Machine learning based peri-surgical risk calculator for abdominal related emergency general surgery: a multicenter retrospective study.

BACKGROUND: Currently, there is a lack of ideal risk prediction tools in the field of emergency general surgery (EGS). The American Association for the Surgery of Trauma recommends developing risk assessment tools specifically for EGS-related diseases. In this study, we sought to utilize machine learning (ML) algorithms to explore and develop a web-based calculator for predicting five perioperative risk events of eight common operations in EGS. METHOD: This study focused on patients with EGS and utilized electronic medical record systems to obtain data retrospectively from five centers in China. Five ML algorithms, including Random Forest (RF), Support Vector Machine, Naive Bayes, XGBoost, and Logistic Regression, were employed to construct predictive models for postoperative mortality, pneumonia, surgical site infection, thrombosis, and mechanical ventilation >48 h. The optimal models for each outcome event were determined based on metrics, including the value of the Area Under the Curve, F1 score, and sensitivity. A comparative analysis was conducted between the optimal models and Emergency Surgery Score (ESS), Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and American Society of Anesthesiologists (ASA) classification. A web-based calculator was developed to determine corresponding risk probabilities. RESULT: Based on 10,993 patients with EGS, we determined the optimal RF model. The RF model also exhibited strong predictive performance compared with the ESS, APACHE II score, and ASA classification. Using this optimal model, we developed an online calculator with a questionnaire-guided interactive interface, catering to both the preoperative and postoperative application scenarios. CONCLUSIONS: We successfully developed an ML-based calculator for predicting the risk of postoperative adverse events in patients with EGS. This calculator accurately predicted the occurrence risk of five outcome events, providing quantified risk probabilities for clinical diagnosis and treatment.

Isocitrate dehydrogenase 2 regulates the proliferation of triple-negative breast cancer through the ferroptosis pathway.

Triple-negative breast cancer (TNBC) is currently the type of breast cancer with the worst prognosis; it lacks specific treatments, such as ER/PR antagonistic endocrine and anti-HER2 targeted therapies. Although immunotherapy with immune checkpoints has shown some efficacy in many solid tumors, clinical data in TNBC suggest significant limitations. The essence of ferroptosis is the impaired metabolism of intracellular lipid oxides, which in turn causes the activation and abnormalities of the immune system, including ROS, and not only plays an important role in liver injury and organ aging but also a large amount of data points to the close correlation between the ferroptosis process and tumor development. In this study, through the analysis of large-throughput biological data of breast tumors, combined with the characteristics of the biological process of ferroptosis, the specific gene IDH2 was found to be significantly highly expressed in TNBC and functionally correlated with ferroptosis. Through clinical specimens validated at the gene and protein levels, in vitro tumor cell line validation, and in vivo mouse models, we found that the high expression of IDH2 in TNBC has a role in inhibiting the ferroptosis process in TNBC, thus promoting the proliferation of TNBC cells and other malignant features.

Methyltransferase-like 3-mediated m6A modification of miR-1908-5p contributes to nasopharyngeal carcinoma progression by targeting homeodomain-only protein homeobox.

BACKGROUND: N6-methyladenosine (m6A) modification interacting microRNAs (miRNAs) have been confirmed to participate in nasopharyngeal carcinoma (NPC) progression. This research investigated miR-1908-5p's function and regulatory mechanism in the tumorigenesis of NPC via m6A modification and targeting a key gene. METHODS: The levels of miR-1908-5p, homeodomain-only protein homeobox (HOPX), and methyltransferase-like 3 (METTL3) expressions were detected via RT-qPCR. The correlation between miR-1908-5p and the HOPX/METTL3 axis, as well as their regulatory mechanism, was investigated by dual luciferase reporter, western blotting, and MeRIP assays. Moreover, the bio-functions of miR-1908-5p, HOPX, and METTL3 in NPC were explored through CCK8, transwell, caspase-3 activity, and xenograft tumor assays. RESULTS: RT-qPCR results indicated a miR-1908-5p upregulation in NPC. Knocking down miR-1908-5p diminished the NPC cell viability and migration in vitro. In vivo, downregulating miR-1908-5p repressed NPC cell tumor growth. Moreover, HOPX was specifically targeted by miR-1908-5p, and HOPX downregulation led to reversal of the anti-tumor impact of the miR-1908-5p inhibitor against NPC cell malignancy. Also, METTL3 could mediate the m6A modification of miR-1908-5p to regulate its influence on NPC cells. CONCLUSION: This study demonstrated that the METTL3-mediated m6A modification of miR-1908-5p enhanced the tumorigenesis of NPC by targeting HOPX. These findings propose new insights for NPC diagnosis and therapy.

Effect of laparoscopic-assisted transvaginal hysterectomy on wound complications in patients with early stage cervical cancer: A meta-analysis.

Laparoscopic-assisted vaginal radical hysterectomy (LARVH) and abdominal radical hysterectomy (ARH) have been widely applied to treat cervical carcinoma. But LARVH and ARH have not been fully investigated in treating cervical carcinoma after injury associated with injury. This research is intended to provide an up-to-date basis for comparing LARVH with ARH in early stage cervical carcinoma. Comparison between LARVH and ARH in cervical carcinoma was carried out through a combination of related research. Eligible articles from databases such as PubMed and Embase were screened using an established search strategy. This report covered the results of LARVH versus ARH in cervical carcinoma. The average difference and the 95% confidence interval (CI) were used for the combination of consecutive variables. The combination of categorical variables was performed with the odds ratio (OR) 95% confidence interval. Through the identification of 1137 publications, eight of them were chosen to be analysed. Among them, 363 were treated with LARVH and 326 were treated with ARH. Eight trials showed that LARVH was associated with a reduced risk of postoperative wound infection than ARH (OR, 0.23; 95% CI, 0.1-0.55, p = 0.0009). Five trials showed that there was no difference in the risk of postoperative bleeding after surgery (OR, 1.17; 95% CI, 0.42-3.29, p = 0.76). We also did not differ significantly in the duration of the surgery (OR, 1.79; 95% CI, -6.58 to 10.15, p = 0.68). So, the two surgical methods differ significantly only in the risk of postoperative wound infection.

KIAA1429 Promotes Nasopharyngeal Carcinoma Progression by Mediating m6A Modification of PTGS2.

Emerging evidence suggests that dysregulation of a N6-methyladenosine (m6A) methyltransferase KIAA1429 participates in the pathogenesis of multiple cancers except for nasopharyngeal carcinoma (NPC). This study is aimed to explore the function of KIAA1429 in NPC progression. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to confirm the mRNA expression in NPC by bioinformatic analysis. The levels of KIAA1429 and PTGS2 was detected by quantitative reverse transcription polymerase chain reaction and Western blotting. To investigate the effects of KIAA1429/PTGS2 knockdown or overexpression vectors on NPC cell malignancy, cell and animal experiments were performed. Finally, MeRIP and mRNA stability assays were used to verify the m6A modification and mRNA stability, respectively. KIAA1429 was upregulated in NPC tissues and cells. After transfecting KIAA1429 knockdown or overexpression vectors in NPC cells, we proved that KIAA1429 overexpression promoted proliferation, migration, invasion, and tumor growth, whereas KIAA1429 knockdown showed the opposite effect. Our results also indicated that KIAA1429 mediated m6A modification of PTGS2, enhancing PTGS2 mRNA stability in NPC cells. In addition, PTGS2 could also regulate the effects of KIAA1429 on NPC cell malignancy. This study confirmed the oncogenic function of KIAA1429 in NPC through m6A-modification of PTGS2, suggesting that targeting KIAA1429-mediated m6A modification of PTGS2 might provide a new therapeutic strategy for NPC.

LncRNA BBOX1-AS1 Contributes to the Development of Nasopharyngeal Carcinoma via miR-204-5p/MUC4 Axis.

OBJECTIVE: Dysregulation of long non-coding RNAs (lncRNAs) is common in nasopharyngeal carcinoma (NPC) progression, and it is important to have an in-depth understanding of their functions in NPC. This study is the first to explore the role of the lncRNA BBOX1-AS1 in NPC development. METHODS: The expression of lncRNA BBOX1-AS1, MUC4, or miR-204-5p was measured in NPC cell lines or tissues via RT-qPCR and western blotting. Wound healing assays and CCK-8 were used to identify cell migration and cell viability, respectively. The protein expression of Bax and Bcl-2 was measured by western blotting. The tumorigenic effect of NPC cells in vivo was verified using xenograft tumors in nude mice. Luciferase reporter and RIP assays were conducted to clarify the association between miR-204-5p and lncRNA BBOX1-AS1 or MUC4. RESULTS: lncRNA BBOX1-AS1 upregulation was observed in NPC cells and tissues. Silencing lncRNA BBOX1-AS1 suppressed the migration and viability of C666-1 and TW03 cells while promoting cell apoptosis. Knockdown of the lncRNA BBOX1-AS1 repressed tumor growth in vivo. Moreover, the tumor suppression effect of silenced lncRNA BBOX1-AS1 might be reversed with the help of the miR-204-5p inhibitor. lncRNA BBOX1-AS1 targets miR-204-5p and regulates MUC4 expression in NPC. MUC4 is a miR-204-5p target and exerts a function similar to that of lncRNA BBOX1-AS1. CONCLUSION: These observations highlight that lncRNA BBOX1-AS1 is an essential NPC progression promoter and suggest that the lncRNA BBOX1-AS1/miR-204-5p/MUC4 axis is a potential therapeutic target in NPC.

Ru(II) Complex Grafted Ti3C2Tx MXene Nano Sheet with Photothermal/Photodynamic Synergistic Antibacterial Activity.

For a long time, the emergence of microbial drug resistance due to the abuse of antibiotics has greatly reduced the therapeutic effect of many existing antibiotics. This makes the development of new antimicrobial materials urgent. Light-assisted antimicrobial therapy is an alternative to antibiotic therapy due to its high antimicrobial efficiency and non-resistance. Here, we develop a nanocomposite material (Ru@MXene) which is based on Ru(bpy)(dcb)2+ connected to MXene nanosheets by ester bonding as a photothermal/photodynamic synergistic antibacterial material. The obtained Ru@MXene nanocomposites exhibit a strengthened antimicrobial capacity compared to Ru or MXene alone, which can be attributed to the higher reactive oxygen species (ROS) yield and the thermal effect. Once exposed to a xenon lamp, Ru@MXene promptly achieved almost 100% bactericidal activity against Escherichia coli (200 µg/mL) and Staphylococcus aureus (100 µg/mL). This is ascribed to its synergistic photothermal therapy (PTT) and photodynamic therapy (PDT) capabilities. Consequently, the innovative Ru@MXene can be a prospective non-drug antimicrobial therapy that avoids antibiotic resistance in practice. Notably, this high-efficiency PTT/PDT synergistic antimicrobial material by bonding Ru complexes to MXene is the first such reported model. However, the toxic effects of Ru@MXene materials need to be studied to evaluate them for further medical applications.

Influence of exposure history on the particle retention capacity and physiological responses of Euonymus japonicus Thunb. var. aurea-marginatus Hort.

Green plants in urban environments experience cyclical particulate matter stress. And this history of exhaust exposure may generate stress memory in plants, which may alter their subsequent response. Studies combining urban pollution characteristics and stress memory are limited. Therefore, we selected E. japonicus var. aurea-marginatus, a common urban greening tree species in the Yangtze River Delta, and conducted an experiment in three periods: the initial pollution period (S1: 28 days), the recovery period (R: 14 days) and the secondary pollution period (S2: 28 days). The experimental design consisted of an elevated pollution treatment (173 µg•cm-3) and an ambient control (34 µg•cm-3) with three replicates. In S2, the net total particle retention and saturated particle retention decreased by 11.5% and 19.3%, respectively, while PM10 and PM2.5 did not change significantly. E. japonicus var. aurea-marginatus exhibited recovery of chlorophyll levels, slower degradation of carotenoid, faster accumulation of ASA, lower accumulation of MDA, reduced activity of SOD under the second pollution period, and the period had a significant effect on the physiological indicators. Collectively, the effect of autoexhaust exposure history on the particle retention capacity of selected plant varied across particle sizes, and stress memory may confer plant resistance to recurrent exhaust pollution via combined regulations of physiological responses. Fine particles which pose a great risk to human health arise predominantly from vehicular traffic and energy production. So, E. japonicus tends to play a stabilising role in particle retention in industrial, traffic and residential areas.

Season impacts on estimating plant's particulate retention: Field experiments and meta-analysis.

Plants can effectively remove atmospheric particles, which contribute to air pollution. However, few studies have focused on seasonal variability of plant dust retention, an essential factor to estimate annual dust removal from the atmosphere. This study conducted a field experiment to explore the seasonal variability of particulate retention on evergreen leaved urban greening shrub plants. We performed a meta-analysis to synthesize the available literature on the subject to discuss our findings further. Results showed that particulate matter deposited on leaf surfaces (sPM) in autumn and winter was significantly higher than in spring and summer. In comparison, the particulate matter trapped in epicuticular waxes (wPM) in summer was significantly higher than in the other three seasons. The seasonal differences also existed in both sPM and wPM among particle sizes. The total dust retention of Rhododendron × pulchrum Sweet, Osmanthus fragrans Lour, and Photinia × fraseri Dress were estimated as 360.89 t, 586.66 t, and 448.84 t per year, respectively. They were significantly different from model estimates if only one season was chosen as an estimator. Furthermore, the meta-analysis revealed significant differences among seasons, particle sizes, and different leaf habits (evergreen or deciduous). In contrast, no significant differences were observed between life forms or between growth forms. Our findings both from field experiment and met-analysis highlights that seasonal variation can significantly affect the dust retention capacity of plants, which should be taken into account into particle matter retention capacity evaluations.

Dynamics of particle retention and physiology in Euonymus japonicus Thunb. var. aurea-marginatus Hort. with severe exhaust exposure under continuous drought.

Frequent drought events and particulate matter pollution from vehicular exhaust seriously affect urban plant growth and provisioning of ecological services. Yet, how plants respond physiologically and morphologically to these two combined stressors remains unknown. Here, we assessed particle retention dynamics and plant morphology and physiology of Euonymus japonicus Thunb. var. aurea-marginatus Hort. under continuous drought with severe exhaust exposure. Our results showed that continuous drought insignificantly lowered particle retention in each of three size fractions by 1.02 µg·cm-2 on average in the first 28 days, but significantly lowered total particle retention by 35.75 µg·cm-2 on the 35th day. We observed evident changes in morphology, leaf mass per area (LMA), pigments, gas exchange in all stressed plants. Compared with single stress, combined drought and pollution caused earlier yellowing and shedding of old leaves, significantly lowered LMA by 1.21 mg·cm-2, caused a greater decline in pigments and net photosynthetic rate (Pn). Large particles may mainly explain pigment reduction, lower weekly LMA increases, and stomatal restriction, while coarse particles may be the main drivers of the decline in Pn. Continuous drought mediated the influence of all three particle sizes on some parameters, such as weakening the impact of total particles on LMA, strengthening the impact of fine particles on photosynthesis. Our findings suggest that drought accelerates the physiological responses of plants to exhaust pollution. Under controlled severe exhaust pollution conditions, the optimal time to maintain high particle retention during continuous drought without decline in physiological conditions for E. japonicus var. aurea-marginatus was 14 days. Some additional interventions after 14 days (it could be postponed appropriately under field conditions) may help ensure healthy growth of plants and retention of particulate matter.

The legacy effects of PM2.5 depositon on Nerium Oleander L.

Green plants have the capability to retain atmospheric particulate matter (PM) on their leaves, which can effectively reduce PM pollution, especially in the urban settings. Some studies reported that the periodic PM pollution could change plant retaining PM capacity, which, indeed, was the reason of physiological responses. In advancing the previous studies, we selected Nerium oleander L. to measure PM retention on leaf surface in a controlled environment by the following periods: initial pollution period (S1), recovery period (R), and secondary pollution period (S2) for a total of 12 weeks. The experimental design was one elevated pollution treatment (166 µg m-3) and one ambient control (28 µg m-3) with three replications. Results showed that during S2, the total retention decreased by 8.87 µg cm-2, which was about 10.4% significant lower than in S1. During the third week, the ascorbic acid content (ASA) in S1 was 6.71 mg g-1 significantly lower than that in S2 in the treatment. The total chlorophyll (Chl T) of the treatment decreased continuously and significantly by 33.8% in S1, but showed no similar trend in S2. The net photosynthetic rate of the treatment was significantly lower than that of the control, and the plants in the treatment showed a consistently high dark respiration rate than that in the control. The correlations between PM retention and ASA, Chl T and RWC were weaker in S1 than that in S2. In addition, air pollution tolerance index (APTI) showed a significant decline in plant pollution tolerance in the treatment during the third week.

Effect of low-dose aspirin on mortality and viral duration of the hospitalized adults with COVID-19.

ABSTRACT: To clarify the effect of aspirin on mortality and viral duration in adults infected with respiratory syndrome coronavirus 2 (SARS-Cov-2).After propensity score-matched (PSM) case-control analyses 24 pairs of patients were enrolled and followed up for 2 months. Both 30-day and 60-day mortality in the aspirin group were significantly lower than that in the non-aspirin group (P = .021 and P = .030, respectively). The viral duration time between the 2 groups was not significantly different (P = .942).Among adults (with hypertension, cardiovascular diseases) infected with SARS-Cov-2, low-dose aspirin medication (100 mg/day) was associated with lower risk of mortality compared with non-aspirin users.

COVID-19 in two infants in China.

INTRODUCTION: Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly around the world and caused more than 487 000 infections and 22 000 deaths worldwide. METHODS: We report two infant cases with coronavirus disease 2019 (COVID-19) in Yichang, Hubei, China. The younger of the two is only 5-months old. We recorded their clinical manifestations, epidemiological history, laboratory examination, and treatment in detail. In addition, we provide computed tomographic images of their chest, which are the most serious imaging manifestation among the infants recorded so far. RESULTS: Although both of them eventually recovered and were discharged from the hospital, they were complicated with varying degrees of liver and myocardial injury. In addition, one of them was complicated with mycoplasma pneumoniae infection. CONCLUSIONS: Pediatricians should consider the potential risks of developing severe illness of infants infected by SARS-CoV-2 and take them seriously.

Intramuscular versus intravenous oxytocin for the third stage of labor after vaginal delivery to prevent postpartum hemorrhage: a meta-analysis of randomized controlled trials.

INTRODUCTION: To examine the effects and safety of oxytocin administered intramuscularly or intravenously for preventing postpartum hemorrhage (PPH) in the third stage of labor after vaginal deliveries. MATERIAL AND METHODS: Before data extraction, the review was registered with the PROSPERO International Prospective Register of Systematic Reviews (registration No. CRD42019145912). We searched the published electronic databases, including Medline, EMBASE, PubMed, Web of Science, CNKI, VIP, Wanfang, the Cochrane Library, clinicaltrial.gov and PROSPERO database, from their inception until February 2019. We included all randomized controlled trials (RCTs) comparing intramuscular and intravenous oxytocin administered just after the birth of the anterior shoulder or soon after the birth of the baby during a vaginal delivery. The primary outcomes were the incidence of PPH and severe PPH. PPH was defined as a blood loss ≥500 ml within 24 hours after vaginal birth. Severe PPH refers to a clinically estimated blood loss equal to or greater than 1000 mL within 24 hours after vaginal birth. Statistical heterogeneity was assessed by the I2 test, the Cochran Q statistic and the Galbraith plot for heterogeneity. RESULTS: Six RCTs, including 7320 women undergoing vaginal delivery, were identified in the meta-analysis. Women who were randomized to have intravenous oxytocin for the third stage of labor had a significantly lower incidence of PPH (relative risk 1.35, 95% CI 1.11-1.64, p = 0.003), severe PPH (relative risk 1.61, 95% CI 1.05-2.46, p = 0.03) and blood transfusion (relative risk 2.50, 95% CI 1.37-4.59, p = 0.003) compared with those who were randomized to have intramuscular oxytocin during the third stage of labor after vaginal delivery. There was no significant difference with regard to changes in hemoglobin level, third stage of labor duration, mean postpartum blood loss, or the incidences of a need for additional uterotonics and of retained placenta or manual removal of placenta between groups. CONCLUSIONS: For women in the third stage of labor who are undergoing a vaginal delivery, the use of intravenous oxytocin reduces the incidence of PPH, severe PPH and blood transfusion and does not increase the risk of adverse effects compared with intramuscular oxytocin.

[Prokaryotic expression and purification of mouse recombinant myelin proteolipid protein polypeptide].

Objective To establish and optimize the prokaryotic expression method for the recombinant mouse myelin proteolipid protein (PLP, 139-208 aa) which is a critical immunogenic polypeptide of PLP. Methods The sequence coding for PLP139-208 polypeptide was cloned into pET-32a(+) vector. Afterwards, the expression vector prepared in this research was transformed into E. coli BL21, and the recombinant PLP polypeptide was induced to express by isopropyl-ß-D-thiogalactoside (IPTG). Two key prokaryotic expression conditions, IPTG's induction length and temperature, were analyzed for further optimization. The recombinant PLP polypeptide was induced to express by the expression method under the optimal expression conditions, and then was purified by Ni-NTA agarose and amylose resin. Finally, the gain of PLP139-208 polypeptide was verified by Western blot analysis. Results The results in the combinatorial optimization revealed that the expression of PLP139-208 was obtained at a satisfactory level when it was incubated at 23DegreesCelsius for 20 hours with the IPTG concentration of 0.5 mmol/L. Conclusion The optimized prokaryotic expression method for the recombinant mouse PLP139-208 was successfully established and effectively performed. This will shed light on the further researches on the improved preparation for experimental autoimmune encephalitis (EAE, an animal model of multiple sclerosis) and the underlying mechanism underlying PLP-induced autoimmune demyelination.

Mfn2 inhibits proliferation and cell-cycle in Hela cells via Ras-NF-κB signal pathway.

BACKGROUND: Mitofusin 2 (Mfn2) is outer membrane protein, as the inhibitor of Ras protein. This study aimed to investigate the effect of Mfn2 on cell proliferation, and cell-cycle in Hela cervical carcinoma cell lines. METHODS: After treated with Adv-mfn2 or Adv-control for 48 h and 60 h, the RNA and protein of Mfn2 in Hela cells were detected by qRT-PCR and western blot. The immunofluorescence assay was performed to observe the expression and sub-location of Mfn2 in Hela cells. The flow cytometry was performed to detect the cell cycle of Hela cells, while western blots were performed to observe the Ras-NF-κB signal pathway. Then, the xenografted cervix carcinoma mouse model was used to confirm the effect of Mfn2 in Hela cells in vivo and the expression of Ras-NF-κB signaling pathway in vivo. RESULTS: In immunofluorescence detection, Mfn2 was located in cytoplasmic, not in the nucleus. In addition, Mfn2 inhibited cell proliferation of Hela cells through reducing PCNA protein expression. Mfn2 induced arrest in G0/G1 phase of the cell cycle in Hela cells. Meanwhile, Mfn2 reduced Cyclin D1 protein expression. Moreover, Mfn2 decreased the Ras signal pathway proteins such as Myc, NF-κB p65, STAT3 in a dose-dependent manner. Then, the in vivo experiment also confirmed that Mfn2 could inhibit the tumor growth, and depress the Cyclin D1, Ras, Myc, NF-κB p65, Erk1/2 and mTOR protein expression. CONCLUSIONS: Mfn2 could significantly inhibit cell proliferation in Hela cells. It might be acted as an potential anti-cancer target through inducing cell cycle arrest in human cervical carcinoma cells.

Comparison of TACE combined with and without iodine-125 seeds implantation therapy for advanced stage hepatocellular carcinoma: a systematic review and meta-analysis.

PURPOSE: Hepatocellular carcinoma (HCC) has the second-highest cancer-related mortality in patients worldwide. Recently, TACE plus Iodine-125 (125I) seed strand endovascular implantation (ISEI) was shown to be feasible in advanced HCC patients. The aim of this study was to evaluate the efficacy and safety of this combined therapy for the treatment of advanced stage HCC by meta-analysis. METHODS: A systematic search in PubMed, EMBASE and Cochrane Library Databases was conducted until April 1st 2018. Outcomes included overall survival (OS), objective response rate (ORR) of primary liver tumor, and procedure-related complications. All statistical analyses were performed using Review Manager 5.3 and Stata 12.0. RESULTS: Nine eligible studies on 1059 advanced HCC patients were included. The results showed that TACE plus ISEI had significantly improved the 6-month OS (OR, 5.01: 95%CI, 3.19~7.86: P<0. 01) and 1-year OS (OR, 4.97: 95%CI, 3.12~7.92: P<0.01) compared to TACE alone. CONCLUSION: The safety and efficacy of TACE plus ISEI is superior to TACE alone for advanced HCC.

TGF-ß1 and TNF-α synergistically induce epithelial to mesenchymal transition of breast cancer cells by enhancing TAK1 activation.

TGF-ß1 is a main inducer of epithelial to mesenchymal transition (EMT). However, many breast cancer cells are not sensitive to the EMT induction by TGF-ß1 alone. So far, the mechanisms underlying the induction of TGF-ß1-insensitive breast cancer cells remains unclear. Here we report that TNF-α can induce EMT and invasiveness of breast cancer cells which are insensitive to TGF-ß1. Intriguingly, TGF-ß1 could cooperate with TNF-α to promote the EMT and invasiveness of breast cancer cells. The prolonged co-stimulation with TGF-ß1 and TNF-α could enhance the sustained activation of Smad2/3, p38 MAPK, ERK, JNK and NF-κB pathways by enhancing the activation of TAK1, which was mediated by the gradually up-regulated TßRs. Except for JNK, all of these pathways were required for the effects of TGF-ß1 and TNF-α. Importantly, the activation of p38 MAPK and ERK pathways resulted in a positive feed-back effect on TAK1 activation by up-regulating the expression of TßRs, favoring the activation of multiple signaling pathways. Moreover, SLUG was up-regulated and required for the TGF-ß1/TNF-α-induced EMT and invasiveness. In addition, SLUG could also enhance the activation of signaling pathways by promoting TßRII expression. These findings suggest that the up-regulation of TßRs contributes to the sustained activation of TAK1 induced by TGF-ß1/TNF-α and the following activation of multiple signaling pathways, resulting in EMT and invasiveness of breast cancer cells.

Transdifferentiation of type II alveolar epithelial cells induces reactivation of dormant tumor cells by enhancing TGF-ß1/SNAI2 signaling.

Dormant tumor cells (DTCs) serve a crucial role in the pathogenesis of metastasis and may compromise the efficacy of existing therapeutic modalities aimed at fully eradicating cancer. However, the mechanisms underlying the dormant-to-proliferating switch of DTCs remain largely unknown. The lung is one of the most common sites of metastatic recurrence. The transdifferentiation of alveolar epithelial cells II (AEC IIs) to AEC Is is a hallmark of alveolar epithelial stimulation. However, the role of AEC II transdifferentiation during the reactivation of DTCs has not been fully elucidated. In the present study, we found that tumor cells promoted the transdifferentiation of AEC IIs. Furthermore, the supernatant of the transdifferentiation of AEC IIs to AEC Is (Super-TDA) promoted the dormant-to-proliferating switch of DTCs via the autocrine effect of TGF-ß1 on the 3D BME culture system in vitro. Monensin and LY2109761 blocked the dormant-to-proliferating switch of DTCs induced by Super-TDA. Although lipopolysaccharide did not directly stimulate the reactivation of DTCs, it promoted DTC reactivation by increasing the secretion of TGF-ß1 in the Super-TDA. We further demonstrated that the upregulation of SNAI2 expression was required for Super-TDA facilitating the DTC dormant-to­proliferating switch. Taken together, our findings demonstrated that tumor cells may promote AEC II transdifferentiation. Furthermore, the transdifferentiation of AEC IIs may, in turn, induce the reactivation of 3D-established DTCs by promoting TGF-ß1/SNAI2 signaling. Targeting this process may provide novel therapeutic strategies for the inhibition of the dormant­to-proliferating switch.

Antivirals for Respiratory Viral Infections: Problems and Prospects.

In the past two decades, several newly emerging and reemerging viral respiratory pathogens including several influenza viruses (avian influenza and pandemic influenza), severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV), have continued to challenge medical and public health systems. Thereafter, the development of cost-effective, broad-spectrum antiviral agents is the urgent mission of both virologists and pharmacologists. Current antiviral developments have focused targets on viral entry, replication, release, and intercellular pathways essential for viral life cycle. Here, we review the current literature on challenges and prospects in the development of these antivirals.