Case report and literature review: management of Paxlovid (nirmatrelvir/ritonavir)-induced acute tacrolimus toxicity in a patient with systemic lupus erythematosus.

Despite the availability of effective vaccines and treatments for SARS-CoV-2, managing COVID-19 in patients with systemic lupus erythematosus (SLE) remains challenging, particularly considering drug-drug interactions (DDIs). Here, we present a case of DDIs between Tacrolimus (Tac) and nirmatrelvir/ritonavir (NMV/r) in a 32-year-old male with SLE. Following self-administration of NMV/r and resumption of Tac after 5 days, the patient experienced acute nephrotoxicity and neurotoxicity, accompanied by supratherapeutic Tac levels, despite Tac being withheld during NMV/r. The primary cause of this acute toxicity is attributed to ritonavir's inhibitory effect on both CYP3A4 enzymes and P-glycoprotein. Upon admission, Tac was discontinued, and supportive therapies were initiated. Phenytoin, a CYP3A4 inducer, was administered to lower Tac levels under the guidance of clinical pharmacists, effectively alleviating the patient's acute toxic symptoms. The half-life of Tac during the treatment of phenytoin was calculated to be 55.87 h. And no adverse reactions to phenytoin were observed. This case underscores the persistence of enzyme inhibition effects and demonstrates the effectiveness and safety of utilizing CYP3A4 enzyme inducers to mitigate Tac concentrations. Furthermore, it emphasizes the importance of healthcare providers and patients being vigilant about DDIs in Tac recipients. Lastly, it highlights the indispensable role of pharmacist involvement in clinical decision-making and close monitoring in complex clinical scenarios. Although our findings are based on a single case, they align with current knowledge and suggest the potential of individualized combination therapy in managing challenging COVID-19 cases in immunocompromised patients.

The prognostic value and potential immunotherapeutic efficacy of ACVR1 in treating gastric cancer.

Background: The discovery of biomarkers has facilitated the treatment of cancer. At present, the relationship between activin A receptor type-1 (ACVR1) and gastric cancer is gradually discovered. The aim of this study was to explore the expression of ACVR1 in gastric cancer and its clinical significance, to study the relationship between ACVR1 and tumor microenvironment (TME) for the prognosis of gastric cancer, and to further identify new targets for immunotherapy in gastric cancer. Methods: ACVR1 was first selected as a study gene according to several cancer and gastric cancer public datasets. Its pancancer expression was explored using the UCSC Xena database. The expression level, prognosis, and clinicopathological features of ACVR1 in gastric cancer were analyzed using The Cancer Genome Atlas (TCGA) database. Immunohistochemistry (IHC)-based experiments were conducted to study the expression of ACVR1 at the protein level. The IHC data were analyzed for correlations between ACVR1 expression and various clinicopathological factors and prognosis. The correlation of this gene with the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, immune infiltration, immune checkpoints, drug therapy, tumor mutation burden (TMB), microsatellite instability (MSI), and mismatch repair (MMR) system was analyzed using R software. Results: TCGA data showed that the expression of ACVR1 was higher in gastric cancer tissues than in paracancerous tissues. Moreover, the IHC experiments indicated that ACVR1 was upregulated in gastric cancer tissues at the protein level. Both univariate Cox and multivariate Cox results showed that the increase of ACVR1 was closely associated with tumor stage, size, lymph node metastasis, and age. High ACVR1 expression was linked to a poor prognosis of gastric cancer. The results also revealed that ACVR1 was closely related to suppressive immune cells and pathways. Analyses of immune checkpoints, antitumor drug, TMB, and immune microenvironment indicated that ACVR1 had an antitumor immune effect, promoting gastric cancer development and leading to poor immunotherapy. Conclusions: High ACVR1 expression can be used as an independent prognostic factor to predict the prognostic survival of patients with gastric cancer. ACVR1 expression in gastric cancer tissues was significantly correlated with immune infiltration and may thus serve as a potential therapeutic target for gastric cancer immunotherapy.

Serum trough concentration threshold and risk factors of cefoperazone-induced coagulopathy in critically ill patients: A retrospective case-control study.

PURPOSE: To analyze the risk factors influencing the development of cefoperazone-induced coagulopathy in critically ill patients and determine the threshold of serum trough concentration. METHODS: A retrospective case-control study was conducted in the intensive care unit patients treated with cefoperazone, and it was approved by the Ethical Committee of Drum Tower Hospital affiliated with the Medical School of Nanjing University (NO.2023-158-01). Patients were divided into the normal group and coagulopathy group based on prothrombin time. The clinical characteristics of the two groups were compared using univariate analysis. The serum concentration threshold and influencing factors of cefoperazone-induced coagulopathy in critically ill patients were analyzed using the receiver operating characteristic curve and multivariate logistic regression analysis. RESULTS: A total of 113 patients were included, and cefoperazone-induced coagulopathy occurred in 39 patients, with an incidence of 34.5%. These patients experienced significant prothrombin time prolongation around day 6 (median) after cefoperazone application. The serum trough concentration threshold of cefoperazone-induced coagulopathy in critically ill patients was 87.765 mg/l. Multivariate logistic regression analysis revealed that the APACHE II score (p = 0.034), prophylactic use of vitamin K1 (p < 0.001), hepatic impairment (p = 0.014), and Cmin ≥ 87.765 mg/l (p = 0.005) were associated with cefoperazone-induced coagulopathy. CONCLUSION: Cefoperazone-induced coagulopathy usually occurs on the 6th day of cefoperazone use in critically ill patients. The risk will increase in patients with an APACHE II score > 25, hepatic impairment, and cefoperazone Cmin ≥ 87.765 mg/l. Vitamin K1 is effective in preventing this adverse reaction.

Silencing FUT4 Inhibits the Progression of Osteosarcoma through Activation of FOXO1.

BACKGROUND: It has been reported that inhibition of Fucosyltransferase4 (FUT4) to activate Forkhead box O1 (FOXO1) can lead to apoptosis of cancer cells, however, the mechanism in osteosarcoma is still unclear. OBJECTIVE: To explore the biological significance of the connection between FUT4 and FOXO1 in osteosarcoma growth. METHODS: In vitro tests were conducted using the human osteoblast cell line and the osteosarcoma cell lines. QRT-PCR assay as well as western blot assay were used to ascertain the relative expression levels of FUT4 and FOXO1 in the cells. By using the CCK-8 assay, colony assay, EDU assay, wound healing assay and Transwell assay, osteosarcoma cells' ability to proliferate, migrate and invade were examined in relation to si- FUT4. TUNEL test was used to evaluate Si-impact FUT4's on KHOS and U2OS apoptosis in osteosarcoma cells. Western blot assay was used to identify the expression of proliferative, migrating and apoptosis-related protein markers in osteosarcoma cells KHOS and U2OS and the expression of important proteins in the Wnt/ ß-catenin signaling pathway. RESULTS: In comparison with osteoblasts, osteosarcoma cells expressed more FUT4. The osteosarcoma cells' capacities to proliferate, invade, and migrate were markedly inhibited by the inhibition of FUT4 expression, which also increased osteosarcoma cell apoptosis. The Wnt/ß-catenin signaling pathway was blocked by upregulating FOXO1 expression, which was in turn inhibited by inhibiting FUT4 expression. CONCLUSION: Osteosarcoma cells express more FUT4. The Wnt/ß-catenin signaling pathway has a significant effect on osteosarcoma cell death, and inhibition of FUT4 expression may target FOXO1 activation to decrease osteosarcoma cells' ability to proliferate, invade, and migrate.

Development and Validation of a Dynamic Nomogram for Predicting 3-Month Mortality in Acute Ischemic Stroke Patients with Atrial Fibrillation.

Background: Acute ischemic stroke (AIS) in patients with atrial fibrillation (AF) carries a substantial risk of mortality, emphasizing the need for effective risk assessment and timely interventions. This study aimed to develop and validate a practical dynamic nomogram for predicting 3-month mortality in AIS patients with AF. Methods: AIS patients with AF were enrolled and randomly divided into training and validation cohorts. The nomogram was developed based on independent risk factors identified by multivariate logistic regression analysis. The prediction performance of the nomogram was evaluated using the area under the receiver operating characteristic curve (AUC-ROC), calibration plots, decision curve analysis (DCA), and Kaplan-Meier survival analysis. Results: A total of 412 patients with AIS and AF entered final analysis, 288 patients in the training cohort and 124 patients in the validation cohort. The nomogram was developed using age, baseline National Institutes of Health Stroke Scale score, early introduction of novel oral anticoagulants, and pneumonia as independent risk factors. The nomogram exhibited good discrimination both in the training cohort (AUC, 0.851; 95% CI, 0.802-0.899) and the validation cohort (AUC, 0.811; 95% CI, 0.706-0.916). The calibration plots, DCA and Kaplan-Meier survival analysis demonstrated that the nomogram was well calibrated and clinically useful, effectively distinguishing the 3-month survival status of patients with AIS and AF, respectively. The dynamic nomogram can be obtained at the website: https://yanxiaodi.shinyapps.io/3-monthmortality/. Conclusion: The dynamic nomogram represents the first predictive model for 3-month mortality and may contribute to managing the mortality risk of patients with AIS and AF.

MSTL-Kace: Prediction of Prokaryotic Lysine Acetylation Sites Based on Multistage Transfer Learning Strategy.

As one of the most important post-translational modifications (PTM), lysine acetylation (Kace) plays an important role in various biological activities. Traditional experimental methods for identifying Kace sites are inefficient and expensive. Instead, several machine learning methods have been developed for Kace site prediction, and hand-crafted features have been used to encode the protein sequences. However, there are still two challenges: the complex biological information may be under-represented by these manmade features and the small sample issue of some species needs to be addressed. We propose a novel model, MSTL-Kace, which was developed based on transfer learning strategy with pretrained bidirectional encoder representations from transformers (BERT) model. In this model, the high-level embeddings were extracted from species-specific BERT models, and a two-stage fine-tuning strategy was used to deal with small sample issue. Specifically, a domain-specific BERT model was pretrained using all of the sequences in our data sets, which was then fine-tuned, or two-stage fine-tuned based on the training data set of each species to obtain the species-specific BERT models. Afterward, the embeddings of residues were extracted from the fine-tuned model and fed to the different downstream learning algorithms. After comparison, the best model for the six prokaryotic species was built by using a random forest. The results for the independent test sets show that our model outperforms the state-of-the-art methods on all six species. The source codes and data for MSTL-Kace are available at https://github.com/leo97king/MSTL-Kace.

Efficacy and Safety of Anticoagulant Therapy Versus Antiplatelet Therapy in Acute Ischemic Stroke Patients with Atrial Fibrillation.

The efficacy and safety of anticoagulant therapy in patients with acute ischemic stroke (AIS) and atrial fibrillation (AF) remain uncertain. This study enrolled 431 AIS and AF patients from Nanjing Drum Tower Hospital between January 2019 and December 2021 and followed for 365 days to determine the associations between anticoagulants and clinical outcomes by assessing modified Rankin Scale (mRS) score, recurrent ischemic stroke/systemic embolism (IS/SE), all-cause mortality, intracranial hemorrhage (ICH) and major bleeding. Final analysis included 400 eligible patients and divided them into antiplatelet group (n = 191) and anticoagulant group (n = 209). Anticoagulant therapy was associated with excellent (mRS 0-1; adjusted odds ratio (aOR), 2.63; 95% confidence interval (CI), 1.61-4.30) and favorable functional outcomes (mRS 0-2; aOR, 2.82; 95% CI, 1.69-4.70) and lower risk of all-cause mortality (adjusted hazard ratio (aHR), 0.35; 95% CI, 0.21-0.57), ICH (aHR, 0.45; 95% CI, 0.23-0.87) and major bleeding (aHR, 0.51; 95% CI, 0.28-0.94), without increasing the risk of recurrent IS/SE (aHR, 0.75; 95% CI, 0.45-1.24). In conclusion, anticoagulant therapy may be a more effective and safer option than antiplatelet therapy for AIS patients with AF.

Cross-sectional associations between questionnaire-measured physical activity and tissue doppler indices of left ventricular diastolic function.

BACKGROUND: The prevalence of left ventricular (LV) diastolic dysfunction has been increasing over the past decade, and to date, effective pharmacotherapies that enhance LV diastolic function have not yet been identified. Though some data has demonstrated the beneficial effects of exercise training on LV diastolic function, little is known about the adaptations of diastolic function to daily physical activity (PA). Accordingly, our study aimed to investigate the impact of daily PA on tissue Doppler indices of LV diastolic function. METHODS: A total of 432 participants were enrolled for clinically indicated echocardiography from July 2019 to July 2020 at Peking University People's Hospital. Participants aged ≥ 18 years were included if they had stable PA in the past six months and normal LV systolic function. A questionnaire was used to collect demographic characteristics, medical history, and daily PA. According to PA Guidelines for Americans, we identified these participants into low-intensity PA (LPA) group and moderate-high-intensity PA (MHPA) group. Propensity score matching (PSM) was performed to match potential confounding factors between the two groups. The clinical characteristics and echocardiographic parameters between LPA group and MHPA group were compared using student's t-test, Mann-Whitney U test, and chi-square test as appropriate. RESULTS: After matching potential confounding factors using PSM with a 1:3 matching ratio, our final analysis included 86 cases in the MHPA group and 214 cases in the LPA group. All demographic characteristics and comorbidities were statistically similar between the two groups. Compared to the LPA group, the MHPA group showed higher septal e' (7.9 ± 2.9 cm/s versus 7.2 ± 2.6 cm/s, P = 0.047). Other echocardiographic parameters associated with LV diastolic function concerning lateral e' and average E/e', also trended towards improved LV diastolic function in the MHPA group, but failed to reach statistical significance. CONCLUSIONS: Our study demonstrated that moderate-high-intensity daily PA was associated with improved septal e', suggesting that moderate-high-intensity PA could potentially ameliorate LV diastolic dysfunction.

Being targeted: How counter-arguing and message relevance mediate the effects of cultural value appeals on disease prevention attitudes and behaviors.

This study investigated the effects of cultural value appeals in health persuasion. Situated in the COVID-19 pandemic, this study examined if and how individualistic and collectivistic appeals can improve attitudes and behaviors related to the use of face masks among European Americans and Asian Americans. Results showed that for European Americans, collectivistic vs. individualistic appeals were more effective to improve attitudes and behavioral intention. Perceived message relevance and counter-arguing were significant mediators explaining the effects. For Asian Americans, both individualistic and collectivistic appeals predicted significant changes in attitudinal and behavioral outcomes. These findings have important theoretical and practical implications.

Systematic analysis of ferroptosis-related long non-coding RNA predicting prognosis in patients with lung squamous cell carcinoma.

Background: Ferroptosis is a novel iron-dependent cell death, and an increasing number of studies have shown that long non-coding RNA (lncRNAs) are involved in the ferroptosis process. However, studies on ferroptosis-related lncRNAs in lung squamous cell carcinoma (LUSC) are limited. In addition, the prognostic role of ferroptosis-related lncRNAs and their relationship with the immune microenvironment and methylation of LUSC is unclear. This study aimed to investigate the potential prognostic value of ferroptosis-related lncRNAs and their involved biological functions in LUSC. Methods: The Cancer Genome Atlas (TCGA) database and the FerrDb website were used to obtain ferroptosis-related genes for LUSC. The "limma" R package and Pearson analysis were used to find ferroptosis-related lncRNAs. The biological functions of the characterized lncRNAs were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We evaluated the prognostic power of this model using Kaplan-Meier analysis, receiver operating characteristic (ROC), and decision curve analysis (DCA). Univariate and multifactor Cox (proportional-hazards) risk model and a nomogram were produced using risk models and clinicopathological parameters for further verification. In addition, the relationship between characterized lncRNAs and tumor immune infiltration and methylation was also discussed. Results: We identified 29 characterized lncRNAs to produce prognostic risk models. Kaplan-Meier analysis revealed the high-risk group was associated with poor prognosis in LUSC (P<0.001), and ROC (AUC =0.658) and DCA suggested that risk models could predict prognosis. Univariate and multifactorial Cox as well as nomogram further validated the prognostic model (P<0.001). Gene set enrichment analysis (GSEA) showed that the high-risk group was associated with pro-tumor pathways and high-frequency mutations in TP53 were present in both groups. Single sample gene set enrichment analysis (ssGSEA) showed significant differences in immune cell infiltration subtypes and corresponding functions between the two groups. Some immune checkpoint and methylation-related genes were significantly different between the two groups (P<0.05). Conclusions: We investigated the potential mechanisms of LUSC development from the perspective of ferroptosis-related lncRNAs, providing new insights into LUSC research, and identified 29 lncRNAs as biomarkers to predict the prognosis of LUSC patients.

Inhibition of Rac1 attenuates radiation-induced lung injury while suppresses lung tumor in mice.

The lung is one of the most sensitive tissues to ionizing radiation, thus, radiation-induced lung injury (RILI) stays a key dose-limiting factor of thoracic radiotherapy. However, there is still little progress in the effective treatment of RILI. Ras-related C3 botulinum toxin substrate1, Rac1, is a small guanosine triphosphatases involved in oxidative stress and apoptosis. Thus, Rac1 may be an important molecule that mediates radiation damage, inhibition of which may produce a protective effect on RILI. By establishing a mouse model of radiation-induced lung injury and orthotopic lung tumor-bearing mouse model, we detected the role of Rac1 inhibition in the protection of RILI and suppression of lung tumor. The results showed that ionizing radiation induces the nuclear translocation of Rac1, the latter then promotes nuclear translocation of P53 and prolongs the residence time of p53 in the nucleus, thereby promoting the transcription of Trp53inp1 which mediates p53-dependent apoptosis. Inhibition of Rac1 significantly reduce the apoptosis of normal lung epithelial cells, thereby effectively alleviating RILI. On the other hand, inhibition of Rac1 could also significantly inhibit the growth of lung tumor, increase the radiation sensitivity of tumor cells. These differential effects of Rac1 inhibition were related to the mutation and overexpression of Rac1 in tumor cells.

BMPER alleviates ischemic brain injury by protecting neurons and inhibiting neuroinflammation via Smad3-Akt-Nrf2 pathway.

AIMS: Bone morphogenetic proteins (BMPs) are a group of proteins related to bone morphogenesis. BMP-binding endothelial regulator (BMPER), a secreted protein that interacts with BMPs, is known to be involved in ischemic injuries. Here, we explored the effects of BMPER on cerebral ischemia and its mechanism of action. METHODS: A mouse model of brain ischemia was induced by middle cerebral artery occlusion (MCAO). An in vitro ischemic model was established by subjecting primary cultured neurons to oxygen-glucose deprivation/reperfusion (OGD/R). Serum levels of BMPs/BMPER were measured in MCAO mice and in patients with acute ischemic stroke (AIS). Brain damages were compared between BMPER- and vehicle-treated mice. Quantitative polymerase chain reaction (qPCR), immunohistochemistry, and immunofluorescence staining were performed to examine neuroinflammation and cell death. BMPER-related pathways were assessed by Western blotting. RESULTS: BMPER level was elevated in MCAO mice and AIS patients. BMPER administration reduced mortality, infarct size, brain edema, and neurological deficit after MCAO. Neuroinflammation and cell death after ischemia were alleviated by BMPER both in vivo and in vitro. BMPER activated the Smad3/Akt/Nrf2 pathway in OGD/R-challenged neurons. CONCLUSION: BMPER is a neuroprotective hormone that alleviates ischemic brain injury via activating the Smad3/Akt/Nrf2 pathway. These findings may provide potential therapeutic strategies for stroke.

High SERPINH1 expression predicts poor prognosis in lung adenocarcinoma.

Background: Serpine Protease Inhibitorclade H1 (SERPINH1) is abnormally expressed in a variety of tumor tissues and is linked to the biological processes of tumorigenesis, migration, invasion, and metastasis. SERPINH1 expression and prognosis in malignant tumors, such as gastric, colorectal, and breast cancers, have previously been studied, but the gene has not yet been investigated in lung adenocarcinoma (LUAD) in terms of prognosis and the potential mechanisms of action. Methods: SERPINH1 was identified as an independent prognostic factor for LUAD in The Cancer Genome Atlas (TCGA) cohort and Affiliated Hospital of Nantong University (NTU) cohort (the LUAD data set) by univariate and multivariate Cox regression analyses. Additionally, we performed immunohistochemical staining to analyze the expression of SERPINH1 in LUAD and normal lung tissue. Based on the TCGA database, we analyzed the correlation of this gene with the tumor mutation burden (TMB), tumor microenvironment, immune infiltration, immune checkpoints, and anti-tumor drugs using the R language-related R package. Results: SERPINH1 was highly expressed in LUAD tissue. Kaplan-Meier survival curves in both the TCGA cohort and the NTU cohort showed that the SERPINH1 low-expression group had a higher survival rate than the high-expression group. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of the SERPINH1 co-expressed genes revealed that the gene was associated with the extracellular matrix and cell proliferation and migration. The analysis of SERPINH1 and the TMB revealed a superior survival advantage for patients with high TMB and high SERPINH1 expression, and worse survival for those with low TMB and high SERPINH1 expression. The analysis of the tumor microenvironment (TME) and immune infiltration revealed that the high and low expression of SERPINH1 was associated with different immune infiltration characteristics. The analysis of the immune checkpoints and anti-tumor drugs showed that immunotherapy and anti-neoplastic treatment were more efficacious in the high SERPINH1 expression group than the low SERPINH1 expression group. Conclusions: Using LUAD tissues and clinical samples, we showed that SERPINH1 can be used as a prognostic biomarker for LUAD. Our findings provide a new approach and strategy for the clinical treatment of LUAD patients.

miR-371b-5p-Engineered Exosomes Enhances Tumor Inhibitory Effect.

Background: Exosomes are well-known natural nanovesicles, that represent one of the recently discovered modes of intercellular communication due to their ability to transmit cellular components. Exosomes have been reported to have potential as natural vectors for carrying functional small RNAs and delivering chemotherapeutic agents to diseased cells. In this study, we aimed to investigate the role of exosomes in carrying miRNA for targeting tumor cells. Methods: We present a novel method for engineering exosomes with functional miR-317b-5b to target tumor cells. MiR-317b-5b exerts its anti-tumor function via its expression in tumors. RT-qPCR was performed to assess the levels of miR-371b-5p, FUT-4. Western blot was performed to measure the levels of CD9, CD81, and FUT-4 proteins. Confocal microscopy was used to observe the internalization of miR-317b-5b in tumor cells. CCK-8, EdU, flow cytometry, wound-healing migration and transwell assays were performed to evaluate cell viability, proliferation, migration, and invasion, respectively. Results: Our findings illustrated that miR-317b-5b-loaded engineered exosomes were internalized by tumor cells. MiR-317b-5b was overexpressed in tumor cells treated with miR-317b-5b-loaded engineered exosomes. The internalization of miR-317b-5b in tumor cells was accompanied by changes of cell viability, proliferation, apoptosis, and migratory and invasive capability. We found that miR-317b-5b-loaded engineered exosomes were presence in tumor tissue sections and miR-317b-5b was overexpressed in tumor tissues of osteosarcoma tumor-bearing mice infected with miR-317b-5b-loaded engineered exosomes. MiR-317b-5b-loaded engineered exosomes had the anti-tumor efficiency in vivo. Conclusion: Our findings show that miR-317b-5b-loaded engineered exosomes can be used as nanocarriers to deliver drug molecules such as miR-317b-5b both in vitro and in vivo to exert its anti-tumor functions.

A metabolism-related gene signature for predicting the prognosis and therapeutic responses in patients with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) often has an insidious onset and rapid progression. Often, when the disease is first diagnosed, the opportune time for surgical intervention has already lapsed. In addition, the effects of systemic treatment is relatively unsatisfactory. Metabolic reprogramming is one of the hallmarks of cancer. This study aimed to identify a set of genes related to metabolism to construct a predictive model for the prognosis of HCC. METHODS: The transcriptomic and clinical data of 352 HCC patients were obtained from The Cancer Genome Atlas (TCGA) Liver Hepatocellular Carcinoma (LIHC) dataset and divided into a training cohort (n=212) and a testing cohort (n=140) at a ratio of 6:4. Univariate Cox regression analysis and the LASSO Cox regression model were used to identify 5 genes to establish a risk score for predicting the prognosis of HCC patients. Subsequently, the molecular characteristics of the model were assessed and the ability of the model to predict the tumor immune microenvironment and patient response to immunotherapy and chemotherapy was also examined. RESULTS: The risk score model was constructed based on the five genes, methyltransferase-like protein 6 (METTL6), RNA polymerase III subunit G (POLR3G), phosphoribosyl pyrophosphate amidotransferase (PPAT), SET Domain Bifurcated 2 (SETDB2), and suppressor of variegation 3-9 homolog 2 (SUV39H2). The Kaplan-Meier survival analysis and time-dependent receiver operating characteristic (ROC) curves demonstrated that high-risk patients had a poorer overall survival (OS) compared to low-risk patients. he nomogram score had a better predictive ability compared to the common factors. Our results finally showed that high-risk cases were associated with cell proliferation and cell cycle related gene sets, high tumor protein P53 (TP53) mutation rate, suppressive immunity and increased sensitivity to cisplatin, gemcitabine and docetaxel. Meanwhile, low-risk cases were associated with cell cycle and immune response related pathways, low TP53 mutation rate, active immunity and more benefit from immunotherapy. CONCLUSIONS: This study provided novel insights into the role of metabolism-related genes in HCC, and demonstrated that our model could be a promising prognostic biomarker for distinguishing the molecular and immune characteristics and inferring the potential response to chemotherapy and immunotherapy.

Promoting Sustained and Exclusive Breastfeeding among Chinese American Pregnant Women.

This study investigated prenatal goal setting and breastfeeding attitudes and intentions for 210 Chinese American pregnant women. In addition, this study assessed impact of person-centered versus factual messages on breastfeeding attitudes and intentions. While pregnant women reported receiving information about Baby-Friendly designated hospitals from healthcare providers, most received no breastfeeding information from those same providers. Although women had positive attitudes toward breastfeeding, they showed lack of knowledge about colostrum, general approval for using infant formula, as well as early introduction of complementary foods. By extension, these attitudes suggested they misunderstood the meaning of exclusive breastfeeding. No differences were observed based on parity, trimester of pregnancy, level of education or income. Person-centered and factual messages were judged as equally effective messages, but intention to breastfeed was more affected by the factual message. Reasons for this result are discussed. Healthcare providers are positioned to proactively engage in maternal preparedness for exclusive breastfeeding. These results suggested a missed opportunity for healthcare providers to communicate the value of sustained exclusive breastfeeding for the recommended first 6 months of an infant's life and underscore a need for all antenatal healthcare providers to collaboratively ensure that breastfeeding information is comprehensively provided throughout the span of antenatal care.

MGMT expression affects the gemcitabine resistance of pancreatic cancer cells.

Pancreatic cancer is a malignant cancer with poor prognosis. This study aimed to explore how O6-methylguanine-DNA methyltransferase (MGMT) affects the gemcitabine resistance of pancreatic cancer cells by the regulatory role of SHH/GLI signaling pathway. MGMT inhibition induced by lomeguatrib (LM) suppressed the proliferation, invasion, migration and autophagy, promoted the apoptosis of PanC-1/GEM cells and up-regulated the GEM inhibition rates for PanC-1/GEM cells. Moreover, MGMT inhibition increased the expression of Caspase-3 and Bax and decreased the expression of Bcl-2, Beclin1 and Atg5 in PanC-1/GEM cells. PVT1 silencing could also produce the similar effects of MGMT inhibition induced by LM on PanC-1/GEM cells. And, PVT1 silencing could inhibit the SHH/GLI signaling pathway in PanC-1/GEM cells by regulating the MGMT expression. miR-409 was demonstrated to be a potential target of PVT1 and SHH was demonstrated to be a potential target of miR-409. Furthermore, GLI overexpression could reverse the effects of PVT1 silencing. In the xenograft model of pancreatic cancer, nude mice were treated with GEM. MGMT inhibition suppressed the tumor growth and autophagy and promoted the apoptosis in tumor tissues. And, PVT1 silencing could inhibit the SHH/GLI signaling pathway in tumor tissues. In conclusion, MGMT inhibition could suppress the proliferation, invasion, migration and autophagy and promote the apoptosis of PanC-1/GEM cells in vitro and in vivo. PVT1 silencing may affect the PanC-1/GEM cells through changing the MGMT expression by inhibiting the SHH/GLI signaling pathway.

Analysis of lncRNA-mRNA networks after MEK1/2 inhibition based on WGCNA in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) responds poorly to treatment. Efforts have been exerted to prolong the survival time of PDA, but the 5-year survival rates remain disappointing. Understanding the molecular mechanisms of PDA development is significant. MEK/ERK pathway signaling has been proven to be important in PDA. lncRNA-mRNA networks have become a vital part of molecular mechanisms in the MEK/ERK pathway. Herein, weighted gene coexpression network analysis was used to investigate the coexpressed lncRNA-mRNA networks in the MEK/ERK pathway based on GSE45765. Differently expressed long noncoding RNA (lncRNA) and messenger RNA (mRNA) were found and 10 modules were identified based on coexpression profiles. Gene ontology and Kyoto Encyclopedia of Genes and Genomes were then performed to analyze the coexpressed lncRNA and mRNA in different modules. PDA cells and tissues were used to validate the analysis results. Finally, we found that NONHSAT185150.1 and B4GALT6 were negatively correlated with MEK1/2. By analyzing GSE45765, the genome-wide profiles of lncRNA-mRNA network after MEK1/2 was established, which might aid the development of drug-targeting MEK1/2 and the investigation of diagnostic markers.

A bidirectional effect of Rac1 inhibition-Protects radiation-induced intestinal injury while inhibits tumor.

AIMS: To investigate whether Rac1 inhibition can alleviate radiation-induced intestinal injury (RIII), meanwhile exist no protection on tumors. MATERIALS AND METHODS: Rac1 inhibition was achieved by its specific inhibitor, NSC23766. Mice were pretreated with different intraperitoneal injections, which were normal saline for NS group (N = 9), and 2.5 mg/kg and 5 mg/kg of NSC23766 for Low-Dose group (N = 9) and High-Dose group (N = 9), respectively. After total body irritation (10Gy), small intestinal tissues were collected for Hematoxylin-Eosin (H&E) staining and Terminal-deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling (TUNEL). Intestinal epithelial and tumor cell lines, namely MODE-k and CT-26, were used to further study the role of Rac1 inhibition on radiation damage. Flow cytometry was used to detect changes in reactive oxygen species production, cell cycles and mitochondrial membrane potential, the latter was also checked by fluorescence microscope. Changes of protein-expression associated with apoptosis and cell cycles were detected by Western blotting to explain the possible molecular mechanism. KEY FINDINGS: Height of intestine villi and depth of crypt were higher (P < 0.01) and apoptosis ratio lower (P < 0.01) in High-Dose group compared with those in NS group. After radiation, Rac1 inhibition pre-treatment improved the vitality (P < 0.01) and reduced the apoptosis (P < 0.01) in MODE-k while yielded opposite results in CT-26, and reduced ROS production of MODE-k (P < 0.01) while had little effect on that of CT-26. Rac1 inhibition differently affected the cell cycles of normal cells and that of tumor cells. SIGNIFICANCE: Inhibition of Rac1 could alleviate RIII, meanwhile assist the killing effect of radiation on tumor cells.

The Impact of Generativity Awareness on Mid- to Old-Age Smokers in China.

Smoking remains a serious health threat to many mid- to old-age Chinese people. Many smoking interventions have been implemented in public areas, but smoking occurring in a private setting, such as at home, has largely been neglected. Generativity is based on evaluating the worth of one's life experience that can be passed on to others. This study evaluated whether generativity awareness can have an impact on smoking reduction. Five hundred and eight Chinese smokers were recruited and demonstrated their strong awareness of generativity, specifically general generativity (e.g., moral ethics), health-related generativity (e.g., living a healthy life), and smoke-free family generativity. The study showed support for a three-dimensional model for generativity, namely general, health, and smoke-free generativity. The three types of generativity varied in their effects on behavioral intention to reduce smoking and to encourage younger family members not to smoke. Family communication patterns also influenced behavioral intention to reduce smoking and to encourage younger family members not to smoke. Theoretical and practical implications are discussed.