High-Efficiency and Stable Colloidal One-Dimensional Core/Shell Nanorod Light-Emitting Diodes.

Anisotropic nanocrystals such as nanorods (NRs) display unique linearly polarized emission, which is expected to break the external quantum efficiency (EQE) limit of quantum dot-based light-emitting diodes (LEDs). However, the progress in achieving a higher EQE using NRs encounters several challenges, primarily involving a low photoluminescence quantum yield (PLQY) of NRs and imbalanced charge injection in NR-LEDs. In this work, we investigated NR-LEDs based on CdSe/CdZnS/ZnS rod-in-rod NRs with a high PLQY and higher linear polarization compared to those of dot-in-rod NRs. The balanced charge injection is achieved using ZnMgO nanoparticles as the electron transport layer and poly-TPD {poly[N,N'-bis(4-butylphenyl)-N,N'-bis(phenyl)benzidine]} as the hole transport layer. Therefore, the NR-LEDs exhibit a maximum EQE of 21.5% and a maximum luminance of >120 000 cd/m2 owing to the high level of in-plane transitions with a dipole moment of 90%. The NR-LEDs also have greatly inhibited droop in EQE under a high current density as well as outstanding operation lifetime and cycle stability.

Changing Paradigm for Vertigo/Dizziness Patients: a Retrospective Before-After Study from Tertiary Hospitals in Northwestern China.

BACKGROUND: Single disciplinary management of patients with vertigo and dizziness is an important challenge for most physicians in China. OBJECTIVE: To assess the impact of a new paradigm of practice (Clinic for Vertigo and Dizziness, CVD) performed by a multidisciplinary team (MDT) on diagnostic spectrum, medical costs, and patient satisfaction. DESIGN: Retrospective before-after study. PARTICIPANTS: Sample of 29,793 patients with vertigo/dizziness as primary complaint. MEASURES: Changes in diagnostic spectrum, medical costs, and patient satisfaction before and after the establishment of a CVD based on a 4-year database in three tertiary hospitals in northwestern China. KEY RESULTS: The most common diagnoses of patients with vertigo and dizziness were Meniere's disease (25.77%), cervical disease (25.00%), cerebral vascular disease (13.96%), vestibular syndrome (10.57%), and other etiologies (6.34%) before the CVD establishment. In contrast, after the CVD establishment, the most common diagnoses were BPPV (23.92%), vestibular migraine (15.83%), Meniere's disease (14.22%), CSD/PPPD (11.61%), and cerebral vascular diseases (4.45%). Extended implementation of a structured questionnaire for vertigo/dizziness and vestibular-oriented examinations (nystagmus, positional tests, HINTS) at the CVD resulted in a remarkable decline in the utility of CT/MRI and X-ray examination (p < 0.001). Meanwhile, medical costs in patients with vertigo/dizziness dropped by 11.5% (p < 0.001), with a significant improvement in patient satisfaction after the establishment of CVD (p < 0.001). CONCLUSIONS AND RELEVANCE: Our study suggested that the MDT paradigm of CVD practice may facilitate the medical management of patients with vertigo/dizziness and improve patient satisfaction.

MEK inhibition overcomes resistance to EphA2-targeted therapy in uterine cancer.

BACKGROUND: Our pilot clinical study of EphA2 inhibitor (dasatinib) plus paclitaxel and carboplatin showed interesting clinical activity in endometrial cancer with manageable toxicity. However, the underlying mechanisms of dasatinib resistance in uterine cancer are unknown. Here, we investigated potential mechanisms underlying resistance to EphA2 inhibitors in uterine cancer and examined the anti-tumor activity of EphA2 inhibitors alone and in combination with a MEK inhibitor. METHODS: We evaluated the antitumor activity of EphA2 inhibitors plus a MEK inhibitor using in vitro and in vivo orthotopic models of uterine cancer. RESULTS: EphA2 inhibitor induced MAPK in dasatinib-resistant uterine cancer cells (HEC-1A and Ishikawa) and BRAF/CRAF heterodimerization in HEC-1A cells. EphA2 inhibitor and trametinib significantly increased apoptosis in cancer cells resistant to EphA2 inhibitors compared with controls (p < 0.01). An in vivo study with the orthotopic HEC-1A model showed significantly greater antitumor response to combination treatment compared with dasatinib alone (p < 0.01). Combination treatment increased EphrinA1 and BIM along with decreased pMAPK, Jagged 1, and c-MYC expression in dasatinib-resistant cells. In addition, Spearman analysis using the TCGA data revealed that upregulation of EphA2 was significantly correlated with JAG1, MYC, NOTCH1, NOTCH3 and HES1 expression (p < 0.001, r = 0.25-0.43). Specifically, MAP3K15 and the NOTCH family genes were significantly related to poor clinical outcome in patients with uterine cancer. CONCLUSIONS: These findings indicate that the MAPK pathway is activated in dasatinib-resistant uterine cancer cells and that EphrinA1-mediated MEK inhibition overcomes dasatinib resistance. Dual targeting of both EphA2 and MEK, combined with chemotherapy, should be considered for future clinical development.

Lapatinib antagonizes multidrug resistance-associated protein 1-mediated multidrug resistance by inhibiting its transport function.

Lapatinib, a tyrosine kinase inhibitor, is used in the treatment of advanced or metastatic breast cancer overexpressing human epidermal receptor 2 (HER2). Lapatinib can modulate the function of ATP-binding cassette (ABC) transporters (ABCB1 and ABCG2), which are the major mechanism responsible for multidrug resistance (MDR) in cancer. In this study, we investigated the effect of lapatinib on multidrug resistance-associated protein 1 (MRP1 [ABCC1]), MRP2 (ABCC2), MRP4 (ABCC4) and lung relative resistance protein (LRP) drug efflux pumps. We demonstrated that lapatinib could enhance the efficacy of conventional chemotherapeutic agents in MRP1-overexpressing cells in vitro and in vivo, but no effect in MRP2-, MPR4- and LRP-overexpressing cells. Furthermore, lapatinib significantly increased the accumulation of rhodamine 123 (Rho123) and doxorubicin (DOX) in MRP1-overexpressing cells. However, lapatinib did not alter the protein or mRNA expression levels of MRP1. Further studies showed that the level of phosphorylation of AKT and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) were not altered at the indicated concentrations of lapatinib. In conclusion, lapatinib enhanced the efficacy of conventional chemotherapeutic agents in MRP1-overexpressing cells by inhibiting MRP1 transport function without altering the level of AKT or ERK1/2 phosphorylation. These findings will encourage the clinical research of lapatinib combined with conventional chemotherapeutic drugs in MRP1-overexpressing cancer patients.

Resveratrol-laden mesoporous silica nanoparticles regulate the autophagy and apoptosis via ROS-mediated p38-MAPK/HIF-1a /p53 signaling in hypertrophic scar fibroblasts.

Background: During the regression of hypertrophic scars, autophagy and apoptosis are the main ways of cell death. Recent investigations demonstrated effective inhibition of resveratrol on hypertrophic scar fibroblasts (HSFs). But its therapeutic value is limited by chemical instability and hydrophobicity, as well as the mechanism of its role in regulation of autophagy and apoptosis remains unknown. Aim of the study: We prepared a mesoporous silica nanoparticle laden with resveratrol (MSN@Res) which can effectively improve the solubility and stability of resveratrol. The purpose of this study was to investigate whether MSN@Res regulate autophagy and apoptosis of HSFs via inhibition of ROS/p38/HIF-1α/p53 signaling axis, as to reveal its pharmacological action and target. Materials and methods: Network pharmacology, molecular docking, and in vitro assays were carried out in this study. An in vitro model of fibroblasts cultivated in hypoxic and ischemic situations was established to simulate the scar in the proliferative phase. Results: MSN@Res surpresses HSFs by reducing physiological autophagy and inducing apoptosis, autosis may be another cell death involed in this process. According to the network pharmacological analysis and molecular docking, the mechanism by which MSN@Res alleviates hypertrophic scar may be closely related to the MAPK signaling pathway. MSN@Res significantly downregulate the expression of HIF-1α and p53 through the inhibition of ROS induced p38-MAPK phosphorylation with corresponding changes in the expression of autophagy and apoptosis related protein. Conclusion: MSN@Res is a novel drug delivery system with excellent chemical stability and drug release performance. It can inhibit protective autophagy of fibroblasts in hypoxic environment, and induce the apoptosis and autosis via the ROS -mediated p38-MAPK/HIF-1α/p53 signaling axis.

[New perspective of anticoagulation in intensive care unit: basic and clinical advances in coagulation factor XII and XI inhibitors].

Anticoagulation therapy stands as a key treatment for thrombotic diseases. The consequential bleeding risk tied to existing anticoagulation methods significantly impacts patient prognosis. In the intensive care unit (ICU), patients often necessitate organ support, leading to the inevitable placement of artificial devices in blood vessels, thereby requiring anticoagulation treatment to avert clot formation that might impede organ support. Nevertheless, these patients commonly encounter a heightened risk of bleeding. Hemophilia B, identified in 1953, manifests as a deficiency in coagulation factor XI (FXI), which focused people's perspective on the endogenous coagulation pathway, that is, the contact pathway. Upon interaction between the surface of artificial devices and FXII, FXII activates, subsequently triggering FXI and initiating the "coagulation cascade" within the contact pathway. Inhibitors targeting the contact pathway encompass two primary categories: FXII inhibitors and FXI inhibitors, capable of impeding this process. This article reviews the role of FXII and FXI in activating the contact pathway, seeking to illuminate their contributions to thrombus formation. By listing the relatively mature drugs and their indications, clinicians are familiar with this new anticoagulant.

Blue ZnSeTe quantum dot light-emitting diodes with low efficiency roll-off enabled by an in situ hybridization of ZnMgO nanoparticles and amino alcohol molecules.

ZnSeTe quantum dots (QDs) have been employed as promising emitters for blue QD-based light-emitting diodes (QLEDs) due to their unique optoelectronic properties and environmental friendliness. However, such QLEDs usually suffer from serious efficiency roll-off primarily stemming from exciton loss at the interface of the QD layer and the ZnMgO (ZMO) electron transport layer (ETL), which remarkably hinders their application in flat-panel displays. Herein, we propose an in situ hybridization strategy that involves the pre-introduction of amino alcohols into the reaction solution. This strategy effectively suppresses the nucleophilic condensation process by facilitating the coordination of ammonium and hydroxyl groups with metal cations (M2+, i.e. Zn2+ and Mg2+). It slows down the growth rate of ZMO nanoparticles (NPs) while simultaneously facilitating M-O coordination, resulting in the synthesis of small-sized and low-defect ZMO NPs. Notably, this in situ hybridization approach not only alleviates emission quenching at the QDs/ETL interface but also elevates the energy level of the ETL for enhancing carrier injection. We further investigated the impact of amino alcohols with varying carbon-chain lengths on the performance of ZMO NPs and the corresponding LED devices. The optimal blue ZnSeTe QLED demonstrates an impressive EQE of 8.6% with only an ∼11% drop when the current density is increased to 200 mA cm-2, and the device operating lifetime extends to over 1300 h. Conversely, the device utilizing traditionally post-treated ZMO NPs as the ETL exhibits 45% efficiency roll-off and device lifetime of merely 190 h.

PPM1G promotes cell proliferation via modulating mutant GOF p53 protein expression in hepatocellular carcinoma.

The serine/threonine protein phosphatase family involves series of cellular processes, such as pre-mRNA splicing. The function of one of its members, protein phosphatase, Mg2+/Mn2+ dependent 1G (PPM1G), remains unclear in hepatocellular carcinoma (HCC). Our results demonstrated that PPM1G was significantly overexpressed in HCC cells and tumor tissues compared with the normal liver tissues at both protein and RNA levels. High PPM1G expression is associated with shorter overall survival (p < 0.0001) and disease-free survival (p = 0.004) in HCC patients. Enhanced expression of PPM1G increases the cell proliferation rate, and knockdown of PPM1G led to a significant reduction in tumor volume in vivo. Further experiments illustrated that upregulated-PPM1G expression increased the protein expression of gain-of-function (GOF) mutant p53. Besides, the immunoprecipitation analysis revealed a direct interaction between PPM1G and GOF mutant p53. Collectively, PPM1G can be a powerful prognostic predictor and potential drug-target molecule.

[The morphological alteration of the diaphragm in patients with chronic obstructive pulmonary disease with three-dimensional reconstruction of 64-slice spiral CT].

OBJECTIVE: To study the morphological alteration of the diaphragm with three-dimensional reconstruction in patients with chronic obstructive pulmonary disease (COPD), and to evaluate the relationship between morphological parameters and pulmonary function. METHODS: Subjects were consecutively recruited in Shanghai East Hospital of Tongji University from July 2010 to April 2011. They were divided into a COPD (30 males) group, including mild (n = 10), moderate (n = 10), and severe/very severe (n = 10), and a control group (20 males); with the age of the subjects ranging from 45 to 80 years old. The subjects were asked to take pulmonary function test. Each subject underwent CT scanning in residual volume (RV) and total lung capacity (TLC) phases. The imaging of CT scanning was used to reconstruct three-dimensional diaphragm with the special computer software. The length of total diaphragm (Ldi), including the part of the zone apposition (Lap) and part of the dome (Ldo) under coronal (C) and sagittal (S) were observed. The surface area of the diaphragm (Adi), surface area (Aap) of the zone of apposition and surface area (Ado) of the dome were measured as well. In addition, the relationship between morphological indexs and pulmonary function were evaluated. RESULTS: In RV phase, compared with the control, Ldi and Lap were significantly lower in COPD, S-Ldi: (23.3 ± 2.9) cm vs (31.1 ± 4.3) cm (t = 4.12, P < 0.05); S-Lap: (5.4 ± 1.9) cm vs (12.7 ± 2.0) cm, (t = 6.96, P < 0.05); the difference was more obvious in sagittal slices as compared to the coronal slices. The reduction of S-Ldi was more pronounced in the part of S-Lap. In RV phase, Adi and Aap were also significant lower in COPD, Adi: (571 ± 119) cm(2) vs (811 ± 95) cm(2) (t = 4.06, P < 0.05). Aap: (270 ± 99) cm(2) vs (471 ± 61) cm(2) (t = 4.33, P < 0.05). Aap decreased more significantly, and accounted for the most part of reduction of Adi. There was a significant positive correlation between Aap and S-Lap with pulmonary function (r = 0.577 - 0.787, all P < 0.05), especially for Aap (r = 0.787). In TLC phase, only C-Ldi and C-Lap decreased significantly (t = 3.08, t = 2.80 respectively, all P < 0.05). CONCLUSIONS: The diaphragmatic length and surface area decreased in patients with COPD, which were more pronounced in the part of the zone of apposition and occurred during RV phase. The dimension of the zone of apposition could be a parameter to reflect the severity of the disease.

The prognosis of preoperative preemptive intubation for acute type A aortic dissection patients: a retrospective propensity score matching study.

Background: Acute type A aortic dissection (AADA) is a life-threatening cardiovascular disease, and improving perioperative mortality remains a significant challenge. The purpose of this study is to investigate the impact of preemptive intubation under adequate sedation and analgesia on the prognosis of AADA patients under the high rupture risk. Methods: The medical records of patients diagnosed with AADA and admitted to Changhai Hospital from January 2019 to January 2020 were retrospectively reviewed. Patients were divided into two groups based on whether they received preoperative preemptive intubation in the cardiac intensive care unit (ICU) before surgery. We used propensity score matching (PSM) analysis to conduct statistical analyses on the preoperative, intraoperative, and postoperative clinical data of the two groups. Results: A total of 134 patients were eventually included in the study. One patient (3.8%) in the pre-intubation group and 15 (13.9%) in the control group died of dissection rupture before surgery. After excluding patients with dissection rupture, there were 25 patients in the pre-intubation group and 93 patients in the non-intubation group. After PSM, there were 17 patients in the pre-intubation group and 68 patients in the non-intubation group. Baseline data analysis showed that the pre-intubation group had a higher Sequential Organ Failure Assessment (SOFA) score (10.2±3.9 vs. 8.0±4.7, P=0.036) and a higher proportion of patients with coronary artery disease (16.0% vs. 1.1%, P=0.007). The rate of massive pericardial effusion was also higher in the intubation group (28.0% vs. 10.8%, P=0.049), and preoperative oxygenation index was lower (273.2±97.3 vs. 322.1±100.9, P=0.032) compared to the control group. The results showed no significant differences in intraoperative and postoperative data for the two groups. Kaplan-Meier survival curves indicated a trend towards a more favorable prognosis for patients in the preemptive intubation group, but this difference was not significant either before or after PSM. Conclusions: Preemptive pre-intubation may benefit high-risk patients with factors such as hypoxia, massive pericardial effusion, and agitation, improving the more critically AADA patients' perioperative outcomes.

Effect of preoperative pulmonary artery pressure on the prognosis of end-stage heart failure patients after heart transplantation.

OBJECTIVE: To evaluate the effect of preoperative pulmonary artery pressure on perioperative outcome of end-stage heart failure patients undergoing heart transplantation. METHODS: Retrospective analysis was undertaken on the clinical data of patients receiving heart transplantation in the Department of Cardiovascular Surgery of our hospital from March 2017 to March 2022. A ROC curve analysis was developed between mean pulmonary artery pressure (mPAP) and postoperative mortality using mPAP as diagnostic criteria. Patients were divided into groups based on this threshold to determine the best mPAP threshold value for predicting postoperative nosocomial mortality, and the differences in preoperative and intraoperative data, postoperative complications, and clinical prognosis of patients in the two groups were compared. Patients were followed up to draw the survival curve of patients in the two groups. RESULTS: The study enlisted the participation of 105 patients. ROC curve research revealed that preoperative pulmonary artery pressure was substantially linked with death following heart transplantation, with mPAP = 30.5mmHg being the best threshold. The group with mPAP ≥ 30.5mmHg had a greater incidence of postoperative ECMO support (28.2% vs. 10.6%, P = 0.021) and a higher incidence of in-hospital mortality (15.4% vs. 1.5%, P = 0.019) than the group with mPAP < 30.5mmHg. The postoperative survival rates of 105 patients were 91.3%, 88.7%, 81.6%, and 77.5% at 1, 2, 3, and 4 years, respectively, however, there was no significant difference between the two groups of patients in the postoperative intermediate-far survival rate (P = 0.431). CONCLUSIONS: Preoperative pulmonary artery pressure in patients with end-stage heart failure is intimately correlated with perioperative prognosis of heart transplant recipients. The optimal cut-off mPAP value in predicting perioperative prognosis of heart transplant recipients is 30.5mmHg. In the high mPAP group, perioperative ECMO support rate and perioperative mortality rate are high, which do not affect the medium and long-term prognosis of the recipients undergoing heart transplantation.

Hydrogen gas alleviates lipopolysaccharide-induced acute lung injury and inflammatory response in mice.

BACKGROUND: Chronic inflammation and oxidant/antioxidant imbalance are two main pathological features associated with lipopolysaccharide (LPS)-induced acute lung injury (ALI). The following study investigated the protective role of hydrogen (H2), a gaseous molecule without known toxicity, in LPS-induced lung injury in mice and explored its potential molecular mechanisms. METHODS: Mice were randomly divided into three groups: H2 control group, LPS group, and LPS + H2 group. The mice were euthanized at the indicated time points, and the specimens were collected. The 72 h survival rates, cytokines contents, pathological changes, expression of Toll-like receptor 4 (TLR4), and oxidative stress indicators were analyzed. Moreover, under different culture conditions, RAW 264.7 mouse macrophages were used to investigate the potential molecular mechanisms of H2 in vitro. Cells were divided into the following groups: PBS group, LPS group, and LPS + H2 group. The cell viability, intracellular ROS, cytokines, and expression of TLR4 and nuclear factor kappa-B (NF-κB) were observed. RESULTS: Hydrogen inhalation increased the survival rate to 80%, reduced LPS-induced lung damage, and decreased inflammatory cytokine release in LPS mice. Besides, H2 showed remarked anti-oxidative activity to reduce the MDA and NO contents in the lung. In vitro data further indicated that H2 down-regulates the levels of ROS, NO, TNF-α, IL-6, and IL-1ß in LPS-stimulated macrophages and inhibits the expression of TLR4 and the activation of nuclear factor kappa-B (NF-κB). CONCLUSION: Hydrogen gas alleviates lipopolysaccharide-induced acute lung injury and inflammatory response most probably through the TLR4-NF-κB pathway.

Impact of early empirical antifungal therapy on prognosis of sepsis patients with positive yeast culture: A retrospective study from the MIMIC-IV database.

Background: Mortality and other clinical outcomes of culture-negative and culture-positive among patients with fungal sepsis have not been documented, and whether antifungal therapy prior to fungal culture reports is related to decreased mortality among patients remains largely controversial. This study aimed to determine the mortality and other clinical outcomes of patients with positive yeast cultures and further investigate the effects of initial empiric antifungal therapy. Methods: A retrospective study was conducted among septic patients using the Medical Information Mart for Intensive Care (MIMIC)-IV database. Patients with sepsis were divided into two groups based on first fungal culture status during intensive care unit (ICU) stay, and initial empirical antifungal therapy was prescribed based on physician's experience prior to fungal culture reports within 48 h. The primary outcome was in-hospital all-cause mortality. The secondary outcomes were 30-day all-cause mortality, 60-day all-cause mortality, length of ICU stay and length of hospital stay. Multivariate logistic regression, propensity score matching (PSM), subgroup analyses and survival curve analyses were performed. Results: This study included 18,496 sepsis patients, of whom 3,477 (18.8%) had positive yeast cultures. Patients with positive yeast cultures had higher in-hospital all-cause mortality, 60-day all-cause mortality, and longer lengths of ICU stay and hospital stay than those with negative yeast cultures after PSM (all p < 0.01). Multivariate logistic regression analysis revealed that positive yeast culture was a risk factor for in-hospital mortality in the extended model. Subgroup analyses showed that the results were robust among the respiratory infection, urinary tract infection, gram-positive bacterial infection and bacteria-free culture subgroups. Interestingly, empiric antifungal therapy was not associated with lower in-hospital mortality among patients with positive yeast cultures, mainly manifested in stratification analysis, which showed that antifungal treatment did not improve outcomes in the bloodstream infection (odds ratio, OR 2.12, 95% CI: 1.16-3.91, p = 0.015) or urinary tract infection groups (OR 3.24, 95% CI: 1.48-7.11, p = 0.003). Conclusion: Culture positivity for yeast among sepsis patients was associated with worse clinical outcomes, and empiric antifungal therapy did not lower in-hospital all-cause mortality in the bloodstream infection or urinary tract infection groups in the ICU.

Molecular Profiles of Serum-Derived Extracellular Vesicles in High-Grade Serous Ovarian Cancer.

Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (R0) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have a response enabling interval cytoreductive surgery. Clinically useful biomarkers for predicting these outcomes are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. In this study, we performed extensive molecular characterization of serum-derived EVs and correlated the findings with therapeutic outcomes in patients with HGSC. Using EV-DNA whole-genome sequencing and EV-RNA sequencing, we identified distinct somatic EV-DNA alterations in cancer-hallmark genes and in ovarian cancer genes, as well as significantly altered oncogenic pathways between the R0 group and NACT groups. We also found significantly altered EV-RNA transcriptomic variations and enriched pathways between the groups. Taken together, our data suggest that the molecular characteristics of EVs could enable prediction of patients with HGSC who could undergo R0 surgery or respond to chemotherapy.

[Expert statement on the construction criteria of critical care department in municipal and district designated hospitals under the pandemic prevention and control].

The global coronavirus disease 2019 epidemic is still in a pandemic state. Aging population with underlying diseases is prone to become severe, and have a higher mortality. The treatment capacity of the critical care department directly determines the treatment success rate of critical illness. At present, there is still a certain gap between domestic and foreign countries in intensive care unit (ICU), which is not only in the allocation of medical staff, but also in the beds and settings. The current medical model cannot fully meet the needs of development. The experience and lessons of many major public health emergencies suggested that "dual track of peace and war" approach in discipline construction of critical care is the best medical model. Following the concept of "combination of peace and war", strengthening the discipline construction of critical care department in municipal and district designated hospitals, allocating reasonable standard ICU, step-down ICU and combat readiness ICU, establishing rapid response team, and strengthening regular training and scientific management may be the key measures to deal with the epidemic.

Adipose-derived stem cells accelerate neovascularization in ischaemic diabetic skin flap via expression of hypoxia-inducible factor-1α.

Skin flaps are frequently performed for diabetic patients in spite of countless detrimental effects of diabetes on flap survival, most of which may result from a defective response of the tissues to low oxygen tension. In this study, the authors explored the feasibility of applying human adipose-derived stem cells (ASCs) to increase the viability of random-patterned skin flaps in streptozotocin-induced diabetic mice. ASCs were isolated from the fresh human lipoaspirates and expanded ex vivo for three passages. After the elevation of caudally based random-patterned skin flaps (3 cm long and 1 cm wide), ASCs suspensions were then injected into the flap (group A). Media containing no ASCs were similarly injected as a control (group B), although nothing was injected into the flap base of mice in control group C. Flap assessments were carried out at post-operative day 7 for evaluation of flap viability. The flap survival rate of group A was significantly higher than those of groups B and C, whereas no difference was observed between groups B and C. Histological examination also demonstrated a statistically significant increase in capillary density in group A over both groups B and C. Furthermore, it was found that ASCs not only augmented the expression of vascular endothelial growth factor and hypoxia-inducible factor-1α (HIF-1α) in flap tissues from dermis of diabetes mice, but also promoted their expression in dermal fibroblasts from diabetic mice. Thus, ASCs could enhance the survival of random-patterned skin flaps in streptozotocin-induced diabetic mice via elevated expression of HIF-1α.

Fulminant myocarditis induced by immune checkpoint inhibitor nivolumab: a case report and review of the literature.

BACKGROUND: Nivolumab, an anti-programmed cell death protein 1 antibody, is commonly used as an immune checkpoint inhibitor in various cancers. Various adverse events are associated with these therapies, including hepatitis, dermatitis, and myocarditis. Myocarditis is a relatively rare but potentially fatal immune-mediated adverse reaction. CASE PRESENTATION: We report a case of colon cancer in a 56-year-old Chinese patient with lung and liver metastasis who developed fulminant myocarditis by nivolumab and survived with the support of extracorporeal membrane oxygenation. After six cycles (within 3 months) of nivolumab treatment, the patient developed chest tightness and was hospitalized. A diagnosis of fulminant myocarditis associated with immunotherapy was confirmed based on the clinical manifestations and laboratory examinations. He recovered well and was discharged on day 45 after management with extracorporeal membrane oxygenation, intravenous methylprednisolone, and immunoglobulin. CONCLUSIONS: This case illustrates a severe cardiovascular complication of immunotherapy, strongly suggesting the necessity of close monitoring for outpatient usage of nivolumab. Additionally, our experience provided an efficient management strategy of extracorporeal membrane oxygenation in terms of life-threatening conditions.

Erratum: Antitumor activity of gambogic acid on NCI-H1993 xenografts via MET signaling pathway downregulation.

[This corrects the article DOI: 10.3892/ol.2015.3719.].

Gain-of-function p53 protein transferred via small extracellular vesicles promotes conversion of fibroblasts to a cancer-associated phenotype.

Tumor and stromal interactions consist of reciprocal signaling through cytokines, growth factors, direct cell-cell interactions, and extracellular vesicles (EVs). Small EVs (≤200 nm) have been considered critical messengers of cellular communication during tumor development. Here, we demonstrate that gain-of-function (GOF) p53 protein can be packaged into small EVs and transferred to fibroblasts. GOF p53 protein is selectively bound by heat shock protein 90 (HSP90), a chaperone protein, and packaged into small EVs. Inhibition of HSP90 activity blocks packaging of GOF, but not wild-type, p53 in small EVs. GOF p53-containing small EVs result in their conversion to cancer-associated fibroblasts. In vivo studies reveal that GOF p53-containing small EVs can enhance tumor growth and promote fibroblast transformation into a cancer-associated phenotype. These findings provide a better understanding of the complex interactions between cancer and stromal cells and may have therapeutic implications.

Rational Combination of CRM1 Inhibitor Selinexor and Olaparib Shows Synergy in Ovarian Cancer Cell Lines and Mouse Models.

CRM1 inhibitors have demonstrated antitumor effects in ovarian and other cancers; however, rational combinations are largely unexplored. We performed a high-throughput drug library screen to identify drugs that might combine well with selinexor in ovarian cancer. Next, we tested the combination of selinexor with the top hit from the drug screen in vitro and in vivo Finally, we assessed for mechanisms underlying the identified synergy using reverse phase protein arrays (RPPA). The drug library screen assessing 688 drugs identified olaparib (a PARP inhibitor) as the most synergistic combination with selinexor. Synergy was further demonstrated by MTT assays. In the A2780luc ip1 mouse model, the combination of selinexor and olaparib yielded significantly lower tumor weight and fewer tumor nodules compared with the control group (P < 0.04 and P < 0.03). In the OVCAR5 mouse model, the combination yielded significantly fewer nodules (P = 0.006) and markedly lower tumor weight compared with the control group (P = 0.059). RPPA analysis indicated decreased expression of DNA damage repair proteins and increased expression of tumor suppressor proteins in the combination treatment group. Collectively, our preclinical findings indicate that combination with selinexor to expand the utility and efficacy of PARP inhibitors in ovarian cancer warrants further exploration.