and older Chinese individuals. Methods: The data was collected through the China Health and Retirement Longitudinal Study (CHARLS), conducted in 2011, 2013, and 2015, encompassing 17,284 individuals aged ≥45 years. We excluded individuals without follow-up data. 2,631 participants finished the baseline survey. The definition of ADL disability encompasses difficulty in engaging in either basic activities of daily living (BADL) or instrumental activities of daily living (IADL). Frailty was assessed according to the Fried criteria. Logistic regression was utilized to examine odds ratios (ORs) and 95% confidence intervals (CIs) for assessing the cross-sectional relationships between ADL with frailty at baseline. The prediction effects were explored using Cox proportional hazards analysis, testing hazard ratios (HRs) and 95%CIs. Results: In cross-sectional analysis, BADL [OR = 6.660 (4.519-9.815)], IADL [OR = 5.950 (4.490-7.866)], and ADL [OR = 5.658 (4.278-7.483)] exhibited significant associations with frailty; frailty demonstrated significant associations with BADL [OR = 6.741 (4.574-9.933)], IADL [OR = 6.042 (4.555-8.016)] and ADL [OR = 5.735 (4.333-7.591)]. In longitudinal analysis, IADL and ADL were significantly associated with frailty in participants without baseline frailty in the short-term period [IADL: HR = 1.971 (1.150-3.379), ADL: HR = 1.920 (1.146-3.215)], IADL exhibited a significant association with frailty in the long-term period [HR = 2.056 (1.085-3.895)]. There was no significant link observed between frailty and an elevated risk of disability onset in BADL, IADL and ADL during the short-term period. When considering the long-term perspective, frailty exhibited a significant association with an elevated risk of disability onset in BADL [HR= 1.820 (1.126-2.939)] and IADL [HR = 1.724 (1.103-2.694)]. Conclusion: In middle-aged and older adults, ADL and IADL disability predicted frailty after 2-year follow-up, IADL disability predicted frailty after 4-year follow-up. Moreover, frailty did not predict BADL, IADL and ADL disability after 2-year follow-up. However, frailty predicted BADL and IADL disability after 4-year follow-up.

Comparison of brain gray matter volume changes in peritoneal dialysis and hemodialysis patients with chronic kidney disease: a VBM study.

Objective: This study aims to compare gray matter volume changes in patients with chronic kidney disease (CKD) undergoing peritoneal dialysis (PD) and hemodialysis (HD) using voxel-based morphometry (VBM). Methods: A total of 27 PD patients, 25 HD patients, and 42 healthy controls were included. VBM analysis was performed, and cognitive function was assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment Scale (MoCA). The correlation between cognitive function and changes in brain gray matter volume was analyzed. Results: Both peritoneal dialysis and hemodialysis patients had partial gray matter volume reduction compared to the controls, but the affected brain regions were not uniform. The hemodialysis patients had greater volume reduction in certain brain regions than the PD patients. The MMSE and MoCA scores were positively correlated with gray matter volume changes. Conclusion: Different dialysis modalities cause damage to specific areas of the brain, which can be detected using VBM. VBM, combined with cognitive function assessment, can help detect structural brain changes and cognitive impairment in patients with different dialysis modalities. The comprehensive application of VBM in the field of neurological function deserves further exploration.

Biological and genomic characterization of 4 novel bacteriophages isolated from sewage or the environment using non-aureus Staphylococci strains.

Non-aureus staphylococci (NAS) are an essential group of bacteria causing antimicrobial resistant intramammary infections in livestock, particularly dairy cows. Therefore, bacteriophages emerge as a potent bactericidal agent for NAS mastitis. This study aimed to obtain NAS-specific bacteriophages using bacterial strains isolated from cows with mastitis, subsequently evaluating their morphological, genomic, and lytic characteristics. Four distinct NAS bacteriophages were recovered from sewage or the environment of Chinese dairy farms; PT1-1, PT94, and PT1-9 were isolated using Staphylococcus chromogenes and PT1-4 using Staphylococcus gallinarum. Both PT1-1 (24/54, 44 %) and PT94 (28/54, 52 %) had broader lysis than PT1-4 (3/54, 6 %) and PT1-9 (10/54, 19 %), but PT1-4 and PT1-9 achieved cross-species lysis. All bacteriophages had a short latency period and good environmental tolerance, including surviving at pH=4-10 and at 30-60℃. Except for PT1-9, all bacteriophages had excellent bactericidal efficacy within 5 h of co-culture with host bacteria in vitro at various multiplicity of infection (MOIs). Based on whole genome sequencing, average nucleotide identity (ANI) analysis of PT1-1 and PT94 can be classified as the same species, consistent with whole-genome synteny analysis. Although motifs shared by the 4 bacteriophages differed little from those of other bacteriophages, a phylogenetic tree based on functional proteins indicated their novelty. Moreover, based on whole genome comparisons, we inferred that cross-species lysis of bacteriophage may be related to the presence of "phage tail fiber." In conclusion 4 novel NAS bacteriophages were isolated; they had good biological properties and unique genomes, with potential for NAS mastitis therapy.

A Study on the Maximum Reliability of Multi-UAV Cooperation Relay Systems.

This paper studies the maximum reliability of multi-hop relay UAVs, in which UAVs provide wireless services for remote users as a coded cooperative relay without an end-to-end direct communication link. In this paper, the analytical expressions of the total power loss and total bit error rate are derived as reliability measures. First, based on the environmental statistical parameters, a LOS probability model is proposed. Then, the problem of minimizing the bit error rate of static and mobile UAVs is studied. The goal is to minimize the total bit error rate by jointly optimizing the height, elevation, power and path loss and introducing the maximum allowable path loss constraints, transmission power allocation constraints, and UAV height and elevation constraints. At the same time, the total path loss is minimized to achieve maximum ground communication coverage. However, the formulated joint optimization problem is nonconvex and generally difficult to solve. Therefore, we decomposed the problem into two subproblems and proposed an effective joint optimization iteration algorithm. Finally, the simulation results are given, and the analysis shows that the optimal height of different reliability measures is slightly different; thus, using the mobility of UAVs can improve the reliability of communication performance.

Obesity and lipid indices as predictors of depressive symptoms in middle-aged and elderly Chinese: insights from a nationwide cohort study.

BACKGROUND: Depressive symptoms are one of the most common psychiatric disorders, with a high lifetime prevalence rate among middle-aged and elderly Chinese. Obesity may be one of the risk factors for depressive symptoms, but there is currently no consensus on this view. Therefore, we investigate the relationship and predictive ability of 13 obesity- and lipid-related indices with depressive symptoms among middle-aged and elderly Chinese. METHODS: The data were obtained from The China Health and Retirement Longitudinal Study (CHARLS). Our analysis includes individuals who did not have depressive symptoms at the baseline of the CHARLS Wave 2011 study and were successfully follow-up in 2013 and 2015. Finally, 3790 participants were included in the short-term (from 2011 to 2013), and 3660 participants were included in the long-term (from 2011 to 2015). The average age of participants in short-term and long-term was 58.47 years and 57.88 years. The anthropometric indicators used in this analysis included non-invasive [e.g. waist circumference (WC), body mass index (BMI), and a body mass index (ABSI)], and invasive anthropometric indicators [e.g. lipid accumulation product (LAP), triglyceride glucose index (TyG index), and its-related indices (e.g. TyG-BMI, and TyG-WC)]. Receiver operating characteristic (ROC) analysis was used to examine the predictive ability of various indicators for depressive symptoms. The association of depressive symptoms with various indicators was calculated using binary logistic regression. RESULTS: The overall incidence of depressive symptoms was 20.79% in the short-term and 27.43% in the long-term. In males, WC [AUC = 0.452], LAP [AUC = 0.450], and TyG-WC [AUC = 0.451] were weak predictors of depressive symptoms during the short-term (P < 0.05). In females, BMI [AUC = 0.468], LAP [AUC = 0.468], and TyG index [AUC = 0.466] were weak predictors of depressive symptoms during the long-term (P < 0.05). However, ABSI cannot predict depressive symptoms in males and females during both periods (P > 0.05). CONCLUSION: The research indicates that in the middle-aged and elderly Chinese, most obesity- and lipid-related indices have statistical significance in predicting depressive symptoms, but the accuracy of these indicators in prediction is relatively low and may not be practical predictors.

Impact of tumor size on overall survival and cancer-specific survival of early-onset colon and rectal cancer: a retrospective cohort study.

PURPOSE: This study aimed to investigate the impact of tumor size on survival in early-onset colon and rectal cancer. METHODS: Early-onset colon and rectal cancer patients were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. Tumor size was analyzed as both continuous and categorical variables. Several statistical techniques, including restricted cubic spline (RCS), Cox proportional hazard model, subgroup analysis, propensity score matching (PSM), and Kaplan-Meier survival analysis, were employed to demonstrate the association between tumor size and overall survival (OS) and cancer-specific survival (CSS) of early-onset colon and rectal cancer. RESULTS: Seventeen thousand five hundred fifty-one (76.7%) early-onset colon and 5323 (23.3%) rectal cancer patients were included. RCS analysis confirmed a linear association between tumor size and survival. Patients with a tumor size > 5 cm had worse OS and CSS, compared to those with a tumor size ≤ 5 cm for both early-onset colon and rectal cancer. Notably, subgroup analysis showed that a smaller tumor size (≤ 50 mm) was associated with worse survival in stage II early-onset colon cancer, although not statistically significant. After PSM, Kaplan-Meier survival curves showed that the survival of patients with tumor size ≤ 50 mm was better than that of patients with tumor size > 50 mm. CONCLUSION: Patients with tumors larger than 5 cm were associated with worse survival in early-onset colon and rectal cancer. However, smaller tumor size may indicate a more biologically aggressive phenotype, correlating with poorer survival in stage II early-onset colon cancer.

Four-years change of BMI and waist circumference are associated with metabolic syndrome in middle-aged and elderly Chinese.

The purpose of the study was to determine whether changes in body mass index (BMI) and waist circumference (WC) in middle-aged and elderly Chinese are associated with metabolic syndrome. In this cohort investigation, 3697 middle-aged and elderly people aged 45 or over were recruited from the China Health and Retirement Longitudinal Study (CHARLS). The National Cholesterol Education Program Adult Treatment Panel III (2005) defined metabolic syndrome (MetS). With Cox regression analysis, we calculated hazard ratio (HR) and 95% confidence intervals (CIs) for MetS based on BMI-WC change categories. To assess the prevalence of MetS, the changes in BMI and WC levels were classified into four quartiles based on their relative and absolute changes. In subjects whose BMI and WC decreased (HR = 0.338; 95% CIs 0.264, 0.433) as well as those whose BMI increased and their WC decreased (HR = 0.375; 95% CIs 0.228, 0.499), metabolic syndrome risk was significantly lower compared with those with increases in both BMI and WC. Regarding the absolute changes in BMI, the lowest percentile of BMI was significantly lower in both males (HR = 0.302; 95% CIs 0.204, 0.448) and females (HR = 0.486; 95% CIs 0.354, 0.667) for the risk of metabolic syndrome. Similar results were observed in the absolute changes in WC, with the lowest quantile of WC having a significant impact on MetS risk in males (HR = 0.170; 95% CIs 0.107, 0.270) and females (HR = 0.303; 95% CIs 0.217, 0.424). The risk of metabolic syndrome was significantly associated with changes in BMI and WC in middle-aged and elderly Chinese. A reduced BMI and WC are associated with lower metabolic syndrome risks in middle-aged and elderly people.

Optimal obesity- and lipid-related indices for predicting type 2 diabetes in middle-aged and elderly Chinese.

To investigate the screening and predicting functions of obesity- and lipid-related indices for type 2 diabetes (T2D) in middle-aged and elderly Chinese, as well as the ideal predicted cut-off value. This study's data comes from the 2011 China Health and Retirement Longitudinal Study (CHARLS). A cross-sectional study design was used to investigate the relationship of T2D and 13 obesity- and lipid-related indices, including body mass index (BMI), waist circumference (WC), waist-height ratio (WHtR), visceral adiposity index (VAI), a body shape index (ABSI), body roundness index (BRI), lipid accumulation product (LAP), conicity index (CI), Chinese visceral adiposity index (CVAI), triglyceride- glucose index (TyG index) and its correlation index (TyG-BMI, TyG-WC, TyG-WHtR). The unadjusted and adjusted correlations between 13 indices and T2D were assessed using binary logistic regression analysis. The receiver operating characteristic curve (ROC) was used to determine the usefulness of anthropometric indices for screening for T2D and determining their cut­off value, sensitivity, specificity, and area under the curve (AUC). The study comprised 9488 people aged 45 years or above in total, of whom 4354 (45.89%) were males and 5134 (54.11%) were females. Among them were 716 male cases of T2D (16.44%) and 870 female cases of T2D (16.95%). A total of 13 obesity- and lipid-related indices were independently associated with T2D risk after adjusted for confounding factors (P < 0.05). According to ROC analysis, the TyG index was the best predictor of T2D among males (AUC = 0.780, 95% CI 0.761, 0.799) and females (AUC = 0.782, 95% CI 0.764, 0.799). The AUC values of the 13 indicators were higher than 0.5, indicating that they have predictive values for T2D in middle-aged and elderly Chinese. The 13 obesity- and lipid-related indices can predict the risk of T2D in middle­aged and elderly Chinese. Among 13 indicators, the TyG index is the best predictor of T2D in both males and females. TyG-WC, TyG-BMI, TyG-WHtR, LAP, and CVAI all outperformed BMI, WC, and WHtR in predicting T2D.

Unveiling the promise of PD1/PD-L1: A new dawn in immunotherapy for cholangiocarcinoma.

Cholangiocarcinoma (CCA), a rare yet notably aggressive cancer, has experienced a surge in incidence in recent years. Presently, surgical resection remains the most effective curative strategy for CCA. Nevertheless, a majority of patients with CCA are ineligible for surgical removal at the time of diagnosis. For advanced stages of CCA, the combination of gemcitabine and cisplatin is established as the standard chemotherapy regimen. Despite this, treatment efficacy is often hindered by the development of resistance. In recent times, immune checkpoint inhibitors, particularly those that block programmed death 1 and its ligand (PD1/PD-L1), have emerged as promising strategies against a variety of cancers and are being increasingly integrated into the therapeutic landscape of CCA. A growing body of research supports that the use of PD1/PD-L1 monoclonal antibodies in conjunction with chemotherapy may significantly improve patient outcomes. This article seeks to meticulously review the latest studies on PD1/PD-L1 involvement in CCA, delving into their expression profiles, prognostic significance, contribution to oncogenic processes, and their potential clinical utility.

Validation of the Chinese version of the Oslo-3 Social Support Scale among nursing students: a study based on Classical Test Theory and Item Response Theory models.

BACKGROUND: Nursing students are encountering a range of health issues. Assessing social support is a key component in most questionnaire surveys related to health status, aiming to investigate the relationships and mechanisms between health status and social support to enhance overall health. Therefore, it is essential to seek out appropriate instruments to evaluate social support for nursing students. The Oslo-3 Social Support Scale (OSSS-3) is a reliable and concise instrument for evaluating social support. To date, there have been no studies validating the OSSS-3 based on Item Response Theory (IRT) models. Also, an officially validated Chinese version has not been found. The current research intended to verify the Chinese version of the OSSS-3. METHODS: The OSSS-3 was translated into Chinese and culturally adapted. Subsequently, the OSSS-3 was validated by employing the Classical Test Theory (CTT) and IRT models. RESULTS: The split-half reliability was 0.622. The Cronbach's α coefficient was 0.687. The correlations between each item and total scores varied from 0.723 to 0.835. The retest coefficient was 0.907. The content validity index was 0.933. A single common factor was extracted and accounted for 61.559% of the variance. The item loading values on the single factor were between 0.743 and 0.814. The communalities were between 0.552 and 0.663. There was no variance between males and females (P = 0.055). The difference in scores between the top (30%) and bottom (30%) groups attained significance. IRT models results revealed that the discrimination parameters ranged from 1.39 to 2.33 and difficulty parameters increased monotonically. CONCLUSION: The OSSS-3 demonstrates satisfying psychometric properties and is a proper instrument for measuring social support in Chinese nursing students.

Semaglutide attenuates doxorubicin-induced cardiotoxicity by ameliorating BNIP3-Mediated mitochondrial dysfunction.

AIMS: Doxorubicin is a powerful chemotherapeutic agent for cancer, whose use is limited due to its potential cardiotoxicity. Semaglutide (SEMA), a novel analog of glucagon-like peptide-1 (GLP-1), has received widespread attention for the treatment of diabetes. However, increasing evidence has highlighted its potential therapeutic benefits on cardiac function. Therefore, the objective of this study was to examine the efficacy of semaglutide in ameliorating doxorubicin-induced cardiotoxicity. METHODS AND RESULTS: Doxorubicin-induced cardiotoxicity is an established model to study cardiac function. Cardiac function was studied by transthoracic echocardiography and invasive hemodynamic monitoring. The results showed that semaglutide significantly ameliorated doxorubicin-induced cardiac dysfunction. RNA sequencing suggested that Bnip3 is the candidate gene that impaired the protective effect of semaglutide in doxorubicin-induced cardiotoxicity. To determine the role of BNIP3 on the effect of semaglutide in doxorubicin-induced cardiotoxicity, BNIP3 with adeno-associated virus serotype 9 (AAV9) expressing cardiac troponin T (cTnT) promoter was injected into tail vein of C57/BL6J mice to overexpress BNIP3, specifically in the heart. Overexpression of BNIP3 prevented the improvement in cardiac function caused by semaglutide. In vitro experiments showed that semaglutide, via PI3K/AKT pathway, reduced BNIP3 expression in the mitochondria, improving mitochondrial function. CONCLUSION: Semaglutide ameliorates doxorubicin-induced mitochondrial and cardiac dysfunction via PI3K/AKT pathway, by reducing BNIP3 expression in mitochondria. The improvement in mitochondrial function reduces doxorubicin-mediated cardiac injury and improves cardiac function. Therefore, semaglutide is a potential therapy to reduce doxorubicin-induced acute cardiotoxicity.

Density Analysis of Adsorption Phase in the Thermodynamic Study of Shale Gas Adsorption.

Understanding the adsorption mechanism and precisely predicting the thermodynamic adsorption properties of methane at high pressure are crucial while very challenging for shale gas development. In this study, we demonstrated that the Langmuir adsorption model combining with different empirical methods to determine the adsorption phase density makes the calculated isothermal adsorption heat violate Henry's law at low pressure. For instance, the isothermal adsorption heat calculated by the Langmuir-Freundlich model contradicts Henry's law when the absolute adsorption quantity is zero. Given the current challenge in accurately calculating the adsorption phase density, it is necessary to impose constraints on the parameters of the adsorption model by adhering to Henry's law to maintain thermodynamic consistency. We found that the adsorption phase volume of methane molecules lies between the micropore volume and the total pore volume when shale adsorption reaches saturation. The adsorption mechanism involves not only filling micropores but also monolayer adsorption in meso-macro pores. The high-energy adsorption sites for methane are primarily concentrated in organic matter, while within these methane adsorption areas in shale, the high-energy adsorption sites for water are mainly located in kaolinite within clay minerals. The zero-pressure heat of adsorption is a temperature-independent thermodynamic index, yet it is influenced by the water content. It can therefore be selected as a quantitative measure to evaluate the impact of methane adsorption on water.

Facilitated Unidirectional Electron Transmission by Ru Nano Particulars Distribution on MXene Mo2C@g-C3N4 Heterostructures for Enhanced Photocatalytic H2 Evolution.

Precious metals exhibit promising potential for the hydrogen evolution reaction (HER), but their limited abundance restricts widespread utilization. Loading precious metal nanoparticles (NPs) on 2D/2D heterojunctions has garnered considerable interest since it saves precious metal consumption and facilitates unidirectional electron transmission from semiconductors to active sites. In this study, Ru NPs loaded on MXenes Mo2C by an in-site simple strategy and then formed 2D/2D heterojunctions with 2D g-C3N4 (CN) via electrostatic self-assembly were used to enhance photocatalytic H2 evolution. Evident from energy band structure analyses such as UV-vis and TRPL, trace amounts of Ru NPs as active sites significantly improve the efficiency of the hydrogen evolution reaction. More interestingly, MXene Mo2C, as substrates for supporting Ru NPs, enriches photoexcited electrons from CN, thereby enhancing the unidirectional electron transmission. As a result, the combination of Ru-Mo2C and CN constructs a composite heterojunction (Ru-Mo2C@CN) that shows an improved H2 production rate at 1776.4 µmol∙g-1∙h-1 (AQE 3.58% at 400 nm), which is facilitated by the unidirectional photogenerated electron transmission from the valence band on CN to the active sites on Ru (CN→Mo2C→Ru). The study offers fresh perspectives on accelerated unidirectional photogenerated electron transmission and saved precious metal usage in photocatalytic systems.

Echelon grating refractive index sensor.

There are few reports on optical refractive index sensors that have both high resonant-wavelength resolution (RWR) and high refractive index sensitivity (RIS). Herein, based on an echelon grating, we design a refractive index sensor that combines the two advantages together. The principal fringe of echelon grating has a small full width at half maximum and a good signal-to-noise ratio, leading to a high RWR. The wavefront splitting interference makes the sensor have high RIS. The large free spectral range (FSR) of the principal fringes expands the dynamic range of the sensor. The experimentally realized RWR, RIS, and FSR are 2 × 10-2 nm, 1.14 × 104 nm/RIU (RIU: refractive index unit), and 130 nm, respectively. The detection limit of refractive index is 1.59 × 10-6 RIU. The dynamic range of the sensor is 1.14 × 10-2 RIU. In addition, there are schemes to improve RWR and RIS, which can further reduce the detection limit of refractive index. The echelon grating refractive index sensor features low detection limit, low cost, high stability, and good robustness.

Construction and validation of a hypoxia-related gene signature to predict the prognosis of breast cancer.

BACKGROUND: Among the most common forms of cancer worldwide, breast cancer posed a serious threat to women. Recent research revealed a lack of oxygen, known as hypoxia, was crucial in forming breast cancer. This research aimed to create a robust signature with hypoxia-related genes to predict the prognosis of breast cancer patients. The function of hypoxia genes was further studied through cell line experiments. MATERIALS AND METHODS: In the bioinformatic part, transcriptome and clinical information of breast cancer were obtained from The Cancer Genome Atlas(TCGA). Hypoxia-related genes were downloaded from the Genecards Platform. Differentially expressed hypoxia-related genes (DEHRGs) were identified. The TCGA filtered data was evenly split, ensuring a 1:1 distribution between the training and testing sets. Prognostic-related DEHRGs were identified through Cox regression. The signature was established through the training set. Then, it was validated using the test set and external validation set GSE131769 from Gene Expression Omnibus (GEO). The nomogram was created by incorporating the signature and clinicopathological characteristics. The predictive value of the nomogram was evaluated by C-index and receiver operating characteristiccurve. Immune microenvironment and mutation burden were also examined. In the experiment part, the function of the two most significant hypoxia-related genes were further explored by cell-line experiments. RESULTS: In the bioinformatic part, 141 up-regulated and 157 down-regulated DEHRGs were screened out. A prognostic signature was constructed containing nine hypoxia genes (ALOX15B, CA9, CD24, CHEK1, FOXM1, HOTAIR, KCNJ11, NEDD9, PSME2) in the training set. Low-risk patients exhibited a much more favorable prognosis than higher-risk ones (P < 0.001). The signature was double-validated in the test set and GSE131769 (P = 0.006 and P = 0.001). The nomogram showed excellent predictive value with 1-year OS AUC: 0.788, 3-year OS AUC: 0.783, and 5-year OS AUC: 0.817. Patients in the high-risk group had a higher tumor mutation burden when compared to the low-risk group. In the experiment part, the down-regulation of PSME2 inhibited cell growth ability and clone formation capability of breast cancer cells, while the down-regulation of KCNJ11 did not have any functions. CONCLUSION: Based on 9 DEHRGs, a reliable signature was established through the bioinformatic method. It could accurately predict the prognosis of breast cancer patients. Cell line experiment indicated that PSME2 played a protective role. Summarily, we provided a new insight to predict the prognosis of breast cancer by hypoxia-related genes.

A pharmacokinetic study comparing the biosimilar HEC14028 and Dulaglutide (Trulicity®) in healthy Chinese subjects.

This study aimed to evaluate the pharmacokinetics (PKs), safety, and immunogenicity of the biosimilar HEC14028 compared to reference Trulicity® (dulaglutide) in healthy male Chinese subjects. This study was a single-center, randomized, open, single-dose, parallel-controlled comparative Phase I clinical trial, including a screening period of up to 14 days, a 17-day observation period after administration, and a 7-day safety follow-up period. A total of 68 healthy male subjects were randomly assigned (1:1) to the test group (HEC14028) and the reference group (dulaglutide) (single 0.75 mg abdominal subcutaneous dose). The primary objective was to evaluate the pharmacokinetic characteristics of HEC14028 and compare the pharmacokinetic similarities between HEC14028 and dulaglutide. The primary PK endpoints were maximum plasma concentration (Cmax) and area under the blood concentration-time curve from zero time to the estimated infinite time (AUC0-∞). The study results showed that HEC14028 and dulaglutide were pharmacokinetically equivalent: 90% confidence interval (CI) of Cmax and AUC0-∞ geometric mean ratios were 102.9%-122.0% and 97.1%-116.9%, respectively, which were both within the range of 80.00%-125.00%. No grade 3 or above treatment emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to withdrawal from the trial, or TEAEs leading to death were reported in this study. Both HEC14028 and dulaglutide showed good and similar safety profiles, and no incremental immunogenicity was observed in subjects receiving HEC14028 and dulaglutide.

Identification of Hub Genes in Liver Hepatocellular Carcinoma Based on Weighted Gene Co-expression Network Analysis.

Liver hepatocellular carcinoma (LIHC) is a malignant cancer with high incidence and poor prognosis. To investigate the correlation between hub genes and progression of LIHC and to provided potential prognostic markers and therapy targets for LIHC. Our study mainly used The Cancer Genome Atlas (TCGA) LIHC database and the gene expression profiles of GSE54236 from the Gene Expression Omnibus (GEO) to explore the differential co-expression genes between LIHC and normal tissues. The differential co-expression genes were extracted by Weighted Gene Co-expression Network Analysis (WGCNA) and differential gene expression analysis methods. The Genetic Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were carried out to annotate the function of differential genes. Then the hub genes were validated using protein-protein interaction (PPI) network. And the expression level and prognostic analysis were performed. The probable associations between the expression of hub genes and both tumor purity and infiltration of immune cells were explored by TIMER. A total of 68 differential co-expression genes were extracted. These genes were mainly enriched in complement activation (biological process), collagen trimer (cellular component), carbohydrate binding and receptor ligand activity (molecular function) and cytokine - cytokine receptor interaction. Then we demonstrated that the 10 hub genes (CFP, CLEC1B, CLEC4G, CLEC4M, FCN2, FCN3, PAMR1 and TIMD4) were weakly expressed in LIHC tissues, the qRT-PCR results of clinical samples showed that six genes were significantly downregulated in LIHC patients compared with adjacent tissues. Worse overall survival (OS) and disease-free survival (DFS) in LIHC patients were associated with the lower expression of CFP, CLEC1B, FCN3 and TIMD4. Ten hub genes had positive association with tumor purity. CFP, CLEC1B, FCN3 and TIMD4 could serve as novel potential molecular targets for prognosis prediction in LIHC.

High LGALS3 expression induced by HCP5/hsa-miR-27b-3p correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is widely recognized for its unfavorable prognosis. Increasing evidence has revealed that LGALS3 has an essential function in initiating and developing several malignancies in humans. Nevertheless, thorough analysis of the expression profile, clinical prognosis, pathway prediction, and immune infiltration of LGALS3 has not been fully explored in HCC. METHODS: In this study, an initial pan-cancer analysis was conducted to investigate the expression and prognosis of LGALS3. Following a comprehensive analysis, which included expression analysis and correlation analysis, noncoding RNAs that contribute to the overexpression of LGALS3 were subsequently identified. This identification was further validated using HCC clinical tissue samples. TIMER2 and GEPIA2 were employed to examine the correlation between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration in HCC. The R program was applied to analyze the expression distribution of immune score in in HCC patients with high and low LGALS3 expression. The expression profiles of immune checkpoints were also analyzed. Use R to perform GSVA analysis in order to explore potential signaling pathways. RESULTS: First, we conducted pan-cancer analysis for LGALS3 expression level through an in-depth analysis of public databases and found that HCC has a high LGALS3 gene and protein expression level, which were then verified in clinical HCC specimens. Meanwhile, high LGALS3 gene expression is related to malignant progression and poor prognosis of HCC. Univariate and multivariate analyses confirmed that LGALS3 could serve as an independent prognostic marker for HCC. Next, by combining comprehensive analysis and validation on HCC clinical tissue samples, we hypothesize that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC. KEGG and GO analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly higher immune cell scores and immune checkpoint expression levels. Finally, GSVA analysis was performed to predict potential signaling pathways linked to LGALS3 and HCP5 in immune evasion and metabolic reprogramming of HCC. CONCLUSIONS: Our findings indicated that the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.