Multiple topological states within a common bandgap of two non-trivial photonic crystals.

Topological photonic crystals (PCs) provide an effective method for controlling how light propagates and concentrates through their topological states. However, it remains unclear whether topological states can be obtained by combining two different two-dimensional (2D) PCs with topological non-trivial states. In this Letter, two types of 2D Penrose-square (P-S) PCs are proposed. These PCs can generate topological edge states (TESs) and topological corner states (TCSs) within the low-frequency part of the bandgap. Moreover, by combining these two non-trivial PCs, a total of two groups of TESs and four groups of TCSs can be generated in both the high-frequency and low-frequency parts of the common bandgap. To the best of our knowledge, the two proposed P-S PCs offer a new platform for investigating topological photonics and related devices, providing novel approaches and perspectives for generating topological states in 2D PCs.

Screening for lipid nanoparticles that modulate the immune activity of helper T cells towards enhanced antitumour activity.

Lipid nanoparticles (LNPs) can be designed to potentiate cancer immunotherapy by promoting their uptake by antigen-presenting cells, stimulating the maturation of these cells and modulating the activity of adjuvants. Here we report an LNP-screening method for the optimization of the type of helper lipid and of lipid-component ratios to enhance the delivery of tumour-antigen-encoding mRNA to dendritic cells and their immune-activation profile towards enhanced antitumour activity. The method involves screening for LNPs that enhance the maturation of bone-marrow-derived dendritic cells and antigen presentation in vitro, followed by assessing immune activation and tumour-growth suppression in a mouse model of melanoma after subcutaneous or intramuscular delivery of the LNPs. We found that the most potent antitumour activity, especially when combined with immune checkpoint inhibitors, resulted from a coordinated attack by T cells and NK cells, triggered by LNPs that elicited strong immune activity in both type-1 and type-2 T helper cells. Our findings highlight the importance of optimizing the LNP composition of mRNA-based cancer vaccines to tailor antigen-specific immune-activation profiles.

Explainable prediction of daily hospitalizations for cerebrovascular disease using stacked ensemble learning.

BACKGROUND: With the prevalence of cerebrovascular disease (CD) and the increasing strain on healthcare resources, forecasting the healthcare demands of cerebrovascular patients has significant implications for optimizing medical resources. METHODS: In this study, a stacking ensemble model comprised of four base learners (ridge regression, random forest, gradient boosting decision tree, and artificial neural network) and a meta learner (elastic net) was proposed for predicting the daily number of hospital admissions (HAs) for CD using the historical HAs data, air quality data, and meteorological data in Chengdu, China from 2015 to 2018. To solve the label imbalance problem, a re-weighting method based on label distribution smoothing was integrated into the meta learner. We trained the model using the data from 2015 to 2017 and evaluated its predictive ability using the data in 2018 based on four metrics, including mean absolute error (MAE), root mean square error (RMSE), mean absolute percentage error (MAPE), and coefficient of determination (R2). In addition, the SHapley Additive exPlanations (SHAP) framework was applied to provide explanation for the prediction of our stacking model. RESULTS: Our proposed model outperformed all the base learners and long short-term memory (LSTM) on two datasets. Particularly, compared with the optimal results obtained by individual models, the MAE, RMSE, and MAPE of the stacking model decreased by 13.9%, 12.7%, and 5.8%, respectively, and the R2 improved by 6.8% on CD dataset. The model explanation demonstrated that environmental features played a role in further improving the model performance and identified that high temperature and high concentrations of gaseous air pollutants might strongly associate with an increased risk of CD. CONCLUSIONS: Our stacking model considering environmental exposure is efficient in predicting daily HAs for CD and has practical value in early warning and healthcare resource allocation.

An off-the-shelf multi-well scaffold-supported platform for tumour organoid-based tissues.

Complex 3D bioengineered tumour models provide the opportunity to better capture the heterogeneity of patient tumours. Patient-derived organoids are emerging as a useful tool to study tumour heterogeneity and variation in patient responses. Organoid cultures typically require a 3D microenvironment that can be manufactured easily to facilitate screening. Here we set out to create a high-throughput, "off-the-shelf" platform which permits the generation of organoid-containing engineered microtissues for standard phenotypic bioassays and image-based readings. To achieve this, we developed the Scaffold-supported Platform for Organoid-based Tissues (SPOT) platform. SPOT is a 3D gel-embedded in vitro platform that can be produced in a 96- or 384-well plate format and enables the generation of flat, thin, and dimensionally-defined microgels. SPOT has high potential for adoption due to its reproducible manufacturing methodology, compatibility with existing instrumentation, and reduced within-sample and between-sample variation, which can pose challenges to both data analysis and interpretation. Using SPOT, we generate cultures from patient derived pancreatic ductal adenocarcinoma organoids and assess the cellular response to standard-of-care chemotherapeutic compounds, demonstrating our platform's usability for drug screening. We envision 96/384-SPOT will provide a useful tool to assess drug sensitivity of patient-derived organoids and easily integrate into the drug discovery pipeline.

Real-time optical imaging of the hypoxic status in hemangioma endothelial cells during propranolol therapy.

Infantile hemangioma (IH) is the most common microvascular tumor of infancy involving the area of head and neck. One of the most important independent risk factors of IH is the hypoxia microenvironment. Fluorescent chemosensor provides a noninvasive intervention, high spatiotemporal resolution, ultrasensitive response, and real-time feedback approach to reveal the hypoxic status of cells. Our research group developed an ultrasensitive fluorescent chemosensor, HNT-NTR, and investigated the potential ability of imaging the hypoxic status of hemangioma-derived endothelial cells (HemECs). In this study, we successfully visualized the propranolol (PRN) treatment in HemECs using NHT-NTR with "Turn-off" sensing method. This chemosensor exhibited high sensitivity and selectivity for optical imaging of hypoxic status with fast responsiveness, real-time feedback and durable photostability of the fluorescent signal. It was also confirmed that HNT-NTR could monitor nitroreductase in vivo. Paramountly, we expected this chemosensor to offer an available optical method for imaging of the hypoxic status and visualizing the therapeutic status of PRN therapy in IH with the hypoxia-imaging capability.

The anti-tumor effect of proteasome inhibitor MG132 for human adenoid cystic carcinoma: correlate with the emerging role of Nrf2/Keap1 signaling pathway.

BACKGROUND: Adenoid cystic carcinoma (ACC) is one of the most common malignant salivary gland tumors. Moreover, the unique biological characteristics and complex structures of ACC contribute to its poor survival rates. Recently, proteasome inhibitors have been shown to elicit satisfactory therapeutic effects in the treatment of certain solid tumors, but few studies have been implemented to investigate the effects of proteasome inhibitor therapy for ACC. METHODS: In this present study, cell counting kit-8 assay and flow cytometry assay were performed to examine the effects of proteasome inhibitor (MG132) on cell viability and apoptosis. We applied western blot and immunofluorescence staining to explore the expression of the Nrf2/Keap1 signaling pathway and P62, additionally Nrf2 inhibitor (ML385) was utilized to evaluate the role of Nrf2/Keap1 signaling pathway in MG132-induced cell apoptosis. RESULTS: Our data indicated that MG132 significantly suppressed the growth of ACC-83 cells(MG132 10µM P = 0.0046; 40µM P = 0.0033; 70µM P = 0.0007 versus control) and induced apoptosis (MG132 10µM P = 0.0458; 40µM P = 0.0018; 70µM P = 0.0087 versus control). The application of MG132 induced the up-regulation of Nrf2/Keap1 signaling pathway. Furthermore, inhibition of Nrf2 attenuated the therapeutic effects of MG132 for ACC (both ML385 + MG132 10µM P = 0.0013; 40µM P = 0.0057; 70µM P = 0.0003 versus MG132). P < 0.05 was considered statistically significant. CONCLUSIONS: Our results revealed that proteasome inhibitors MG132 could inhibit the cell viability and induce the apoptosis of ACC through Nrf2/Keap1 signaling pathway.

Cognition and Social Behaviors Related to COVID-19 Among Students in Medical Colleges: A Cross-Sectional Study in Guangdong Province of China.

Background: The COVID-19 pandemic is a public health emergency of international concern. This study aimed to describe the cognition and social behaviors related to COVID-19 among medical college students in China and to explore the relevant factors that have affected individual social behaviors. The study could enrich practical research on the social behaviors of college students during the COVID-19 pandemic. Methods: From February to April 2020, online questionnaire survey was conducted meticulously. Based on their majors, the students were divided into a medical student group (249 cases) and a near-peer medical student group (397 cases). Descriptive statistics was used to elaborate the cognition related to the pandemic and the status quo of social behaviors among these students. A multiple linear regression model was established to analyze the relevant factors affecting individual social behaviors from various perspectives during the pandemic. Results: Regarding the cognition situation: 76.32% of those surveyed had good pandemic awareness, and the average general cognition score was 30.55 ± 3.17 points. In terms of social behaviors, the average scores for purposive rational actions and affective actions during the outbreak were relatively high, scoring 8.85 ± 1.72 points (>10 points) and 4.32 ± 1.41 points (>6 points), respectively, while the average value rational actions score was relatively low at 5.95 ± 1.90 points (>10 points). The results of the multiple linear regression model showed that urban college students had higher scores for purposive rational actions; college students with the CCP membership had higher value rational actions scores; school and major were also significant factors affecting affective actions scoring. The COVID-19 cognition score had a significant effect on the social behavior score in all dimensions (P < 0.001). Conclusions: The cognition of COVID-19 among students in Chinese medical colleges was good, and pandemic cognition was an important factor that affected individual social behaviors. Universities and colleges should strengthen the publicity and education of knowledge related to COVID-19, guide students to internalize their knowledge of the pandemic into positive behaviors, and help to win the battle of pandemic prevention and control.

18F-Choline PET Detected the Third Ventricle Craniopharyngioma.

ABSTRACT: Craniopharyngiomas are rare tumors of low histological malignancy (World Health Organization grade I) in the sellar and suprasellar region of the brain. We report a case of the third ventricular craniopharyngioma detected using 18F-choline PET/CT in a 43-year-old man. MRI of the brain revealed an intense gadolinium enhancement focus in the same area. Histology revealed characteristics of papillary craniopharyngioma. Our findings suggest that craniopharyngioma should be included in the differential diagnosis of 18F-choline-avid brain lesions.

Oral delivery of systemic monoclonal antibodies, peptides and small molecules using gastric auto-injectors.

Oral administration provides a simple and non-invasive approach for drug delivery. However, due to poor absorption and swift enzymatic degradation in the gastrointestinal tract, a wide range of molecules must be parenterally injected to attain required doses and pharmacokinetics. Here we present an orally dosed liquid auto-injector capable of delivering up to 4-mg doses of a bioavailable drug with the rapid pharmacokinetics of an injection, reaching an absolute bioavailability of up to 80% and a maximum plasma drug concentration within 30 min after dosing. This approach improves dosing efficiencies and pharmacokinetics an order of magnitude over our previously designed injector capsules and up to two orders of magnitude over clinically available and preclinical chemical permeation enhancement technologies. We administered the capsules to swine for delivery of clinically relevant doses of four commonly injected medications, including adalimumab, a GLP-1 analog, recombinant human insulin and epinephrine. These multi-day dosing experiments and oral administration in awake animal models support the translational potential of the system.

Ultra-sensitive responsive near-infrared fluorescent nitroreductase probe with strong specificity for imaging tumor and detecting the invasiveness of tumor cells.

Hypoxia plays an important role in cancer progression, which is a characteristic feature of the tumor micro-environment and reflects the invasiveness of tumor cells. Nitroreductase (NTR) is overexpressed in hypoxic tumors, which making it an efficient target for detecting the hypoxic state in tumor. In this work, a new type of nitro-based fluorescent probe, named HNT-NTR, has been proposed, HNT-NTR could detect specifically and rapidly the NTR degree, which reflects the level of hypoxia in bidimensional (2D) tumor cells, three-dimensional (3D) tumor spheres and even the real tumors in vivo without biological toxicity. Most importantly, according to the research, HNT-NTR even could distinguish tumor cells from other normal cells in vivo and reflect the invasiveness of tumor cells by the near-infrared fluorescence intensity, which provides a new way of clinical pathologic diagnosis. All in all, HNT-NTR not only is proven to be an ideal probe for detecting solid tumors in vivo, but also has great potential to distinguish if cells are benign or malignant and even guide therapeutic applications in the clinic.

WTIP upregulates FOXO3a and induces apoptosis through PUMA in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive and heterogeneous clonal hematologic malignancy for which novel therapeutic targets and strategies are required. Emerging evidence suggests that WTIP is a candidate tumor suppressor. However, the molecular mechanisms of WTIP in leukemogenesis have not been explored. Here, we report that WTIP expression is significantly reduced both in AML cell lines and clinical specimens compared with normal controls, and low levels of WTIP correlate with decreased overall survival in AML patients. Overexpression of WTIP inhibits cell proliferation and induces apoptosis both in vitro and in vivo. Mechanistic studies reveal that the apoptotic function of WTIP is mediated by upregulation and nuclear translocation of FOXO3a, a member of Forkhead box O (FOXO) transcription factors involved in tumor suppression. We further demonstrate that WTIP interacts with FOXO3a and transcriptionally activates FOXO3a. Upon transcriptional activation of FOXO3a, its downstream target PUMA is increased, leading to activation of the intrinsic apoptotic pathway. Collectively, our results suggest that WTIP is a tumor suppressor and a potential target for therapeutic intervention in AML.

A novel fluorescent probe for detecting hydrogen sulfide in osteoblasts during lipopolysaccharide-mediated inflammation under periodontitis.

Periodontitis, one of the most common chronic inflammatory diseases, affects the quality of life. Osteogenesis plays an important role in the disease. There is a connection between hydrogen sulfide (H2S) and periodontitis, but according to the study has been published, the precise role of H2S in inflammation remains in doubt. The main reason for the lack of research is that H2S is an endogenous gasotransmitter, difficult to discern through testing. So, we synthesized a novel fluorescence probe which can detect H2S in vitro. By using the novel H2S fluorescence probe, we found that H2S changes in osteoblasts mainly by cystathionine-γ-lyase, and H2S increases under LPS stimulation. H2S could be a potential marker for diagnosis of inflammatory diseases of bone, and might help deepen studies of the changes of H2S level and promote the progression on the researches about pathogenesis of periodontitis.

A microneedle platform for buccal macromolecule delivery.

Alternative means for drug delivery are needed to facilitate drug adherence and administration. Microneedles (MNs) have been previously investigated transdermally for drug delivery. To date, drug loading into MNs has been limited by drug solubility in the polymeric blend. We designed a highly drug-loaded MN patch to deliver macromolecules and applied it to the buccal area, which allows for faster delivery than the skin. We successfully delivered 1-mg payloads of human insulin and human growth hormone to the buccal cavity of swine within 30 s. In addition, we conducted a trial in 100 healthy volunteers to assess potential discomfort associated with MNs when applied in the oral cavity, identifying the hard palate as the preferred application site. We envisage that MN patches applied on buccal surfaces could increase medication adherence and facilitate the painless delivery of biologics and other drugs to many, especially for the pediatric and elderly populations.

[Arctiin antagonizes triptolide-induced renal toxicity in rats via anti-inflammatory pathway].

OBJECTIVE: To investigate the protective effect of arctiin with anti-inflammatory bioactivity against triptolide-induced nephrotoxicity in rats and explore the underlying mechanism. METHODS: Forty SD rats were divided into 4 groups for gastric lavage of normal saline, arctiin (500 mg/kg), triptolide (500 µg/kg), or both arctiin (500 mg/kg) and triptolide (500 µg/kg). Blood samples were collected for analysis of biochemical renal parameters, and the renal tissues were harvested for determining the kidney index and for pathological evaluation with HE staining. In the in vitro experiment, HK-2 cells were treated with arctiin and triptolide either alone or in combination, and the cell viability was determined with MTT assay; the cell morphological changes was observed using laser confocal microscopy, cell apoptosis was detected using flow cytometry, and the expressions of inflammation-related protein expression were detected by Western blotting. RESULTS: In SD rats, arctiin significantly antagonized triptolide-induced elevation of BUN, Scr and kidney index (P < 0.05) and obviously improved renal tissue damages induced by triptolide including cell swelling, vacuolization and spotty necrosis. Arctiin significantly inhibited triptolide-induced cytotoxicity in HK-2 cells and increased the cell viability at 24 h (P < 0.05). Arctiin also attenuated triptolide-induced cell morphological changes, decreased cell apoptosis rate (P < 0.05) and reversed the expressions of IκBα and nuclear p65 (P < 0.05). CONCLUSIONS: Arctiin can protect the kidney from triptolide-induced damages in rats possibly through the anti-inflammatory pathway.

Linalool inhibits the growth of human T cell acute lymphoblastic leukemia cells with involvement of the MAPK signaling pathway.

Linalool can inhibit the malignant proliferation of numerous human malignant solid tumors, including hepatocellular carcinoma, breast cancer, small cell carcinoma and malignant melanoma. However, the role of linalool in T cell acute lymphoblastic leukaemia (T-ALL) remains unclear. In the present study, human T-ALL cell lines (Jurkat, H9, Molt-4 and Raji cells) and peripheral blood mononuclear cells (PBMCs) from healthy donors were treated with various concentrations of linalool (3.75, 7.50, 15.00, 30.00, 60.00 and 120.00 µM, respectively). A CCK-8 assay was used to analyse cell viability and it demonstrated that linalool inhibited the growth of T-ALL cells in a dose-dependent manner, but did not significantly affect normal PBMCs. Flow cytometry was used to detect the cell cycle and apoptosis and demonstrated that linalool reduced the percentage of T-ALL cells at the G0/G1 phase, and induced the apoptosis of T-ALL cells. RNA sequencing was conducted on an Illumina HiSeq X Series 2500 before and after treatment with linalool followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. It was demonstrated that the mitogen-activated protein kinase (MAPK) pathway was involved in the effect of linalool on T-ALL cells. Real-time quantitative PCR and western blotting were performed to verify the mRNA and protein levels, respectively of the genes in the signaling pathway identified. In addition, it was found that linalool significantly inhibited phosphorylated (p)-ERK1/2 protein expression and enhanced p-JNK protein expression of T-ALL cells. In conclusion, the present study revealed that linalool inhibits T-ALL cell survival with involvement of the MAPK signaling pathway. JNK activation and ERK inhibition may play a functional role in apoptosis induction of T-ALL cells. Linalool may be developed as a novel anti T-ALL agent.

A luminal unfolding microneedle injector for oral delivery of macromolecules.

Insulin and other injectable biologic drugs have transformed the treatment of patients suffering from diabetes1,2, yet patients and healthcare providers often prefer to use and prescribe less effective orally dosed medications3-5. Compared with subcutaneously administered drugs, oral formulations create less patient discomfort4, show greater chemical stability at high temperatures6, and do not generate biohazardous needle waste7. An oral dosage form for biologic medications is ideal; however, macromolecule drugs are not readily absorbed into the bloodstream through the gastrointestinal tract8. We developed an ingestible capsule, termed the luminal unfolding microneedle injector, which allows for the oral delivery of biologic drugs by rapidly propelling dissolvable drug-loaded microneedles into intestinal tissue using a set of unfolding arms. During ex vivo human and in vivo swine studies, the device consistently delivered the microneedles to the tissue without causing complete thickness perforations. Using insulin as a model drug, we showed that, when actuated, the luminal unfolding microneedle injector provided a faster pharmacokinetic uptake profile and a systemic uptake >10% of that of a subcutaneous injection over a 4-h sampling period. With the ability to load a multitude of microneedle formulations, the device can serve as a platform to orally deliver therapeutic doses of macromolecule drugs.

Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia.

As a heterogeneous group of clonal disorders, acute myeloid leukemia with internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) mutation usually shows an inferior prognosis. In the present study, we found that homoharringtonine (HHT), a protein translation inhibitor of plant alkaloid in China, exhibited potent cytotoxic effect against FLT3-ITD (+) cell lines and primary leukemia cells, and a remarkable synergistic anti-leukemia action was demonstrated in vitro and in vivo in xenograft mouse models when co-treated with the heat shock protein 90 inhibitor IPI504. Mechanistically, HHT combined with IPI504 synergistically inhibited the growth of leukemia cells by inducing apoptosis and G1 phase arrest. This synergistic action resulted in a prominent reduction of total and phosphorylated FLT3 (p-FLT3) as well as inhibition of its downstream signaling molecules such as STAT5, AKT, ERK and 4E-BP1. Furthermore, co-treatment of HHT and IPI504 led to a synergistic or additive effect on 55.56%(10/18) of acute myeloid leukemia cases tested, including three relapsed/refractory patients. In conclusion, our findings indicate that the combination of HHT and HSP90 inhibitor provides an alternative way for the treatment of FLT3-ITD positive acute myeloid leukemia, especially for relapsed/refractory AML.

Identification of the UBA2-WTIP fusion gene in acute myeloid leukemia.

Identifying and targeting oncogenic fusion genes have revolutionized the treatment of leukemia, such as PML-RARα fusion gene in acute promyelocytic leukemia. Here we identified an intrachromosomal fusion gene located on chromosome 19q.13 between UBA2 and WTIP gene in a case of acute myeloid leukemia. The UBA2-WTIP fusion gene contains the N-terminal E1_enzyme_family, VAE_Ubl domains of UBA2, and the C-terminal LIM domains of WTIP. The UBA2-WTIP fusion was detected by reverse transcriptase polymerase chain reaction and Sanger sequencing in 19 of 56 acute myeloid leukemia samples (33.9%). Ectopic expression of the UBA2-WTIP fusion in human acute myeloid leukemia KG-1a cells showed enhanced cell proliferation both in vitro and in vivo. The UBA2-WTIP fusion induced phosphorylation of STAT3, STAT5 and ERK1/2, and abrogates WTIP-mediated mammalian processing body formation. Finally, triptolide displayed selective cytotoxicity against KG-1a cells harboring the UBA2-WTIP fusion. Collectively, our findings suggest that the UBA2-WTIP fusion is an oncogenic fusion gene, as well as a promising therapeutic target for the treatment of acute myeloid leukemia.

Activation of CaMKIIγ potentiates T-cell acute lymphoblastic leukemia leukemogenesis via phosphorylating FOXO3a.

Ca2+/calmodulin-dependent protein kinase II γ (CaMKIIγ) can regulate the proliferation and differentiation of myeloid leukemia cells and accelerate chronic myeloid leukemia blast crisis, but the role of CaMKIIγ in T-cell acute lymphoblastic leukemia (T-ALL) leukemogenesis remains poorly understood. We observed that activated (autophosphorylated) CaMKIIγ was invariably present in T-ALL cell lines and in the majority of primary T-ALL samples. Overexpression of CaMKIIγ enhanced the proliferation, colony formation, in vivo tumorigenesis and increased DNA damage of T-ALL leukemia cells. Furthermore, inhibition of CaMKIIγ activity with a pharmacologic inhibitor, gene knock-out, dominant-negative constructs or enhancement of CaMKIIγ activity by overexpression constructs revealed that the activated CaMKIIγ could phosphorylate FOXO3a. In Jurkat cells, the activated CaMKIIγ phosphorylated FOXO3a via directly or indirectly phosphorylating AKT, excluded FOXO3a from the nucleus and inhibited its transcriptional activity. These results indicate that the activated CaMKIIγ may play a key role in T-ALL leukemogenesis, and targeting CaMKIIγ might be a value approach in the treatment of T-ALL.