In vivo synergistic tumor therapies based on copper sulfide photothermal therapeutic nanoplatforms.

Tumor cells may be eliminated by increasing their temperature. This is achieved via photothermal therapy (PTT) by penetrating the tumor tissue with near-infrared light and converting light energy into heat using photothermal agents. Copper sulfide nanoparticles (CuS NPs) are commonly used as PTAs in PTT. In this review, we aimed to discuss the synergism between tumor PTT with CuS NPs and other therapies such as chemotherapy, radiotherapy, dynamic therapies (photodynamic, chemodynamic, and sonodynamic therapy), immunotherapy, gene therapy, gas therapy, and magnetic hyperthermia. Furthermore, we summarized the results obtained with a combination of two treatments and at least two therapies, with PTT as one of the included therapies. Finally, we summarized the benefits and drawbacks of various therapeutic options and state of the art CuS-based PTT and provided future directions for such therapies.

The association between monocyte to high-density lipoprotein cholesterol ratio and clinical prognosis of acute ischemic stroke after intravenous thrombolysis therapy.

The monocyte-to-high-density lipoprotein cholesterol (HDL) ratio (MHR) is accepted as a novel marker for demonstrating inflammation. We investigated whether the monocyte-to-HDL ratio is related to the 90-day clinical prognosis of acute ischemic stroke (AIS) after intravenous thrombolysis (IVT). Patients with AIS treated with alteplase IVT were included consecutively, and clinical information and laboratory data were collected. The 90-day prognosis of all patients was determined with a clinical assessment using the modified Rankin Scale (mRS). The optimal cutoff values for patients were evaluated by the receiver operating characteristic (ROC) curve method. Then, a multivariate logistic regression model was used to evaluate the risk factors for poor prognosis of IVT in AIS. We retrospectively enrolled 192 patients who were diagnosed with AIS and received IVT between February 2020 and July 2022, with final follow-up on September 30, 2022. The patients in the poor prognosis group had significantly higher monocyte counts, lower HDL levels, and higher MHR values than the good prognosis group. The optimal cutoff value of the MHR for predicting the 3-month outcome of acute pontine infarction was 0.621. Multivariate logistic regression revealed that the MHR (OR = 4.626, 95% CI: 1.156-18.512, P = .030) was strongly associated with poor prognosis in AIS. The MHR is an independent risk factor for the clinical prognosis of AIS patients receiving IVT therapy and shows a certain predictive value.

Lenvatinib improves anti-PD-1 therapeutic efficacy by promoting vascular normalization via the NRP-1-PDGFRß complex in hepatocellular carcinoma.

Introduction: The limited response to immune checkpoint blockades (ICBs) in patients with hepatocellular carcinoma (HCC) highlights the urgent need for broadening the scope of current immunotherapy approaches. Lenvatinib has been shown a potential synergistic effect with ICBs. This study investigated the optimal method for combining these two therapeutic agents and the underlying mechanisms. Methods: The effect of lenvatinib at three different doses on promoting tissue perfusion and vascular normalization was evaluated in both immunodeficient and immunocompetent mouse models. The underlying mechanisms were investigated by analyzing the vascular morphology of endothelial cells and pericytes. The enhanced immune infiltration of optimal-dose lenvatinib and its synergistic effect of lenvatinib and anti-PD-1 antibody was further evaluated by flow cytometry and immunofluorescence imaging. Results: There was an optimal dose that superiorly normalized tumor vasculature and increased immune cell infiltration in both immunodeficient and immunocompetent mouse models. An adequate concentration of lenvatinib strengthened the integrity of human umbilical vein endothelial cells by inducing the formation of the NRP-1-PDGFRß complex and activating the Crkl-C3G-Rap1 signaling pathway in endothelial cells. Additionally, it promoted the interaction between endothelial cells and pericytes by inducing tyrosine-phosphorylation in pericytes. Furthermore, the combination of an optimal dose of lenvatinib and an anti-PD-1 antibody robustly suppressed tumor growth. Conclusions: Our study proposes a mechanism that explains how the optimal dose of lenvatinib induces vascular normalization and confirms its enhanced synergistic effect with ICBs.

Targeted delivery of a PD-1-blocking scFv by CD133-specific CAR-T cells using nonviral Sleeping Beauty transposition shows enhanced antitumour efficacy for advanced hepatocellular carcinoma.

BACKGROUND: CD133 is considered a marker for cancer stem cells (CSCs) in several types of tumours, including hepatocellular carcinoma (HCC). Chimeric antigen receptor-specific T (CAR-T) cells targeting CD133-positive CSCs have emerged as a tool for the clinical treatment of HCC, but immunogenicity, the high cost of clinical-grade recombinant viral vectors and potential insertional mutagenesis limit their clinical application. METHODS: CD133-specific CAR-T cells secreting PD-1 blocking scFv (CD133 CAR-T and PD-1 s cells) were constructed using a sleeping beauty transposon system from minicircle technology, and the antitumour efficacy of CD133 CAR-T and PD-1 s cells was analysed in vitro and in vivo. RESULTS: A univariate analysis showed that CD133 expression in male patients at the late stage (II and III) was significantly associated with worse progression-free survival (PFS) (P = 0.0057) and overall survival (OS) (P = 0.015), and a multivariate analysis showed a trend toward worse OS (P = 0.041). Male patients with advanced HCC exhibited an approximately 20-fold higher PD-L1 combined positive score (CPS) compared with those with HCC at an early stage. We successfully generated CD133 CAR-T and PD-1 s cells that could secrete PD-1 blocking scFv based on a sleeping beauty system involving minicircle vectors. CD133 CAR-T and PD-1 s cells exhibited significant antitumour activity against HCC in vitro and in xenograft mouse models. Thus, CD133 CAR-T and PD-1 s cells may be a therapeutically tractable strategy for targeting CD133-positive CSCs in male patients with advanced HCC. CONCLUSIONS: Our study provides a nonviral strategy for constructing CAR-T cells that could also secrete checkpoint blockade inhibitors based on a Sleeping Beauty system from minicircle vectors and revealed a potential benefit of this strategy for male patients with advanced HCC and high CD133 expression (median immunohistochemistry score > 2.284).

Dietary Supplementation with Different Types of Potassium and Magnesium during Late Gestation and Lactation Modulates the Reproductive Performance, Antioxidant Capacity, and Immune Function of Sows.

The objective of this study was to investigate the effects of dietary supplementation with different types of potassium and magnesium on the reproductive performance, antioxidant capacity, and immunity of sows. Forty-five Landrace × Yorkshire sows at the late gestation stage (85 d) were randomly assigned to three groups (n = 15). Sows in the control group (CON), potassium chloride and magnesium sulfate group (PM), and potassium-magnesium sulfate group (PMS) were fed with a basal diet, a basal diet supplemented with magnesium sulfate (0.20%) and potassium chloride (0.15%), or a basal diet supplemented with potassium-magnesium sulfate (0.45%), respectively. The results showed that dietary supplementation with PMS did not yield significant effects on the reproductive performance compared with the CON group (p > 0.05). However, it significantly elevated the level of insulin-like growth factor 1 (IGF-1) in plasma and immunoglobulin A (IgA) in colostrum (p < 0.05). Furthermore, PMS significantly augmented the activities of catalase (CAT) and superoxide dismutase (SOD) while reducing the levels of malondialdehyde (MDA) in comparison to the CON group (p < 0.05). Compared with the PM group, the PMS group significantly reduced the incidence rate of intrauterine growth restriction (IUGR) (p < 0.05) and significantly decreased the concentration of the proinflammatory cytokine (TNF-α) level in plasma (p < 0.05). These results indicated that dietary supplementation with PMS during late gestation could enhance sows' antioxidant capacity and the IgA level in colostrum. These findings will provide a theoretical reference for the use of magnesium and potassium in sow production to improve sows' health.

BMP9-induced vascular normalisation improves the efficacy of immunotherapy against hepatitis B virus-associated hepatocellular carcinoma.

BACKGROUND: In the past decade, the field of tumour immunotherapy has made a great progress. However, the efficacy of immune checkpoint blocking (ICB) in the treatment of hepatocellular carcinoma (HCC) remains limited. Cytotoxic lymphocyte trafficking into tumours is critical for the success of ICB. Therefore, additional strategies that increase cytotoxic lymphocyte trafficking into tumours are urgently needed to improve patient immune responses. METHODS: Paired adjacent tissue and cancerous lesions with HBV-associated HCC were subjected to RNA-seq analysis. Bone morphogenetic protein (BMP9), which reflects vessel normalisation, was identified through Cytoscape software, clinical specimens and Gene Expression Omnibus (GEO) datasets for HCC. The functional effects and mechanism of BMP9 on the tumour vasculature were evaluated in cells and animals. An ultrasound-targeted microbubble destruction (UTMD)-mediated BMP9 delivery strategy was used to normalise the vasculature and evaluate therapeutic efficacy mediated by cytotoxic lymphocytes (NK cells) in combination with a PD-L1 antibody in human cancer xenografts of immune-deficient mice. RESULTS: We discovered that hepatitis B virus (HBV) infection-induced downregulation of BMP9 expression correlated with a poor prognosis and pathological vascular abnormalities in patients with HCC. BMP9 overexpression in HBV-infected HCC cells promoted intra-tumoural cytotoxic lymphocyte infiltration via vascular normalisation by inhibiting the Rho-ROCK-myosin light chain (MLC) signalling cascade, resulting in enhanced efficacy of immunotherapy. Furthermore, UTMD-mediated BMP9 delivery restored the anti-tumour function of cytotoxic lymphocytes (NK cells) and showed therapeutic efficacy in combination with a PD-L1 antibody in human cancer xenografts of immune-deficient mice. CONCLUSIONS: HBV-induced BMP9 downregulation causes vascular abnormalities that inhibit intra-tumoural cytotoxic lymphocyte infiltration, providing a rationale for developing and combining immunotherapy with BMP9-based therapy to treat HBV-associated HCC.

Click chemistry extracellular vesicle/peptide/chemokine nanocarriers for treating central nervous system injuries.

Central nervous system (CNS) injuries, including stroke, traumatic brain injury, and spinal cord injury, are essential causes of death and long-term disability and are difficult to cure, mainly due to the limited neuron regeneration and the glial scar formation. Herein, we apply extracellular vesicles (EVs) secreted by M2 microglia to improve the differentiation of neural stem cells (NSCs) at the injured site, and simultaneously modify them with the injured vascular targeting peptide (DA7R) and the stem cell recruiting factor (SDF-1) on their surface via copper-free click chemistry to recruit NSCs, inducing their neuronal differentiation, and serving as the nanocarriers at the injured site (Dual-EV). Results prove that the Dual-EV could target human umbilical vascular endothelial cells (HUVECs), recruit NSCs, and promote the neuronal differentiation of NSCs in vitro. Furthermore, 10 miRNAs are found to be upregulated in Dual-M2-EVs compared to Dual-M0-EVs via bioinformatic analysis, and further NSC differentiation experiment by flow cytometry reveals that among these miRNAs, miR30b-3p, miR-222-3p, miR-129-5p, and miR-155-5p may exert effect of inducing NSC to differentiate into neurons. In vivo experiments show that Dual-EV nanocarriers achieve improved accumulation in the ischemic area of stroke model mice, potentiate NSCs recruitment, and increase neurogenesis. This work provides new insights for the treatment of neuronal regeneration after CNS injuries as well as endogenous stem cells, and the click chemistry EV/peptide/chemokine and related nanocarriers for improving human health.

Smartphone-based platforms implementing microfluidic detection with image-based artificial intelligence.

The frequent outbreak of global infectious diseases has prompted the development of rapid and effective diagnostic tools for the early screening of potential patients in point-of-care testing scenarios. With advances in mobile computing power and microfluidic technology, the smartphone-based mobile health platform has drawn significant attention from researchers developing point-of-care testing devices that integrate microfluidic optical detection with artificial intelligence analysis. In this article, we summarize recent progress in these mobile health platforms, including the aspects of microfluidic chips, imaging modalities, supporting components, and the development of software algorithms. We document the application of mobile health platforms in terms of the detection objects, including molecules, viruses, cells, and parasites. Finally, we discuss the prospects for future development of mobile health platforms.

Extracellular matrix physical properties govern the diffusion of nanoparticles in tumor microenvironment.

Nanoparticles (NPs) are confronted with limited and disappointing delivery efficiency in tumors clinically. The tumor extracellular matrix (ECM), whose physical traits have recently been recognized as new hallmarks of cancer, forms a main steric obstacle for NP diffusion, yet the role of tumor ECM physical traits in NP diffusion remains largely unexplored. Here, we characterized the physical properties of clinical gastric tumor samples and observed limited distribution of NPs in decellularized tumor tissues. We also performed molecular dynamics simulations and in vitro hydrogel experiments through single-particle tracking to investigate the diffusion mechanism of NPs and understand the influence of tumor ECM physical properties on NP diffusion both individually and collectively. Furthermore, we developed an estimation matrix model with evaluation scores of NP diffusion efficiency through comprehensive analyses of the data. Thus, beyond finding that loose and soft ECM with aligned structure contribute to efficient diffusion, we now have a systemic model to predict NP diffusion efficiency based on ECM physical traits and provide critical guidance for personalized tumor diagnosis and treatment.

In Situ Forming Epidermal Bioelectronics for Daily Monitoring and Comprehensive Exercise.

Conventional epidermal bioelectronics usually do not conform well with natural skin surfaces and are susceptible to motion artifact interference, due to incompatible dimensions, insufficient adhesion, imperfect compliance, and usually require complex manufacturing and high costs. We propose in situ forming hydrogel electrodes or electronics (ISF-HEs) that can establish highly conformal interfaces on curved biological surfaces without auxiliary adhesions. The ISF-HEs also have favorable flexibility and soft compliance comparable to human skin (≈0.02 kPa-1), which can stably maintain synchronous movements with deformed skins. Thus, the as-prepared ISF-HEs can accurately monitor large and tiny human motions with short response time (≈180 ms), good biocompatibility, and excellent performance. The as-obtained nongapped hydrogel electrode-skin interfaces achieve ultralow interfacial impedance (≈50 KΩ), nearly an order of magnitude lower than commercial Ag|AgCl electrodes as well as other reported dry and wet electrodes, regardless of the intrinsic micro-obstacles (wrinkles, hair) and skin deformation interference. Therefore, the ISF-HEs can collect high-quality electrocardiography and surface electromyography (sEMG) signals, with high signal-to-noise ratio (SNR ≈ 32.04 dB), reduced signal crosstalk, and minimized motion artifact interference. Simultaneously monitoring human motions and sEMG signals have also been implemented for the general exercise status assessment, such as the shooting competition in the Olympics. The as-prepared ISF-HEs can be considered as supplements/substitutes of conventional electrodes in percutaneously noninvasive monitoring of multifunctional physiological signals for health and exercise status.

Targeting Tumor Physical Microenvironment for Improved Radiotherapy.

Radiotherapy has led to important clinical advances; existing cancer radiotherapy resistance is one remaining major challenge. Recently, biophysical cues in the tumor microenvironment (TME) have been regarded as the new hallmarks of cancer, playing pivotal roles in various cancer behaviors and treatment responses, including radiotherapy resistance. With recent advances in micro/nanotechnologies and functional biomaterials, radiotherapy exerts great influence on biophysical cues in TME, which, in turn, significantly affect the response to radiotherapy. Besides, various strategies have emerged that target biophysical cues in TME, to potentially enhance radiotherapy efficacy. Therefore, this paper reviews the four biophysical cues (i.e., extracellular matrix (ECM) microarchitecture, ECM stiffness, interstitial fluid pressure, and solid stress) that may play important roles in radiotherapy resistance, their possible mechanisms for inducing it, and their change after radiotherapy. The emerging therapeutic strategies targeting the biophysical microenvironment, to explore the mechanism of radiotherapy resistance and develop effective strategies to revert it for improved treatment efficacy are further summarized.

SPC25 promotes proliferation and stemness of hepatocellular carcinoma cells via the DNA-PK/AKT/Notch1 signaling pathway.

The imbalance of kinetochore-microtubule attachment during cell mitosis is a response to the initiation and progression of human cancers. Spindle component 25 (SPC25) is indispensable for spindle apparatus organization and chromosome segregation. SPC25 plays an important role in the development of malignant tumors, but its role in hepatocellular carcinoma (HCC) is yet to be determined. In this study, we aimed to preliminarily investigate the role of SPC25 in HCC progression and the molecular mechanisms underlying the process. We identified SPC25 as a clinically notable molecule significantly correlated with the grade of malignancy and poor survival in both The Cancer Genome Atlas (TCGA) cohort and the HCC patient cohort from our center. Mechanistically, SPC25 promoted the incidence of DNA damage and activated the DNA-PK/Akt/Notch1 signaling cascade in HCC cells; the NICD/ RBP-Jκ complex directly targeted SOX2 and NANOG in a transcriptional manner to regulate the proliferation and self-renewal of HCC cells. Our study suggests that HCC-intrinsic SPC25/DNA-PK/Akt/Notch1 signaling is an important mechanism to promote carcinogenesis by regulating the proliferation and stemness program, which provides possible biomarkers for predicting HCC progression and poor survival, as well as potential therapeutic targets for HCC patients.

ECM dimensionality tunes actin tension to modulate endoplasmic reticulum function and spheroid phenotypes of mammary epithelial cells.

Patient-derived organoids and cellular spheroids recapitulate tissue physiology with remarkable fidelity. We investigated how engagement with a reconstituted basement membrane in three dimensions (3D) supports the polarized, stress resilient tissue phenotype of mammary epithelial spheroids. Cells interacting with reconstituted basement membrane in 3D had reduced levels of total and actin-associated filamin and decreased cortical actin tension that increased plasma membrane protrusions to promote negative plasma membrane curvature and plasma membrane protein associations linked to protein secretion. By contrast, cells engaging a reconstituted basement membrane in 2D had high cortical actin tension that forced filamin unfolding and endoplasmic reticulum (ER) associations. Enhanced filamin-ER interactions increased levels of PKR-like ER kinase effectors and ER-plasma membrane contact sites that compromised calcium homeostasis and diminished cell viability. Consequently, cells with decreased cortical actin tension had reduced ER stress and survived better. Consistently, cortical actin tension in cellular spheroids regulated polarized basement membrane membrane deposition and sensitivity to exogenous stress. The findings implicate cortical actin tension-mediated filamin unfolding in ER function and underscore the importance of tissue mechanics in organoid homeostasis.

CMTM6 inhibits tumor growth and reverses chemoresistance by preventing ubiquitination of p21 in hepatocellular carcinoma.

Hepatocellular carcinoma is one of the most common malignancies and has a poor prognosis. The ubiquitin-proteasome pathway is required for the degradation of most short-lived proteins. CMTM6 has been implicated in the progression of various tumors, but its biological function and the underlying molecular mechanisms in HCC are still unknown. In this study, we found that the expression of CMTM6 was significantly reduced in HCC and predicted better prognosis of HCC patients. Through in vitro and in vivo experiments, CMTM6 was shown to inhibit the proliferation of HCC cells by blocking the G1/S phase transition. Mechanistically, CMTM6 interacted with p21 and prevented its ubiquitination mediated by SCFSKP2, CRL4CDT2 and APC/CCDC20 in a cell-cycle-independent manner. As a result, CMTM6 stabilized p21 protein, leading to the inactivation of pRB/E2F pathway. Additionally, CMTM6 sensitized HCC cells to doxorubicin and cisplatin, positively correlated with better clinical outcomes of the transarterial chemoembolization (TACE) treatment for postoperative recurrence. Taken together, our study reports a novel mechanism by which p21 can be stabilized by CMTM6 and pinpoints a crucial role of the CMTM6-p21 axis in suppressing the progression of HCC and sensitizing patients with postoperative recurrence to TACE treatment.

CircITGB6 promotes ovarian cancer cisplatin resistance by resetting tumor-associated macrophage polarization toward the M2 phenotype.

BACKGROUND: Platinum resistance is a major challenge in the clinical treatment of advanced ovarian cancer (OC). Accumulating evidence shows that the tumor-promotive M2 macrophage is linked to the limiting chemotherapy efficacy of multiple malignancies including OC. Circular RNAs (circRNAs) are a novel class of non-coding RNAs which function as the critical regulator in biological process of cancer. However, their impact on macrophage polarization and chemoresistance of OC remain unclear. METHODS: Platinum-resistant circRNAs were screened using circRNA deep sequencing and validated using in situ hybridization in OC tissues with or without platinum resistance. The role of circITGB6 in inducing cisplatin (CDDP) resistance was evaluated by clone formation, immunofluorescence and annexin V assays in vitro, and by intraperitoneal tumor model in vivo. The mechanism underlying circITGB6-mediated tumor-associated macrophage (TAM) polarization into M2 phenotype was investigated using RNA pull-down, luciferase reporter, electrophoretic mobility shift, RNA binding protein immunoprecipitation (RIP), ELISA and immunofluorescence assays. RESULTS: We identified that a novel circRNA, circITGB6, robustly elevated in tumor tissues and serums from patients with OC with platinum resistance, was correlated with poor prognosis. circITGB6 overexpression promoted an M2 macrophage-dependent CDDP resistance in both vivo and vitro. Mechanistic research determined that circITGB6 directly interacted with IGF2BP2 and FGF9 mRNA to form a circITGB6/IGF2BP2/FGF9 RNA-protein ternary complex in the cytoplasm, thereby stabilizing FGF9 mRNA and inducing polarization of TAMs toward M2 phenotype. Importantly, blocking M2 macrophage polarization with an antisense oligonucleotide targeting circITGB6 markedly reversed the circITGB6-induced CDDP resistance of OC in vivo. CONCLUSIONS: This study reveals a novel mechanism for platinum resistance in OC and demonstrates that circITGB6 may serve as a potential prognostic marker and a therapeutic target for patients with OC.

Cancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy.

Malignant transformation and tumour progression are associated with cancer-cell softening. Yet how the biomechanics of cancer cells affects T-cell-mediated cytotoxicity and thus the outcomes of adoptive T-cell immunotherapies is unknown. Here we show that T-cell-mediated cancer-cell killing is hampered for cortically soft cancer cells, which have plasma membranes enriched in cholesterol, and that cancer-cell stiffening via cholesterol depletion augments T-cell cytotoxicity and enhances the efficacy of adoptive T-cell therapy against solid tumours in mice. We also show that the enhanced cytotoxicity against stiffened cancer cells is mediated by augmented T-cell forces arising from an increased accumulation of filamentous actin at the immunological synapse, and that cancer-cell stiffening has negligible influence on: T-cell-receptor signalling, production of cytolytic proteins such as granzyme B, secretion of interferon gamma and tumour necrosis factor alpha, and Fas-receptor-Fas-ligand interactions. Our findings reveal a mechanical immune checkpoint that could be targeted therapeutically to improve the effectiveness of cancer immunotherapies.

Inhibition of DTYMK significantly restrains the growth of HCC and increases sensitivity to oxaliplatin.

Most patients with hepatocellular carcinoma (HCC) are in the middle or advanced stage at the time of diagnosis, and the therapeutic effect is limited. Therefore, this study aimed to verify whether deoxythymidylate kinase (DTYMK) increased in HCC and was an effective therapeutic target in HCC. The findings revealed that the DTYMK level significantly increased and correlated with poor prognosis in HCC. However, nothing else is known, except that DTYMK could catalyze the phosphorylation of deoxythymidine monophosphate (dTMP) to form deoxythymidine diphosphate (dTDP). A number of experiments were performed to study the function of DTYMK in vitro and in vivo to resolve this knowledge gap. The knockdown of DTYMK was found to significantly inhibit the growth of HCC and increase the sensitivity to oxaliplatin, which is commonly used in HCC treatment. Moreover, DTYMK was found to competitively combine with miR-378a-3p to maintain the expression of MAPK activated protein kinase 2 (MAPKAPK2) and thus activate the phospho-heat shock protein 27 (phospho-HSP27)/nuclear factor NF-kappaB (NF-κB) axis, which mediated the drug resistance, proliferation of tumor cells, and infiltration of tumor-associated macrophages by inducing the expression of C-C motif chemokine ligand 5 (CCL5). Thus, this study demonstrated a new mechanism and provided a new insight into the role of mRNA in not only encoding proteins to regulate the process of life but also regulating the expression of other genes and tumor microenvironment through the competing endogenous RNA (ceRNA) mechanism.

Configurational fingerprints of multicellular living systems.

Cells cooperate as groups to achieve structure and function at the tissue level, during which specific material characteristics emerge. Analogous to phase transitions in classical physics, transformations in the material characteristics of multicellular assemblies are essential for a variety of vital processes including morphogenesis, wound healing, and cancer. In this work, we develop configurational fingerprints of particulate and multicellular assemblies and extract volumetric and shear order parameters based on this fingerprint to quantify the system disorder. Theoretically, these two parameters form a complete and unique pair of signatures for the structural disorder of a multicellular system. The evolution of these two order parameters offers a robust and experimentally accessible way to map the phase transitions in expanding cell monolayers and during embryogenesis and invasion of epithelial spheroids.

Targeting Hypoxic Tumors with Hybrid Nanobullets for Oxygen-Independent Synergistic Photothermal and Thermodynamic Therapy.

Hypoxia is a feature of solid tumors and it hinders the therapeutic efficacy of oxygen-dependent cancer treatment. Herein, we have developed all-organic oxygen-independent hybrid nanobullets ZPA@HA-ACVA-AZ for the "precise strike" of hypoxic tumors through the dual-targeting effects from surface-modified hyaluronic acid (HA) and hypoxia-dependent factor carbonic anhydrase IX (CA IX)-inhibitor acetazolamide (AZ). The core of nanobullets is the special zinc (II) phthalocyanine aggregates (ZPA) which could heat the tumor tissues upon 808-nm laser irradiation for photothermal therapy (PTT), along with the alkyl chain-functionalized thermally decomposable radical initiator ACVA-HDA on the side chain of HA for providing oxygen-independent alkyl radicals for ablating hypoxic cancer cells by thermodynamic therapy (TDT). The results provide important evidence that the combination of reverse hypoxia hallmarks CA IX as targets for inhibition by AZ and synergistic PTT/TDT possess incomparable therapeutic advantages over traditional (reactive oxygen species (ROS)-mediated) cancer treatment for suppressing the growth of both hypoxic tumors and their metastasis.

Three-Dimensional Linear Restoration of a Tunnel Based on Measured Track and Uncontrolled Mobile Laser Scanning.

Traditional precision measurement adopts discrete artificial static observation, which cannot meet the demands of the dynamic, continuous, fine and high-precision holographic measurement of large-scale infrastructure construction and complex operation and maintenance management. Due to its advantages of fast, accurate and convenient measurement, mobile laser scanning technology is becoming a popular technology in the maintenance and measurement of infrastructure construction such as tunnels. However, in some environments without satellite signals, such as indoor areas and underground spaces, it is difficult to obtain 3D data by means of mobile measurement technology. This paper proposes a method to restore the linear of the point cloud obtained by mobile laser scanning based on the measured track center line. In this paper, the measured track position is interpolated with a cubic spline to calculate the translations, and the rotation parameters are calculated by combining the simulation design data. The point cloud of the cross-section of the tunnel under the local coordinate system is converted to the absolute coordinate system to calculate the tunnel line. In addition, the method is verified by experiments combined with the subway tunnel data, and the overall point error can be controlled to within 0.1 m. The average deviation in the horizontal direction is 0.0551 m, and that in the vertical direction is 0.0274 m. Compared with the previous methods, this method can effectively avoid the obvious deformation of the tunnel and the sharp increase in the error, and can process the tunnel point cloud data more accurately and quickly. It also provides better data support for subsequent tunnel analysis such as 3D display, completion survey, systematic hazard management and so on.