Effects of Surface IR783 Density on the In Vivo Behavior and Imaging Performance of Liposomes.

Background: Nanoparticles conjugated with fluorescent probes have versatile applications, serving not only for targeted fluorescent imaging but also for evaluating the in vivo profiles of designed nanoparticles. However, the relationship between fluorophore density and nanoparticle behavior remains unexplored. Methods: The IR783-modified liposomes (IR783-sLip) were prepared through a modified ethanol injection and extrusion method. The cellular uptake efficiency of IR783-sLip was characterized by flow cytometry and fluorescence microscope imaging. The effects of IR783 density on liposomal in vivo behavior were investigated by pharmacokinetic studies, biodistribution studies, and in vivo imaging. The constitution of protein corona was analyzed by the Western blot assay. Results: Dense IR783 modification improved cellular uptake of liposomes in vitro but hindered their blood retention and tumor imaging performance in vivo. We found a correlation between IR783 density and protein corona absorption, particularly IgM, which significantly impacted the liposome performance. Meanwhile, we observed that increasing IR783 density did not consistently improve the effectiveness of tumor imaging. Conclusions: Increasing the density of modified IR783 on liposomes is not always beneficial for tumor near-infrared (NIR) imaging yield. It is not advisable to prematurely evaluate novel nanomaterials through fluorescence dye conjugation without carefully optimizing the density of the modifications.

Quaternary 2D monolayer Cu2Cl2Se2Hg2: anisotropic carrier mobility and tunable bandgap for transistor and photocatalytic applications.

Despite the advantages of quaternary two-dimensional (2D) materials, fewer studies have been done on them than binary 2D materials. Calculations of quaternary 2D monolayer Cu2Cl2Se2Hg2based on density functional theory and Green's function surface analysis provide insights into its structural, dynamic, and thermal stability. This material has a direct band gap of 0.91/2.0 eV (Perdew-Burke-Ernzerhof/Heyd-Scuseria-Ernzerhof) and demonstrates anisotropic carrier mobility. The electron mobility in theadirection is 1.2 × 103cm2V-1s-1, which is significantly higher than the hole mobility of 0.48 × 103cm2V-1s-1. In thebdirection, the electron mobility is 1.01 × 103cm2V-1s-1and is 8.9 times larger than the hole mobility of 0.11 × 103cm2V-1s-1. The light absorption coefficients of Cu2Cl2Se2Hg2are 1.0 × 105cm-1and 2.5 × 105cm-1in the visible and ultraviolet ranges, respectively. Uniaxial strain leads to an anisotropic alteration in the band gap and band edge position. By manipulating the strain direction and level in Cu2Cl2Se2Hg2, it is possible to increase the current ON/OFF ratio for field-effect transistors (FETs) and to facilitate photocatalytic water splitting through a redox reaction. The research reveals that Cu2Cl2Se2Hg2, a 2D monolayer in the quaternary form, has promising capabilities as an alternative for creating crystal-oriented FETs and photocatalytic water splitting systems.

Indoor Visible Light Positioning System Based on Point Classification Using Artificial Intelligence Algorithms.

In RSSI-based indoor visible light positioning systems, when only RSSI is used for trilateral positioning, the receiver height needs to be known to calculate distance. Meanwhile, the positioning accuracy is greatly affected by multi-path effect interference, with the influence of the multi-path effect varying across different areas of the room. If only one single processing is used for positioning, the positioning error in the edge area will increase sharply. In order to address these problems, this paper proposes a new positioning scheme, which uses artificial intelligence algorithms for point classification. Firstly, height estimation is performed according to the received power data structure from different LEDs, which effectively extends the traditional RSSI trilateral positioning from 2D to 3D. The location points in the room are then divided into three categories: ordinary points, edge points and blind points, and corresponding models are used to process different types of points, respectively, to reduce the influence of the multi-path effect. Next, processed received power data are used in the trilateral positioning method for calculating the location point coordinates, and to reduce the room edge corner positioning error, so as to reduce the indoor average positioning error. Finally, a complete system is built in an experimental simulation to verify the effectiveness of the proposed schemes, which are shown to achieve centimeter-level positioning accuracy.

SETD7 promotes metastasis of triple-negative breast cancer by YY1 lysine methylation.

Breast cancer has gradually become the predominant cause for cancer-associated death in women. The metastatic dissemination and underlying mechanisms of triple-negative breast cancer (TNBC) are not sufficiently understood. (Su(var)3-9, enhancer of zeste, Trithorax) domain-containing protein 7 (SETD7) is vital for promoting the metastasis of TNBC, as demonstrated in this study. Clinical outcomes were significantly worse in primary metastatic TNBC with upregulated SETD7. Overexpression of SETD7 in vitro and in vivo promotes migration of TNBC cells. Two highly conserved lysine (K) residues K173 and K411 of Yin Yang 1 (YY1) are methylated by SETD7. Further, we found that SETD7-mediated K173 residue methylation protects YY1 from the ubiquitin-proteasome degradation. Mechanistically, it was found that the SETD7/YY1 axis regulates epithelial-mesenchymal transition (EMT) and tumor cell migration via the ERK/MAPK pathway in TNBC. The findings indicated that TNBC metastasis is driven by a novel pathway, which may be a promising target for advanced TNBC treatment.

2D Violet phosphorene with highly anisotropic mobility and its vdW heterojunction design for device applications.

Recently, the crystal structure of violet phosphorus and its monolayer violet phosphorene (VP) have been reconfirmed experimentally, and they were verified to be more thermally stable than their allotrope, black phosphorus. Here, we calculated the carrier mobility of monolayer VP using density functional theory. It is found that the carrier mobility is highly anisotropic and the hole mobility reaches 9.86 × 103 cm2 V-1 s-1 in the a-direction, endowing the potential application of VP in p-type semiconductor channel materials. Moreover, the Schottky barrier of the graphene/VP heterojunction turns into an ohmic contact when the electric field strength is >2 V nm-1. Therefore, VP and graphene/VP heterojunctions have potential prospects in electronic devices.

Direct Comparison Between the Addition of Pembrolizumab or Bevacizumab for Chemotherapy-Based First-Line Treatment of Advanced Non-Squamous Non-Small Cell Lung Cancer Lacking Driver Mutations.

BACKGROUND: The addition of bevacizumab or pembrolizumab to pemetrexed-platinum chemotherapy has produced significant clinical benefits to patients with untreated, advanced non-squamous non-small cell lung cancer (NSCLC) lacking targetable genetic aberrations. However, the direct comparison between these two first-line treatments needs to be investigated. METHODS: We retrospectively investigated the medical records of 102 patients with stage IIIB~IV non-squamous NSCLC, and without sensitizing EGFR/ALK/ROS1 alterations. All patients received pembrolizumab or bevacizumab plus pemetrexed-platinum chemotherapy as the first-line treatment between December 2018 to April 2021 at Fudan University Shanghai Cancer Center. Assessments included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). We also evaluated the prognostic biomarkers in the overall population and explored potential predictive biomarkers to aid the selection of optimal treatment regimens. RESULTS: The median PFS was 10.0 months in the pembrolizumab group and 9.2 months in bevacizumab group (HR = 1.006; P = 0.982), while the median OS was not reached in either group (HR= 1.193; P =0.714). ORR was 36.7% versus 43.4% (P = 0.548) and DCR was 89.8% versus 92.5% (P = 0.735) in the pembrolizumab and bevacizumab groups, respectively. In the overall study population, baseline lymphocyte to monocyte ratio (LMR) >1.95 (HR = 0.312, P < 0.001) was an indicator of longer PFS. The presence of baseline bone metastasis (HR = 4.107, P = 0.009), baseline lactate dehydrogenase (LDH) >300 U/L (HR = 4.300, P = 0.025) and LMR ≤1.95 (HR = 5.291, P = 0.039) were associated with inferior OS. Baseline neutrophil-to-lymphocyte ratio (NLR) ≤3.10 was predictive of significantly favorable OS in the bevacizumab combination treatment (HR = 5.073, P = 0.039). The safety profiles were generally comparable between the two groups. CONCLUSIONS: In patients with chemotherapy-naive, advanced, non-squamous NSCLC who lack driver mutations, the efficacy and safety of pembrolizumab and bevacizumab when combined with pemetrexed-platinum were comparable. For patients with baseline NLR ≤3.10, the bevacizumab combination therapy elicited significantly better OS benefits.

Case Report: EGFR-Positive Early-Stage Lung Adenocarcinoma Transforming to Squamous Cell Carcinoma After TKI Treatment.

The histological transformation from epidermal growth factor receptor (EGFR)-mutated adenocarcinoma (ADC) to squamous cell carcinoma (SCC) after tyrosine kinase inhibitor (TKI) treatment is rare. We present a case of a patient who transitioned from early-stage primary lung ADC with partial squamous differentiation, EGFR mutation and amplification, to adrenal gland metastasis as SCC with EGFR amplification disappearance 115-months after surgery, during which gefitinib and local radiotherapy were utilized for the metastasis in the right femoral head and mediastinal lymph nodes. This case might indicate a possible mechanism of EGFR inhibition resistance with SCC transition and EGFR amplification loss from the initially well-responding ADC, especially those with SCC or partial squamous differentiation. The optimal post-progression therapy for ADC-SCC patients is challenging and further studies are needed.

Virus-mimetic systems for cancer diagnosis and therapy.

Over past decades, various strategies have been developed to enhance the delivery efficiency of therapeutics and imaging agents to tumor tissues. However, the therapeutic outcome of tumors to date have not been significantly improved, which can be partly attributed to the weak targeting ability, fast elimination, and low stability of conventional delivery systems. Viruses are the most efficient agents for gene transfer, serving as a valuable source of inspiration for designing nanoparticle-based delivery systems. Based on the properties of viruses, including well-defined geometry, precise composition, easy modification, stable construction, and specific infection, researchers attempt to design biocompatible delivery vectors by mimicking virus assembly and using the vector system to selectively concentrate drugs or imaging probes in tumors with mitigated toxicity and improved efficacy. In this review, we introduce common viruses features and provide an overview of various virus-mimetic strategies for cancer therapy and diagnosis. The challenges faced by virus-mimetic systems are also discussed. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

The optimal timing and courses of bevacizumab added to chemotherapy for non-squamous non-small cell lung cancer: revelations from the real-world experience in a single Chinese cancer center.

BACKGROUND: Bevacizumab combined with platinum-based chemotherapy has been approved in the first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC) without driver genes, but this regimen for second-line or later-line treatment of non-squamous NSCLC remains to be further tested. Our study aimed to provide data on the safety and effectiveness of bevacizumab (Bev)-containing chemotherapy in different-line settings for patients with NSCLC in the Chinese real-world clinical routine practice and to explore predictors for progression-free survival (PFS) and overall survival (OS). METHODS: We reviewed the medical records of 194 patients with non-squamous NSCLC who received Bev plus chemotherapy as the first-, second- or third- or later-line treatment between December 2009 and January 2020 at Fudan University, Shanghai Cancer Center. Clinical characteristics, treatment history, clinical evaluation, and adverse effects of each patient were deeply analyzed. PFS and OS were estimated by the Kaplan-Meier method. Univariate and multivariate analyses were conducted to find predictors of longer PFS and OS. RESULTS: One hundred ninety-four patients were enrolled in this study, including 102 (52.6%), 58 (29.9%) and 34 (17.5%) patients received Bev in combination with the first-line chemotherapy (Bev + Che1), second-line chemotherapy (Bev + Che2) and third-/later-line chemotherapy (Bev + Che3), respectively. Administration of Bev in combination with the first-line chemotherapy and >6 courses were independent predictors of significantly prolonged PFS. Whereas, patients older than 65 years or with ECOG PS ≥2 may not benefit more from Bev added to the first-line chemotherapy compared to second-/later-line chemotherapy. PFS of patients received treatment with/without chemotherapy as maintenance therapy showed no significant difference (P=0.354) in >6 courses Bev cohort. As for OS, Bev plus the first-line chemotherapy and number of metastatic sites <3 were independent predictors. The most common adverse effects (AE) were leukopenia, neutropenia, hypertension, and proteinuria. Twenty patients suffered from AE ≥ Grade 3. CONCLUSIONS: Bev, in combination with the front-line chemotherapy, is proven beneficial for survival well-tolerated.

Natural IgM dominates in vivo performance of liposomes.

Prevalent deposition of plasma proteins on nano-surface alters the synthetic identity of liposomes in blood circulation. The key plasma protein(s) that can dominate in vivo fate of liposomes are of central importance for preclinical design and precise medication of liposome-based therapeutics. Herein, natural IgM, but not IgG, is identified to ubiquitously absorb on liposomal surface and takes the lead in complement activation of different species. The absorbed natural IgM, which negatively correlates with the in vivo performance of liposomes, becomes a potential indicator to guide the de novo design and optimization of liposomes. More importantly, the varying natural IgM levels in cancer patients may be one of the causal factors for clinical differences in response to liposome-based therapeutics. Clinical monitoring of the natural IgM level and its binding with liposomes becomes crucial to optimize the therapeutic regimen prior to the application of liposome-based therapeutics.

Real World Experience of Crizotinib in 104 Patients With ALK Rearrangement Non-small-cell Lung Cancer in a Single Chinese Cancer Center.

Purpose: Our study aimed to provide data on effectiveness, safety of crizotinib treatment, brain metastases, progression patterns, and sequential therapy beyond crizotinib treatment in patients with advanced ALK-positive NSCLC in China. Methods: We reviewed the medical records of crizotinib-treated NSCLC patients with ALK-rearrangement between May 2014 and May 2018 at Fudan University Shanghai Cancer Center. All patients received crizotinib with 250 mg twice daily. Main outcome measures were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), the second PFS (PFS2), overall survival (OS), and adverse events. Results: One hundred and four patients with ALK-positive NSCLC were included in this retrospective study. ORR and DCR were 82.7 and 98.1%, respectively. The estimated PFS and OS were 13.0 months (95% CI 9.0-17.0 months) and 36.0 months (95% CI 31.0-41.0 months), respectively. Multivariable analysis showed that young age, presence of baseline adrenal gland metastases and non-adenocarcinoma were independent predictive factors for poorer PFS. Presence of baseline adrenal gland metastases, non-adenocarcinoma, intrathoracic progression and shorter crizotinib treatment time were associated with worse OS. Patients without baseline brain metastases (BBM) who were administered with crizotinib as first-line therapy can achieve a significantly longer PFS than those who received crizotinib as second or later line therapy (p = 0.006). For patients with BBM receiving sequential therapy beyond the first disease progression after crizotinib treatment (1st PD), crizotinib beyond progressive disease (CBPD) plus local therapy can lead to a significantly longer PFS2 (67.0 vs. 21.0 weeks; p = 0.046). Additionally, the OS was significantly longer in patients achieving 1st PD who received CBPD plus local therapy than those who did not receive CBPD or local therapy (35.0 vs. 24.0 months, p = 0.041). Presence of brain metastases at any time was in association with worse PFS. No unexpected adverse effects were reported. Conclusions: Crizotinib was effective and well tolerated in Chinese patients with ALK-positive, advanced NSCLC in real-world clinical practice. For patients without BBM, crizotinib as first-line therapy can lead to a longer PFS than second-or later line therapy. CBPD plus local therapy after 1st PD beyond crizotinib is feasible and effective in clinical routine practice.