Neoadjuvant PD-(L)1 blockade plus platinum-based chemotherapy for potentially resectable oncogene-positive non-small cell lung cancer.

BACKGROUND: Whether programmed cell death-1/ligand-1 (PD-1/PD-L1) blockade-based neoadjuvant treatment may benefit locally advanced oncogene-mutant non-small cell lung cancer (NSCLC) patients remains controversial. This retrospective study was designed to observe the efficacy and safety of neoadjuvant PD-1/PD-L1 blockade plus chemotherapy versus chemotherapy and corresponding tyrosine kinase inhibitors (TKIs) in patients with resectable oncogene-positive NSCLC. METHODS: Patients with potential resectable NSCLC harbouring oncogene alterations who had received neoadjuvant treatment were retrospectively recruited, and an oncogene-negative cohort of patients who received neoadjuvant PD-(L)1 blockade-based neoadjuvant treatment was reviewed for comparison during the same period. The primary aim was to observe the treatment efficacy and event-free survival (EFS) of these agents. Safety profile, molecular target, and immunologic factor data, including PD-L1 expression and tumour mutational burden (TMB), were also obtained. RESULTS: A total of 46 patients were recruited. Thirty-one of them harboured oncogene alterations, including EGFR, KRAS, ERBB2, ROS1, MET, RET, ALK, and FGFR3 alterations. Among the oncogene-positive patients, 18 patients received neoadjuvant PD-(L)1 blockade immunotherapy plus chemotherapy (oncogene-positive IO group), 13 patients were treated with neoadjuvant chemotherapy and/or corresponding TKIs or TKIs alone (oncogene-positive chemo/TKIs group), and the other 15 patients were oncogene negative and received neoadjuvant PD-(L)1 blockade plus chemotherapy (oncogene-negative IO group). The pathological complete response (pCR) and major pathological response (MPR) rates were 22.2% (4 of 18) and 44.4% (8 of 18) in the oncogene-positive IO group, 0% (P = 0.120) and 23.1% (3 of 13) (P = 0.276) in the oncogene-positive chemo/TKIs group, and 46.7% (7 of 15) (P = 0.163) and 80.0% (12 of 15) (P = 0.072) in the oncogene-negative IO group, respectively. By the last follow-up, the median EFS time had not reached in the oncogene-positive IO group, and was 29.5 months in the oncogene-positive chemo/TKIs group and 38.4 months in the oncogene-negative IO group. CONCLUSION: Compared with chemotherapy/TKIs treatment, neoadjuvant treatment with PD-(L)1 blockade plus platinum-based chemotherapy was associated with higher pCR/MPR rates in patients with partially resectable oncogene-mutant NSCLC, while the pCR/MPR rates were lower than their oncogene-negative counterparts treated with PD-(L)1 blockade-based treatment. Specifically, oncogene alteration types and other predictors of response to immunotherapy should be taken into account in clinical practice.

Manganese-induced Photothermal-Ferroptosis for synergistic tumor therapy.

Ferroptosis-related tumor therapy based on nanomedicines has recently gained significant attention. However, the therapeutic performance is still hindered by the tumor's physical barriers such as the fibrotic tumor matrix and elevated interstitial fluid pressure, as well as chemical barriers like glutathione (GSH) overabundance. These physicochemical barriers impede the bioavailability of nanomedicines and compromise the therapeutic efficacy of lipid reactive oxygen species (ROS). Thus, this study pioneers a manganese-mediated overcoming of physicochemical barriers in the tumor microenvironment using organosilica-based nanomedicine (MMONs), which bolsters the synergy of photothermal-ferroptosis treatment. The MMONs display commendable proficiency in overcoming tumor physical barriers, due to their MnO2-mediated shape-morphing and softness-transformation ability, which facilitates augmented cellular internalization, enhanced tumor accumulation, and superior drug penetration. Also, the MMONs possess excellent capability in chemical barrier overcoming, including MnO2-mediated dual GSH clearance and enhanced ROS generation, which facilitates ferroptosis and heat shock protein inhibition. Notably, the resulting integration of physical and chemical barrier overcoming leads to amplified photothermal-ferroptosis synergistic tumor therapy both in vitro and in vivo. Accordingly, the comparative proteomic analysis has identified promoted ferroptosis with a transient inhibitory response observed in the mitochondria. This research aims to improve treatment strategies to better fight the complex defenses of tumors.

Octamer-binding transcription factor 4-positive circulating tumor cell predicts worse treatment response and survival in advanced cholangiocarcinoma patients who receive immune checkpoint inhibitors treatment.

BACKGROUND: Octamer-binding transcription factor 4-positive circulating tumor cell (OCT4+CTC) exhibits high stemness and invasive potential, which may influence the efficacy of immune checkpoint inhibitors (ICI). This study aimed to assess the prognostic role of OCT4+CTC in advanced cholangiocarcinoma (CCA) patients who received ICI treatment. METHODS: In total, 40 advanced CCA patients who received ICI treatment were included, and CTC and OCT4 counts were detected via a Canpatrol system and an RNA in situ hybridization method before ICI treatment. Patients were subsequently divided into none CTC, OCT4-CTC, and OCT4+CTC groups. Patients were followed up for a median of 10.4 months. RESULTS: The percentages of patients in none CTC, OCT4-CTC, and OCT4+CTC groups were 25.0%, 30.0%, and 45.0%, respectively. The proportion of patients with lymph node metastasis was highest in OCT4+CTC group, followed by none CTC group, and lowest in OCT4-CTC group (P = 0.025). The objective response rate (ORR) was lowest in OCT4+CTC group, moderate in OCT4-CTC group, and highest in none CTC group (P = 0.009), while disease control rate was not different among three groups (P = 0.293). In addition, progression-free survival (PFS) (P < 0.001) and overall survival (OS) (P = 0.001) were shorter in the OCT4+CTC group than in none CTC & OCT4-CTC group. Moreover, OCT4+CTC (versus none CTC) was independently linked with poorer PFS [hazard ratio (HR) = 6.752, P = 0.001] and OS (HR = 6.674, P = 0.003) in advanced CCA patients. CONCLUSION: OCT4+CTC relates to lymph node metastasis and shows a good predictive value for poor treatment response and survival in advanced CCA patients who receive ICI treatment.

Predicting short-term major postoperative complications in intestinal resection for Crohn's disease: A machine learning-based study.

BACKGROUND: Due to the complexity and numerous comorbidities associated with Crohn's disease (CD), the incidence of postoperative complications is high, significantly impacting the recovery and prognosis of patients. Consequently, additional studies are required to precisely predict short-term major complications following intestinal resection (IR), aiding surgical decision-making and optimizing patient care. AIM: To construct novel models based on machine learning (ML) to predict short-term major postoperative complications in patients with CD following IR. METHODS: A retrospective analysis was performed on clinical data derived from a patient cohort that underwent IR for CD from January 2017 to December 2022. The study participants were randomly allocated to either a training cohort or a validation cohort. The logistic regression and random forest (RF) were applied to construct models in the training cohort, with model discrimination evaluated using the area under the curves (AUC). The validation cohort assessed the performance of the constructed models. RESULTS: Out of the 259 patients encompassed in the study, 5.0% encountered major postoperative complications (Clavien-Dindo ≥ III) within 30 d following IR for CD. The AUC for the logistic model was 0.916, significantly lower than the AUC of 0.965 for the RF model. The logistic model incorporated a preoperative CD activity index (CDAI) of ≥ 220, a diminished preoperative serum albumin level, conversion to laparotomy surgery, and an extended operation time. A nomogram for the logistic model was plotted. Except for the surgical approach, the other three variables ranked among the top four important variables in the novel ML model. CONCLUSION: Both the nomogram and RF exhibited good performance in predicting short-term major postoperative complications in patients with CD, with the RF model showing more superiority. A preoperative CDAI of ≥ 220, a diminished preoperative serum albumin level, and an extended operation time might be the most crucial variables. The findings of this study can assist clinicians in identifying patients at a higher risk for complications and offering personalized perioperative management to enhance patient outcomes.

Beneficial Effects of Low-Dose Intravenous Dexmedetomidine Premedication in Patient Undergoing Laparoscopic Cholecystectomy Under General Anesthesia: A Prospective, Double-Blind, Randomized Controlled Trial.

Purpose: Dexmedetomidine (Dex) is a potent and highly selective α2-adrenergic receptor agonist. Within an appropriate dose range, Dex can effectively attenuate the surgical stress response, provide intraoperative hemodynamic stability, and improve the patient recovery quality. High-dose Dex can delay patient awakening from anesthesia and increase the incidence of bradycardia. This randomized controlled trial aimed to investigate the effects of low-dose intravenous Dex premedication in patients undergoing laparoscopic cholecystectomy (LC). Material and Methods: In total, 100 patients undergoing LC were equally randomized into Group C (premedication with saline) and Group D (premedication with 0.5 µg/kg Dex). The patients were premedicated with saline or Dex, depending on the group, before anesthesia induction. Following this, anesthesia induction and endotracheal intubation was performed, and anesthesia was maintained during surgery. Following the completion of the surgery, the patients were transferred the post-anesthesia care unit (PACU) and stayed there until they met the PACU discharge criteria. The hemodynamic parameters, consumption of anesthetics, surgical duration, postoperative awakening time, extubation time, postoperative pain, and complications were recorded. Results: No significant differences were observed in the heart rate (HR) and mean arterial pressure (MAP) between the two groups before premedication (P>0.05). The MAP and HR immediately after endotracheal intubation and immediately after extubation were significantly lower in Group D than in Group C (P<0.05 for both). The incidence of bradycardia was significantly higher in Group D than in Group C (P<0.05), while atropine was used in neither group. Propofol and remifentanil consumption was significantly lower in Group D than in Group C (P<0.05). The postoperative awakening and extubation times were significantly shorter in Group D than in Group C (P<0.05). The postoperative visual analog scale scores for pain and incidence of nausea, vomiting, and cough were significantly lower in Group D than in Group C (P<0.05 for all). Conclusion: Our data suggest that premedication with dexmedetomidine (0.5 µg/kg) before general anesthesia induction can effectively attenuate intraoperative stress response and postoperative pain, maintain perioperative hemodynamic stability, and decrease the incidence of adverse events, which might be an effective and safe anesthetic protocol during LC worthy of further clinical application.

ACT001 alleviates inflammation and pyroptosis through the PPAR-γ/NF-κB signaling pathway in LPS-induced alveolar macrophages.

BACKGROUND: ACT001 is an anti-inflammatory agent that has been widely investigated for its role in tumors, intracranial diseases, and fibrotic diseases, but its effect on acute lung injury is less known. OBJECTIVE: The purpose of this study was to investigate the effect and mechanism of ACT001 on regulating inflammation and pyroptosis in lipopolysaccharide (LPS)-induced alveolar macrophages. METHODS: NR8383 alveolar macrophages treated with LPS were used to replicate the proinflammatory macrophage phenotype observed during acute lung injury. After ACT001 treatment, we measured the secretion and expression levels of critical inflammatory cytokines, the rate of pyroptosis, and the expression of NLRP3 inflammasome-associated proteins and pyroptosis-associated proteins. In addition, we assessed the role of the PPAR-γ/NF-κB signaling pathways and further validated the results with a PPAR-γ inhibitor. RESULTS: Our findings confirmed that ACT001 reduced the expression and release of inflammatory factors, attenuated cell pyroptosis, and downregulated the expression of NLRP3, ASC, caspase-1 p20, and GSDMD-N. These effects may be achieved by activating PPAR-γ expression and then inhibiting the NF-κB signaling pathway. When macrophages were treated with the PPAR-γ inhibitor, the protective effects of ACT001 were reversed. CONCLUSION: ACT001 significantly ameliorated inflammation and pyroptosis via the PPAR-γ/NF-κB signaling pathways in LPS-induced NR8383 alveolar macrophages.

DARS2 promotes the occurrence of lung adenocarcinoma via the ERK/c-Myc signaling pathway.

BACKGROUND: DARS2 expression is upregulated in lung adenocarcinoma (LUAD) which correlates with tumor patient stage and prognosis. The mechanism of DARS2 involvement in LUAD still needs to be further explored. METHODS: In this study, we found that DARS2 expression in LUAD tissue was significantly higher than that in normal tissue. At the same time, the Kaplan-Meier curve showed that the survival prognosis of LUAD patients with high expression of DARS2 was significantly worse than low expression of DARS2. The expression of DARS2 was detected in LUAD and adjacent normal tissues by IHC staining, histochemical scoring and a survival curve was generated. In addition, we demonstrated that the knockdown and overexpression of DARS2 significantly affected the proliferation, invasion, and migration of LUAD cells in vitro and in vivo. Finally, western blot and rescue assay were performed on LUAD cells to further explore and verify the signaling pathway. RESULTS: DARS2 expression was significantly upregulated in LUAD tissues and cell lines. What is more, the increased expression of DARS2 was closely related to proliferation, invasion and metastasis. The tumorigenic assay in nude mice further showed that the tumorigenic ability of nude mice was significantly improved with the increase in DARS2 expression. Finally, we determined that DARS2 plays its role in LUAD by targeting the ERK/c-Myc signaling pathway. CONCLUSION: Our data revealed the oncogenic role of DARS2 in LUAD, indicating that DARS2 may be a predictive biomarker and novel therapeutic target for LUAD.

Magnetic induction heating and drug release properties of magnetic carbon nanotubes.

AIM: The use of magnetic carbon nanotubes for multi-modal cancer treatment, incorporating both hyperthermia and drug delivery functions, has drawn substantial interest. Yet, the present method of regulating hyperthermia temperature involves manually adjusting the magnetic field intensity, adding to the complexity and difficulty of clinical applications. This study seeks to design novel magnetic carbon nanotubes capable of self-temperature regulation, and investigate their drug loading and release characteristics. METHODS: Using the co-precipitation method, we synthesized magnetic carbon nanotubes with a Curie temperature of 43 °C. A comprehensive investigation was conducted to analyze their morphology, crystal structure, and magnetic characteristics. To enhance their functionality, chitosan and sodium alginate modifications were introduced, enabling the loading of the antitumor drug doxorubicin hydrochloride (DOX) into these magnetic carbon nanotubes. Subsequently, the loading and release properties of DOX were investigated within the modified magnetic nanotubes. RESULTS: Under alternating magnetic field, magnetic carbon nanotubes exhibit self-regulating properties by undergoing a magnetic phase transition, maintaining temperatures around 43 °C as required for hyperthermia. On the other hand, during magnetic induction heating, the release percentage of DOX reached 23.5% within 2 h and 71.7% within 70 h at tumor pH conditions, indicating their potential for sustained drug release. CONCLUSIONS: The prepared magnetic carbon nanotubes can effectively regulate the temperature during hyperthermia treatment while ensuring controlled drug release, which presents a promising method for preparing nanomaterials that synergistically enhance magnetic hyperthermia and chemotherapy drugs.

The Associations between Organophosphate Pesticides (OPs) and Respiratory Disease, Diabetes Mellitus, and Cardiovascular Disease: A Review and Meta-Analysis of Observational Studies.

Although some epidemiological studies have identified the associations between exposure to organophosphate pesticides (Ops) and respiratory diseases, diabetes mellitus (DM), and cardiovascular diseases (CVDs), controversial results still exist. In this review and meta-analysis, we aimed to investigate the overall pooled effect estimates and the possible mechanisms of the relationship between OP exposure and adverse health outcomes. In this study, Web of Science, PubMed, Embase, OVID, and the Cochrane Library were systematically searched until September 2022. Nineteen observational studies that focused on the general population or occupational populations examined the associations between OP exposure and respiratory diseases, DM, and CVD were included. Based on the overall pooled results, a significantly positive association was observed between OP exposure and respiratory diseases (OR: 1.12, 95% CI: 1.06-1.19). A significant link was also observed between various individual species of OP exposure and respiratory diseases, with an OR value of 1.11 (95% CI: 1.05-1.18). In particular, there was a significant association of OPs with wheezing and asthma, with OR values of 1.19 (95% CI: 1.08-1.31) and 1.13 (95% CI: 1.05-1.22), respectively. In addition, a significant association was also observed between OP exposure and DM (OR: 1.18, 95% CI: 1.07-1.29). However, no significant association was observed between OP exposure and CVD (OR: 1.00, 95% CI: 0.94-1.05). Exposure to OPs was associated with a significantly increased risk of respiratory diseases and DM, but there was no evidence of a significant association between OP exposure and CVD. Considering the moderate strength of the results, further evidence is needed to confirm these associations.

Hydrogels provide microenvironments to mesenchymal stem cells for craniofacial bone regeneration: Review.

The anatomical and physiological architecture of the craniofacial bone is intricate. Hence, the exact management of osteogenesis is necessary for the regeneration of the deficiencies that present in this area. Stem-based tissue engineering approaches, as opposed to conventional surgical intervention, induce bone growth with minimal postoperative risk and expense. Mesenchymal stem/stromal cells (MSC)'s pluripotent differentiation potential, anti-inflammatory and immunomodulatory properties underpin its versatility as a therapeutic agent in bone tissues. Inspired by the native stem cell niche, hydrogels are preferred choices to mediate cells and adapt to 3-D environment because of their outstanding swelling capabilities and similarity to natural extracellular matrices (ECMs). Due to their remarkable biocompatibility and capacity for stimulating bone regeneration, bone regeneration hydrogels have also received a great deal of interest. This review explores the opportunities of MSC based regenerative skeletal therapies, introduces the application of hydrogel scaffolds as artificial bone microenvironments for stem cells to explore its usage in craniofacial bone tissue engineering.

Cyclin O promotes lung cancer progression and cetuximab resistance via cell cycle regulation and CDK13 interaction.

Background: Cyclin O (CCNO) is a novel cyclin family protein containing a cyclin-like domain, which plays a role in cell cycle regulation. Recent research suggests that inhibition of CCNO leads to cell apoptosis in gastric cancer, cervical squamous cell carcinoma, and post-operative lung cancer. Methods: The protein expression and signal transduction were detected by Western blot (WB) and immunohistochemistry (IHC). Overexpression or lacking CCNO stable cell lines were transfected with lentiviruses and selected with puromycin. The tumor behaviors of lung adenocarcinoma (LUAD) cells were assessed: cell proliferation by 5-Ethynyl-2'-deoxyuridine (EdU) staining and Cell Counting Kit-8 (CCK8) assay, cell cycle and by flow cytometry analysis, and migration and invasion using wound healing and Transwell system. Co-immunoprecipitation was used to detect protein-protein interactions. Xenograft models for evaluating tumor growth and anti-tumor drug efficacy. Results: A higher expression of CCNO was observed in LUAD cancer tissues and predicted the overall survival of LUAD patients. Moreover, CCNO expression was negatively correlated with cancer cell proliferation, migration, and invasion. Co-immunoprecipitation and western blot indicated that CCNO interacted with CDK13 to promote cancer cell proliferation signaling activation. Furthermore, CCNO promoted tumor cell growth and cetuximab resistance in vivo, and a CDK13 inhibitor effectively inhibited the oncological effect of CCNO. Conclusions: The current study suggests that CCNO may be a driver in the development of LUAD and that its function is related to CDK13 interaction that promotes proliferation signaling activation.

EIF4A3 Acts on the PI3K-AKT-ERK1/2-P70S6K Pathway through FLOT1 to Influence the Development of Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is a major lung cancer subtype. In this study, we discovered that the eukaryotic translation initiation factor EIF4A3 expression was significantly higher in LUAD tissues and that this higher expression was closely linked to a poor prognosis for LUAD. In addition, we demonstrated that the knockdown of EIF4A3 significantly inhibited the proliferation, invasion, and migration of LUAD cells in vitro and in vivo. The findings of mass spectrometry analysis revealed that EIF4A3 could interact with Flotillin-1 in LUAD cells and that EIF4A3 could positively regulate the expression of FLOT1 at the protein level. Meanwhile, transcriptome sequencing showed that EIF4A3 could influence the development of LUAD by affecting PI3K-AKT-ERK1/2-P70S6K and PI3K class III-mediated autophagy in the Apelin pathway. In addition, we confirmed that Flotillin-1 expression was upregulated in LUAD based on the existing literature, and knockdown of FLOT1 could inhibit the proliferation and migration of LUAD cells. In addition, the knockdown of Flotillin-1 reversed the increase of cell proliferation and migration caused by EIF4A3 overexpression. Furthermore, we found that the activation of PI3K-AKT-ERK1/2-P70S6K signaling pathway and PI3K class III-mediated autophagy caused by EIF4A3 overexpression was rescued by the knockdown of FLOT1. In a word, we proved that EIF4A3 positively regulates the expression of FLOT1 and plays a procancer role in LUAD. IMPLICATIONS: Our study revealed the role of EIF4A3 in prognosis and tumor progression in LUAD, indicating that EIF4A3 could be used as the molecular diagnostic and prognostic therapeutic target.

Comparison of Secondary Prevention Following Hysteroscopic Adhesiolysis in the Improvement of Reproductive Outcomes: A Retrospective Cohort Study.

Intrauterine adhesion (IUA) is primarily caused by endometrial injury, and hysteroscopic adhesiolysis is presently the main treatment. However, postoperative recurrence and poor pregnancy outcomes remain intractable. In this study, we aim to assess the effects of different treatments on clinical symptoms and reproductive outcomes in IUA. This retrospective study was conducted in a tertiary university-affiliated women's hospital. The study included 1449 consecutive women who desired to have a baby and were diagnosed with IUA through hysteroscopy from January 2016 to December 2021. Patients with IUA underwent hysteroscopic electric resection (E) or cold scissors separation (C), as well as hormone therapy and one or both of the following secondary prevention measures: intrauterine devices (IUD) and hyaluronic acid gel (HA). The pregnancy rate (PR) was significantly higher in the E + IUD + HA (90.23% CI: 85.82, 94.64%) than in other groups (p = 0.000) groups. The rates of full-term birth (p = 0.000) and live birth (p = 0.000) were significantly higher in the E + IUD + HA (67.82% and 68.97%, respectively) and E + HA (62.41% and 63.91%, respectively) groups. Multivariate logistic regression analysis revealed a significantly higher PR in women who received second-look hysteroscopy (OR 1.571, 95% CI: 1.009-2.224, p = 0.013) and E + IUD + HA (OR 4.772, 95% CI: 2.534-8.987, p = 0.000). Combining hysteroscopic electric resection with IUDs and HA gel could prevent adhesion recurrence and improve postoperative pregnancy and live birth outcomes in IUA. Furthermore, postoperative second-look hysteroscopy may increase the PR and shorten the waiting period.

Pan-cancer analysis reveals NAA50 as a cancer prognosis and immune infiltration-related biomarker.

Background: N-Alpha-Acetyltransferase 50 (NAA50) has acetyltransferase activity and is important for chromosome segregation. However, the function and mechanism of NAA50 expression in cancer development was still unclear. Here, we systematically researched the function and mechanism of NAA50 in pan-cancer, and further verified the results of NAA50 in lung adenocarcinoma (LUAD). Methods: In this study, using the online databases TIMER2.0, SangerBox3.0, HPA, UCSC, GEPIA, cBioPortal, UALCAN, TISIDB, CancerSEA and LinkedOmics, we focused on the relevance between NAA50 and oncogenesis, progression, methylation, immune infiltration, function and prognosis. In addition, the proliferation of cells was detected by CCK-8 and Edu assay. Finally, we analyzed the relationship between the expression of NAA50 and cell cycle related proteins. Results: Pan-cancer analysis indicated that NAA50 was overexpressed in most cancers. And there was a significant correlation between NAA50 expression and the prognosis of cancer patients. In the meantime, NAA50 gene changes occur in a variety of tumors. Compared with normal tissues, the methylation level of NAA50 promoter increased in most cancer tissues. In addition, the results exhibited that in most cancers, NAA50 was significantly positively correlated with bone myeloid-derived suppressor cell (MDSC) infiltration and negatively correlated with T cell NK infiltration. Moreover, functional enrichment indicated that NAA50 regulates cell cycle and proliferation in LUAD. In vitro experiments testified that knockout of NAA50 could significantly inhibit the proliferation of LUAD. Conclusion: NAA50 may be a potential biomarker and oncogene of pan-cancer, especially LUAD, which may promote the occurrence and development of tumors through different mechanisms. Furthermore, NAA50 was bound up with to immune cell infiltration in pan-cancer, meaning NAA50 may be an important therapeutic target for human cancers.

Dexmedetomidine Promotes Angiogenesis and Vasculogenic Mimicry in Human Hepatocellular Carcinoma through α 2-AR/HIF-1α/VEGFA Pathway.

Objective: Dexmedetomidine (DEX), the most specific α 2-adrenergic receptor agonist widely used for its sedative and analgesic properties, has been reported to upregulate HIF-1α expression to protect hypoxic and ischemic tissues. However, it is largely unclear whether DEX can also upregulate Hypoxia-inducible factor-1 alpha (HIF-1α) expression and its downstream vascular endothelial growth factor-A (VEGFA) in cancer tissues with oxygen-deficient tumor microenvironment. Methods: We used SMMC-7721 cells, MHCC97-H cells, and a mouse model of orthotopic hepatic carcinoma to explore the effect of DEX on angiogenesis and vasculogenic mimicry (VM) and its mechanism. Under normoxic (20% O 2) and hypoxic (1% O 2) conditions, DEX was used to intervene cells, and yohimbine was used to rescue them. Results: The results showed that DEX promoted angiogenesis and VM in human liver cancer cells within a certain dose range, and the addition of yohimbine inhibited this effect. DEX could activate HIF-1α/VEGFA pathway, which was further verified by silencing HIF-1α. Consistently, in vivo results also showed that DEX can up-regulate HIF-1α/VEGFA expression, and enhance the number of VM channels and microvessel density (MVD). Conclusion: We believe that HIF-1α/VEGFA might be an important signaling pathway by which DEX promotes angiogenesis and VM formation in human hepatocellular carcinoma, whereas α 2-adrenergic receptor mediation might be the critical mechanisms.

Higher benefit-risk ratio of COVID-19 vaccination in patients with schizophrenia and major depressive disorder versus patients with bipolar disorder when compared to controls.

Patients with major psychiatric disorders (MPD) that include schizophrenia (SCH), bipolar disorder (BP), and major depressive disorder (MDD) are at increased risk for coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccines in MPD patients have not been fully evaluated. This study aimed to investigate adverse events (AEs)/side effects and efficacy of COVID-19 vaccines in MPD patients. This retrospective study included 2034 patients with SCH, BP, or MDD who voluntarily received either BBIBP-CorV or Sinovac COVID-19 vaccines, and 2034 matched healthy controls. The incidence of AEs/side effects and the efficacy of COIVD-19 vaccinations among the two groups were compared. The risk ratio (RR) of side effects in patients with MPD was 0.60 (95% confidence interval [CI]: 0.53-0.68) after the first dose and 0.80 (95% CI: 0.65-0.99) following the second dose, suggesting a significantly lower risk in the MPD group versus healthy controls. The RRs of AEs did not differ between patients and controls. Notably, fully vaccinated patients exhibited a decreased risk of influenza with or without fever compared with controls (RR=0.38, 95% CI: 0.31-0.46; RR=0.23, 95% CI: 0.17-0.30; respectively). Further subgroup comparisons revealed a significantly lower risk of influenza with fever in MDD (RR=0.13, 95% CI: 0.08-0.21) and SCH (RR=0.24, 95% CI: 0.17-0.34) than BP (RR=0.85, 95% CI: 0.69-1.06) compared to controls. We conclude that the benefit-risk ratio of COVID-19 vaccination was more favorable in SCH or MDD versus BP when compared with controls. These data indicate that COVID-19 vaccines are safe and protective in patients with MPD from COVID-19.

Recent Progress in Phase Regulation, Functionalization, and Biosensing Applications of Polyphase MoS2.

The disulfide compounds of molybdenum (MoS2 ) are layered van der Waals materials that exhibit a rich array of polymorphic structures. MoS2 can be roughly divided into semiconductive phase and metallic phase according to the difference in electron filling state of the 4d orbital of Mo atom. The two phases show completely different properties, leading to their diverse applications in biosensors. But to some extent, they compensate for each other. This review first introduces the relationship between phase state and the chemical/physical structures and properties of MoS2 . Furthermore, the synthetic methods are summarized and the preparation strategies for metastable phases are highlighted. In addition, examples of electronic and chemical property designs of MoS2 by means of doping and surface modification are outlined. Finally, studies on biosensors based on MoS2 in recent years are presented and classified, and the roles of MoS2 with different phases are highlighted. This review offers references for the selection of materials to construct different types of biosensors based on MoS2 , and provides inspiration for sensing performance enhancement.

Predicting miRNA-disease associations based on graph attention network with multi-source information.

BACKGROUND: There is a growing body of evidence from biological experiments suggesting that microRNAs (miRNAs) play a significant regulatory role in both diverse cellular activities and pathological processes. Exploring miRNA-disease associations not only can decipher pathogenic mechanisms but also provide treatment solutions for diseases. As it is inefficient to identify undiscovered relationships between diseases and miRNAs using biotechnology, an explosion of computational methods have been advanced. However, the prediction accuracy of existing models is hampered by the sparsity of known association network and single-category feature, which is hard to model the complicated relationships between diseases and miRNAs. RESULTS: In this study, we advance a new computational framework (GATMDA) to discover unknown miRNA-disease associations based on graph attention network with multi-source information, which effectively fuses linear and non-linear features. In our method, the linear features of diseases and miRNAs are constructed by disease-lncRNA correlation profiles and miRNA-lncRNA correlation profiles, respectively. Then, the graph attention network is employed to extract the non-linear features of diseases and miRNAs by aggregating information of each neighbor with different weights. Finally, the random forest algorithm is applied to infer the disease-miRNA correlation pairs through fusing linear and non-linear features of diseases and miRNAs. As a result, GATMDA achieves impressive performance: an average AUC of 0.9566 with five-fold cross validation, which is superior to other previous models. In addition, case studies conducted on breast cancer, colon cancer and lymphoma indicate that 50, 50 and 48 out of the top fifty prioritized candidates are verified by biological experiments. CONCLUSIONS: The extensive experimental results justify the accuracy and utility of GATMDA and we could anticipate that it may regard as a utility tool for identifying unobserved disease-miRNA relationships.